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Sample records for mesolimbic dopaminergic system

  1. On the physiology of jouissance: interpreting the mesolimbic dopaminergic reward functions from a psychoanalytic perspective

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    Bazan, Ariane; Detandt, Sandrine

    2013-01-01

    Jouissance is a Lacanian concept, infamous for being impervious to understanding and which expresses the paradoxical satisfaction that a subject may derive from his symptom. On the basis of Freud’s “experience of satisfaction” we have proposed a first working definition of jouissance as the (benefit gained from) the motor tension underlying the action which was [once] adequate in bringing relief to the drive and, on the basis of their striking reciprocal resonances, we have proposed that central dopaminergic systems could embody the physiological architecture of Freud’s concept of the drive. We have then distinguished two constitutive axes to jouissance: one concerns the subject’s body and the other the subject’s history. Four distinctive aspects of these axes are discussed both from a metapsychological and from a neuroscience point of view. We conclude that jouissance could be described as an accumulation of body tension, fuelling for action, but continuously balancing between reward and anxiety, and both marking the physiology of the body with the history of its commemoration and arising from this inscription as a constant push to act and to repeat. Moreover, it seems that the mesolimbic accumbens dopaminergic pathway is a reasonable candidate for its underlying physiological architecture. PMID:24223543

  2. Activation instead of blocking mesolimbic dopaminergic reward circuitry is a preferred modality in the long term treatment of reward deficiency syndrome (RDS: a commentary

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    Waite Roger L

    2008-11-01

    Full Text Available Abstract Background and hypothesis Based on neurochemical and genetic evidence, we suggest that both prevention and treatment of multiple addictions, such as dependence to alcohol, nicotine and glucose, should involve a biphasic approach. Thus, acute treatment should consist of preferential blocking of postsynaptic Nucleus Accumbens (NAc dopamine receptors (D1-D5, whereas long term activation of the mesolimbic dopaminergic system should involve activation and/or release of Dopamine (DA at the NAc site. Failure to do so will result in abnormal mood, behavior and potential suicide ideation. Individuals possessing a paucity of serotonergic and/or dopaminergic receptors, and an increased rate of synaptic DA catabolism due to high catabolic genotype of the COMT gene, are predisposed to self-medicating any substance or behavior that will activate DA release, including alcohol, opiates, psychostimulants, nicotine, gambling, sex, and even excessive internet gaming. Acute utilization of these substances and/or stimulatory behaviors induces a feeling of well being. Unfortunately, sustained and prolonged abuse leads to a toxic" pseudo feeling" of well being resulting in tolerance and disease or discomfort. Thus, a reduced number of DA receptors, due to carrying the DRD2 A1 allelic genotype, results in excessive craving behavior; whereas a normal or sufficient amount of DA receptors results in low craving behavior. In terms of preventing substance abuse, one goal would be to induce a proliferation of DA D2 receptors in genetically prone individuals. While in vivo experiments using a typical D2 receptor agonist induce down regulation, experiments in vitro have shown that constant stimulation of the DA receptor system via a known D2 agonist results in significant proliferation of D2 receptors in spite of genetic antecedents. In essence, D2 receptor stimulation signals negative feedback mechanisms in the mesolimbic system to induce mRNA expression causing

  3. The Mesolimbic Dopaminergic Dysfunction in Psychosis: A Review of the Literature

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    Pedro Alves de Moura

    2015-11-01

    Full Text Available Background: For several decades now it is thought that dopamine hyperactivity on the mesolimbic pathway is implied on the genesis of schizophrenic psychotic symptoms. Aims: In this review we sought to interconnect the various areas of current knowledge, seeking to relate them to clinical practice. Methods: A systematic English language PUBMED search was done, using MeSH (medical subject headings terms “mesolimbic” and “psychosis”, until April 2014, including reviews. Results and Conclusions: We found 111 papers, and excluded 56 after an abstract review. We selected 14 papers of the remaining 55. We present evidence on the part played by the neurodevelopment, acetylcholine nicotinic receptor regulation, influence of KCNQ potassium channels, neurotransmitter peptides, adenosine and phosphodiesterase 10A, as well as advances on understanding the etiology of schizophrenia on the development of psychotic symptoms associated not only with this disease but also with several disturbances on which they can occur, as well as a possible relation between these various influences, where it has been possible to do so. It is, therefore, an enunciation of the neurobiological substrate underlying psychotic symptoms.

  4. Do dopaminergic gene polymorphisms affect mesolimbic reward activation of music listening response? Therapeutic impact on Reward Deficiency Syndrome (RDS).

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    Blum, Kenneth; Chen, Thomas J H; Chen, Amanda L H; Madigan, Margaret; Downs, B William; Waite, Roger L; Braverman, Eric R; Kerner, Mallory; Bowirrat, Abdalla; Giordano, John; Henshaw, Harry; Gold, Mark S

    2010-03-01

    Using fMRI, Menon and Levitin [9] clearly found for the first time that listening to music strongly modulates activity in a network of mesolimbic structures involved in reward processing including the nucleus accumbens (NAc) and the ventral tegmental area (VTA), as well as the hypothalamus, and insula, which are thought to be involved in regulating autonomic and physiological responses to rewarding and emotional stimuli. Importantly, responses in the NAc and VTA were strongly correlated pointing to an association between dopamine release and NAc response to music. Listing to pleasant music induced a strong response and significant activation of the VTA-mediated interaction of the NAc with the hypothalamus, insula, and orbitofrontal cortex. Blum et al. [10] provided the first evidence that the dopamine D2 receptor gene (DRD2) Taq 1 A1 allele significantly associated with severe alcoholism whereby the author's suggested that they found the first "reward gene" located in the mesolimbic system. The enhanced functional and effective connectivity between brain regions mediating reward, autonomic, and cognitive processing provides insight into understanding why listening to music is one of the most rewarding and pleasurable human experiences. However, little is known about why some people have a more or less powerful mesolimbic experience when they are listening to music. It is well-known that music may induce an endorphinergic response that is blocked by naloxone, a known opioid antagonist (Goldstein [19]). Opioid transmission in the NAc is associated with dopamine release in the VTA. Moreover, dopamine release in the VTA is linked to polymorphisms of the DRD2 gene and even attention-deficit hyperactivity disorder (ADHD), whereby carriers of the DRD2 A1 allele show a reduced NAc release of dopamine (DA). Thus it is conjectured that similar mechanisms in terms of adequate dopamine release and subsequent activation of reward circuitry by listening to music might also be

  5. Imaging of dopaminergic system in movement disorders

    International Nuclear Information System (INIS)

    Kim, Yu Kyeong; Kim, Sang Eun

    2007-01-01

    Parkinson's disease is a common neurodegenerative disorder that is mainly caused by dopaminergic neuron loss in the substantia nigra. Several radiopharmaceutics have been developed to evaluated the integrity of dopaminergic neuronal system. In vivo PET and SPECT imaging of presynaptic dopamine imaging are already applied to Parkinson's disease and other parkinsonism, and can demonstrate the dopaminergic dysfunction. This review summarized the use of the presynaptic dopaminergic imaging in PD as biomarkers in evaluation of disease progression as well as in diagnosis of PD

  6. Anticipatory pleasure predicts effective connectivity in the mesolimbic system

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    Zhi eLi

    2015-08-01

    Full Text Available Convergent evidence suggests the important role of the mesolimbic pathway in anticipating monetary rewards. However, the underlying mechanism of how the sub-regions interact with each other is still not clearly understood. Using dynamic causal modeling, we constructed a reward-related network for anticipating monetary reward using the Monetary Incentive Delay Task. Twenty-six healthy adolescents (Female/Male = 11/15; age = 18.69±1.35 years; education = 12±1.58 years participated in the present study. The best-fit network involved the right substantia nigra/ventral tegmental area, the right nucleus accumbens and the right thalamus, which were all activated during anticipation of monetary gain and loss. The substantia nigra/ventral tegmental area directly activates the nucleus accumbens and the thalamus. More importantly, monetary gain modulated the connectivity from the substantia nigra/ventral tegmental area to the nucleus accumbens and this was significantly correlated with subjective anticipatory pleasure (r = 0.649, p < 0.001. Our findings suggest that activity in the mesolimbic pathway during the anticipation of monetary reward could to some extent be predicted by subjective anticipatory pleasure.

  7. Neuronal and molecular effects of cannabidiol on the mesolimbic dopamine system: Implications for novel schizophrenia treatments.

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    Renard, Justine; Norris, Christopher; Rushlow, Walter; Laviolette, Steven R

    2017-04-01

    Growing clinical and pre-clinical evidence points to a critical role for cannabidiol (CBD), the largest phytochemical component of cannabis, as a potential pharmacotherapy for various neuropsychiatric disorders. In contrast to delta-9-tetrahydrocannabinol (THC), which is associated with acute and neurodevelopmental pro-psychotic side-effects, CBD possesses no known psychoactive or dependence-producing properties. However, evidence has demonstrated that CBD strongly modulates the mesolimbic dopamine (DA) system and may possess promising anti-psychotic properties. Despite the psychotropic differences between CBD and THC, little is known regarding their molecular and neuronal effects on the mesolimbic DA system, nor how these differential effects may relate to their potential pro vs. anti-psychotic properties. This review summarizes clinical and pre-clinical evidence demonstrating CBD's modulatory effects on DA activity states within the mesolimbic pathway, functional interactions with the serotonin 5-HT 1A receptor system, and their downstream molecular signaling effects. Together with clinical evidence showing that CBD may normalize affective and cognitive deficits associated with schizophrenia, CBD may represent a promising treatment for schizophrenia, acting through novel molecular and neuronal mesolimbic substrates. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Cannabidiol Modulates Fear Memory Formation Through Interactions with Serotonergic Transmission in the Mesolimbic System

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    Norris, Christopher; Loureiro, Michael; Kramar, Cecilia; Zunder, Jordan; Renard, Justine; Rushlow, Walter; Laviolette, Steven R

    2016-01-01

    Emerging evidence suggests that the largest phytochemical component of cannabis, cannabidiol (CBD), may possess pharmacotherapeutic properties in the treatment of neuropsychiatric disorders. CBD has been reported to functionally interact with both the mesolimbic dopamine (DA) and serotonergic (5-HT) receptor systems. However, the underlying mechanisms by which CBD may modulate emotional processing are not currently understood. Using a combination of in vivo electrophysiological recording and fear conditioning in rats, the present study aimed to characterize the behavioral, neuroanatomical, and pharmacological effects of CBD within the mesolimbic pathway, and its possible functional interactions with 5-HT and DAergic transmission. Using targeted microinfusions of CBD into the shell region of the mesolimbic nucleus accumbens (NASh), we report that intra-NASh CBD potently blocks the formation of conditioned freezing behaviors. These effects were challenged with DAergic, cannabinoid CB1 receptor, and serotonergic (5-HT1A) transmission blockade, but only 5-HT1A blockade restored associative conditioned freezing behaviors. In vivo intra-ventral tegmental area (VTA) electrophysiological recordings revealed that behaviorally effective doses of intra-NASh CBD elicited a predominant decrease in spontaneous DAergic neuronal frequency and bursting activity. These neuronal effects were reversed by simultaneous blockade of 5-HT1A receptor transmission. Finally, using a functional contralateral disconnection procedure, we demonstrated that the ability of intra-NASh CBD to block the formation of conditioned freezing behaviors was dependent on intra-VTA GABAergic transmission substrates. Our findings demonstrate a novel NAc→VTA circuit responsible for the behavioral and neuronal effects of CBD within the mesolimbic system via functional interactions with serotonergic 5-HT1A receptor signaling. PMID:27296152

  9. INFLUENCE OF DOPAMINERGIC SYSTEM ON INTERNET ADDICTION

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    Jelena Jović

    2011-03-01

    Full Text Available Internet addiction is a clinical anomaly with strong negative consequences on social, work-related, family, financial, and economic function of a person. It is regarded as a serious public health issue. The basic idea of this paper is to, based on the currently available body of research work on this topic, point out to neurobiological pathos of Internet addiction, and its connection to the dopaminergic system. Dopamine contains all physiological functions of neurotransmitters and it is a part of chatecholamine family. Five dopaminergic receptors (D1 - D5 belong to the super family of receptors related to G-protein. Through these receptors, dopamine achieves its roles: regulation of voluntary movement, regulation of center of pleasure, hormonal regulation, and regulation of hypertension. In order to recognize an Internet user as an addict, he or she needs to comply with the criteria suggested by the American Psychiatric Association (APA. Phenomenological, neurobiological, and pharmacological data indicates similarities in pathopsychology of substance addiction and pathological gambling, which are indirectly related to the similarity with the Internet addiction. Responding to stimuli from the game, addicts have shown more brain activity in the nape region, left dorsolateral, prefrontal cortex, and left parachipocampal gyrus than in the control group. After the six-week bupropion therapy, desire to play Internet and video games, the total duration of playing, and induced brain activity in dorsolateral prefrontal cortex are lowered with the addicts.

  10. The dopaminergic system in the aging brain of Drosophila

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    Katherine E White

    2010-12-01

    Full Text Available Drosophila models of Parkinson’s disease are characterised by two principal phenotypes: the specific loss of dopaminergic neurons in the aging brain and defects in motor behavior. However, an age-related analysis of these baseline parameters in wildtype Drosophila is lacking. Here we analysed the dopaminergic system and motor behavior in aging Drosophila. Dopaminergic neurons in the adult brain can be grouped into bilateral symmetric clusters, each comprising a stereotypical number of cells. Analysis of TH>mCD8::GFP and cell type-specific MARCM clones revealed that dopaminergic neurons show cluster-specific, stereotypical projection patterns with terminal arborization in target regions that represent distinct functional areas of the adult brain. Target areas include the mushroom bodies, involved in memory formation and motivation, and the central complex, involved in the control of motor behavior, indicating that similar to the mammalian brain, dopaminergic neurons in the fly brain are involved in the regulation of specific behaviors. Behavioral analysis revealed that Drosophila show an age-related decline in startle-induced locomotion and negative geotaxis. Motion tracking however, revealed that walking activity and exploration behavior, but not centrophobism increase at late stages of life. Analysis of TH>Dcr2, mCD8::GFP revealed a specific effect of Dcr2 expression on walking activity but not on exploratory or centrophobic behavior, indicating that the siRNA pathway may modulate distinct dopaminergic behaviors in Drosophila. Moreover, dopaminergic neurons were maintained between early- and late life, as quantified by TH>mCD8::GFP and anti-TH labelling, indicating that adult onset, age-related degeneration of dopaminergic neurons does not occur in the aging brain of Drosophila. Taken together, our data establish baseline parameters in Drosophila for the study of Parkinson’s disease as well as other disorders affecting dopaminergic neurons

  11. Phytocannabinoids modulate emotional memory processing through interactions with the ventral hippocampus and mesolimbic dopamine system: implications for neuropsychiatric pathology.

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    Hudson, Roger; Rushlow, Walter; Laviolette, Steven R

    2018-02-01

    Growing clinical and preclinical evidence suggests a potential role for the phytocannabinoid cannabidiol (CBD) as a pharmacotherapy for various neuropsychiatric disorders. In contrast, delta-9-tetrahydrocannabinol (THC), the primary psychoactive component in cannabis, is associated with acute and neurodevelopmental propsychotic side effects through its interaction with central cannabinoid type 1 receptors (CB1Rs). CB1R stimulation in the ventral hippocampus (VHipp) potentiates affective memory formation through inputs to the mesolimbic dopamine (DA) system, thereby altering emotional salience attribution. These changes in DA activity and salience attribution, evoked by dysfunctional VHipp regulatory actions and THC exposure, could predispose susceptible individuals to psychotic symptoms. Although THC can accelerate the onset of schizophrenia, CBD displays antipsychotic properties, can prevent the acquisition of emotionally irrelevant memories, and reverses amphetamine-induced neuronal sensitization through selective phosphorylation of the mechanistic target of rapamycin (mTOR) molecular signaling pathway. This review summarizes clinical and preclinical evidence demonstrating that distinct phytocannabinoids act within the VHipp and associated corticolimbic structures to modulate emotional memory processing through changes in mesolimbic DA activity states, salience attribution, and signal transduction pathways associated with schizophrenia-related pathology.

  12. Differential actions of dizocilpine (MK-801) on the mesolimbic and mesocortical dopamine systems: role of neuronal activity.

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    Mathé, J M; Nomikos, G G; Blakeman, K H; Svensson, T H

    1999-01-01

    The significance of impulse activity in the dopamine neurons of the ventral tegmental area for the dopamine release evoked by systemic administration of the psychotomimetic drug dizocilpine (MK-801) was investigated. Dual probe microdialysis was utilized in freely moving rats implanted with one probe in the ventral tegmental area and a second ipsilateral probe in either the nucleus accumbens or the medial prefrontal cortex. Dialysates were analyzed with high-performance liquid chromatography with electrochemical detection for dopamine. The ventral tegmental area was perfused with the sodium channel blocker tetrodotoxin (1 microM) or vehicle (perfusion solution). A total of 2 h after the onset of tetrodotoxin perfusion of the ventral tegmental area, MK-801 (0.1 mg/kg) was injected subcutaneously. Tetrodotoxin perfusion of the ventral tegmental area significantly reduced dialysate levels of dopamine both in the nucleus accumbens and the medial prefrontal cortex to approximately 30% of baseline. When given alone, MK-801 caused a significant, i.e. 50%, increase in extracellular dopamine levels in the nucleus accumbens, and an even larger increase in the medial prefrontal cortex, i.e. 150%. Tetrodotoxin perfusion of the ventral tegmental area completely blocked the systemic MK-801 induced increase in extracellular concentrations of dopamine in the nucleus accumbens. However, the MK-801-evoked increase in dopamine levels in the medial prefrontal cortex was not significantly affected. Thus, the present results allow the conclusion that basal dopamine output in mesolimbic and mesocortical dopamine nerve terminal regions is predominantly dependent on nerve impulses generated in the ventral tegmental area. Moreover, also the MK-801 evoked dopamine release in the mesolimbic projection is almost entirely dependent on the impulse activity of the dopamine neurons, in agreement with our previous results. However, the MK-801 evoked dopamine release in the mesocortical projection

  13. Elucidating the Biological Basis for the Reinforcing Actions of Alcohol in the Mesolimbic Dopamine System: The Role of Active Metabolites of Alcohol

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    Gerald A Deehan

    2013-08-01

    Full Text Available The development of successful pharmacotherapeutics for the treatment of alcoholism is predicated upon understanding the biological action of alcohol. A limitation of the alcohol research field has been examining the effects of alcohol only and ignoring the multiple biological active metabolites of alcohol. The concept that alcohol is a ‘pro-drug’ is not new. Alcohol is readily metabolized to acetaldehyde within the brain. Acetaldehyde is a highly reactive compound that forms a number of condensation products, including salsolinol and iso-salsolinol (acetaldehyde and dopamine. Recent experiments have established that numerous metabolites of ethanol do have direct CNS action, and could, in part or whole, mediate the reinforcing actions of alcohol within the mesolimbic dopamine system. The mesolimbic dopamine system originates in the ventral tegmental area (VTA and projects to forebrain regions that include the nucleus accumbens (Acb and the medial prefrontal cortex (mPFC and is thought to be the neurocircuitry governing the rewarding properties of drugs of abuse. Within this neurocircuitry there is convincing evidence that; 1 biologically active metabolites of alcohol can directly or indirectly increase the activity of VTA dopamine neurons, 2 alcohol and alcohol metabolites are reinforcing within the mesolimbic dopamine system, 3 inhibiting the alcohol metabolic pathway inhibits the biological consequences of alcohol exposure, 4 alcohol consumption can be reduced by inhibiting/attenuating the alcohol metabolic pathway in the mesolimbic dopamine system, 5 alcohol metabolites can alter neurochemical levels within the mesolimbic dopamine system, and 6 alcohol interacts with alcohol metabolites to enhance the actions of both compounds. The data indicate that there is a positive relationship between alcohol and alcohol metabolites in regulating the biological consequences of consuming alcohol and the potential of alcohol use escalating to

  14. Renin angiotensin system and gender differences in dopaminergic degeneration

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    Rodriguez-Perez Ana I

    2011-08-01

    Full Text Available Abstract Background There are sex differences in dopaminergic degeneration. Men are approximately two times as likely as premenopausal women of the same age to develop Parkinson's disease (PD. It has been shown that the local renin angiotensin system (RAS plays a prominent role in sex differences in the development of chronic renal and cardiovascular diseases, and there is a local RAS in the substantia nigra and dopaminergic cell loss is enhanced by angiotensin via type 1 (AT1 receptors. Results In the present study, we observed that intrastriatal injection of 6-hydroxydopamine induced a marked loss of dopaminergic neurons in the substantia nigra of male rats, which was significantly higher than the loss induced in ovariectomized female rats given estrogen implants (i.e. rats with estrogen. However, the loss of dopaminergic neurons was significantly lower in male rats treated with the AT1 antagonist candesartan, and similar to that observed in female rats with estrogen. The involvement of the RAS in gender differences in dopaminergic degeneration was confirmed with AT1a-null mice lesioned with the dopaminergic neurotoxin MPTP. Significantly higher expression of AT1 receptors, angiotensin converting enzyme activity, and NADPH-oxidase complex activity, and much lower levels of AT2 receptors were observed in male rats than in female rats with estrogen. Conclusions The results suggest that brain RAS plays a major role in the increased risk of developing PD in men, and that manipulation of brain RAS may be an efficient approach for neuroprotective treatment of PD in men, without the feminizing effects of estrogen.

  15. The dopaminergic system and aggression in laying hens

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    The dopaminergic system regulates aggression in humans and other mammals. To investigate if birds with genetic propensity for high and low aggressiveness may exhibit distinctly different aggressive mediation via dopamine (DA) D1 and D2 receptor pathways, two high aggressive (DXL and LGPS) and one lo...

  16. THE ROLE OF THE DOPAMINERGIC SYSTEM IN GRATIFICATION PROCESSES.

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    Elettra Unti

    2013-04-01

    Full Text Available Gratification is one of the functions necessary for the satisfaction of basic needs geared towards welfare and reproduction, which evolved in higher animal species. Over the years, several studies on the mechanisms through which gratification exerts its effects on the nervous system and is associated with feelings of pleasure have shown that the dopaminergic system is the most important circuit acting as a biological basis for gratification. This article will review the current knowledge on the response of the midbrain dopaminergic system to appetitive and aversive stimuli, as well as the role played within this context by the Lateral Habenula, a structure that has attracted great interest among researchers in the recent years.

  17. Concurrent maternal and pup postnatal tobacco smoke exposure in Wistar rats changes food preference and dopaminergic reward system parameters in the adult male offspring.

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    Pinheiro, C R; Moura, E G; Manhães, A C; Fraga, M C; Claudio-Neto, S; Abreu-Villaça, Y; Oliveira, E; Lisboa, P C

    2015-08-20

    Children from pregnant smokers are more susceptible to become obese adults and to become drug or food addicts. Drugs and food activate the mesolimbic reward pathway, causing a sense of pleasure that induces further consumption. Here, we studied the relationship between tobacco smoke exposure during lactation with feeding, behavior and brain dopaminergic reward system parameters at adulthood. Nursing Wistar rats and their pups were divided into two groups: tobacco smoke-exposed (S: 4times/day, from the 3rd to the 21th day of lactation), and ambient air-exposed (C). On PN175, both offspring groups were subdivided for a food challenge: S and C that received standard chow (SC) or that chose between high-fat (HFD) and high-sucrose diets (HSDs). Food intake was recorded after 30min and 12h. Offspring were tested in the elevated plus maze and open field on PN178-179; they were euthanized for dopaminergic analysis on PN180. SSD (self-selected diet) animals presented a higher food intake compared to SC ones. S-SSD animals ate more than C-SSD ones at 30min and 12h. Both groups preferred the HFD. However, S-SSD animals consumed relatively more HFD than C-SSD at 30min. No behavioral differences were observed between groups. S animals presented lower tyrosine hydroxylase (TH) content in the ventral tegmental area, lower TH, dopaminergic receptor 2, higher dopaminergic receptor 1 contents in the nucleus accumbens and lower OBRb in hypothalamic arcuate nucleus. Tobacco-smoke exposure during lactation increases preference for fat in the adult progeny possibly due to alterations in the dopaminergic system. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  18. Activation of the GLP-1 receptors in the nucleus of the solitary tract reduces food reward behavior and targets the mesolimbic system.

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    Jennifer E Richard

    Full Text Available The gut/brain peptide, glucagon like peptide 1 (GLP-1, suppresses food intake by acting on receptors located in key energy balance regulating CNS areas, the hypothalamus or the hindbrain. Moreover, GLP-1 can reduce reward derived from food and motivation to obtain food by acting on its mesolimbic receptors. Together these data suggest a neuroanatomical segregation between homeostatic and reward effects of GLP-1. Here we aim to challenge this view and hypothesize that GLP-1 can regulate food reward behavior by acting directly on the hindbrain, the nucleus of the solitary tract (NTS, GLP-1 receptors (GLP-1R. Using two models of food reward, sucrose progressive ratio operant conditioning and conditioned place preference for food in rats, we show that intra-NTS microinjections of GLP-1 or Exendin-4, a stable analogue of GLP-1, inhibit food reward behavior. When the rats were given a choice between palatable food and chow, intra-NTS Exendin-4 treatment preferentially reduced intake of palatable food but not chow. However, chow intake and body weight were reduced by the NTS GLP-1R activation if chow was offered alone. The NTS GLP-1 activation did not alter general locomotor activity and did not induce nausea, measured by PICA. We further show that GLP-1 fibers are in close apposition to the NTS noradrenergic neurons, which were previously shown to provide a monosynaptic connection between the NTS and the mesolimbic system. Central GLP-1R activation also increased NTS expression of dopamine-β-hydroxylase, a key enzyme in noradrenaline synthesis, indicating a biological link between these two systems. Moreover, NTS GLP-1R activation altered the expression of dopamine-related genes in the ventral tegmental area. These data reveal a food reward-suppressing role of the NTS GLP-1R and indicate that the neurobiological targets underlying food reward control are not limited to the mesolimbic system, instead they are distributed throughout the CNS.

  19. Chronic intake of a cafeteria diet and subsequent abstinence. Sex-specific effects on gene expression in the mesolimbic reward system.

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    Ong, Zhi Yi; Wanasuria, Ayumi F; Lin, Mark Z P; Hiscock, Jennifer; Muhlhausler, Beverly S

    2013-06-01

    Studies examining the impact of chronic palatable food intake on the mesolimbic reward system have been conducted almost exclusively in males. This study aimed to determine the effects of chronic intake of a palatable cafeteria diet and subsequent abstinence on fat mass, food intake and key gene expression of the mesolimbic reward system in both males and females. Albino Wistar rats were fed for 8 weeks on standard chow (Control, n=5 males, 5 females) or cafeteria diet (CD; n=16 males, 16 females). The cafeteria diet was then removed from a subset of CD rats for 72 h (CD-Withdrawal group, CD-W). The nucleus accumbens (NAc) was isolated and mRNA expression of tyrosine hydroxylase (TH), dopamine active transporter (DAT), D1 and D2 dopamine receptors, and μ-opioid receptor determined by qRT-PCR. Chronic cafeteria diet intake increased fat mass in all CD rats but body weight and chow intake were reduced during the period of cafeteria diet abstinence. TH mRNA was reduced in male CD and CD-W rats, but increased in female CD and CD-W rats. D1 mRNA was reduced in CD and CD-W females, but increased in CD males, compared to Controls. μ-opioid receptor expression was reduced in CD and CD-W males but not females. These data highlight the importance of investigating sex differences in the neurobiological response to palatable food intake and the need for future studies in this area to include both sexes. Copyright © 2013 Elsevier Ltd. All rights reserved.

  20. Maternal nicotine exposure during lactation alters food preference, anxiety-like behavior and the brain dopaminergic reward system in the adult rat offspring.

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    Pinheiro, C R; Moura, E G; Manhães, A C; Fraga, M C; Claudio-Neto, S; Younes-Rapozo, V; Santos-Silva, A P; Lotufo, B M; Oliveira, E; Lisboa, P C

    2015-10-01

    The mesolimbic reward pathway is activated by drugs of abuse and palatable food, causing a sense of pleasure, which promotes further consumption of these substances. Children whose parents smoke are more vulnerable to present addictive-like behavior to drugs and food.We evaluated the association between maternal nicotine exposure during lactation with changes in feeding, behavior and in the dopaminergic reward system. On postnatal day (PN) 2,Wistar rat dams were implanted with minipumps releasing nicotine (N; 6 mg/kg/day, s.c.) or saline (C) for 14 days. On PN150 and PN160, offspring were divided into 4 groups for a food challenge: N and C that received standard chow(SC); and N and C that could freely self-select (SSD) between high-fat and high-sugar diets (HFD and HSD, respectively). Offspring were tested in the elevated plus maze (EPM) and open field (OF) arena on PN152–153. On PN170, offspring were euthanized for central dopaminergic analysis. SSD animals showed an increased food intake compared to SC ones and a preference for HFD. However, N-SSD animals consumed relatively more HSD than C-SSD ones. Regarding behavior, N animals showed an increase in the time spent in the EPM center and a reduction in relative activity in the OF center. N offspring presented lower dopamine receptor (D2R) and transporter (DAT) contents in the nucleus accumbens, and lower D2R in the arcuate nucleus. Postnatal exposure to nicotine increases preference for sugar and anxiety levels in the adult progeny possibly due to a decrease in dopaminergic action in the nucleus accumbens and arcuate nucleus.

  1. The dopaminergic system in the aging brain of Drosophila.

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    White, Katherine E; Humphrey, Dickon M; Hirth, Frank

    2010-01-01

    Drosophila models of Parkinson's disease are characterized by two principal phenotypes: the specific loss of dopaminergic (DA) neurons in the aging brain and defects in motor behavior. However, an age-related analysis of these baseline parameters in wildtype Drosophila is lacking. Here we analyzed the DA system and motor behavior in aging Drosophila. DA neurons in the adult brain can be grouped into bilateral symmetric clusters, each comprising a stereotypical number of cells. Analysis of TH > mCD8::GFP and cell type-specific MARCM clones revealed that DA neurons show cluster-specific, stereotypical projection patterns with terminal arborization in target regions that represent distinct functional areas of the adult brain. Target areas include the mushroom bodies, involved in memory formation and motivation, and the central complex, involved in the control of motor behavior, indicating that similar to the mammalian brain, DA neurons in the fly brain are involved in the regulation of specific behaviors. Behavioral analysis revealed that Drosophila show an age-related decline in startle-induced locomotion and negative geotaxis. Motion tracking however, revealed that walking activity, and exploration behavior, but not centrophobism increase at late stages of life. Analysis of TH > Dcr2, mCD8::GFP revealed a specific effect of Dcr2 expression on walking activity but not on exploratory or centrophobic behavior, indicating that the siRNA pathway may modulate distinct DA behaviors in Drosophila. Moreover, DA neurons were maintained between early- and late life, as quantified by TH > mCD8::GFP and anti-TH labeling, indicating that adult onset, age-related degeneration of DA neurons does not occur in the aging brain of Drosophila. Taken together, our data establish baseline parameters in Drosophila for the study of Parkinson's disease as well as other disorders affecting DA neurons and movement control.

  2. Mesolimbic lipid sensing and the regulation of feeding behaviour

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    Cansell Celine

    2015-07-01

    Full Text Available In both developed and emerging countries, sedentary life style and over exposition to high energy dense foods has led to a thermodynamic imbalance and consequently obesity. Despite genetic predisposition, obesity often involves a behavioral component in which, similar to drugs of abuse, compulsive consumption of palatable food rich in lipids and sugar drives energy intake far beyond metabolic demands. Food intake is modulated by sensory inputs, such as tastes and odours, as well as by affective or emotional states. The mesolimbic pathway is well established as a main actor of the rewarding aspect of feeding. Particularly, the hedonic and motivational aspects of food are closely tied to the release of the neurotransmitter dopamine (DA in striatal structure such as the Nucleus Accumbens (Nacc. In both rodent and humans several studies shows an attenuated activity of dopaminergic signal associated with obesity and there is evidence that consumption of palatable food per se leads to DA signalling alterations. Furthermore impaired cognition in obese mice is improved by selectively lowering triglycerides (TG and intracerebroventricular administration of TG induces by itself acquisition impairment in several cognitive paradigms in normal body weight mice. Together, these observations raise the possibility that nutritional lipids, particularly TG, directly affect cognitive and reward processes by modulating the mesolimbic pathway and might contribute to the downward spiral of compulsive consumption of palatable and obesity. This review is an attempt to capture recent evolution in the field that might point toward a direct action of nutritional lipid in the mesolimbic pathway.

  3. Effects of Chronic Hypergravity on the Dopaminergic Neuronal System in Drosophila Melanogaster

    Science.gov (United States)

    Pelos, Andrew; Hosamani, Ravikumar; Bhattacharya, Sharmila

    2017-01-01

    Upon atmospheric exitre-entry and during training, astronauts are subjected to temporary periods of hypergravity, which has been implicated in the activation of oxidative stress pathways contributing to mitochondrial dysfunction and neuronal degeneration. The pathogenesis of Parkinsons disease and other neurodegenerative disorders is associated with oxidative damage to neurons involved in dopamine systems of the brain. Our study aims to examine the effects of a hypergravitational developmental environment on the degeneration of dopaminergic systems in Drosophila melanogaster. Male and female flies (Gal4-UAS transgenic line) were hatched and raised to adulthood in centrifugal hypergravity (97rpm, 3g). The nuclear expression of the reporter, Green Fluorescent Protein (GFP) is driven by the dopaminergic enzyme tyrosine hydroxylase (TH) promoter, allowing for the targeted visualization of dopamine producing neurons. After being raised to adulthood and kept in hypergravity until 18 days of age, flies were dissected and the expression of TH was measured by fluorescence confocal microscopy. TH expression in the fly brains was used to obtain counts of healthy dopaminergic neurons for flies raised in chronic hypergravity and control groups. Dopaminergic neuron expression data were compared with those of previous studies that limited hypergravity exposure to late life in order to determine the flies adaptability to the gravitational environment when raised from hatching through adulthood. Overall, we observed a significant effect of chronic hypergravity exposure contributing to deficits in dopaminergic neuron expression (p 0.003). Flies raised in 3g had on average lower dopaminergic neuron counts (mean 97.7) when compared with flies raised in 1g (mean 122.8). We suspect these lower levels of TH expression are a result of oxidative dopaminergic cell loss in flies raised in hypergravity. In future studies, we hope to further elucidate the mechanism by which hypergravity

  4. Chronic Hypergravity Induces Changes in the Dopaminergic Neuronal System in Drosophila Melanogaster

    Science.gov (United States)

    Pelos, Andrew; Hosamani, Ravikumar; Bhattacharya, Sharmila

    2017-01-01

    Upon atmospheric exitre-entry and during training, astronauts are subjected to temporary periods of hypergravity, which has been implicated in the activation of oxidative stress pathways contributing to mitochondrial dysfunction and neuronal degeneration. The pathogenesis of Parkinsons disease and other neurodegenerative disorders is associated with oxidative damage to neurons involved in dopamine systems of the brain. Our study aims to examine the effects of a hypergravitational developmental environment on the degeneration of dopaminergic systems in Drosophila melanogaster. Male and female flies (Gal4-UAS transgenic line) were hatched and raised to adulthood in centrifugal hypergravity (97rpm, 3g). The nuclear expression of the reporter, Green Fluorescent Protein (GFP) is driven by the dopaminergic enzyme tyrosine hydroxylase (TH) promoter, allowing for the targeted visualization of dopamine producing neurons. After being raised to adulthood and kept in hypergravity until 18 days of age, flies were dissected and the expression of TH was measured by fluorescence confocal microscopy. TH expression in the fly brains was used to obtain counts of healthy dopaminergic neurons for flies raised in chronic hypergravity and control groups. Dopaminergic neuron expression data were compared with those of previous studies that limited hypergravity exposure to late life in order to determine the flies adaptability to the gravitational environment when raised from hatching through adulthood. Overall, we observed a significant effect of chronic hypergravity exposure contributing to deficits in dopaminergic neuron expression (p 0.003). Flies raised in 3g had on average lower dopaminergic neuron counts (mean 97.7) when compared with flies raised in 1g (mean 122.8). We suspect these lower levels of TH expression are a result of oxidative dopaminergic cell loss in flies raised in hypergravity. In future studies, we hope to further elucidate the mechanism by which hypergravity

  5. Circadian Rhythms, the Mesolimbic Dopaminergic Circuit, and Drug Addiction

    OpenAIRE

    McClung, Colleen A.

    2007-01-01

    Drug addiction is a devastating disease that affects millions of individuals worldwide. Through better understanding of the genetic variations that create a vulnerability for addiction and the molecular mechanisms that underlie the progression of addiction, better treatment options can be created for those that suffer from this condition. Recent studies point to a link between abnormal or disrupted circadian rhythms and the development of addiction. In addition, studies suggest a role for spe...

  6. The dopaminergic neurons of the A11 system in RLS autopsy brains appear normal.

    Science.gov (United States)

    Earley, Christopher J; Allen, Richard P; Connor, James R; Ferrucci, Luigi; Troncoso, Juan

    2009-12-01

    Although the positive clinical benefits of levodopa have fostered the concept of an abnormality in the dopaminergic system in Restless Legs Syndrome (RLS), research into the nigro-striatal (PET/SPECT studies) or tubero-infundibular (i.e., prolactin secretion) dopaminergic pathways has shown limited positive results. Some research groups have focused on the A11 dopaminergic system in the hypothalamus as this is the primary source of descending dopaminergic input into the spinal cord, an area of the nervous system believed by some investigators to be involved in RLS symptom development. Some investigators have now proposed lesioning or toxin-inhibiting the A11 system as a model of RLS, even though there has been no clear clinical or autopsy data to suggest that RLS is a neurodegenerative disorder. In this study, the A11 cell bodies were identified in 6 RLS and 6 aged-matched control autopsy cases. Cells were stained for tyrosine hydroxylase (TH), and stereological measure of the individual TH (+) cell volume was made. Regional assessment of gliosis as assessed by immunostaining for glial fibrillary acidic protein (GFAP) was made in the surrounding tissue. General histological staining was also performed on the tissue. This study found no significant difference between RLS or control cases on any measure used: TH (+) cell volume, fractional GFAP staining, or general histological examination. Nor was there histological indication of any significant inflammation or concurrent ongoing pathology in these RLS cases. The findings do not support the concept of dramatic cell loss or of a neurodegenerative process in the A11 hypothalamic region of patients with RLS. However, that does not exclude the possibility that the A11 system is involved in RLS symptoms. Changes at the cellular level in dopaminergic metabolism or at the distal synapse with changes in receptors or transporters were not evaluated in this study.

  7. Imbalance between thyroid hormones and the dopaminergic system might be central to the pathophysiology of restless legs syndrome: a hypothesis

    Directory of Open Access Journals (Sweden)

    Jose Carlos Pereira Jr.

    2010-01-01

    Full Text Available Data collected from medical literature indicate that dopaminergic agonists alleviate Restless Legs Syndrome symptoms while dopaminergic agonists antagonists aggravate them. Dopaminergic agonists is a physiological regulator of thyroid-stimulating hormone. Dopaminergic agonists infusion diminishes the levels of thyroid hormones, which have the ability to provoke restlessness, hyperkinetic states, tremors, and insomnia. Conditions associated with higher levels of thyroid hormones, such as pregnancy or hyperthyroidism, have a higher prevalence of Restless Legs Syndrome symptoms. Low iron levels can cause secondary Restless Legs Syndrome or aggravate symptoms of primary disease as well as diminish enzymatic activities that are involved in dopaminergic agonists production and the degradation of thyroid hormones. Moreover, as a result of low iron levels, dopaminergic agonists diminishes and thyroid hormones increase. Iron therapy improves Restless Legs Syndrome symptoms in iron deprived patients. Medical hypothesis. To discuss the theory that thyroid hormones, when not counterbalanced by dopaminergic agonists, may precipitate the signs and symptoms underpinning Restless Legs Syndrome. The main cause of Restless Legs Syndrome might be an imbalance between the dopaminergic agonists system and thyroid hormones.

  8. Imaging of the dopaminergic neurotransmission system using single-photon emission tomography and positron emission tomography in patients with parkinsonism

    NARCIS (Netherlands)

    Booij, J.; Tissingh, G.; Winogrodzka, A.; van Royen, E. A.

    1999-01-01

    Parkinsonism is a feature of a number of neurodegenerative diseases, including Parkinson's disease, multiple system atrophy and progressive supranuclear palsy. The results of post-mortem studies point to dysfunction of the dopaminergic neurotransmitter system in patients with parkinsonism. Nowadays,

  9. Inhibition of opioid systems in the hypothalamus as well as the mesolimbic area suppresses feeding behavior of mice.

    Science.gov (United States)

    Ikeda, H; Ardianto, C; Yonemochi, N; Yang, L; Ohashi, T; Ikegami, M; Nagase, H; Kamei, J

    2015-12-17

    Opioid receptors, especially μ-opioid receptors, in the ventral tegmental area (VTA) and nucleus accumbens (NAcc) are reported to regulate food motivation. However, the roles of μ-, δ- and κ-opioid receptors are not fully understood. Moreover, since μ-, δ- and κ-opioid receptors are reported to distribute in the hypothalamus, these receptors in the hypothalamus might regulate feeding behavior. Thus, the present study investigated the role of μ-, δ- and κ-opioid receptors in the VTA, the NAcc and the hypothalamus in the regulation of feeding behavior. Male ICR mice were subjected to a feeding test after food deprivation for 16h. The mRNA levels of proopiomelanocortin (POMC), preproenkephalin (PENK) and prodynorphin (PDYN), the precursors of endogenous opioid peptides, were measured by reverse transcription-polymerase chain reaction (RT-PCR). The systemic injection of non-selective (naloxone) and selective μ (β-funaltrexamine; β-FNA), δ (naltrindole) and κ (norbinaltorphimine; norBNI) opioid receptor antagonists markedly reduced food intake. In contrast, the systemic injection of preferential μ (morphine), selective δ (KNT-127) and κ (U-50,488) opioid receptor agonists did not change food intake. The mRNA levels of POMC, PENK and PDYN were decreased in the hypothalamus and the midbrain after food deprivation, whereas the mRNA levels of PENK and PDYN, but not POMC, were decreased in the ventral striatum. The injection of naloxone into the NAcc, VTA and lateral hypothalamus (LH), but not the ventromedial nucleus of the hypothalamus, significantly decreased food intake. The injection of β-FNA and naltrindole into the LH, but not the VTA or NAcc, decreased food intake. The injection of norBNI into the LH and VTA, but not the NAcc, decreased food intake. These results indicate that μ-, δ- and κ-opioid receptors in the LH play a more important role in the regulation of feeding behavior than those receptors in the VTA and the NAcc. Copyright © 2015

  10. Brain dopaminergic system changes in drug addiction: a review of positron emission tomography findings

    OpenAIRE

    Hou, Haifeng; Wang, Chunyan; Jia, Shaowei; Hu, Shu; Tian, Mei

    2014-01-01

    Dopamine (DA) is considered crucial for the rewarding effects of drugs of abuse, but its role in addiction remains unclear. Positron emission tomography (PET) is the first technology used for in vivo measurement of components of the dopaminergic system in the human brain. In this article, we review the major findings from PET imaging studies on the involvement of DA in drug addiction, including presynaptic DA synthesis, vesicular monoamine transporter 2, the DA transporter, and postsynaptic D...

  11. Imaging of the dopaminergic neurotransmission system using single-photon emission tomography and positron emission tomography in patients with parkinsonism

    International Nuclear Information System (INIS)

    Booij, J.; Tissingh, G.; Winogrodzka, A.; Royen, E.A. van

    1999-01-01

    Parkinsonism is a feature of a number of neurodegenerative diseases, including Parkinson's disease, multiple system atrophy and progressive supranuclear palsy. The results of post-mortem studies point to dysfunction of the dopaminergic neurotransmitter system in patients with parkinsonism. Nowadays, by using single-photon emission tomography (SPET) and positron emission tomography (PET) it is possible to visualise both the nigrostriatal dopaminergic neurons and the striatal dopamine D 2 receptors in vivo. Consequently, SPET and PET imaging of elements of the dopaminergic system can play an important role in the diagnosis of several parkinsonian syndromes. This review concentrates on findings of SPET and PET studies of the dopaminergic neurotransmitter system in various parkinsonian syndromes. (orig.)

  12. Atrial Natriuretic Peptide and Renal Dopaminergic System: A Positive Friendly Relationship?

    Directory of Open Access Journals (Sweden)

    Marcelo Roberto Choi

    2014-01-01

    Full Text Available Sodium metabolism by the kidney is accomplished by an intricate interaction between signals from extrarenal and intrarenal sources and between antinatriuretic and natriuretic factors. Renal dopamine plays a central role in this interactive network. The natriuretic hormones, such as the atrial natriuretic peptide, mediate some of their effects by affecting the renal dopaminergic system. Renal dopaminergic tonus can be modulated at different steps of dopamine metabolism (synthesis, uptake, release, catabolism, and receptor sensitization which can be regulated by the atrial natriuretic peptide. At tubular level, dopamine and atrial natriuretic peptide act together in a concerted manner to promote sodium excretion, especially through the overinhibition of Na+, K+-ATPase activity. In this way, different pathological scenarios where renal sodium excretion is dysregulated, as in nephrotic syndrome or hypertension, are associated with impaired action of renal dopamine and/or atrial natriuretic peptide, or as a result of impaired interaction between these two natriuretic systems. The aim of this review is to update and comment on the most recent evidences demonstrating how the renal dopaminergic system interacts with atrial natriuretic peptide to control renal physiology and blood pressure through different regulatory pathways.

  13. Investigations into potential extrasynaptic communication between the dopaminergic and nitrergic systems

    Directory of Open Access Journals (Sweden)

    Miso eMitkovski

    2012-09-01

    Full Text Available Nitric oxide is unconstrained by cell membranes and can therefore act along a broad distance as a volume transmitter. Spillover of nitric oxide between neurons may have a major impact on central nervous system diseases and particularly on neurodegeneration. There is evidence whereby communication between nitrergic and dopaminergic systems plays an essential role in the control of the nigrostriatal pathway. However, there is sparse information for either the coexistence or overlap of nitric oxide and dopaminergic structures. The present study used double-labeling immunofluorescent microscopy to investigate the degree of cellular co-localization between nitric oxide synthase and tyrosine hydroxylase, enzymes responsible for the synthesis of nitric oxide and dopamine, respectively, was examined in neurons of the nigrostriatal pathway regions in the rat brain. After perfusional fixation, the brains were cut and double immunostained. A proximity analysis of tyrosine hydroxylase and nitric oxide synthase structures was made using confocal laser scanning microscopy, in nigrostriatal regions of the rat brain. We used image acquired at the optical limit and generated binary masks at 2µm-wide margin from the respective maximum projections. Co-localization between the two antigens was infrequent (<10% in most areas examined. However, tyrosine hydroxylase labeling was particularly concentrated close to nitric oxide synthase dendrites/axons and the cell bodies. These results further substantiate an extrasynaptic substrate for interaction between nitrergic and dopaminergic systems, thereby modulating sensitivity to neural inputs and its gene expression.

  14. Leptin and insulin signaling in dopaminergic neurons: relationship between energy balance and reward system.

    Science.gov (United States)

    Khanh, Doan V; Choi, Yun-Hee; Moh, Sang Hyun; Kinyua, Ann W; Kim, Ki Woo

    2014-01-01

    The central actions of leptin and insulin are essential for the regulation of energy and glucose homeostasis. In addition to the crucial effects on the hypothalamus, emerging evidence suggests that the leptin and insulin signaling can act on other brain regions to mediate the reward value of nutrients. Recent studies have indicated the midbrain dopaminergic neurons as a potential site for leptin' and insulin's actions on mediating the feeding behaviors and therefore affecting the energy balance. Although molecular details about the integrative roles of leptin and insulin in this subset of neurons remain to be investigated, substantial body of evidence by far imply that the signaling pathways regulated by leptin and insulin may play an essential role in the regulation of energy balance through the control of food-associated reward. This review therefore describes the convergence of energy regulation and reward system, particularly focusing on leptin and insulin signaling in the midbrain dopaminergic neurons.

  15. Acrolein acts as a neurotoxin in the nigrostriatal dopaminergic system of rat: involvement of ?-synuclein aggregation and programmed cell death

    OpenAIRE

    Wang, Yi-Ting; Lin, Hui-Ching; Zhao, Wei-Zhong; Huang, Hui-Ju; Lo, Yu-Li; Wang, Hsiang-Tsui; Maan-Yuh Lin, Anya

    2017-01-01

    Clinical studies report significant increases in acrolein (an ?,?-unsaturated aldehyde) in the substantia nigra (SN) of patients with Parkinson?s disease (PD). In the present study, acrolein-induced neurotoxicity in the nigrostriatal dopaminergic system was investigated by local infusion of acrolein (15, 50, 150?nmoles/0.5??l) in the SN of Sprague-Dawley rats. Acrolein-induced neurodegeneration of nigrostriatal dopaminergic system was delineated by reductions in tyrosine hydroxylase (TH) leve...

  16. Brain dopaminergic system changes in drug addiction: a review of positron emission tomography findings.

    Science.gov (United States)

    Hou, Haifeng; Wang, Chunyan; Jia, Shaowei; Hu, Shu; Tian, Mei

    2014-10-01

    Dopamine (DA) is considered crucial for the rewarding effects of drugs of abuse, but its role in addiction remains unclear. Positron emission tomography (PET) is the first technology used for in vivo measurement of components of the dopaminergic system in the human brain. In this article, we review the major findings from PET imaging studies on the involvement of DA in drug addiction, including presynaptic DA synthesis, vesicular monoamine transporter 2, the DA transporter, and postsynaptic DA receptors. These results have corroborated the role of DA in addiction and increased the understanding of its underlying mechanisms.

  17. Molecular basis of the dopaminergic system in the cricket Gryllus bimaculatus.

    Science.gov (United States)

    Watanabe, Takayuki; Sadamoto, Hisayo; Aonuma, Hitoshi

    2013-12-01

    In insects, dopamine modulates various aspects of behavior such as learning and memory, arousal and locomotion, and is also a precursor of melanin. To elucidate the molecular basis of the dopaminergic system in the field cricket Gryllus bimaculatus DeGeer, we identified genes involved in dopamine biosynthesis, signal transduction, and dopamine re-uptake in the cricket. Complementary DNA of two isoforms of tyrosine hydroxylase (TH), which convert tyrosine into L-3,4-dihydroxyphenylalanine, was isolated from the cricket brain cDNA library. In addition, four dopamine receptor genes (Dop1, Dop2, Dop3, and DopEcR) and a high-affinity dopamine transporter gene were identified. The two TH isoforms contained isoform-specific regions in the regulatory ACT domain and showed differential expression patterns in different tissues. In addition, the dopamine receptor genes had a receptor subtype-specific distribution: the Dop1, Dop2, and DopEcR genes were broadly expressed in various tissues at differential expression levels, and the Dop3 gene was restrictedly expressed in neuronal tissues and the testicles. Our findings provide a fundamental basis for understanding the dopaminergic regulation of diverse physiological processes in the cricket.

  18. Interactive dopaminergic and noradrenergic systems in the regulation of thirst in the rat.

    Science.gov (United States)

    Zabik, J E; Sprague, J E; Odio, M

    1993-07-01

    Twenty-three hours of fluid deprivation led to elevated plasma levels of corticosterone and free fatty acids, as well as increased whole brain dopamine levels, in rats. Drinking could be initiated in water-replete rats by administration of single doses of the dopamine agonist, pergolide, the dopamine beta-hydroxylase inhibitor, diethyldithiocarbamate, the alpha-adrenergic antagonist, phenoxybenzamine, or the beta-adrenergic agonist, isoproterenol. In each case, the response to these agents was reduced or ameliorated by cotreatment with the dopamine antagonist, pimozide. Taken together, the results of the stress and pharmacological studies support the concept that drinking is initiated by a dopaminergically mediated thirst drive, which in turn is regulated by a noradrenergically mediated satiety system.

  19. Metformin, besides exhibiting strong in vivo anti-inflammatory properties, increases mptp-induced damage to the nigrostriatal dopaminergic system

    International Nuclear Information System (INIS)

    Ismaiel, Afrah A.K.; Espinosa-Oliva, Ana M.; Santiago, Martiniano; García-Quintanilla, Albert; Oliva-Martín, María J.; Herrera, Antonio J.; Venero, José L.; Pablos, Rocío M. de

    2016-01-01

    Metformin is a widely used oral antidiabetic drug with known anti-inflammatory properties due to its action on AMPK protein. This drug has shown a protective effect on various tissues, including cortical neurons. The aim of this study was to determine the effect of metformin on the dopaminergic neurons of the substantia nigra of mice using the animal model of Parkinson's disease based on the injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, an inhibitor of the mitochondrial complex I. In vivo and in vitro experiments were used to study the activation of microglia and the damage of the dopaminergic neurons. Our results show that metformin reduced microglial activation measured both at cellular and molecular levels. Rather than protecting, metformin exacerbated dopaminergic damage in response to MPTP. Our data suggest that, contrary to other brain structures, metformin treatment could be deleterious for the dopaminergic system. Hence, metformin treatment may be considered as a risk factor for the development of Parkinson's disease. - Highlights: • Metformin treatment decreases microglial activation in the MPTP model of Parkinson's disease. • Metformin treatment increases the neurodegeneration in the MPTP model of Parkinson's disease, both in vivo and vitro. • Metformin treatment could be a risk factor for the development of Parkinson's disease.

  20. An Efficient and Versatile System for Visualization and Genetic Modification of Dopaminergic Neurons in Transgenic Mice.

    Directory of Open Access Journals (Sweden)

    Karsten Tillack

    Full Text Available The brain dopaminergic (DA system is involved in fine tuning many behaviors and several human diseases are associated with pathological alterations of the DA system such as Parkinson's disease (PD and drug addiction. Because of its complex network integration, detailed analyses of physiological and pathophysiological conditions are only possible in a whole organism with a sophisticated tool box for visualization and functional modification.Here, we have generated transgenic mice expressing the tetracycline-regulated transactivator (tTA or the reverse tetracycline-regulated transactivator (rtTA under control of the tyrosine hydroxylase (TH promoter, TH-tTA (tet-OFF and TH-rtTA (tet-ON mice, to visualize and genetically modify DA neurons. We show their tight regulation and efficient use to overexpress proteins under the control of tet-responsive elements or to delete genes of interest with tet-responsive Cre. In combination with mice encoding tet-responsive luciferase, we visualized the DA system in living mice progressively over time.These experiments establish TH-tTA and TH-rtTA mice as a powerful tool to generate and monitor mouse models for DA system diseases.

  1. Positron emission tomography molecular imaging of dopaminergic system in drug addiction.

    Science.gov (United States)

    Hou, Haifeng; Tian, Mei; Zhang, Hong

    2012-05-01

    Dopamine (DA) is involved in drug reinforcement, but its role in drug addiction remains unclear. Positron emission tomography (PET) is the first technology used for the direct measurement of components of the dopaminergic system in the living human brain. In this article, we reviewed the major findings of PET imaging studies on the involvement of DA in drug addiction, especially in heroin addiction. Furthermore, we summarized PET radiotracers that have been used to study the role of DA in drug addiction. To investigate presynaptic function in drug addiction, PET tracers have been developed to measure DA synthesis and transport. For the investigation of postsynaptic function, several radioligands targeting dopamine one (D1) receptor and dopamine two (D2) receptor are extensively used in PET imaging studies. Moreover, we also summarized the PET imaging findings of heroin addiction studies, including heroin-induced DA increases and the reinforcement, role of DA in the long-term effects of heroin abuse, DA and vulnerability to heroin abuse and the treatment implications. PET imaging studies have corroborated the role of DA in drug addiction and increase our understanding the mechanism of drug addiction. Copyright © 2012 Wiley Periodicals, Inc.

  2. IBZM- and CIT-SPECT of the dopaminergic system in Parkinsonism

    International Nuclear Information System (INIS)

    Tissingh, G.; Winogradzka, A.; Wolters, E.C.; Booij, J.; Royen, E.A. van

    1997-01-01

    Parkinsonism is most of the time caused by idiopathic Parkinson's disease (IPD). Considering the differences in therapeutic response and prognosis. in viva discrimination between IPD and 'Parkinsonism-plus' syndromes is important. Recently, ligands have become available for imaging the pre- and postsynaptic dopaminergic system by Single Photon Emission Computed Tomography (SPECT). Visualization of postsynaptic D 2 dopamine receptors using 123 I-iodobenzamide ( 123 I-IBZM) may contribute to the differential diagnosis between IPD and 'Parkinsonism-plus' syndromes as IPD is a pure presynaptic disease. Imaging of the presynaptic dopamine transporters using [ 123 I]β-CIT (2β-carbomethoxy-3β-(4-iodophenyl)tropane) may be used as a diagnostic technique. Early disease detection in subjects suspected to be at risk for developing IPD has become possible using [ 123 I]β-CIT or other ligands for the dopamine transporter. Furthermore, with SPECT one is probably able to monitor in an objective way the efficacy of new pharmacological therapies. (author)

  3. Age-Dependent Effects of Methylphenidate on the Human Dopaminergic System in Young vs Adult Patients With Attention-Deficit/Hyperactivity Disorder: A Randomized Clincal Trial

    NARCIS (Netherlands)

    Schrantee, A.; Tamminga, H.G.H.; Bouziane, C.; Bottelier, M.A.; Bron, E.E.; Mutsaerts, H.-J.M.M.; Zwinderman, A.H.; Groote, I.R.; Rombouts, S.A.R.B.; Lindauer, R.J.L.; Klein, S.; Niessen, W.J.; Opmeer, B.C.; Boer, F.; Lucassen, P.J.; Andersen, S.L.; Geurts, H.M.; Reneman, L.

    2016-01-01

    Importance: Although numerous children receive methylphenidate hydrochloride for the treatment of attention-deficit/hyperactivity disorder (ADHD), little is known about age-dependent and possibly lasting effects of methylphenidate on the human dopaminergic system. Objectives: To determine whether

  4. Age-dependent effects of methylphenidate on the human dopaminergic system in young vs adult patients with attention-deficit/hyperactivity disorder: A randomized clinical trial

    NARCIS (Netherlands)

    Schrantee, A. (Anouk); Tamminga, H.G.H. (Hyke G. H.); C. Bouziane (Cheima); Bottelier, M.A. (Marco A.); E.E. Bron (Esther); H.J.M.M. Mutsaerts (Henri J. M.); A.H. Zwinderman (Ailko); Groote, I.R. (Inge R.); S.A.R.B. Rombouts (Serge); Lindauer, R.J.L. (Ramon J. L.); S. Klein (Stefan); W.J. Niessen (Wiro); B.C. Opmeer (Brent); Boer, F. (Frits); P.J. Lucassen; Andersen, S.L. (Susan L.); H.M. Geurts (Hilde ); L. Reneman (Liesbeth)

    2016-01-01

    textabstractIMPORTANCE Although numerous children receivemethylphenidate hydrochloride for the treatment of attention-deficit/hyperactivity disorder (ADHD), little is known about age-dependent and possibly lasting effects of methylphenidate on the human dopaminergic system. OBJECTIVES To determine

  5. Age-Dependent Effects of Methylphenidate on the Human Dopaminergic System in Young vs Adult Patients With Attention-Deficit/Hyperactivity Disorder: A Randomized Clinical Trial

    NARCIS (Netherlands)

    Schrantee, Anouk; Tamminga, Hyke G. H.; Bouziane, Cheima; Bottelier, Marco A.; Bron, Esther E.; Mutsaerts, Henk-Jan M. M.; Zwinderman, Aeilko H.; Groote, Inge R.; Rombouts, Serge A. R. B.; Lindauer, Ramon J. L.; Klein, Stefan; Niessen, Wiro J.; Opmeer, Brent C.; Boer, Frits; Lucassen, Paul J.; Andersen, Susan L.; Geurts, Hilde M.; Reneman, Liesbeth

    2016-01-01

    Although numerous children receive methylphenidate hydrochloride for the treatment of attention-deficit/hyperactivity disorder (ADHD), little is known about age-dependent and possibly lasting effects of methylphenidate on the human dopaminergic system. To determine whether the effects of

  6. Influence of the dopaminergic system, CREB, and transcription factor-κB on cocaine neurotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Planeta, C.S. [Laboratório de Neuropsicofarmacologia, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, Araraquara, SP (Brazil); Lepsch, L.B.; Alves, R.; Scavone, C. [Departamento de Farmacologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP (Brazil)

    2013-10-15

    Cocaine is a widely used drug and its abuse is associated with physical, psychiatric and social problems. Abnormalities in newborns have been demonstrated to be due to the toxic effects of cocaine during fetal development. The mechanism by which cocaine causes neurological damage is complex and involves interactions of the drug with several neurotransmitter systems, such as the increase of extracellular levels of dopamine and free radicals, and modulation of transcription factors. The aim of this review was to evaluate the importance of the dopaminergic system and the participation of inflammatory signaling in cocaine neurotoxicity. Our study showed that cocaine activates the transcription factors NF-κB and CREB, which regulate genes involved in cellular death. GBR 12909 (an inhibitor of dopamine reuptake), lidocaine (a local anesthetic), and dopamine did not activate NF-κB in the same way as cocaine. However, the attenuation of NF-κB activity after the pretreatment of the cells with SCH 23390, a D1 receptor antagonist, suggests that the activation of NF-κB by cocaine is, at least partially, due to activation of D1 receptors. NF-κB seems to have a protective role in these cells because its inhibition increased cellular death caused by cocaine. The increase in BDNF (brain-derived neurotrophic factor) mRNA can also be related to the protective role of both CREB and NF-κB transcription factors. An understanding of the mechanisms by which cocaine induces cell death in the brain will contribute to the development of new therapies for drug abusers, which can help to slow down the progress of degenerative processes.

  7. Influence of the dopaminergic system, CREB, and transcription factor-κB on cocaine neurotoxicity

    International Nuclear Information System (INIS)

    Planeta, C.S.; Lepsch, L.B.; Alves, R.; Scavone, C.

    2013-01-01

    Cocaine is a widely used drug and its abuse is associated with physical, psychiatric and social problems. Abnormalities in newborns have been demonstrated to be due to the toxic effects of cocaine during fetal development. The mechanism by which cocaine causes neurological damage is complex and involves interactions of the drug with several neurotransmitter systems, such as the increase of extracellular levels of dopamine and free radicals, and modulation of transcription factors. The aim of this review was to evaluate the importance of the dopaminergic system and the participation of inflammatory signaling in cocaine neurotoxicity. Our study showed that cocaine activates the transcription factors NF-κB and CREB, which regulate genes involved in cellular death. GBR 12909 (an inhibitor of dopamine reuptake), lidocaine (a local anesthetic), and dopamine did not activate NF-κB in the same way as cocaine. However, the attenuation of NF-κB activity after the pretreatment of the cells with SCH 23390, a D1 receptor antagonist, suggests that the activation of NF-κB by cocaine is, at least partially, due to activation of D1 receptors. NF-κB seems to have a protective role in these cells because its inhibition increased cellular death caused by cocaine. The increase in BDNF (brain-derived neurotrophic factor) mRNA can also be related to the protective role of both CREB and NF-κB transcription factors. An understanding of the mechanisms by which cocaine induces cell death in the brain will contribute to the development of new therapies for drug abusers, which can help to slow down the progress of degenerative processes

  8. Influence of the dopaminergic system, CREB, and transcription factor-B on cocaine neurotoxicity

    Directory of Open Access Journals (Sweden)

    C.S. Planeta

    2013-11-01

    Full Text Available Cocaine is a widely used drug and its abuse is associated with physical, psychiatric and social problems. Abnormalities in newborns have been demonstrated to be due to the toxic effects of cocaine during fetal development. The mechanism by which cocaine causes neurological damage is complex and involves interactions of the drug with several neurotransmitter systems, such as the increase of extracellular levels of dopamine and free radicals, and modulation of transcription factors. The aim of this review was to evaluate the importance of the dopaminergic system and the participation of inflammatory signaling in cocaine neurotoxicity. Our study showed that cocaine activates the transcription factors NF-κB and CREB, which regulate genes involved in cellular death. GBR 12909 (an inhibitor of dopamine reuptake, lidocaine (a local anesthetic, and dopamine did not activate NF-κB in the same way as cocaine. However, the attenuation of NF-κB activity after the pretreatment of the cells with SCH 23390, a D1 receptor antagonist, suggests that the activation of NF-κB by cocaine is, at least partially, due to activation of D1 receptors. NF-κB seems to have a protective role in these cells because its inhibition increased cellular death caused by cocaine. The increase in BDNF (brain-derived neurotrophic factor mRNA can also be related to the protective role of both CREB and NF-κB transcription factors. An understanding of the mechanisms by which cocaine induces cell death in the brain will contribute to the development of new therapies for drug abusers, which can help to slow down the progress of degenerative processes.

  9. Celecoxib reduces brain dopaminergic neuronaldysfunction, and improves sensorimotor behavioral performance in neonatal rats exposed to systemic lipopolysaccharide.

    Science.gov (United States)

    Kaizaki, Asuka; Tien, Lu-Tai; Pang, Yi; Cai, Zhengwei; Tanaka, Sachiko; Numazawa, Satoshi; Bhatt, Abhay J; Fan, Lir-Wan

    2013-04-05

    Cyclooxygenase-2 (COX-2) is induced in inflammatory cells in response to cytokines and pro-inflammatory molecules, suggesting that COX-2 has a role in the inflammatory process. The objective of the current study was to examine whether celecoxib, a selective COX-2 inhibitor, could ameliorate lipopolysaccharide (LPS)-induced brain inflammation, dopaminergic neuronal dysfunction and sensorimotor behavioral impairments. Intraperitoneal (i.p.) injection of LPS (2 mg/kg) was performed in rat pups on postnatal Day 5 (P5), and celecoxib (20 mg/kg) or vehicle was administered (i.p.) five minutes after LPS injection. Sensorimotor behavioral tests were carried out 24 h after LPS exposure, and brain injury was examined on P6. Our results showed that LPS exposure resulted in impairment in sensorimotor behavioral performance and injury to brain dopaminergic neurons, as indicated by loss of tyrosine hydroxylase (TH) immunoreactivity, as well as decreases in mitochondria activity in the rat brain. LPS exposure also led to increases in the expression of α-synuclein and dopamine transporter proteins and enhanced [3H]dopamine uptake. Treatment with celecoxib significantly reduced LPS-induced sensorimotor behavioral disturbances and dopaminergic neuronal dysfunction. Celecoxib administration significantly attenuated LPS-induced increases in the numbers of activated microglia and astrocytes and in the concentration of IL-1β in the neonatal rat brain. The protective effect of celecoxib was also associated with an attenuation of LPS-induced COX-2+ cells, which were double labeled with TH + (dopaminergic neuron) or glial fibrillary acidic protein (GFAP) + (astrocyte) cells. Systemic LPS administration induced brain inflammatory responses in neonatal rats; these inflammatory responses included induction of COX-2 expression in TH neurons and astrocytes. Application of the COX-2 inhibitor celecoxib after LPS treatment attenuated the inflammatory response and improved LPS-induced impairment

  10. The effects of Vitex agnus castus extract and its interaction with dopaminergic system on LH and testosterone in male mice.

    Science.gov (United States)

    Nasri, Sima; Oryan, Shahrbano; Rohani, Ali Haeri; Amin, Gholam Reza

    2007-07-15

    The purpose of this study was to evaluate the probable effects of Vitex agnus castus (Vac.) on the male reproductive physiology. It is a well known fact that LH secretion from the anterior pituitary of mammals is controlled by many neurotransmiters such as dopamine. In this experiment, we have studied the effect of Vac. extract on the LH and testosterone hormones and its interaction with the dopaminergic system on male mice. In order to evaluate these effects, we used the hydroalcoholic Vac. extract (for extraction we used percolation technique) injection with the following doses: 65, 165, 265, 365 and 465 mg kg-', bromocriptine as a dopamine receptor agonist (5, 10, 20 mg kg(-1)) and haloperidol as a dopamine receptor antagonist (1, 1.5, 2, 2.5, 3 mg kg(-1)). To study the interaction between Vac. extract and dopaminergic system, we injected the optimum doses of Vac. with bromocriptine or haloperidol at the same time. Intraperitoneal injections were applied in all experiments, once a day for 30 days. The control group remained intact and the sham group received vehicle. After the last injection, we collected the animal blood serums for hormonal assays. LH and testosterone were measured by Radio Immuno Assay (RIA). LH and testosterone, showed significant decrease in bromocriptine group and haloperidol increased these hormones. Vac. extract decreased significantly the LH and testosterone levels. The coadministration of Vac. extract and bromocriptine decreased LH and testosterone. Coadministration of Vac. extract and haloperidol decreased LH and testosterone levels. These results suggest: dopamine regulates the gonadotroph-leydig cells axis. It appears that Vac. exertes effects through dopaminergic system and other pathways. The findings of this study show we can use Vac. extract for pathological cases of increasing LH and testosterone.

  11. Preclinical assessment of dopaminergic system in rats by MicroPET using three positron-emitting radiopharmaceuticals

    Energy Technology Data Exchange (ETDEWEB)

    Lara-Camacho, V. M., E-mail: victormlc13@hotmail.com; Ávila-García, M. C., E-mail: victormlc13@hotmail.com; Ávila-Rodríguez, M. A., E-mail: victormlc13@hotmail.com [Unidad PET, Facultad de Medicina, Universidad Nacional Autónoma de México, 04510, México, D.F. (Mexico)

    2014-11-07

    Different diseases associated with dysfunction of dopaminergic system such as Parkinson, Alzheimer, and Schizophrenia are being widely studied with positron emission tomography (PET) which is a noninvasive method useful to assess the stage of these illnesses. In our facility we have recently implemented the production of [{sup 11}C]-DTBZ, [{sup 11}C]-RAC, and [{sup 18}F]-FDOPA, which are among the most common PET radiopharmaceuticals used in neurology applications to get information about the dopamine pathways. In this study two healthy rats were imaged with each of those radiotracers in order to confirm selective striatum uptake as a proof of principle before to release them for human use.

  12. Effect of Early Overfeeding on Palatable Food Preference and Brain Dopaminergic Reward System at Adulthood: Role of Calcium Supplementation.

    Science.gov (United States)

    Conceição, E P S; Carvalho, J C; Manhães, A C; Guarda, D S; Figueiredo, M S; Quitete, F T; Oliveira, E; Moura, E G; Lisboa, P C

    2016-05-01

    Rats raised in small litters (SL) are obese and hyperphagic. In the present study, we evaluated whether obesity is associated with changes in the mesocorticolimbic dopaminergic reward system in these animals at adulthood. We also assessed the anti-obesity effects of dietary calcium supplementation. To induce early overfeeding, litters were adjusted to three pups on postnatal day (PN)3 (SL group). Control litters were kept with 10 pups each until weaning (NL group). On PN120, SL animals were subdivided into two groups: SL (standard diet) and SL-Ca [SL with calcium supplementation (10 g calcium carbonate/kg rat chow) for 60 days]. On PN175, animals were subjected to a food challenge: animals could choose between a high-fat (HFD) or a high-sugar diet (HSD). Food intake was recorded after 30 min and 12 h. Euthanasia occurred on PN180. SL rats had higher food intake, body mass and central adiposity. Sixty days of dietary calcium supplementation (SL-Ca) prevented these changes. Only SL animals preferred the HFD at 12 h. Both SL groups had lower tyrosine hydroxylase content in the ventral tegmental area, lower dopaminergic transporter content in the nucleus accumbens, and higher type 2 dopamine receptor (D2R) content in the hypothalamic arcuate nucleus (ARC). They also had higher neuropeptide Y (NPY) and lower pro-opiomelanocortin contents in the ARC. Calcium treatment normalised only D2R and NPY contents. Precocious obesity induces long-term effects in the brain dopaminergic system, which can be associated with an increased preference for fat at adulthood. Calcium treatment prevents this last alteration, partially through its actions on ARC D2R and NPY proteins. © 2016 British Society for Neuroendocrinology.

  13. Endogenous Opioid-Induced Neuroplasticity of Dopaminergic Neurons in the Ventral Tegmental Area Influences Natural and Opiate Reward

    NARCIS (Netherlands)

    Pitchers, Kyle K.; Coppens, Caroline M.; Beloate, Lauren N.; Fuller, Jonathan; Van, Sandy; Frohmader, Karla S.; Laviolette, Steven R.; Lehman, Michael N.; Coolen, Lique M.

    2014-01-01

    Natural reward and drugs of abuse converge on the mesolimbic pathway and activate common mechanism of neural plasticity in the nucleus accumbens. Chronic exposure to opiates induces plasticity in dopaminergic neurons of the ventral tegmental area (VTA), which regulates morphine reward tolerance.

  14. Structural plasticity in mesencephalic dopaminergic neurons produced by drugs of abuse: critical role of BDNF and dopamine.

    Directory of Open Access Journals (Sweden)

    Ginetta eCollo

    2014-11-01

    Full Text Available Mesencephalic dopaminergic neurons were suggested to be a critical physiopathology substrate for addiction disorders. Among neuroadaptive processes to addictive drugs, structural plasticity has attracted attention. While structural plasticity occurs at both pre- and post-synaptic levels in the mesolimbic dopaminergic system, the present review focuses only on dopaminergic neurons. Exposures to addictive drugs determine two opposite structural responses, hypothrophic plasticity produced by opioids and cannabinoids (in particular during the early withdrawal phase and hypertrophic plasticity, mostly driven by psychostimulants and nicotine. In vitro and in vivo studies indentified BDNF and extracellular dopamine as two critical factors in determining structural plasticity, the two molecules sharing similar intracellular pathways involved in cell soma and dendrite growth, the MEK-ERK1/2 and the PI3K-Akt-mTOR, via preferential activation of TrkB and dopamine D3 receptors, respectively. At present information regarding specific structural changes associated to the various stages of the addiction cycle is incomplete. Encouraging neuroimaging data in humans indirectly support the preclinical evidence of hypotrophic and hypertrophic effects, suggesting a possible differential engagement of dopamine neurons in parallel and partially converging circuits controlling motivation, stress and emotions.

  15. White noise improves learning by modulating activity in dopaminergic midbrain regions and right superior temporal sulcus.

    Science.gov (United States)

    Rausch, Vanessa H; Bauch, Eva M; Bunzeck, Nico

    2014-07-01

    In neural systems, information processing can be facilitated by adding an optimal level of white noise. Although this phenomenon, the so-called stochastic resonance, has traditionally been linked with perception, recent evidence indicates that white noise may also exert positive effects on cognitive functions, such as learning and memory. The underlying neural mechanisms, however, remain unclear. Here, on the basis of recent theories, we tested the hypothesis that auditory white noise, when presented during the encoding of scene images, enhances subsequent recognition memory performance and modulates activity within the dopaminergic midbrain (i.e., substantia nigra/ventral tegmental area, SN/VTA). Indeed, in a behavioral experiment, we can show in healthy humans that auditory white noise-but not control sounds, such as a sinus tone-slightly improves recognition memory. In an fMRI experiment, white noise selectively enhances stimulus-driven phasic activity in the SN/VTA and auditory cortex. Moreover, it induces stronger connectivity between SN/VTA and right STS, which, in addition, exhibited a positive correlation with subsequent memory improvement by white noise. Our results suggest that the beneficial effects of auditory white noise on learning depend on dopaminergic neuromodulation and enhanced connectivity between midbrain regions and the STS-a key player in attention modulation. Moreover, they indicate that white noise could be particularly useful to facilitate learning in conditions where changes of the mesolimbic system are causally related to memory deficits including healthy and pathological aging.

  16. Influence of a long-term powdered diet on the social interaction test and dopaminergic systems in mice.

    Science.gov (United States)

    Niijima-Yaoita, Fukie; Tsuchiya, Masahiro; Saito, Hiroko; Nagasawa, Yuka; Murai, Shigeo; Arai, Yuichiro; Nakagawasai, Osamu; Nemoto, Wataru; Tadano, Takeshi; Tan-No, Koichi

    2013-10-01

    It is well known that the characteristics of mastication are important for the maintenance of our physical well-being. In this study, to assess the importance of the effects of food hardness during mastication, we investigated whether a long-term powdered diet might cause changes in emotional behavior tests, including spontaneous locomotor activity and social interaction (SI) tests, and the dopaminergic system of the frontal cortex and hippocampus in mice. Mice fed a powdered diet for 17 weeks from weaning were compared with mice fed a standard diet (control). The dopamine turnover and expression of dopamine receptors mRNA in the frontal cortex were also evaluated. Spontaneous locomotor activity, SI time and dopamine turnover of the frontal cortex were increased in powdered diet-fed mice. On the other hand, the expression of dopamine-4 (D4) receptors mRNA in the frontal cortex was decreased in powdered diet-fed mice. Moreover, we examined the effect of PD168077, a selective D4 agonist, on the increased SI time in powdered diet-fed mice. Treatment with PD168077 decreased the SI time. These results suggest that the masticatory dysfunction induced by long-term powdered diet feeding may cause the increased SI time and the changes in the dopaminergic system, especially dopamine D4 receptor subtype in the frontal cortex. Copyright © 2013 Elsevier Ltd. All rights reserved.

  17. Role of genetic polymorphisms of the dopaminergic system in Parkinson's disease patients with impulse control disorders.

    Science.gov (United States)

    Vallelunga, Annamaria; Flaibani, Raffaella; Formento-Dojot, Patrizia; Biundo, Roberta; Facchini, Silvia; Antonini, Angelo

    2012-05-01

    The mechanisms underlying the development of impulse control disorders (ICDs) like compulsive gambling, buying, sexual, and eating behaviors in Parkinson's disease (PD) are debated. We assessed whether allelic variants of dopamine D2 receptors (DRD2), catechol-O-methyltransferase (COMT) and dopamine transporter (DAT) were associated with the development of ICDs in PD. We enrolled 89 idiopathic PD patients (48 without ICDs and 41 with ICDs). All patients were screened with the Minnesota Impulsive Disorders Interview (MIDI) and fulfilled DSM-IV criteria for the ICD positive cohort. Differences in the frequency of the genotypes between ICDs and non-ICDs groups were assessed using the χ(2) test. Genotyping was performed for variants of the DRD2 Taq1A (rs1800497), COMT Val(158)Met (rs4680), DAT1 (3' UTR 40bp VNTR). Variants of DRD2 Taq1A, COMT and DAT1 were not associated with the risk of developing ICDs. In our study, there were no differences in the frequency of variant of DRD2 Taq1A, COMT and DAT1 between the two groups. Polymorphisms of dopaminergic genes do not play a relevant role in the development of ICD in PD suggesting that ICD originate from inability to filter inappropriate behaviors triggered by dopaminergic therapy. Copyright © 2011. Published by Elsevier Ltd.

  18. Preparation of radiopharmaceuticals labelled with bromine positron emitting isotopes for the study of dopaminergic receptors of the central nervous system using positron emission tomography

    International Nuclear Information System (INIS)

    Loc'h, C.

    1988-04-01

    The in vivo study of dopaminergic receptors of the central nervous system using positron emission tomography requires the preparation of radiopharmaceuticals labelled with β + emitting isotopes. The chemical and pharmacological properties of these ligands are evaluated. Cyclotron produced 75 and 76 bromine β + emitting isotopes are incorporated into dopaminergic ligands by electrophilic substitution using peracetic acid in a no-carrier added form. Purity, lipophilicity and specific activity are analyzed. Pharmacological criteria (specificity, saturability, displacement, localization) required for ligand-receptor binding studies are evaluated in vitro on striatal membranes and in vivo in the rat. Positron emission tomographic studies show that the study of dopaminergic D2 receptors is possible using 75 and 76 bromine labelled bromospiperone and bromolisuride. These ligands are used in physiological and pharmacological studies of the central nervous system [fr

  19. Cannabinoid Receptor Type 1 Expression in the Developing Avian Retina: Morphological and Functional Correlation With the Dopaminergic System

    Directory of Open Access Journals (Sweden)

    Luzia da Silva Sampaio

    2018-03-01

    Full Text Available The avian retina has been used as a model to study signaling by different neuro- and gliotransmitters. It is unclear how dopaminergic and cannabinoid systems are related in the retina. Here we studied the expression of type 1 and 2 cannabinoid receptors (CB1 and CB2, as well as monoacylglycerol lipase (MAGL, the enzyme that degrades 2-arachidonoylglycerol (2-AG, during retina development. Our data show that CB1 receptor is highly expressed from embryonic day 5 (E5 until post hatched day 7 (PE7, decreasing its levels throughout development. CB1 is densely found in the ganglion cell layer (GCL and inner plexiform layer (IPL. CB2 receptor was also found from E5 until PE7 with a decrease in its contents from E9 afterwards. CB2 was mainly present in the lamination of the IPL at PE7. MAGL is expressed in all retinal layers, mainly in the IPL and OPL from E9 to PE7 retina. CB1 and CB2 were found both in neurons and glia cells, but MAGL was only expressed in Müller glia. Older retinas (PE7 show CB1 positive cells mainly in the INL and co-expression of CB1 and tyrosine hydroxylase (TH are shown in a few cells when both systems are mature. CB1 co-localized with TH and was heavily associated to D1 receptor labeling in primary cell cultures. Finally, cyclic AMP (cAMP was activated by the selective D1 agonist SKF38393, and inhibited when cultures were treated with WIN55, 212–2 (WIN in a CB1 dependent manner. The results suggest a correlation between the endocannabinoid and dopaminergic systems (DSs during the avian retina development. Activation of CB1 limits cAMP accumulation via D1 receptor activation and may influence embryological parameters during avian retina differentiation.

  20. Reassessing wanting and liking in the study of mesolimbic influence on food intake

    Science.gov (United States)

    2016-01-01

    Humans and animals such as rats and mice tend to overconsume calorie-dense foods, a phenomenon that likely contributes to obesity. One often-advanced explanation for why we preferentially consume sweet and fatty foods is that they are more “rewarding” than low-calorie foods. “Reward” has been subdivided into three interdependent psychological processes: hedonia (liking a food), reinforcement (formation of associations among stimuli, actions, and/or the food), and motivation (wanting the food). Research into these processes has focused on the mesolimbic system, which comprises both dopamine neurons in the ventral tegmental area and neurons in their major projection target, the nucleus accumbens. The mesolimbic system and closely connected structures are commonly referred to as the brain’s “reward circuit.” Implicit in this title is the assumption that “rewarding” experiences are generally the result of activity in this circuit. In this review, I argue that food intake and the preference for calorie-dense foods can be explained without reference to subjective emotions. Furthermore, the contribution of mesolimbic dopamine to food intake and preference may not be a general one of promoting or coordinating behaviors that result in the most reward or caloric intake but may instead be limited to the facilitation of a specific form of neural computation that results in conditioned approach behavior. Studies on the neural mechanisms of caloric intake regulation must address how sensory information about calorie intake affects not just the mesolimbic system but also many other forms of computation that govern other types of food-seeking and food-oriented behaviors. PMID:27534877

  1. Cannabis-sensitive dopaminergic markers in postmortem central nervous system: changes in schizophrenia.

    Science.gov (United States)

    Dean, Brian; Bradbury, Robyn; Copolov, David Leon

    2003-04-01

    This study investigated if changes in pre-synaptic markers on dopaminergic neurons (dopamine transporter [DAT], tyrosine hydroxylase [TH]) were present in the caudate from subjects with schizophrenia who had Delta(9)(-)tetrahydrocannabinol (THC) in their blood at autopsy. These changes were posited because animal studies show that treatment with THC decreases dopamine uptake and TH in the striatum. Studies utilized caudate, obtained postmortem, from 14 schizophrenic and 14 control subjects. [(3)H]mazindol binding to caudate, measured using autoradiography, was taken as a measure of DAT; TH levels were estimated using an antihuman TH antibody and Western blotting. There was decreased [(3)H]mazindol binding to DAT in the caudate from the schizophrenic subjects with no detectable blood THC levels (THC(-)) compared with THC(-) control subjects (mean +/- SEM: 240 +/- 19 vs. 296 +/- 14 fmol/mg estimated tissue equivalents, p =.01). There were no significant differences between levels of DAT in the caudate from schizophrenic and control subjects that had THC in their blood. Tyrosine hydroxylase was not different in any diagnostic cohort. Our data suggests that DAT is decreased in the caudate from THC(-) subjects with schizophrenia, a change that may be reversed by ingesting THC from cannabis.

  2. The dopaminergic system in patients with functional dyspepsia analysed by single photon emission computed tomography (SPECT) and an alpha-methyl-para-tyrosine (AMPT) challenge test

    Energy Technology Data Exchange (ETDEWEB)

    Braak, Breg; Klooker, Tamira K. [Academic Medical Center, Department of Gastroenterology and Hepatology, Amsterdam (Netherlands); Booij, Jan [Academic Medical Center, Department of Nuclear Medicine, Amsterdam (Netherlands); Wijngaard, Rene M.J. van den [Academic Medical Center, Tytgat Institute of Liver and Intestinal Research, Amsterdam (Netherlands); Boeckxstaens, Guy E.E. [Academic Medical Center, Department of Gastroenterology and Hepatology, Amsterdam (Netherlands); University Hospital Leuven, Catholic University Leuven, Department of Gastroenterology, Leuven (Belgium)

    2012-04-15

    Functional dyspepsia (FD) is a chronic condition characterized by upper abdominal symptoms without an identifiable cause. While the serotonergic system is thought to play a key role in the regulation of gut physiology, the role of the dopaminergic system, which is important in the regulation of visceral pain and stress, is under-studied. Therefore, this study investigated the dopaminergic system and its relationship with drinking capacity and symptoms in FD patients. In FD patients and healthy volunteers (HV) the dopaminergic system was investigated by in-vivo assessment of central dopamine D2 receptors (D2Rs) with [{sup 123}I]IBZM SPECT and by an acute, but reversible, dopamine depletion alpha-methyl-para-tyrosine (AMPT) challenge test. A nutrient drink test was performed to investigate the association between maximal ingested volume, evoked symptoms, and D2Rs. The HV subjects comprised 12 women and 8 men (mean age 31 {+-} 3 years), and the FD patients comprised 5 women and 3 men (mean age 39 {+-} 5 years). The FD patients had a lower left plus right average striatal binding potential (BP{sub NP}) for the caudate nucleus (p = 0.02), but not for putamen (p = 0.15), which in the FD patients was correlated with maximal ingested volume (r = 0.756, p = 0.03). The D2R BP{sub NP} in the putamen was correlated with nausea (r = 0.857, p = 0.01). The acute dopamine depletion test, however, failed to reveal differences in prolactin release between the FD patients and the HV subjects. These preliminary data suggest that chronic rather than acute alterations in the dopaminergic system may be involved in the pathogenesis of FD. Further studies are required to reproduce our novel findings and to evaluate to what extent the dopaminergic changes may be secondary to abnormalities in serotonergic pathways. (orig.)

  3. Neurochemical changes induced by acute and chronic administration of 1,2,3,4-tetrahydroisoquinoline and salsolinol in dopaminergic structures of rat brain.

    Science.gov (United States)

    Antkiewicz-Michaluk, L; Romañska, I; Papla, I; Michaluk, J; Bakalarz, M; Vetulani, J; Krygowska-Wajs, A; Szczudlik, A

    2000-01-01

    The finding that endogenous tetrahydroisoquinolines may be involved in the etiology of Parkinson's disease suggests that their administration may cause changes resembling those observed in parkinsonian brain. We tested, using a high-performance liquid chromatography method, how single and chronic administration of 1,2, 3,4-tetrahydroisoquinoline and salsolinol affects dopamine and serotonin metabolism in the neurons of extrapyramidal and mesolimbic dopaminergic systems. We report that chronic administration of tetrahydroisoquinoline and salsolinol causes a decrease in a dopamine metabolism: the effect of tetrahydroisoquinoline was limited to the striatum, while salsolinol caused also a dramatic decline of dopamine level in the substantia nigra. The effect of both compounds on serotonin metabolism was small or absent. The tetrahydroisoquinolines produced no changes in the nucleus accumbens. The results indicate that tetrahydroisoquinoline and salsolinol specifically affect the nigrostriatal dopamine system, but only when administered chronically, and thus are compatible with the view that endogenous tetrahydroisoquinolines may participate in pathogenesis of Parkinson's disease.

  4. Acute high fat diet consumption activates the mesolimbic circuit and requires orexin signaling in a mouse model.

    Directory of Open Access Journals (Sweden)

    Spring Valdivia

    Full Text Available Overconsumption of palatable energy-dense foods has negative health implications and it is associated with obesity and several eating disorders. Currently, little is known about the neuronal circuitries activated by the acute ingestion of a rewarding stimulus. Here, we used a combination of immunohistochemistry, pharmacology and neuronal tracing analyses to examine the role of the mesolimbic system in general, and the orexin neurons in particular, in a simple experimental test in which naïve mice are allowed to spontaneously eat a pellet of a high fat diet (HFD for 2 h. We found that acute HFD activates c-Fos expression in several reward-related brain areas, including the ventral tegmental area (VTA, nucleus accumbens, central amygdala and lateral hypothalamic area. We also found that: i- HFD-mediated orosensory stimulation was required for the mesolimbic pathway activation, ii- acute HFD differentially activates dopamine neurons of the paranigral, parabrachial pigmented and interfascicular sub-regions of the VTA, and iii- orexin neurons of the lateral hypothalamic area are responsive to acute HFD. Moreover, orexin signaling blockade, with the orexin 1 receptor antagonist SB-334867, reduces acute HFD consumption and c-Fos induction in the VTA but not in the other mesolimbic nuclei under study. Finally, we found that most orexin neurons responsive to acute HFD innervate the VTA. Our results show that acute HFD consumption recruits the mesolimbic system and that the full manifestation of this eating behavior requires the activation of orexin signaling.

  5. SPECT brain imaging of the dopaminergic system in Parkinsonism using 123I and 99mTc labeled agents

    International Nuclear Information System (INIS)

    Du Yong

    2004-01-01

    SPECT brain imaging of the dopaminergic system using 123 I and 99m Tc labeled agents, especially the simultaneous imaging of both pre- and postsynaptic neurons, promises to provide accurate diagnosis and differentiation of Parkinsonism. However, there are many degrading factors that affect the quality and quantitative accuracy of the SPECT images. These degrading factors limit the potential clinical applications of brain SPECT imaging. In this work, we studied these degrading factors by developing and validating a Monte Carlo (MC) method that provides accurate SPECT simulation with detailed modeling of the photon interactions inside the collimator detector system. To compensate for the partial volume effect (PVE) in the SPECT images caused by finite spatial resolution, we developed a new PVE compensation method that takes into account the effects of nonlinearity in iterative reconstruction-based compensation for image degrading factors, including attenuation, scatter, and collimator detector response. Compensation using the new method greatly improved the quantitative accuracy of brain SPECT images. We have also developed model-based method that can accurately estimate the downscatter and crosstalk contamination in the 123 I imaging and the simultaneous 123 I/ 99m Tc dual-isotope imaging. Based on the model-based method, two different approaches to model-based downscatter and crosstalk contamination compensation were proposed. Both methods are based on iterative reconstruction and include compensation for other imaging degrading factors. The model-based downscatter and crosstalk compensation method provided greatly improved accuracy of activity estimates with little effect on the precision. Finally, optimization of energy windows for simultaneous 123 I/ 99m Tc acquisition was performed to find the energy windows with the best trade-off between minimizing the crosstalk and maximizing the detection efficiency for simultaneous acquisitions. In summary, comprehensive

  6. Semax, an ACTH(4-10) analogue with nootropic properties, activates dopaminergic and serotoninergic brain systems in rodents.

    Science.gov (United States)

    Eremin, Kirill O; Kudrin, Vladimir S; Saransaari, Pirjo; Oja, Simo S; Grivennikov, Igor A; Myasoedov, Nikolay F; Rayevsky, Kirill S

    2005-12-01

    Corticotrophin (ACTH) and its analogues, particularly Semax (Met-Glu-His-Phe-Pro-Gly-Pro), demonstrate nootropic activity. Close functional and anatomical links have been established between melanocortinergic and monoaminergic brain systems. The aim of present work was to investigate the effects of Semax on neurochemical parameters of dopaminergic- and serotonergic systems in rodents. The tissue content of 5-hydroxyindoleacetic acid (5-HIAA) in the striatum was significantly increased (+25%) 2 h after Semax administration. The extracellular striatal level of 5-HIAA gradually increased up to 180% within 1-4 h after Semax (0.15 mg/kg, ip) administration. This peptide alone failed to alter the tissue and extracellular concentrations of dopamine and its metabolites. Semax injected 20 min prior D: -amphetamine dramatically enhanced the effects of the latter on the extracellular level of dopamine and on the locomotor activity of animals. Our results reveal the positive modulatory effect of Semax on the striatal serotonergic system and the ability of Semax to enhance both the striatal release of dopamine and locomotor behavior elicited by D-amphetamine.

  7. Chewing Prevents Stress-Induced Hippocampal LTD Formation and Anxiety-Related Behaviors: A Possible Role of the Dopaminergic System

    Directory of Open Access Journals (Sweden)

    Yumie Ono

    2015-01-01

    Full Text Available The present study examined the effects of chewing on stress-induced long-term depression (LTD and anxiogenic behavior. Experiments were performed in adult male rats under three conditions: restraint stress condition, voluntary chewing condition during stress, and control condition without any treatments except handling. Chewing ameliorated LTD development in the hippocampal CA1 region. It also counteracted the stress-suppressed number of entries to the center region of the open field when they were tested immediately, 30 min, or 60 min after restraint. At the latter two poststress time periods, chewing during restraint significantly increased the number of times of open arm entries in the elevated plus maze, when compared with those without chewing. The in vivo microdialysis further revealed that extracellular dopamine concentration in the ventral hippocampus, which is involved in anxiety-related behavior, was significantly greater in chewing rats than in those without chewing from 30 to 105 min after stress exposure. Development of LTD and anxiolytic effects ameliorated by chewing were counteracted by administering the D1 dopamine receptor antagonist SCH23390, which suggested that chewing may activate the dopaminergic system in the ventral hippocampus to suppress stress-induced anxiogenic behavior.

  8. LRRK2 knockout mice have an intact dopaminergic system but display alterations in exploratory and motor co-ordination behaviors

    Directory of Open Access Journals (Sweden)

    Hinkle Kelly M

    2012-05-01

    Full Text Available Abstract Mutations in the LRRK2 gene are the most common cause of genetic Parkinson’s disease. Although the mechanisms behind the pathogenic effects of LRRK2 mutations are still not clear, data emerging from in vitro and in vivo models suggests roles in regulating neuronal polarity, neurotransmission, membrane and cytoskeletal dynamics and protein degradation. We created mice lacking exon 41 that encodes the activation hinge of the kinase domain of LRRK2. We have performed a comprehensive analysis of these mice up to 20 months of age, including evaluation of dopamine storage, release, uptake and synthesis, behavioral testing, dendritic spine and proliferation/neurogenesis analysis. Our results show that the dopaminergic system was not functionally comprised in LRRK2 knockout mice. However, LRRK2 knockout mice displayed abnormal exploratory activity in the open-field test. Moreover, LRRK2 knockout mice stayed longer than their wild type littermates on the accelerated rod during rotarod testing. Finally, we confirm that loss of LRRK2 caused degeneration in the kidney, accompanied by a progressive enhancement of autophagic activity and accumulation of autofluorescent material, but without evidence of biphasic changes.

  9. MPTP-Parkinsonism is accompanied by persistent expression of a delta-FosB-like protein in dopaminergic pathways.

    Science.gov (United States)

    Pérez-Otaño, I; Mandelzys, A; Morgan, J I

    1998-01-01

    Parkinson's disease (PD) is characterized by the relatively selective and progressive loss of dopaminergic neurons in the substantia nigra. During the early stages of PD, there are marked compensatory changes in the dopaminergic system, although little is known of how these responses are orchestrated. Since the induction of cellular immediate-early genes (cIEG) has been linked to adaptive responses in the nervous system, we examined their expression in the N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) murine model of PD. MPTP elicited an induction of c-fos, fosB, Delta-fosB and c-jun mRNAs in the striatum that persisted for 24 h. There was a parallel increase in AP-1-like DNA binding activity for up to 7 days post-treatment. At 7 days, AP-1 complexes were specifically supershifted with antisera to FosB and JunD. Immunoblotting of MPTP-treated striata with a FosB-specific antiserum revealed elevated levels of approximately 35 and approximately 46 kDa cross-reactive proteins. Only the 35 kDa protein was increased at 7 days. Thus, the persistent AP-1 complex seen in the MPTP-treated striatum is composed of JunD and a 35 kDa FosB-related protein, possibly Delta-FosB. In situ hybridization revealed elevated expression of fosB and Delta-fosB in the MPTP-treated brain. Expression of both transcripts was highest in ventral striatum, nucleus accumbens and other terminal fields of the mesolimbic system, such as the olfactory tubercle and Islands of Calleja. Thus, the increased fosB expression accompanying MPTP treatment was predominantly associated with dopaminergic pathways. Since FosB was expressed in both vulnerable and spared neuronal populations, we suggest that Delta-FosB-JunD heterodimers play a role in the adaptive response to MPTP neurotoxicity.

  10. Smoking-specific parenting and smoking onset in adolescence: the role of genes from the dopaminergic system (DRD2, DRD4, DAT1 genotypes.

    Directory of Open Access Journals (Sweden)

    Marieke Hiemstra

    Full Text Available Although only few studies have shown direct links between dopaminergic system genes and smoking onset, this does not rule out the effect of a gene-environment interaction on smoking onset. Therefore, the aim of this study was to examine the associations between smoking-specific parenting (i.e., frequency and quality of communication and house rules and smoking onset while considering the potential moderating role of dopaminergic system genes (i.e., DRD2, DRD4, and DAT1 genotypes. Data from five annual waves of the 'Family and Health' project were used. At time 1, the sample comprised 365 non-smoking adolescents (200 younger adolescents, mean age = 13.31, SD = .48; 165 older adolescents, mean age = 15.19, SD = .57. Advanced longitudinal analyses were used (i.e., logistic regression analyses, (dual latent growth curves, and cross-lagged path models. The results showed a direct effect of quality of communication on smoking onset. No direct effects were found for frequency of communication and house rules. Furthermore, no direct and moderating effects of the DRD2, DRD4, or DAT1 genotypes were found. In conclusion, the findings indicated that the effects of smoking-specific parenting on smoking are similar for adolescent carriers and non-carriers of the dopaminergic system genes.

  11. Cannabidiol Counteracts Amphetamine-Induced Neuronal and Behavioral Sensitization of the Mesolimbic Dopamine Pathway through a Novel mTOR/p70S6 Kinase Signaling Pathway.

    Science.gov (United States)

    Renard, Justine; Loureiro, Michael; Rosen, Laura G; Zunder, Jordan; de Oliveira, Cleusa; Schmid, Susanne; Rushlow, Walter J; Laviolette, Steven R

    2016-05-04

    antipsychotic effects are entirely unknown. Using preclinical behavioral procedures combined with molecular analyses and in vivo neuronal electrophysiology, our findings identify a functional role for the nucleus accumbens as a critical brain region whereby CBD can produce effects similar to antipsychotic medications by triggering molecular signaling pathways associated with the effects of classic antipsychotic medications. Specifically, we report that CBD can attenuate both behavioral and dopaminergic neuronal correlates of mesolimbic dopaminergic sensitization, via a direct interaction with mTOR/p70S6 kinase signaling within the mesolimbic pathway. Copyright © 2016 the authors 0270-6474/16/365160-10$15.00/0.

  12. The nigrostriatal dopaminergic system assessed in vivo by positron emission tomography in healthy volunteer subjects and patients with Parkinson's disease

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    Leenders, K.L.; Salmon, E.P.; Tyrrell, P.; Perani, D.; Brooks, D.J.; Sager, H.; Jones, T.; Marsden, C.D.; Frackowiak, R.S. (Hammersmith Hospital, London (England))

    1990-12-01

    A group of healthy control subjects and patients with Parkinson's disease were investigated using positron emission tomography and two tracers as indicators of different specific properties of the presynaptic dopaminergic system in caudate nucleus and putamen. The first tracer, 6-L-(18F)-fluorodopa, was used as an analog of levodopa to assess its regional brain uptake, conversion into, and retention as dopamine and further metabolites. The second tracer, (11C)-nomifensine was employed as an indicator of striatal monaminergic reuptake sites that are principally dopaminergic. We have used this tracer to assess dopaminergic nerve terminal density. In patients with Parkinson's disease, striatal uptake of both tracers was decreased, putamen being significantly more affected than caudate. Side-to-side differences of uptake in putamen, but not caudate, correlated with corresponding left-right differences of scored clinical motor performance. Both 6-L(18F)-fluorodopa and (11C)-nomifensine tracer uptake in putamen was decreased on average to 40% of normal values, suggesting that a substantial part of the cellular elements of the dopaminergic nigrostriatal system is still intact in living parkinsonian patients. This is in contrast to the generally extreme depletion of endogenous dopamine in the putamen of patients found at postmortem. Our results lend support to the search for drug treatments that protect against further nigrostriatal cell loss and that could be exhibited as soon as the disease manifests clinically. If successful, a sufficient striatal nerve terminal pool would remain so that the effectiveness of levodopa as a dopamine repletor could persist.

  13. Role of Prefrontal Serotonergic and Dopaminergic Systems in Encounter-Induced Hyperactivity in Methamphetamine-Sensitized Mice.

    Science.gov (United States)

    Tanaka, Tatsunori; Ago, Yukio; Umehara, Chiaki; Imoto, Emina; Hasebe, Shigeru; Hashimoto, Hitoshi; Takuma, Kazuhiro; Matsuda, Toshio

    2017-05-01

    Isolation-reared mice show social encounter-induced hyperactivity with activation of prefrontal serotonergic and dopaminergic systems, but it is not known whether this stress response is observed in other pathological conditions. Here we examined whether the social encounter stimulation induces abnormal behavior during withdrawal in chronic methamphetamine-treated mice. To induce methamphetamine-induced behavioral sensitization, male mice were injected with methamphetamine (1 mg/kg) once daily for 7 days. The encounter with an intruder elicited hyperactivity 24 h after the last injection of methamphetamine in methamphetamine-sensitized mice. This response was observed even as long as 2 weeks after withdrawal of methamphetamine. The encounter increased c-Fos expression in the prefrontal cortex, dorsal raphe nucleus and ventral tegmental area in methamphetamine-sensitized mice, while it did not in control mice. Furthermore, the encounter increased extracellular serotonin (5-HT) and dopamine, but not noradrenaline, levels in the prefrontal cortex in methamphetamine-sensitized mice. Local injection of 5,7-dihydroxytryptamine and 6-hydroxydopamine into the prefrontal cortex attenuated encounter-induced hyperactivity in methamphetamine-sensitized mice and it markedly decreased prefrontal 5-HT and dopamine levels, respectively. Pharmacological analysis showed that the encounter-induced hyperactivity is mediated by dopamine D1 receptors and 5-HT2A receptors and attenuated by anxiolytics and antidepressants such as diazepam, osemozotan and selective 5-HT reuptake inhibitors. The effect of paroxetine was blocked by the 5-HT3 receptor antagonist azasetron. The present study shows that psychological stress elicits hyperactivity with activation of prefrontal 5-HT and dopamine systems in methamphetamine-dependent mice and suggests that the abnormal behavior is associated with anxiety and depression. © The Author 2016. Published by Oxford University Press on behalf of CINP.

  14. Role of TAAR1 within the Subregions of the Mesocorticolimbic Dopaminergic System in Cocaine-Seeking Behavior.

    Science.gov (United States)

    Liu, Jian-Feng; Siemian, Justin N; Seaman, Robert; Zhang, Yanan; Li, Jun-Xu

    2017-01-25

    A novel G-protein coupled receptor, trace amine-associated receptor 1 (TAAR1), has been shown to be a promising target to prevent stimulant relapse. Our recent studies showed that systemic administration of TAAR1 agonists decreased abuse-related behaviors of cocaine. However, the role of TAAR1 in specific subregions of the reward system in drug addiction is unknown. Here, using a local pharmacological activation method, we assessed the role of TAAR1 within the subregions of the mesocorticolimbic system: that is, the VTA, the prelimbic cortex (PrL), and infralimbic cortex of medial prefrontal cortex, the core and shell of NAc, BLA, and CeA, on cue- and drug-induced cocaine-seeking in the rat cocaine reinstatement model. We first showed that TAAR1 mRNA was expressed throughout these brain regions. Rats underwent cocaine self-administration, followed by extinction training. RO5166017 (1.5 or 5.0 μg/side) or vehicle was microinjected into each brain region immediately before cue- and drug-induced reinstatement of cocaine-seeking. The results showed that microinjection of RO5166017 into the VTA and PrL decreased both cue- and drug priming-induced cocaine-seeking. Microinjection of RO5166017 into the NAc core and shell inhibited cue- and drug-induced cocaine-seeking, respectively. Locomotor activity or food reinforced operant responding was unaffected by microinjection of RO5166017 into these brain regions. Cocaine-seeking behaviors were not affected by RO5166017 when microinjected into the substantia nigra, infralimbic cortex, BLA, and CeA. Together, these results indicate that TAAR1 in different subregions of the mesocorticolimbic system distinctly contributes to cue- and drug-induced reinstatement of cocaine-seeking behavior. TAAR1 has been indicated as a modulator of the dopaminergic system. Previous research showed that systemic administration of TAAR1 agonists could attenuate cocaine-related behaviors, suggesting that TAAR1 may be a promising drug target for the

  15. Omission of expected reward sensitizes the brain dopaminergic system of classically conditioned Atlantic salmon

    DEFF Research Database (Denmark)

    Vindas, M.A.; Höglund, Erik; Folkedal, O.

    across treatments and generations is one particularly attractive feature of fish model systems. Both animal welfare considerations and fundamental scientific questions regarding the evolution of learning and memory have directed particular attention towards possible cognitive and emotional processes...... signalling system, manifest as a potentiated response to novel, stressful stimuli. Similarities between fish and mammals in this response to unpredictability illustrates a role for teleost fish as models to understand the development of different types of DA dysfunction...

  16. Dopaminergic receptor agents and the basal ganglia : pharmacological properties and interactions with the GABA-ergic system

    NARCIS (Netherlands)

    Timmerman, Wigerline

    1992-01-01

    In the present series of studies, attention was focussed particularly on dopaminergic D2 receptor compounds, with emphasis on the enantiomers of the potent and selective dopamine D2 receptor agonist N-0437. Drugs that display activity at D2 receptors are of great interest as potentially new

  17. Naloxone treatment alters gene expression in the mesolimbic reward system in 'junk food' exposed offspring in a sex-specific manner but does not affect food preferences in adulthood.

    Science.gov (United States)

    Gugusheff, J R; Ong, Z Y; Muhlhausler, B S

    2014-06-22

    We have previously reported that the opioid receptor blocker, naloxone, is less effective in reducing palatable food intake in offspring exposed to a maternal cafeteria diet during the perinatal period, implicating a desensitization of the central opioid pathway in the programming of food preferences. The present study aimed to investigate the effect of a maternal cafeteria diet and naloxone treatment on the development of the mesolimbic reward pathway and food choices in adulthood. We measured mRNA expression of key components of the reward pathway (mu-opioid receptor, proenkephalin, tyrosine hydroxylase, D1 and D2 receptors and the dopamine active transporter (DAT)) in the nucleus accumbens (NAc) and ventral tegmental area (VTA) of the offspring of control and cafeteria fed (JF) dams at weaning and after a 10-day naloxone treatment post-weaning and determined food preferences in adulthood in the remaining offspring. Naloxone treatment decreased the expression of DAT by 8.2 fold in female control offspring but increased it by 4.3 fold in female offspring of JF dams relative to the saline-injected reference groups. Proenkephalin mRNA expression was higher in the NAc of female JF offspring compared to controls, independent of naloxone treatment (Pfood preferences in adulthood in either control or JF offspring. These data indicate that prenatal exposure to a cafeteria diet alters the impact of opioid signaling blockade in the early post-weaning period on gene expression in the central reward pathway in a sex specific manner, but that these changes in gene expression do not appear to have any persistent impact on food preferences in adulthood. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. Polymorphisms in dopaminergic system genes; association with criminal behavior and self-reported aggression in violent prison inmates from Pakistan.

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    Muhammad Imran Qadeer

    Full Text Available Genetic factors contribute to antisocial and criminal behavior. Dopamine transporter DAT-1 (SLC6A3 and DRD2 gene for the dopamine-2 receptor are dopaminergic system genes that regulate dopamine reuptake and signaling, and may be part of the pathogenesis of psychiatric disorders including antisocial behaviors and traits. No previous studies have analyzed DAT-1 and DRD2 polymorphisms in convicted murderers, particularly from Indian subcontinent. In this study we investigated the association of 40 bp VNTR polymorphism of DAT-1 and Taq1 variant of DRD2 gene (rs1800479 with criminal behavior and self-reported aggression in 729 subjects, including 370 men in Pakistani prisons convicted of first degree murder(s and 359 control men without any history of violence or criminal tendency. The 9R allele of DAT-1 VNTR polymorphism was more prevalent in convicted murderers compared with control samples, for either one or two risk alleles (OR = 1.49 and 3.99 respectively, P = 0.003. This potential association of DAT-1 9R allele polymorphism with murderer phenotype was confirmed assuming different genetic models of inheritance. However, no genetic association was found for DRD2 Taq1 polymorphism. In addition, a combined haplotype (9R-A2 of DAT-1 and DRD2 genes was associated with this murderer phenotype. Further, 9R allele of DAT-1 was also associated with response to verbal abuse and parental marital complications, but not with other measures pertinent to self-reported aggression. These results suggest that 9R allele, which may influence levels of intra-synaptic dopamine in the brain, may contribute to criminal tendency in this sample of violent murderers of Pakistani origin. Future studies are needed to replicate this finding in other populations of murderers and see if this finding extends to other forms of violence and lesser degrees of aggression.

  19. High vitamin A intake during pregnancy modifies dopaminergic reward system and decreases preference for sucrose in Wistar rat offspring.

    Science.gov (United States)

    Sánchez-Hernández, Diana; Poon, Abraham N; Kubant, Ruslan; Kim, Hwanki; Huot, Pedro S P; Cho, Clara E; Pannia, Emanuela; Reza-López, Sandra A; Pausova, Zdenka; Bazinet, Richard P; Anderson, G Harvey

    2016-01-01

    High multivitamin (HV) content in gestational diets has long-term metabolic effects in rat offspring. These changes are associated with in utero modifications of gene expression in hypothalamic food intake regulation. However, the role of fat-soluble vitamins in mediating these effects has not been explored. Vitamin A is a plausible candidate due to its role in gene methylation. Vitamin A intake above requirements during pregnancy affects the development of neurocircuitries involved in food intake and reward regulation. Pregnant Wistar rats were fed AIN-93G diets with the following content: recommended multivitamins (1-fold multivitamins: RV), high vitamin A (10-fold vitamin A: HA) or HV with only recommended vitamin A (10-fold multivitamins, 1-fold vitamin A: HVRA). Body weight, food intake and preference, mRNA expression and DNA methylation of hippocampal dopamine-related genes were assessed in male offspring brains at different developmental windows: birth, weaning and 14weeks postweaning. HA offspring had changes in dopamine-related gene expression at all developmental windows and DNA hypermethylation in the dopamine receptor 2 promoter region compared to RV offspring. Furthermore, HA diet lowered sucrose preference but had no effect on body weight and expression of hypothalamic genes. In contrast, HVRA offspring showed only at adulthood changes in expression of hippocampal genes and a modest effect on hypothalamic genes. High vitamin A intake alone in gestational diets has long-lasting programming effects on the dopaminergic system that are further translated into decreased sucrose preference but not food intake. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Targeting the-Dopaminergic Nervous System: Altering Behavior in Larval Zebrafish

    Science.gov (United States)

    Zebrafish (Dania rerio) are becoming an important model system in studying the effects of environmental chemicals on behavior. In order to develop a rapid in vivo screen to prioritize toxic chemicals, we have begun assessing the acute locomotor effects of drugs that act on the do...

  1. Behavioral and electrophysiological effects of endocannabinoid and dopaminergic systems on salient stimuli

    Directory of Open Access Journals (Sweden)

    Daniela eLaricchiuta

    2014-05-01

    Full Text Available Rewarding effects have been related to enhanced dopamine (DA release in corticolimbic and basal ganglia structures. The DAergic and endocannabinoid interaction in the responses to reward is described. This study investigated the link between endocannabinoid and DAergic transmission in the processes that are related to response to two types of reward, palatable food and novelty. Mice treated with drugs acting on endocannabinoid system (ECS (URB597, AM251 or DAergic system (haloperidol were submitted to approach-avoidance conflict tasks with palatable food or novelty. In the same mice, the cannabinoid type-1 (CB1-mediated GABAergic transmission in medium spiny neurons of the dorsomedial striatum was analyzed. The endocannabinoid potentiation by URB597 magnified approach behavior for reward (food and novelty and in parallel inhibited dorsostriatal GABAergic neurotransmission. The decreased activity of CB1 receptor by AM251 (alone or with URB597 or of DAergic D2 receptor by haloperidol had inhibitory effects toward the reward and did not permit the inhibition of dorsostriatal GABAergic transmission. When haloperidol was coadministered with URB597, a restoration effect on reward and reward-dependent motor activity was observed, only if the reward was the palatable food. In parallel, the coadministration led to restoring inhibition of CB1-mediated GABAergic transmission. Thus, in the presence of simultaneous ECS activation and inhibition of DAergic system the response to reward appears to be a stimulus-dependent manner.

  2. SPECT imaging of dopaminergic system: a preliminary study of nine patients with clinically uncertain Parkinsonism

    International Nuclear Information System (INIS)

    Dey, S. K.; Gopinath, G.; Buscombe, J. R.

    2004-01-01

    Parkinsonism is the result of various neuro degenerative disorders, the common and related causes are Parkinson's disease (PD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). In each of these three causes, there is degeneration of presynaptic neurons in corpus striatum. Nine patients having clinically uncertain parkinsonian symptoms undergone brain SPECT imaging using the tracer (I-123 Ioflupane) that binds to dopamine transporter (DaT) in the pre-synaptic nerve terminals in basal ganglia. There was significantly decreased tracer uptake in the tail (putamen) portion of basal ganglia in five patients confirming presence of presynaptic neuro degeneration and reported as parkinsonism. Three patients revealed normal tracer uptake with one equivocal result. DaT imaging can effectively confirm parkinsonism and discriminate from normal subjects as well as other clinical simulators like essential tremor and dopa-responsive dystonia where no neuro degeneration occur.(author)

  3. Omission of expected reward sensitizes the brain dopaminergic system of classically conditioned Atlantic salmon

    DEFF Research Database (Denmark)

    Vindas, M.A.; Höglund, Erik; Folkedal, O.

    across treatments and generations is one particularly attractive feature of fish model systems. Both animal welfare considerations and fundamental scientific questions regarding the evolution of learning and memory have directed particular attention towards possible cognitive and emotional processes......For several reasons, such as easy maintenance, rapid generation times, and increasingly mapped genomes, teleost fishes are emerging as an alternative to small mammals in biomedical, neural, and behavioral research. Behavioral, genetic, and physiological screening of high numbers of individuals....... There was also a general downregulation of dopamine receptor D1 gene expression in the telencephalon of OER groups, which suggests a coping mechanism in response to unbalanced DA metabolism. These results indicate that animals subjected to unpredictable reward conditions develop a senzitation of the DA...

  4. Repeated social defeat and the rewarding effects of cocaine in adult and adolescent mice: dopamine transcription factors, proBDNF signaling pathways, and the TrkB receptor in the mesolimbic system.

    Science.gov (United States)

    Montagud-Romero, Sandra; Nuñez, Cristina; Blanco-Gandia, M Carmen; Martínez-Laorden, Elena; Aguilar, María A; Navarro-Zaragoza, Javier; Almela, Pilar; Milanés, Maria-Victoria; Laorden, María-Luisa; Miñarro, José; Rodríguez-Arias, Marta

    2017-07-01

    Repeated social defeat (RSD) increases the rewarding effects of cocaine in adolescent and adult rodents. The aim of the present study was to compare the long-term effects of RSD on the conditioned rewarding effects of cocaine and levels of the transcription factors Pitx3 and Nurr1 in the ventral tegmental area (VTA), the dopamine transporter (DAT), the D2 dopamine receptor (D2DR) and precursor of brain-derived neurotrophic factor (proBDNF) signaling pathways, and the tropomyosin-related kinase B (TrkB) receptor in the nucleus accumbens (NAc) in adult and adolescent mice. Male adolescent and young adult OF1 mice were exposed to four episodes of social defeat and were conditioned 3 weeks later with 1 mg/kg of cocaine. In a second set of mice, the expressions of the abovementioned dopaminergic and proBDNF and TrkB receptor were measured in VTA and NAc, respectively. Adolescent mice experienced social defeats less intensely than their adult counterparts and produced lower levels of corticosterone. However, both adult and adolescent defeated mice developed conditioned place preference for the compartment associated with this low dose of cocaine. Furthermore, only adolescent defeated mice displayed diminished levels of the transcription factors Pitx3 in the VTA, without changes in the expression of DAT and D2DR in the NAc. In addition, stressed adult mice showed a decreased expression of proBDNF and the TrkB receptor, while stressed adolescent mice exhibited increased expression of latter without changes in the former. Our findings suggest that dopaminergic pathways and proBDNF signaling and TrkB receptors play different roles in social defeat-stressed mice exposed to cocaine.

  5. Serotonergic modulation of the activity of mesencephalic dopaminergic systems: Therapeutic implications.

    Science.gov (United States)

    De Deurwaerdère, Philippe; Di Giovanni, Giuseppe

    2017-04-01

    Since their discovery in the mammalian brain, it has been apparent that serotonin (5-HT) and dopamine (DA) interactions play a key role in normal and abnormal behavior. Therefore, disclosure of this interaction could reveal important insights into the pathogenesis of various neuropsychiatric diseases including schizophrenia, depression and drug addiction or neurological conditions such as Parkinson's disease and Tourette's syndrome. Unfortunately, this interaction remains difficult to study for many reasons, including the rich and widespread innervations of 5-HT and DA in the brain, the plethora of 5-HT receptors and the release of co-transmitters by 5-HT and DA neurons. The purpose of this review is to present electrophysiological and biochemical data showing that endogenous 5-HT and pharmacological 5-HT ligands modify the mesencephalic DA systems' activity. 5-HT receptors may control DA neuron activity in a state-dependent and region-dependent manner. 5-HT controls the activity of DA neurons in a phasic and excitatory manner, except for the control exerted by 5-HT 2C receptors which appears to also be tonically and/or constitutively inhibitory. The functional interaction between the two monoamines will also be discussed in view of the mechanism of action of antidepressants, antipsychotics, anti-Parkinsonians and drugs of abuse. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Repeated dexamphetamine treatment alters the dopaminergic system and increases the phMRI response to methylphenidate.

    Directory of Open Access Journals (Sweden)

    Anouk Schrantee

    Full Text Available Dexamphetamine (AMPH is a psychostimulant drug that is used both recreationally and as medication for attention deficit hyperactivity disorder. Preclinical studies have demonstrated that repeated exposure to AMPH can induce damage to nerve terminals of dopamine (DA neurons. We here assessed the underlying neurobiological changes in the DA system following repeated AMPH exposure and pre-treated rats with AMPH or saline (4 times 5 mg/kg s.c., 2 hours apart, followed by a 1-week washout period. We then used pharmacological MRI (phMRI with a methylphenidate (MPH challenge, as a sensitive and non-invasive in-vivo measure of DAergic function. We subsequently validated the DA-ergic changes post-mortem, using a.o. high-performance liquid chromatography (HPLC and autoradiography. In the AMPH pre-treated group, we observed a significantly larger BOLD response to the MPH challenge, particularly in DA-ergic brain areas and their downstream projections. Subsequent autoradiography studies showed that AMPH pre-treatment significantly reduced DA transporter (DAT density in the caudate-putamen (CPu and nucleus accumbens, whereas HPLC analysis revealed increases in the DA metabolite homovanillic acid in the CPu. Our results suggest that AMPH pre-treatment alters DAergic responsivity, a change that can be detected with phMRI in rats. These phMRI changes likely reflect increased DA release together with reduced DAT binding. The ability to assess subtle synaptic changes using phMRI is promising for both preclinical studies of drug discovery, and for clinical studies where phMRI can be a useful tool to non-invasively investigate DA abnormalities, e.g. in neuropsychiatric disorders.

  7. L-DOPA modulates cell viability through the ERK-c-Jun system in PC12 and dopaminergic neuronal cells.

    Science.gov (United States)

    Park, Keun Hong; Shin, Keon Sung; Zhao, Ting Ting; Park, Hyun Jin; Lee, Kyung Eun; Lee, Myung Koo

    2016-02-01

    L-DOPA causes neurotoxicity by modulating the Epac-ERK system in PC12 cells. This study investigated the effects of a single treatment with L-DOPA and multiple treatments with L-DOPA (MT-LD) on ERK1/2 and JNK1/2-c-Jun systems. In PC12 cells, a toxic L-DOPA concentration (200 μM) induced sustained ERK1/2 and JNK1/2 phosphorylation that was inhibited by the Epac inhibitor brefeldin A, but not by the PKA inhibitor H89. This ERK1/2 and JNK1/2 phosphorylation was also inhibited by ERK1/2 (U0126) and JNK1/2 (SP600125) inhibitors, respectively, but sustained ERK1/2 phosphorylation was not affected by JNK1/2 phosphorylation. A non-toxic L-DOPA concentration (20 μM) induced c-Jun phosphorylation (Ser73) via transient ERK1/2 phosphorylation, whereas the toxic L-DOPA concentration induced c-Jun phosphorylation (Ser63) and c-Jun expression via Epac-sustained ERK1/2-JNK1/2 phosphorylation, which then enhanced cleaved caspase-3 expression. MT-LD (20 μM) initially enhanced c-Jun phosphorylation (Ser73) (for 1-4 days), but later (5-6 days) induced c-Jun phosphorylation (Ser63) and c-Jun expression. In the 6-hydroxydopamine-lesioned rat model of Parkinson's disease, L-DOPA administration (10 mg/kg) protected against neurotoxicity through c-Jun phosphorylation (Ser73) for 1-2 weeks. However, L-DOPA administration (10 or 30 mg/kg) showed neurotoxicity through c-Jun phosphorylation (Ser63) and c-Jun expression via ERK1/2 phosphorylation for 3-4 weeks. Thus, in PC12 cells, non-toxic L-DOPA treatment maintained cell survival through c-Jun phosphorylation (Ser73). By contrast, toxic L-DOPA treatment or MT-LD (20 μM) induced c-Jun phosphorylation (Ser63) and c-Jun expression via Epac-dependent sustained ERK1/2 and JNK1/2 phosphorylation, which subsequently led to cell death. These results were validated by those obtained after long-term L-DOPA administration in a rat model of Parkinson's disease. Our data indicate that L-DOPA causes neurotoxicity via the ERK1/2-c-Jun system in

  8. Volatile solvents as drugs of abuse: focus on the cortico-mesolimbic circuitry.

    Science.gov (United States)

    Beckley, Jacob T; Woodward, John J

    2013-12-01

    Volatile solvents such as those found in fuels, paints, and thinners are found throughout the world and are used in a variety of industrial applications. However, these compounds are also often intentionally inhaled at high concentrations to produce intoxication. While solvent use has been recognized as a potential drug problem for many years, research on the sites and mechanisms of action of these compounds lags behind that of other drugs of abuse. In this review, we first discuss the epidemiology of voluntary solvent use throughout the world and then consider what is known about their basic pharmacology and how this may explain their use as drugs of abuse. We next present data from preclinical and clinical studies indicating that these substances induce common addiction sequelae such as dependence, withdrawal, and cognitive impairments. We describe how toluene, the most commonly studied psychoactive volatile solvent, alters synaptic transmission in key brain circuits such as the mesolimbic dopamine system and medial prefrontal cortex (mPFC) that are thought to underlie addiction pathology. Finally, we make the case that activity in mPFC circuits is a critical regulator of the mesolimbic dopamine system's ability to respond to volatile solvents like toluene. Overall, this review provides evidence that volatile solvents have high abuse liability because of their selective effects on critical nodes of the addiction neurocircuitry, and underscores the need for more research into how these compounds induce adaptations in neural circuits that underlie addiction pathology.

  9. Connectome and molecular pharmacological differences in the dopaminergic system in restless legs syndrome (RLS): plastic changes and neuroadaptations that may contribute to augmentation.

    Science.gov (United States)

    Earley, Christopher J; Uhl, George R; Clemens, Stefan; Ferré, Sergi

    2017-03-01

    Restless legs syndrome (RLS) is primarily treated with levodopa and dopaminergics that target the inhibitory dopamine receptor subtypes D3 and D2. The initial success of this therapy led to the idea of a hypodopaminergic state as the mechanism underlying RLS. However, multiple lines of evidence suggest that this simplified concept of a reduced dopamine function as the basis of RLS is incomplete. Moreover, long-term medication with the D2/D3 agonists leads to a reversal of the initial benefits of dopamine agonists and augmentation, which is a worsening of symptoms under therapy. The recent findings on the state of the dopamine system in RLS that support the notion that a dysfunction in the dopamine system may in fact induce a hyperdopaminergic state are summarized. On the basis of these data, the concept of a dynamic nature of the dopamine effects in a circadian context is presented. The possible interactions of cell adhesion molecules expressed by the dopaminergic systems and their possible effects on RLS and augmentation are discussed. Genome-wide association studies (GWAS) indicate a significantly increased risk for RLS in populations with genomic variants of the cell adhesion molecule receptor type protein tyrosine phosphatase D (PTPRD), and PTPRD is abundantly expressed by dopamine neurons. PTPRD may play a role in the reconfiguration of neural circuits, including shaping the interplay of G protein-coupled receptor (GPCR) homomers and heteromers that mediate dopaminergic modulation. Recent animal model data support the concept that interactions between functionally distinct dopamine receptor subtypes can reshape behavioral outcomes and change with normal aging. Additionally, long-term activation of one dopamine receptor subtype can increase the receptor expression of a different receptor subtype with opposite modulatory actions. Such dopamine receptor interactions at both spinal and supraspinal levels appear to play important roles in RLS. In addition, these

  10. Synaptophysin and the dopaminergic system in hippocampus are involved in the protective effect of rutin against trimethyltin-induced learning and memory impairment.

    Science.gov (United States)

    Zhang, Lei; Zhao, Qi; Chen, Chun-Hai; Qin, Qi-Zhong; Zhou, Zhou; Yu, Zheng-Ping

    2014-09-01

    This study aimed to investigate the protective effect of rutin against trimethyltin-induced spatial learning and memory impairment in mice. This study focused on the role of synaptophysin, growth-associated protein 43 and the action of the dopaminergic system in mechanisms associated with rutin protection and trimethyltin-induced spatial learning and memory impairment. Cognitive learning and memory was measured by Morris Water Maze. The expression of synaptophysin and growth-associated protein 43 in hippocampus was analyzed by western blot. The concentrations of dopamine, homovanillic acid, and dihyroxyphenylacetic acid in hippocampus were detected using reversed phase high-performance liquid chromatography with electrochemical detection. Trimethyltin-induced spatial learning impairment showed a dose-dependent mode. Synaptophysin but not growth-associated protein 43 was decreased in the hippocampus after trimethyltin administration. The concentration of dopamine decreased, while homovanillic acid increased in the hippocampus after trimethyltin administration. Mice pretreated with 20 mg/kg of rutin for 7 consecutive days exhibited improved water maze performance. Moreover, rutin pretreatment reversed the decrease of synaptophysin expression and dopamine alteration. These results suggest that rutin may protect against spatial memory impairment induced by trimethyltin. Synaptophysin and the dopaminergic system may be involved in trimethyltin-induced neuronal damage in hippocampus.

  11. Hypothesizing Music Intervention Enhances Brain Functional Connectivity Involving Dopaminergic Recruitment: Common Neuro-correlates to Abusable Drugs.

    Science.gov (United States)

    Blum, Kenneth; Simpatico, Thomas; Febo, Marcelo; Rodriquez, Chris; Dushaj, Kristina; Li, Mona; Braverman, Eric R; Demetrovics, Zsolt; Oscar-Berman, Marlene; Badgaiyan, Rajendra D

    2017-07-01

    The goal of this review is to explore the clinical significance of music listening on neuroplasticity and dopaminergic activation by understanding the role of music therapy in addictive behavior treatment. fMRI data has shown that music listening intensely modifies mesolimbic structural changes responsible for reward processing (e.g., nucleus accumbens [NAc]) and may control the emotional stimuli's effect on autonomic and physiological responses (e.g., hypothalamus). Music listening has been proven to induce the endorphinergic response blocked by naloxone, a common opioid antagonist. NAc opioid transmission is linked to the ventral tegmental area (VTA) dopamine release. There are remarkable commonalities between listening to music and the effect of drugs on mesolimbic dopaminergic activation. It has been found that musical training before the age of 7 results in changes in white-matter connectivity, protecting carriers with low dopaminergic function (DRD2A1 allele, etc.) from poor decision-making, reward dependence, and impulsivity. In this article, we briefly review a few studies on the neurochemical effects of music and propose that these findings are relevant to the positive clinical findings observed in the literature. We hypothesize that music intervention enhances brain white matter plasticity through dopaminergic recruitment and that more research is needed to explore the efficacy of these therapies.

  12. Neurogenetic Impairments of Brain Reward Circuitry Links to Reward Deficiency Syndrome (RDS): Potential Nutrigenomic Induced Dopaminergic Activation

    Science.gov (United States)

    Blum, K; Oscar-Berman, M; Giordano, J; Downs, BW; Simpatico, T; Han, D; Femino, John

    2012-01-01

    Work from our laboratory in both in-patient and outpatient facilities utilizing the Comprehensive Analysis of Reported Drugs (CARD)™ found a significant lack of compliance to prescribed treatment medications and a lack of abstinence from drugs of abuse during active recovery. This unpublished, ongoing research provides an impetus to develop accurate genetic diagnosis and holistic approaches that will safely activate brain reward circuitry in the mesolimbic dopamine system. This editorial focuses on the neurogenetics of brain reward systems with particular reference to genes related to dopaminergic function. The terminology “Reward Deficiency Syndrome” (RDS), used to describe behaviors found to have an association with gene-based hypodopaminergic function, is a useful concept to help expand our understanding of Substance Use Disorder (SUD), process addictions, and other obsessive, compulsive and impulsive behaviors. This editorial covers the neurological basis of pleasure and the role of natural and unnatural reward in motivating and reinforcing behaviors. Additionally, it briefly describes the concept of natural dopamine D2 receptor agonist therapy coupled with genetic testing of a panel of reward genes, the Genetic Addiction Risk Score (GARS). It serves as a spring-board for this combination of novel approaches to the prevention and treatment of RDS that was developed from fundamental genomic research. We encourage further required studies. PMID:23264886

  13. Dorsal-to-Ventral Shift in Midbrain Dopaminergic Projections and Increased Thalamic/Raphe Serotonergic Function in Early Parkinson Disease.

    Science.gov (United States)

    Joutsa, Juho; Johansson, Jarkko; Seppänen, Marko; Noponen, Tommi; Kaasinen, Valtteri

    2015-07-01

    Loss of nigrostriatal neurons leading to dopamine depletion in the dorsal striatum is the pathologic hallmark of Parkinson disease contributing to the primary motor symptoms of the disease. However, Parkinson pathology is more widespread in the brain, affecting also other dopaminergic pathways and neurotransmitter systems, but these changes are less well characterized. This study aimed to investigate the mesencephalic striatal and extrastriatal dopaminergic projections together with extrastriatal serotonin transporter binding in Parkinson disease. Two hundred sixteen patients with Parkinson disease and 204 control patients (patients without neurodegenerative parkinsonism syndromes and normal SPECT imaging) were investigated with SPECT using the dopamine/serotonin transporter ligand (123)I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane ((123)I-FP-CIT) in the clinical setting. The group differences and midbrain correlations were analyzed voxel by voxel over the entire brain. We found that Parkinson patients had lower (123)I-FP-CIT uptake in the striatum and ventral midbrain but higher uptake in the thalamus and raphe nuclei than control patients. In patients with Parkinson disease, the correlation of the midbrain tracer uptake was shifted from the putamen to widespread corticolimbic areas. All findings were highly significant at the voxel level familywise error-corrected P value of less than 0.05. Our findings show that Parkinson disease is associated not only with the degeneration of the nigrostriatal dopamine neurotransmission, but also with a parallel shift toward mesolimbic and mesocortical function. Furthermore, Parkinson disease patients seem to have upregulation of brain serotonin transporter function at the early phase of the disease. © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  14. The dopaminergic system of the telencephalo-diencephalic areas of the vertebrate brain in the organization of the sleep-waking cycle.

    Science.gov (United States)

    Oganesyan, G A; Romanova, I V; Aristakesyan, E A; Kuzik, V V; Makina, D M; Morina, I Yu; Khramenkova, A E; Artamokhina, I V; Belova, V A

    2009-10-01

    The aim of the present work was to study the involvement of the dopaminergic system of the telencephalic and diencephalic areas of the vertebrate brain in the organization of the sleep-waking cycle in cold-blooded and warm-blooded vertebrates. Immunohistochemical studies of tyrosine hydroxylase content, this being the key enzyme in dopamine synthesis, in the striatum, supraoptic and arcuate nuclei, and zona incerta of the hypothalamus of sturgeon and mammals (rats) of three age groups (14 and 30 days and adults), in conditions of tactile and sleep-deprivation stressors. In fish, transient stress was followed by the detection of tyrosine hydroxylase-immunoreactive cells in all parts of the brain. In prolonged stress, tyrosine hydroxylase-immunoreactive cells and fibers were not found in the forebrain, though they were well represented in the hypothalamic nuclei. In 14-day-old rat pups, 2-h sleep deprivation increased the tyrosine hydroxylase content of fibers in the caudate nucleus and cells in the zona incerta of the hypothalamus, while 30-day-old animals subjected to 6-h sleep deprivation showed increases in tyrosine hydroxylaseimmunoreactive material contents in cells in the paraventricular nucleus and decreases in the quantity in fibers. In adult rats, the arcuate nucleus and zona incerta showed decreases in the content of tyrosine hydroxylase-immunoreactive material on the background of sleep deprivation, with increases during postdeprivation sleep. These data are discussed in the light of the phylo- and ontogenetic development of the neurosecretory and neurotransmitter functions of the dopaminergic system in the evolutionarily ancient diencephalic and evolutionarily young telencephalic areas of the vertebrate brain as major systems triggering and maintaining the functional states of the body during the sleep-waking cycle.

  15. Long Withdrawal of Methylphenidate Induces a Differential Response of the Dopaminergic System and Increases Sensitivity to Cocaine in the Prefrontal Cortex of Spontaneously Hypertensive Rats.

    Directory of Open Access Journals (Sweden)

    Maurício dos Santos Pereira

    Full Text Available Methylphenidate (MPD is one of the most prescribed drugs for alleviating the symptoms of Attention Deficit/Hyperactivity Disorder (ADHD. However, changes in the molecular mechanisms related to MPD withdrawal and susceptibility to consumption of other psychostimulants in normal individuals or individuals with ADHD phenotype are not completely understood. The aims of the present study were: (i to characterize the molecular differences in the prefrontal dopaminergic system of SHR and Wistar strains, (ii to establish the neurochemical consequences of short- (24 hours and long-term (10 days MPD withdrawal after a subchronic treatment (30 days with Ritalin® (Methylphenidate Hydrochloride; 2.5 mg/kg orally, (iii to investigate the dopaminergic synaptic functionality after a cocaine challenge in adult MPD-withdrawn SHR and Wistar rats. Our results indicate that SHR rats present reduced [3H]-Dopamine uptake and cAMP accumulation in the prefrontal cortex (PFC and are not responsive to dopaminergic stimuli in when compared to Wistar rats. After a 24-hour withdrawal of MPD, SHR did not present any alterations in [3H]-Dopamine Uptake, [3H]-SCH 23390 binding and cAMP production; nonetheless, after a 10-day MPD withdrawal, the results showed a significant increase of [3H]-Dopamine uptake, of the quantity of [3H]-SCH 23390 binding sites and of cAMP levels in these animals. Finally, SHR that underwent a 10-day MPD withdrawal and were challenged with cocaine (10 mg/kg i.p. presented reduced [3H]-Dopamine uptake and increased cAMP production. Wistar rats were affected by the 10-day withdrawal of MPD in [3H]-dopamine uptake but not in cAMP accumulation; in addition, cocaine was unable to induce significant modifications in [3H]-dopamine uptake and in cAMP levels after the 10-day withdrawal of MPD. These results indicate a mechanism that could explain the high comorbidity between ADHD adolescent patients under methylphenidate treatment and substance abuse in adult

  16. Role of the Dopaminergic System in the Acquisition, Expression and Reinstatement of MDMA-Induced Conditioned Place Preference in Adolescent Mice

    Science.gov (United States)

    Vidal-Infer, Antonio; Roger-Sánchez, Concepción; Daza-Losada, Manuel; Aguilar, María A.; Miñarro, José; Rodríguez-Arias, Marta

    2012-01-01

    Background The rewarding effects of 3,4-methylenedioxy-metamphetamine (MDMA) have been demonstrated in conditioned place preference (CPP) procedures, but the involvement of the dopaminergic system in MDMA-induced CPP and reinstatement is poorly understood. Methodology/Principal Findings In this study, the effects of the DA D1 antagonist SCH 23390 (0.125 and 0.250 mg/kg), the DA D2 antagonist Haloperidol (0.1 and 0.2 mg/kg), the D2 antagonist Raclopride (0.3 and 0.6 mg/kg) and the dopamine release inhibitor CGS 10746B (3 and 10 mg/kg) on the acquisition, expression and reinstatement of a CPP induced by 10 mg/kg of MDMA were evaluated in adolescent mice. As expected, MDMA significantly increased the time spent in the drug-paired compartment during the post-conditioning (Post-C) test, and a priming dose of 5 mg/kg reinstated the extinguished preference. The higher doses of Haloperidol, Raclopride and CGS 10746B and both doses of SCH 23390 blocked acquisition of the MDMA-induced CPP. However, only Haloperidol blocked expression of the CPP. Reinstatement of the extinguished preference was not affected by any of the drugs studied. Analysis of brain monoamines revealed that the blockade of CPP acquisition was accompanied by an increase in DA concentration in the striatum, with a concomitant decrease in DOPAC and HVA levels. Administration of haloperidol during the Post-C test produced increases in striatal serotonin, DOPAC and HVA concentrations. In mice treated with the higher doses of haloperidol and CGS an increase in SERT concentration in the striatum was detected during acquisition of the CPP, but no changes in DAT were observed. Conclusions/Significance These results demonstrate that, in adolescent mice, the dopaminergic system is involved in the acquisition and expression of MDMA-induced CPP, but not in its reinstatement. PMID:22916213

  17. Phasic Mesolimbic Dopamine Signaling Encodes the Facilitation of Incentive Motivation Produced by Repeated Cocaine Exposure

    OpenAIRE

    Ostlund, SB; LeBlanc, KH; Kosheleff, AR; Wassum, KM; Maidment, NT

    2014-01-01

    Drug addiction is marked by pathological drug seeking and intense drug craving, particularly in response to drug-related stimuli. Repeated psychostimulant administration is known to induce long-term alterations in mesolimbic dopamine (DA) signaling that are hypothesized to mediate this heightened sensitivity to environmental stimuli. However, there is little direct evidence that drug-induced alteration in mesolimbic DA function underlies this hypersensitivity to motivational cues. In the curr...

  18. GABAergic Control of Nigrostriatal and Mesolimbic Dopamine in the Rat Brain

    Directory of Open Access Journals (Sweden)

    Susanne Nikolaus

    2018-03-01

    Full Text Available Purpose: The present study assessed the effects of the GABAA receptor (R agonist muscimol (MUS, and the GABAAR antagonist bicuculline (BIC on neocortical and subcortical radioligand binding to dopamine D2/3Rs in relation to motor and exploratory behaviors in the rat.Methods: D2/3R binding was measured with small animal SPECT in baseline and after challenge with either 1 mg/kg MUS or 1 mg/kg BIC, using [123I]IBZM as radioligand. Motor/exploratory behaviors were assessed for 30 min in an open field prior to radioligand administration. Anatomical information was gained with a dedicated small animal MRI tomograph. Based on the Paxinos rat brain atlas, regions of interest were defined on SPECT-MRI overlays. Estimations of the binding potentials in baseline and after challenges were obtained by computing ratios of the specifically bound compartments to the cerebellar reference region.Results: After MUS, D2/3R binding was significantly reduced in caudateputamen, nucleus accumbens, thalamus, substania nigra/ventral tegmental area, and posterior hippocampus relative to baseline (0.005 ≤ p ≤ 0.012. In all these areas, except for the thalamus, D2/3R binding was negatively correlated with grooming in the first half and positively correlated with various motor/exploratory behaviors in the second half of the testing session. After BIC, D2/3R binding was significantly elevated in caudateputamen (p = 0.022 and thalamus (p = 0.047 relative to baseline. D2/3R binding in caudateputamen and thalamus was correlated negatively with sitting duration and sitting frequency and positively with motor/exploratory behaviors in the first half of the testing time.Conclusions: Findings indicate direct GABAergic control over nigrostriatal and mesolimbic dopamine levels in relation to behavioral action. This may be of relevance for neuropsychiatric conditions such as anxiety disorder and schizophrenia, which are characterized by both dopaminergic and GABAergic dysfunction.

  19. Quantification of dopaminergic neurotransmission SPECT studies with 123I-labelled radioligands. A comparison between different imaging systems and data acquisition protocols using Monte Carlo simulation.

    Science.gov (United States)

    Crespo, Cristina; Gallego, Judith; Cot, Albert; Falcón, Carles; Bullich, Santiago; Pareto, Deborah; Aguiar, Pablo; Sempau, Josep; Lomeña, Francisco; Calviño, Francisco; Pavía, Javier; Ros, Domènec

    2008-07-01

    (123)I-labelled radioligands are commonly used for single-photon emission computed tomography (SPECT) imaging of the dopaminergic system to study the dopamine transporter binding. The aim of this work was to compare the quantitative capabilities of two different SPECT systems through Monte Carlo (MC) simulation. The SimSET MC code was employed to generate simulated projections of a numerical phantom for two gamma cameras equipped with a parallel and a fan-beam collimator, respectively. A fully 3D iterative reconstruction algorithm was used to compensate for attenuation, the spatially variant point spread function (PSF) and scatter. A post-reconstruction partial volume effect (PVE) compensation was also developed. For both systems, the correction for all degradations and PVE compensation resulted in recovery factors of the theoretical specific uptake ratio (SUR) close to 100%. For a SUR value of 4, the recovered SUR for the parallel imaging system was 33% for a reconstruction without corrections (OSEM), 45% for a reconstruction with attenuation correction (OSEM-A), 56% for a 3D reconstruction with attenuation and PSF corrections (OSEM-AP), 68% for OSEM-AP with scatter correction (OSEM-APS) and 97% for OSEM-APS plus PVE compensation (OSEM-APSV). For the fan-beam imaging system, the recovered SUR was 41% without corrections, 55% for OSEM-A, 65% for OSEM-AP, 75% for OSEM-APS and 102% for OSEM-APSV. Our findings indicate that the correction for degradations increases the quantification accuracy, with PVE compensation playing a major role in the SUR quantification. The proposed methodology allows us to reach similar SUR values for different SPECT systems, thereby allowing a reliable standardisation in multicentric studies.

  20. Quantification of dopaminergic neurotransmission SPECT studies with 123I-labelled radioligands. A comparison between different imaging systems and data acquisition protocols using Monte Carlo simulation

    International Nuclear Information System (INIS)

    Crespo, Cristina; Aguiar, Pablo; Gallego, Judith; Cot, Albert; Falcon, Carles; Ros, Domenec; Bullich, Santiago; Pareto, Deborah; Sempau, Josep; Lomena, Francisco; Calvino, Francisco; Pavia, Javier

    2008-01-01

    123 I-labelled radioligands are commonly used for single-photon emission computed tomography (SPECT) imaging of the dopaminergic system to study the dopamine transporter binding. The aim of this work was to compare the quantitative capabilities of two different SPECT systems through Monte Carlo (MC) simulation. The SimSET MC code was employed to generate simulated projections of a numerical phantom for two gamma cameras equipped with a parallel and a fan-beam collimator, respectively. A fully 3D iterative reconstruction algorithm was used to compensate for attenuation, the spatially variant point spread function (PSF) and scatter. A post-reconstruction partial volume effect (PVE) compensation was also developed. For both systems, the correction for all degradations and PVE compensation resulted in recovery factors of the theoretical specific uptake ratio (SUR) close to 100%. For a SUR value of 4, the recovered SUR for the parallel imaging system was 33% for a reconstruction without corrections (OSEM), 45% for a reconstruction with attenuation correction (OSEM-A), 56% for a 3D reconstruction with attenuation and PSF corrections (OSEM-AP), 68% for OSEM-AP with scatter correction (OSEM-APS) and 97% for OSEM-APS plus PVE compensation (OSEM-APSV). For the fan-beam imaging system, the recovered SUR was 41% without corrections, 55% for OSEM-A, 65% for OSEM-AP, 75% for OSEM-APS and 102% for OSEM-APSV. Our findings indicate that the correction for degradations increases the quantification accuracy, with PVE compensation playing a major role in the SUR quantification. The proposed methodology allows us to reach similar SUR values for different SPECT systems, thereby allowing a reliable standardisation in multicentric studies. (orig.)

  1. Quantification of dopaminergic neurotransmission SPECT studies with {sup 123}I-labelled radioligands. A comparison between different imaging systems and data acquisition protocols using Monte Carlo simulation

    Energy Technology Data Exchange (ETDEWEB)

    Crespo, Cristina; Aguiar, Pablo [Universitat de Barcelona - IDIBAPS, Unitat de Biofisica i Bioenginyeria, Departament de Ciencies Fisiologiques I, Facultat de Medicina, Barcelona (Spain); Gallego, Judith [Universitat Politecnica de Catalunya, Institut de Tecniques Energetiques, Barcelona (Spain); Institut de Bioenginyeria de Catalunya, Barcelona (Spain); Cot, Albert [Universitat de Barcelona - IDIBAPS, Unitat de Biofisica i Bioenginyeria, Departament de Ciencies Fisiologiques I, Facultat de Medicina, Barcelona (Spain); Universitat Politecnica de Catalunya, Seccio d' Enginyeria Nuclear, Departament de Fisica i Enginyeria Nuclear, Barcelona (Spain); Falcon, Carles; Ros, Domenec [Universitat de Barcelona - IDIBAPS, Unitat de Biofisica i Bioenginyeria, Departament de Ciencies Fisiologiques I, Facultat de Medicina, Barcelona (Spain); CIBER en Bioingenieria, Biomateriales y Nanomedicina (CIBER-BBN), Barcelona (Spain); Bullich, Santiago [Hospital del Mar, Center for Imaging in Psychiatry, CRC-MAR, Barcelona (Spain); Pareto, Deborah [CIBER en Bioingenieria, Biomateriales y Nanomedicina (CIBER-BBN), Barcelona (Spain); PRBB, Institut d' Alta Tecnologia, Barcelona (Spain); Sempau, Josep [Universitat Politecnica de Catalunya, Institut de Tecniques Energetiques, Barcelona (Spain); CIBER en Bioingenieria, Biomateriales y Nanomedicina (CIBER-BBN), Barcelona (Spain); Lomena, Francisco [IDIBAPS, Servei de Medicina Nuclear, Hospital Clinic, Barcelona (Spain); Calvino, Francisco [Universitat Politecnica de Catalunya, Institut de Tecniques Energetiques, Barcelona (Spain); Universitat Politecnica de Catalunya, Seccio d' Enginyeria Nuclear, Departament de Fisica i Enginyeria Nuclear, Barcelona (Spain); Pavia, Javier [CIBER en Bioingenieria, Biomateriales y Nanomedicina (CIBER-BBN), Barcelona (Spain); IDIBAPS, Servei de Medicina Nuclear, Hospital Clinic, Barcelona (Spain)

    2008-07-15

    {sup 123}I-labelled radioligands are commonly used for single-photon emission computed tomography (SPECT) imaging of the dopaminergic system to study the dopamine transporter binding. The aim of this work was to compare the quantitative capabilities of two different SPECT systems through Monte Carlo (MC) simulation. The SimSET MC code was employed to generate simulated projections of a numerical phantom for two gamma cameras equipped with a parallel and a fan-beam collimator, respectively. A fully 3D iterative reconstruction algorithm was used to compensate for attenuation, the spatially variant point spread function (PSF) and scatter. A post-reconstruction partial volume effect (PVE) compensation was also developed. For both systems, the correction for all degradations and PVE compensation resulted in recovery factors of the theoretical specific uptake ratio (SUR) close to 100%. For a SUR value of 4, the recovered SUR for the parallel imaging system was 33% for a reconstruction without corrections (OSEM), 45% for a reconstruction with attenuation correction (OSEM-A), 56% for a 3D reconstruction with attenuation and PSF corrections (OSEM-AP), 68% for OSEM-AP with scatter correction (OSEM-APS) and 97% for OSEM-APS plus PVE compensation (OSEM-APSV). For the fan-beam imaging system, the recovered SUR was 41% without corrections, 55% for OSEM-A, 65% for OSEM-AP, 75% for OSEM-APS and 102% for OSEM-APSV. Our findings indicate that the correction for degradations increases the quantification accuracy, with PVE compensation playing a major role in the SUR quantification. The proposed methodology allows us to reach similar SUR values for different SPECT systems, thereby allowing a reliable standardisation in multicentric studies. (orig.)

  2. Culture shapes a mesolimbic response to signals of dominance and subordination that associates with behavior.

    Science.gov (United States)

    Freeman, Jonathan B; Rule, Nicholas O; Adams, Reginald B; Ambady, Nalini

    2009-08-01

    It has long been understood that culture shapes individuals' behavior, but how this is accomplished in the human brain has remained largely unknown. To examine this, we made use of a well-established cross-cultural difference in behavior: American culture tends to reinforce dominant behavior whereas, conversely, Japanese culture tends to reinforce subordinate behavior. In 17 Americans and 17 Japanese individuals, we assessed behavioral tendencies towards dominance versus subordination and measured neural responses using fMRI during the passive viewing of stimuli related to dominance and subordination. In Americans, dominant stimuli selectively engaged the caudate nucleus, bilaterally, and the medial prefrontal cortex (mPFC), whereas these were selectively engaged by subordinate stimuli in Japanese. Correspondingly, Americans self-reported a tendency towards more dominant behavior whereas Japanese self-reported a tendency towards more subordinate behavior. Moreover, activity in the right caudate and mPFC correlated with behavioral tendencies towards dominance versus subordination, such that stronger responses in the caudate and mPFC to dominant stimuli were associated with more dominant behavior and stronger responses in the caudate and mPFC to subordinate stimuli were associated with more subordinate behavior. The findings provide a first demonstration that culture can flexibly shape functional activity in the mesolimbic reward system, which in turn may guide behavior.

  3. Attenuation and scatter correction in I-123 FP-CIT SPECT do not affect the clinical diagnosis of dopaminergic system neurodegeneration.

    Science.gov (United States)

    Akahoshi, Miho; Abe, Koichiro; Uchiyama, Yumiko; Momose, Mitsuru; Fukushima, Kenji; Kitagawa, Kazuo; Sakai, Shuji

    2017-11-01

    The purpose of this study was to assess the influence of different reconstruction factors in N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-I-123 iodophenyl)nortropane (I-123 FP-CIT) single-photon emission computed tomography (SPECT) images for the diagnosis of dopaminergic system neurodegeneration (DSND).Seventy-three patients (38 females, 35 males) suspected of DSND were included in this study. The patients were divided into 3 groups on the basis of their final clinical diagnoses; patients with Parkinson disease (group 1, n = 36), patients with other DSND (group 2, n = 19), patients without DSND (group 3, n = 18). FP-CIT accumulation in the striata was evaluated visually and semiquantitatively. SPECT images were classified visually as normal or abnormal based on the previous report. For semiquantitative analysis, we used DaTView software (Aze Corporation), and specific binding ratios (SBR) and asymmetry indices (AI) were calculated. Visual and semiquantitative evaluations for different reconstruction factors were compared among the 3 groups.In the visual evaluation, there were no differences among DSND diagnostic capabilities of attenuation and scatter correction by computed tomography attenuation correction scatter correction, computed tomography attenuation correction, Chang attenuation correction, and non-attenuation and -scatter correction. In the semiquantitative evaluation, receiver operating characteristic analysis of SBR and AI for clinical DSND diagnostic ability (group 1+2 vs 3) showed no significant difference among the reconstruction factors by multiple comparisons.Although the values of SBR and AI were changed and image quality could be improved when attenuation correction and/or scatter correction were applied, the clinical impact of these reconstruction factors for the diagnosis of DSND was negligible.

  4. Managing Parkinson's disease with continuous dopaminergic stimulation

    NARCIS (Netherlands)

    Wolters, Erik; Lees, Andrew J.; Volkmann, Jens; van Laar, Teus; Hovestadt, Ad

    The pathophysiology of Parkinson's disease is marked by the loss of dopaminergic neurons, which leads to striatal dopaminergic deficiency. This causes resting tremor, hypokinesia, rigidity, bradykinesia, and loss of postural reflexes. Most current treatments for Parkinson's disease aim to restore

  5. Connectivity and ultrastructure of dopaminergic innervation of the inner ear and auditory efferent system of a vocal fish.

    Science.gov (United States)

    Perelmuter, Jonathan T; Forlano, Paul M

    2017-06-15

    Dopamine (DA) is a conserved modulator of vertebrate neural circuitry, yet our knowledge of its role in peripheral auditory processing is limited to mammals. The present study combines immunohistochemistry, neural tract tracing, and electron microscopy to investigate the origin and synaptic characteristics of DA fibers innervating the inner ear and the hindbrain auditory efferent nucleus in the plainfin midshipman, a vocal fish that relies upon the detection of mate calls for reproductive success. We identify a DA cell group in the diencephalon as a common source for innervation of both the hindbrain auditory efferent nucleus and saccule, the main hearing endorgan of the inner ear. We show that DA terminals in the saccule contain vesicles but transmitter release appears paracrine in nature, due to the apparent lack of synaptic contacts. In contrast, in the hindbrain, DA terminals form traditional synaptic contacts with auditory efferent neuronal cell bodies and dendrites, as well as unlabeled axon terminals, which, in turn, form inhibitory-like synapses on auditory efferent somata. Our results suggest a distinct functional role for brain-derived DA in the direct and indirect modulation of the peripheral auditory system of a vocal nonmammalian vertebrate. © 2017 Wiley Periodicals, Inc.

  6. Involvement of dopaminergic and cholinergic systems in social isolation-induced deficits in social affiliation and conditional fear memory in mice.

    Science.gov (United States)

    Okada, R; Fujiwara, H; Mizuki, D; Araki, R; Yabe, T; Matsumoto, K

    2015-07-23

    , when analyzed 30 min after the administration of the test drugs, tacrine significantly attenuated the SI-induced decrease in p-CaMKII, p-CREB, and Egr-1 in a manner reversible by scopolamine. Our results suggest that SI-induced deficits in social affiliation and conditioned fear memory were mediated by functional alterations to central dopaminergic and cholinergic systems, respectively. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  7. Systemic administration of valproic acid and zonisamide promotes the survival and differentiation of induced pluripotent stem cell–derived dopaminergic neurons

    Directory of Open Access Journals (Sweden)

    Tatsuya eYoshikawa

    2013-02-01

    Full Text Available Cell replacement therapy using embryonic stem cells (ESCs and induced pluripotent stem cells (iPSCs is a promising strategy for the treatment of neurologic diseases such as Parkinson’s disease (PD. However, a limiting factor for effective cell transplantation is the low survival rate of grafted cells, especially neurons. In this study, we modified the host environment and investigated whether the simultaneous administration of soluble factors can improve the survival and differentiation of murine iPSC-derived dopaminergic (DA neurons in host brains. With the goal of applying this technology in clinical settings in the near future, we selected drugs that were already approved for clinical use. The drugs included two commonly used anticonvulsants, valproic acid (VPA and zonisamide (ZNS, and estradiol (E2, also known as biologically active estrogen. Following neural induction of murine iPSCs, we collected neural progenitor cells by sorting PSA-NCAM+ cells, then treated the PSA-NCAM+ cells with drugs for four days. An immunofluorescence study revealed that 0.01 mM and 0.1 mM of VPA and 10 nM of E2 increased the percentage of tyrosine hydroxylase+ (TH: a DA neuron marker cells in vitro. Furthermore, 0.1 mM of VPA increased the percentage of TH+ cells that simultaneously express the midbrain markers FOXA2 and NURR1. Next, in order to determine the effects of the drugs in vivo, the iPSC-derived NPCs were transplanted into the striata of intact SD rats. The animals received intraperitoneal injections of one of the drugs for four weeks, then were subjected to an immunofluorescence study. VPA administration (150 mg/kg/daily increased the number of NeuN+ postmitotic neurons and TH+ DA neurons in the grafts. Furthermore, VPA (150 mg/kg/daily and ZNS (30 mg/kg/daily increased the number of TH+FOXA2+ midbrain DA neurons. These results suggest that the systemic administration of VPA and ZNS may improve the efficiency of cell replacement therapy using i

  8. Preserved dopaminergic homeostasis and dopamine-related behaviour in hemizygous TH-Cre mice

    DEFF Research Database (Denmark)

    Thomsen, Annika Højrup Runegaard; Jensen, Kathrine L; Fitzpatrick, Ciarán M

    2017-01-01

    assessment of the dopaminergic system in hemizygous tyrosine hydroxylase (TH)-Cre mice in comparison to wild-type (WT) controls. Our data show that TH-Cre mice display preserved dopaminergic homeostasis with unaltered levels of TH and dopamine as well as unaffected dopamine turnover in striatum. TH-Cre mice...

  9. Examination of the presynaptic dopaminergic system using positron emission tomography in a family with autosomal dominant parkinsonism and dementia due to pallido-ponto-nigral degeneration (PPNO)

    Energy Technology Data Exchange (ETDEWEB)

    Cordes, M. [Neurodegenerative Disorders Centre, Univ. of British Columbia, Vancouver, BC (Canada)]|[Strahlenklinik und Poliklinik, Universitaetsklinikum Rudolf Virchow, Freie Univ. Berlin (Germany); Wszolek, Z.K. [Neurodegenerative Disorders Centre, Univ. of British Columbia, Vancouver, BC (Canada)]|[Section of Neurology, Univ. of Nebraska Medical Center, Omaha, NE (United States); Pfeiffer, R.F. [Section of Neurology, Univ. of Nebraska Medical Center, Omaha, NE (United States); Calne, D.B. [Neurodegenerative Disorders Centre, Univ. of British Columbia, Vancouver, BC (Canada)

    1993-12-31

    We report positron emission tomography (PET) examinations of presynaptic nigrostriatal dopaminergic function in a large family with an autosomal dominant neuro-degenerative disorder characterized pathologically by pallido-ponto-nigral degeneration, and clinically by parkinsonism, dystonia, paresis of conjugate gaze, apraxia of eyelid opening and closing, pyramidal tract dysfunction, and urinary incontinence. Dopaminergic function was studied and quantified with [{sup 18}F]-L-6-fluorodopa (6 FD) and PET in five affected patients, 13 individuals at-risk, and 15 similarly aged controls. The rate constant K{sub i} (mL/striatum/min) for 6 FD was decreased in all patients. None of the individuals at risk had reduced 6 FD uptake. In fact, three of them had increased values. Repeat scans have revealed a fall in 6 FD uptake in two out of the three with initially high constants. This may reflect a preclinical stage of involvement, but longer observation is necessary. (orig.) [Deutsch] Wir berichten ueber Untersuchungen der praesynaptischen dopaminergen Funktion mit der Positronenemissionstomographie bei einer grossen Familie mit autosomal-dominant vererbtem Parkinsonismus und Demenz. Die Erkrankung ist pathologisch-anatomisch gekennzeichnet durch eine pallido-ponto-nigrale Degeneration. Klinisch bestehen ein Parkinsonismus, Dystonien, eine Apraxie der Augenoeffnung und -schliessung, pyramidale Dysfunktionen und eine Harninkontinenz. Die praesynaptische dopaminerge Funktion wurde untersucht und quantifiziert mittels [{sup 18}F]-L-6-Fluorodopa (6FD) PET bei fuenf erkrankten Patienten, 13 Risikopatienten und 15 Kontrollpersonen vergleichbaren Alters. Die Transportkonstante K{sub i} (ml/Striatum/min) fuer die striatale Aufnahme des Radiotracers war bei allen erkrankten Patienten erniedrigt. Von den 13 Risikopatienten hatte keiner eine reduzierte Aufnahme von 6FD. Drei Risikopatienten zeigten sogar Werte fuer K{sub i}, die oberhalb des Referenzbereiches der Kontrollpersonen lagen

  10. Increased 3H-spiperone binding sites in mesolimbic area related to methamphetamine-induced behavioral hypersensitivity

    International Nuclear Information System (INIS)

    Akiyama, K.; Sato, M.; Otsuki, S.

    1982-01-01

    The specific 3 H-spiperone binding to membrane homogenates of the striatum, mesolimbic area, and frontal cortex was examined in two groups of rats pretreated once daily with saline or 4 mg/kg of methamphetamine (MAP) for 14 days. At 7 days following cessation of chronic pretreatment, all rats received an injection of 4 mg/kg of MAP and were decapitated 1 hr after the injection. In the chronic saline-pretreatment group, the single administration of MAP induced significant changes in the number (Bmax) of specific 3 H-spiperone binding sites (a decrease in the striatum and an increase in the mesolimbic area and frontal cortex), but no significant changes in the affinity (KD) in any brain area. The chronic MAP pretreatment markedly augmented the changes in Bmax in the striatum and mesolimbic area. The increase in specific 3 H-spiperone binding sites in the mesolimbic area is discussed in relation to MAP-induced behavioral hypersensitivity

  11. Mesolimbic confidence signals guide perceptual learning in the absence of external feedback.

    Science.gov (United States)

    Guggenmos, Matthias; Wilbertz, Gregor; Hebart, Martin N; Sterzer, Philipp

    2016-03-29

    It is well established that learning can occur without external feedback, yet normative reinforcement learning theories have difficulties explaining such instances of learning. Here, we propose that human observers are capable of generating their own feedback signals by monitoring internal decision variables. We investigated this hypothesis in a visual perceptual learning task using fMRI and confidence reports as a measure for this monitoring process. Employing a novel computational model in which learning is guided by confidence-based reinforcement signals, we found that mesolimbic brain areas encoded both anticipation and prediction error of confidence-in remarkable similarity to previous findings for external reward-based feedback. We demonstrate that the model accounts for choice and confidence reports and show that the mesolimbic confidence prediction error modulation derived through the model predicts individual learning success. These results provide a mechanistic neurobiological explanation for learning without external feedback by augmenting reinforcement models with confidence-based feedback.

  12. Antiallodynic Activity of Ceftriaxone and Clavulanic Acid in Acute Administration is Associated with Serum TNF-α Modulation and Activation of Dopaminergic and Opioidergic Systems.

    Science.gov (United States)

    Ochoa-Aguilar, A; Sotomayor-Sobrino, M A; Jaimez, R; Rodríguez, R; Plancarte-Sánchez, R; Ventura-Martinez, R

    2017-03-01

    Preclinical Research The aim of this study was to determine the antiallodynic effect of acute administration of the β-lactam antimicrobials, ceftriaxone (CFX) and clavulanic acid (CLAV), for the control of established pain on a model of neuropathic pain (NP). We also investigated the involvement of dopaminergic and opioidergic pathways as well as alterations in serum concentrations of TNF-α in the antiallodynic actions of these drugs. CFX, CLAV, or gabapentin (GAP), a reference drug, were administered i.p. twelve days after constriction of the sciatic nerve in rats. Mechanic and cold allodynia were evaluated for 3 h and alterations in serum concentration of TNF-α determined. Both CFX and CLAV had antiallodynic effects in response to mechanical and cold stimulation, similar to GAP. The antiallodynic effects of CFX and CLAV were blocked by haloperidol (HAL), a D2 receptor antagonist, and by naloxone (NLX), an opioid receptor antagonist. Additionally, serum TNF-α levels were attenuated following CFX and CLAV administration. These results suggest that acute administration of CFX and CLAV may represent a promising approach for treating the acute allodynia of NP, and that the mechanisms involved in these effects involve activation of dopaminergic and opioidergic pathways as well as modulation of TNF-α production. Drug Dev Res 78 : 105-115, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  13. Compulsive habits in restless legs syndrome patients under dopaminergic treatment.

    Science.gov (United States)

    Pourcher, Emmanuelle; Rémillard, Sophie; Cohen, Henri

    2010-03-15

    behaviors while receiving standard dosage DA agonist treatment. These behaviors are clearly linked to short-term satisfaction and underline the role of dopaminergic mesolimbic stimulation in the reinforcement process of rewarding behavioral sequences.

  14. Dopaminergic Input to the Inferior Colliculus in Mice

    Directory of Open Access Journals (Sweden)

    Alexander A Nevue

    2016-01-01

    Full Text Available The response of sensory neurons to stimuli can be modulated by a variety of factors including attention, emotion, behavioral context, and disorders involving neuromodulatory systems. For example, patients with Parkinson’s disease have disordered speech processing, suggesting that dopamine alters normal representation of these salient sounds. Understanding the mechanisms by which dopamine modulates auditory processing is thus an important goal. The principal auditory midbrain nucleus, the inferior colliculus (IC, is a likely location for dopaminergic modulation of auditory processing because it contains dopamine receptors and nerve terminals immunoreactive for tyrosine hydroxylase (TH, the rate-limiting enzyme in dopamine synthesis. However, the sources of dopaminergic input to the IC are unknown. In this study, we iontophoretically injected a retrograde tracer into the IC of mice and then stained the tissue for TH. We also immunostained for dopamine beta-hydroxylase (DBH, an enzyme critical for the conversion of dopamine to norepinephrine, to differentiate between dopaminergic and noradrenergic inputs. Retrogradely labeled neurons that were positive for TH were seen bilaterally, with strong ipsilateral dominance, in the subparafascicular thalamic nucleus (SPF. All retrogradely labeled neurons that we observed in other brain regions were TH-negative. Projections from the SPF were confirmed using an anterograde tracer, revealing TH-positive and DBH-negative anterogradely labeled fibers and terminals in the IC. While the functional role of this dopaminergic input to the IC is not yet known, it provides a potential mechanism for context dependent modulation of auditory processing.

  15. Maternal “junk-food” feeding of rat dams alters food choices and development of the mesolimbic reward pathway in the offspring

    Science.gov (United States)

    Ong, Z. Y.; Muhlhausler, B. S.

    2011-01-01

    Individuals exposed to high-fat, high-sugar diets before birth have an increased risk of obesity in later life. Recent studies have shown that these offspring exhibit increased preference for fat, leading to suggestions that perinatal exposure to high-fat, high-sugar foods results in permanent changes within the central reward system that increase the subsequent drive to overconsume palatable foods. The present study has determined the effect of a maternal “junk-food” diet on the expression of key components of the mesolimbic reward pathway in the offspring of rat dams at 6 wk and 3 mo of age. We show that offspring of junk-food-fed (JF) dams exhibit higher fat intake from weaning until at least 3 mo of age (males: 16±0.6 vs. 11±0.8 g/kg/d; females: 19±1.3 vs. 13±0.4 g/kg/d; Pjunk-food intake in postnatal life.—Ong, Z. Y., Muhlhausler, B. S. Maternal “junk-food” feeding of rat dams alters food choices and development of the mesolimbic reward pathway in the offspring. PMID:21427213

  16. Risk preference following adolescent alcohol use is associated with corrupted encoding of costs but not rewards by mesolimbic dopamine.

    Science.gov (United States)

    Nasrallah, Nicholas A; Clark, Jeremy J; Collins, Annie L; Akers, Christina A; Phillips, Paul E; Bernstein, Ilene L

    2011-03-29

    Several emerging theories of addiction have described how abused substances exploit vulnerabilities in decision-making processes. These vulnerabilities have been proposed to result from pharmacologically corrupted neural mechanisms of normal brain valuation systems. High alcohol intake in rats during adolescence has been shown to increase risk preference, leading to suboptimal performance on a decision-making task when tested in adulthood. Understanding how alcohol use corrupts decision making in this way has significant clinical implications. However, the underlying mechanism by which alcohol use increases risk preference remains unclear. To address this central issue, we assessed dopamine neurotransmission with fast-scan cyclic voltammetry during reward valuation and risk-based decision making in rats with and without a history of adolescent alcohol intake. We specifically targeted the mesolimbic dopamine system, the site of action for virtually all abused substances. This system, which continuously develops during the adolescent period, is central to both reward processing and risk-based decision making. We report that a history of adolescent alcohol use alters dopamine signaling to risk but not to reward. Thus, a corruption of cost encoding suggests that adolescent alcohol use leads to long-term changes in decision making by altering the valuation of risk.

  17. Differential alteration of the nigrostriatal dopaminergic system in Wilson's disease investigated with [123I]ss-CIT and high-resolution SPET

    International Nuclear Information System (INIS)

    Barthel, H.; Sorger, D.; Kluge, R.; Kuehn, H.-J.; Wagner, A.; Hermann, W.

    2001-01-01

    Wilson's disease (WD) is a copper deposition disorder which can result in a number of extrapyramidal motoric symptoms such as parkinsonism. Therefore, this study was carried out to investigate, for the first time, nigrostriatal dopaminergic function in WD in relation to different courses and severity of the disease. Using high-resolution single-photon emission tomography (SPET) after administration of 2ss-carbomethoxy-3ss-(4[ 123 I]iodophenyl)tropane ([ 123 I]ss-CIT), striatal dopamine transporters (DAT) were imaged in 43 WD patients and a control group of ten subjects. From the SPET images, specific [ 123 I]ss-CIT binding ratios were obtained for the caudate heads, putamina and entire corpus striatum. In addition, to evaluate a putative dissociation between the caudate and putaminal [ 123 I]ss-CIT binding ratios, the ratio between these binding ratios was calculated (CA/PU ratio). The SPET data were compared with clinical data on the course of the disease (CD), the severity of neurological symptoms and the degree of hepatic alteration. Whereas the specific regional [ 123 I]ss-CIT binding ratios in patients with asymptomatic/hepatic CD did not differ from those in the control group (e.g. striatal ratios: 13.4±3.0 vs 11.7±2.8), in patients with neurological CD the ratios were significantly reduced for all striatal substructures (P=0.003 after one-factor ANOVA). For the different subgroups a tendency was detected towards a stepwise decrease in the specific [ 123 I]ss-CIT binding ratios from pseudo-sclerosis CD (9.4±2.3), through pseudo-parkinsonian CD (9.1±2.1) to arrhythmic-hyperkinetic CD (8.5±1.6). However, these group differences reached significance only for the comparison with asymptomatic/hepatic CD (P=0.02). The CA/PU ratio was significantly higher in WD than in the control group (1.30±0.19 vs 1.11±0.08; P=0.003). Severity of neurological symptoms was significantly correlated with all specific regional [ 123 I]ss-CIT binding ratios (r=-0.49 to -0

  18. Long-term voluntary wheel running is rewarding and produces plasticity in the mesolimbic reward pathway.

    Science.gov (United States)

    Greenwood, Benjamin N; Foley, Teresa E; Le, Tony V; Strong, Paul V; Loughridge, Alice B; Day, Heidi E W; Fleshner, Monika

    2011-03-01

    The mesolimbic reward pathway is implicated in stress-related psychiatric disorders and is a potential target of plasticity underlying the stress resistance produced by repeated voluntary exercise. It is unknown, however, whether rats find long-term access to running wheels rewarding, or if repeated voluntary exercise reward produces plastic changes in mesolimbic reward neurocircuitry. In the current studies, young adult, male Fischer 344 rats allowed voluntary access to running wheels for 6 weeks, but not 2 weeks, found wheel running rewarding, as measured by conditioned place preference (CPP). Consistent with prior reports and the behavioral data, 6 weeks of wheel running increased ΔFosB/FosB immunoreactivity in the nucleus accumbens (Acb). In addition, semi quantitative in situ hybridization revealed that 6 weeks of wheel running, compared to sedentary housing, increased tyrosine hydroxylase (TH) mRNA levels in the ventral tegmental area (VTA), increased delta opioid receptor (DOR) mRNA levels in the Acb shell, and reduced levels of dopamine receptor (DR)-D2 mRNA in the Acb core. Results indicate that repeated voluntary exercise is rewarding and alters gene transcription in mesolimbic reward neurocircuitry. The duration-dependent effects of wheel running on CPP suggest that as the weeks of wheel running progress, the rewarding effects of a night of voluntary wheel running might linger longer into the inactive cycle thus providing stronger support for CPP. The observed plasticity could contribute to the mechanisms by which exercise reduces the incidence and severity of substance abuse disorders, changes the rewarding properties of drugs of abuse, and facilitates successful coping with stress. Copyright © 2010 Elsevier B.V. All rights reserved.

  19. Long term voluntary wheel running is rewarding and produces plasticity in the mesolimbic reward pathway

    Science.gov (United States)

    Greenwood, Benjamin N.; Foley, Teresa E.; Le, Tony V.; Strong, Paul V.; Loughridge, Alice B.; Day, Heidi E.W.; Fleshner, Monika

    2011-01-01

    The mesolimbic reward pathway is implicated in stress-related psychiatric disorders and is a potential target of plasticity underlying the stress resistance produced by repeated voluntary exercise. It is unknown, however, whether rats find long-term access to running wheels rewarding, or if repeated voluntary exercise reward produces plastic changes in mesolimbic reward neurocircuitry. In the current studies, young adult, male Fischer 344 rats allowed voluntary access to running wheels for 6 weeks, but not 2 weeks, found wheel running rewarding, as measured by conditioned place preference (CPP). Consistent with prior reports and the behavioral data, 6 weeks of wheel running increased ΔFosB/FosB immunoreactivity in the nucleus accumbens (Acb). In addition, semi quantitative in situ hybridization revealed that 6 weeks of wheel running, compared to sedentary housing, increased tyrosine hydroxylase (TH) mRNA levels in the ventral tegmental area (VTA), increased delta opioid receptor (DOR) mRNA levels in the Acb shell, and reduced levels of dopamine receptor (DR)-D2 mRNA in the Acb core. Results indicate that repeated voluntary exercise is rewarding and alters gene transcription in mesolimbic reward neurocircuitry. The duration-dependent effects of wheel running on CPP suggest that as the weeks of wheel running progress, the rewarding effects of a night of voluntary wheel running might linger longer into the inactive cycle thus providing stronger support for CPP. The observed plasticity could contribute to the mechanisms by which exercise reduces the incidence and severity of substance abuse disorders, changes the rewarding properties of drugs of abuse, and facilitates successful coping with stress. PMID:21070820

  20. A mouse model of the schizophrenia-associated 1q21.1 microdeletion syndrome exhibits altered mesolimbic dopamine transmission

    DEFF Research Database (Denmark)

    Nielsen, Jacob; Fejgin, Kim; Sotty, Florence

    2017-01-01

    and basic functions such as reflexes, ASR, thermal pain sensitivity, and motor performance were unaltered. Similarly, anxiety related measures, baseline prepulse inhibition, and seizure threshold were unaltered. In addition to the central nervous system-related phenotypes, Df(h1q21)/+ mice exhibited reduced...... head-to tail length, which is reminiscent of the short stature reported in humans with 1q21.1 deletion. With aspects of both construct and face validity, the Df(h1q21)/+ model may be used to gain insight into schizophrenia-relevant alterations in dopaminergic transmission....

  1. Mesolimbic confidence signals guide perceptual learning in the absence of external feedback

    Science.gov (United States)

    Guggenmos, Matthias; Wilbertz, Gregor; Hebart, Martin N; Sterzer, Philipp

    2016-01-01

    It is well established that learning can occur without external feedback, yet normative reinforcement learning theories have difficulties explaining such instances of learning. Here, we propose that human observers are capable of generating their own feedback signals by monitoring internal decision variables. We investigated this hypothesis in a visual perceptual learning task using fMRI and confidence reports as a measure for this monitoring process. Employing a novel computational model in which learning is guided by confidence-based reinforcement signals, we found that mesolimbic brain areas encoded both anticipation and prediction error of confidence—in remarkable similarity to previous findings for external reward-based feedback. We demonstrate that the model accounts for choice and confidence reports and show that the mesolimbic confidence prediction error modulation derived through the model predicts individual learning success. These results provide a mechanistic neurobiological explanation for learning without external feedback by augmenting reinforcement models with confidence-based feedback. DOI: http://dx.doi.org/10.7554/eLife.13388.001 PMID:27021283

  2. Chronic low-level arsenic exposure causes gender-specific alterations in locomotor activity, dopaminergic systems, and thioredoxin expression in mice

    International Nuclear Information System (INIS)

    Bardullas, U.; Limon-Pacheco, J.H.; Giordano, M.; Carrizales, L.; Mendoza-Trejo, M.S.; Rodriguez, V.M.

    2009-01-01

    Arsenic (As) is a toxic metalloid widely present in the environment. Human exposure to As has been associated with the development of skin and internal organ cancers and cardiovascular disorders, among other diseases. A few studies report decreases in intelligence quotient (IQ), and sensory and motor alterations after chronic As exposure in humans. On the other hand, studies of rodents exposed to high doses of As have found alterations in locomotor activity, brain neurochemistry, behavioral tasks, and oxidative stress. In the present study both male and female C57Bl/6J mice were exposed to environmentally relevant doses of As such as 0.05, 0.5, 5.0, or 50 mg As/L of drinking water for 4 months, and locomotor activity was assessed every month. Male mice presented hyperactivity in the group exposed to 0.5 mg As/L and hypoactivity in the group exposed to 50 mg As/L after 4 months of As exposure, whereas female mice exposed to 0.05, 0.5, and 5.0 mg As/L exhibited hyperactivity in every monthly test during As exposure. Furthermore, striatal and hypothalamic dopamine content was decreased only in female mice. Also decreases in tyrosine hydroxylase (TH) and cytosolic thioredoxin (Trx-1) mRNA expression in striatum and nucleus accumbens were observed in male and female mice, respectively. These results indicate that chronic As exposure leads to gender-dependent alterations in dopaminergic markers and spontaneous locomotor activity, and down-regulation of the antioxidant capacity of the brain.

  3. PET measurements od dopaminergic pathways in the brain

    Energy Technology Data Exchange (ETDEWEB)

    Perlmutter, J.S. [Washington Univ., St. Louis, MO (United States). School of Medicine. Dept. of Neurology and Neurological Surgery, Anatomy and Neurobiology; Moerlein, S.M. [Washington Univ., St. Louis, MO (United States). School of Medicine. Dept. of Biochemistry and Molecular Biophysics, Mallinckrodt Institute of Radiology

    1999-06-01

    Position emission tomography (PET) measurements of dopaminergic pathways have revealed several new insights into the role of dopamine in the pathophysiology and pharmacology of brain diseases such as Parkinson's disease (PD), dystonia and schizophrenia. PET studies of regional blood flow of metabolism identifies sites of regional pathology. Drug-induced changes in flow or metabolism indicate the function of dopamine-mediated pathways. Measurements of radioligand binding 'in vivo' with PET reveals abnormalities associated with specific diseases and the actions of various drugs that effect the dopaminergic system. Finally, PET measurements of the uptake of analogues of levodopa provide clues to the function of dopamine pathways potentially important for diagnosis and treatment of disease like PD.

  4. PET measurements od dopaminergic pathways in the brain

    International Nuclear Information System (INIS)

    Perlmutter, J.S.; Moerlein, S.M.

    1999-01-01

    Position emission tomography (PET) measurements of dopaminergic pathways have revealed several new insights into the role of dopamine in the pathophysiology and pharmacology of brain diseases such as Parkinson's disease (PD), dystonia and schizophrenia. PET studies of regional blood flow of metabolism identifies sites of regional pathology. Drug-induced changes in flow or metabolism indicate the function of dopamine-mediated pathways. Measurements of radioligand binding 'in vivo' with PET reveals abnormalities associated with specific diseases and the actions of various drugs that effect the dopaminergic system. Finally, PET measurements of the uptake of analogues of levodopa provide clues to the function of dopamine pathways potentially important for diagnosis and treatment of disease like PD

  5. Dopaminergic Activity in the Medial Prefrontal Cortex Modulates Fear Conditioning

    Directory of Open Access Journals (Sweden)

    Parvin Babaei

    2011-07-01

    Full Text Available "nThe purpose of the present study was to determine the role of medial prefrontal cortex (mPFC dopaminergic system in fear conditioning response considering individual differences. Animals were initially counterbalanced and classified based on open field test, and then were given a single infusion of the dopamine agonist, amphetamine (AMPH and antagonist, clozapine (CLZ into the medial prefrontal cortex. Rats received tone-shock pairing in a classical fear conditioning test and then exposed to the tone alone. Freezing responses were measured as conditioned fear index. The results showed that both AMPH and CLZ infusion in mPFC reduced the expression of conditioned fear. This finding indicates that elevation or reduction in the dopaminergic activity is associated with the decrease of fear responses, despite preexisting individual-typological differences.

  6. Mesolimbic dopamine function is not altered during continuous chronic treatment of rats with typical or atypical neuroleptic drugs

    International Nuclear Information System (INIS)

    Rupniak, N.M.J.; Hall, M.D.; Kelly, E.; Fleminger, S.; Kilpatrick, G.; Jenner, P.; Marsden, C.D.

    1985-01-01

    Rats were treated continuously for up to 20 months with either haloperidol (1.4-1.6 mg/kg/day), sulpiride (102-109 mg/kg/day) or clozapine (24-27 mg/kg/day). Bsub(max) for specific mesolimbic binding of 3 H-spiperone, 3 H-N, n-propylnorapomorphine or 3 H-piflutixol did not differ in tissue taken from animals treated for up to 12 months with haloperidol, sulpiride or clozapine by comparison to age-matched control rats. Mesolimbic dopamine (50 μM)-stimulated adenylate cyclase activity was not altered in any drug treatment group. Spontaneous locomotor activity was transiently decreased during treatment with haloperidol for 1 or 3 months, but not by chronic sulpiride or clozapine treatment. Locomotor activity was not consistently increased in any drug treatment group. After 20 months of continuous drug treatment, focal bilateral application of dopamine (12.5 or 25 μg) into the nucleus accumbens caused equivalent increases in locomotor activity in control rats and in animals receiving haloperidol, sulpiride of clozapine. These findings suggest that dopamine receptor blockade is not maintained in the mesolimbic area following chronic treatment with haloperidol, sulpiride or clozapine, and indicate that, under these conditions, clozapine and sulpiride may not act selectively on mesolimbic dopamine receptors. (Author)

  7. Mesolimbic Dopamine Encodes Prediction Errors in a State-Dependent Manner

    Directory of Open Access Journals (Sweden)

    Georgios K. Papageorgiou

    2016-04-01

    Full Text Available Mesolimbic dopamine encodes the benefits of a course of action. However, the value of an appetitive reward depends strongly on an animal’s current state. To investigate the relationship between dopamine, value, and physiological state, we monitored sub-second dopamine release in the nucleus accumbens core while rats made choices between food and sucrose solution following selective satiation on one of these reinforcers. Dopamine signals reflected preference for the reinforcers in the new state, decreasing to the devalued reward and, after satiation on food, increasing for the valued sucrose solution. These changes were rapid and selective, with dopamine release returning to pre-satiation patterns when the animals were re-tested in a standard food-restricted state. Such rapid and selective adaptation of dopamine-associated value signals could provide an important signal to promote efficient foraging for a varied diet.

  8. The melanoma-linked "redhead" MC1R influences dopaminergic neuron survival.

    Science.gov (United States)

    Chen, Xiqun; Chen, Hongxiang; Cai, Waijiao; Maguire, Michael; Ya, Bailiu; Zuo, Fuxing; Logan, Robert; Li, Hui; Robinson, Katey; Vanderburg, Charles R; Yu, Yang; Wang, Yinsheng; Fisher, David E; Schwarzschild, Michael A

    2017-03-01

    Individuals with Parkinson disease are more likely to develop melanoma, and melanoma patients are reciprocally at higher risk of developing Parkinson disease. Melanoma is strongly tied to red hair/fair skin, a phenotype of loss-of-function polymorphisms in the MC1R (melanocortin 1 receptor) gene. Loss-of-function variants of MC1R have also been linked to increased risk of Parkinson disease. The present study is to investigate the role of MC1R in dopaminergic neurons in vivo. Genetic and pharmacological approaches were employed to manipulate MC1R, and nigrostriatal dopaminergic integrity was determined by comprehensive behavioral, neurochemical, and neuropathological measures. MC1R e/e mice, which carry an inactivating mutation of MC1R and mimic the human redhead phenotype, have compromised nigrostriatal dopaminergic neuronal integrity, and they are more susceptible to dopaminergic neuron toxins 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Furthermore, a selective MC1R agonist protects against MPTP-induced dopaminergic neurotoxicity. Our findings reveal a protective role of MC1R in the nigrostriatal dopaminergic system, and they provide a rationale for MC1R as a potential therapeutic target for Parkinson disease. Together with its established role in melanoma, MC1R may represent a common pathogenic pathway for melanoma and Parkinson disease. Ann Neurol 2017;81:395-406. © 2016 American Neurological Association.

  9. Simultaneous activation of mitophagy and autophagy by staurosporine protects against dopaminergic neuronal cell death.

    Science.gov (United States)

    Ha, Ji-Young; Kim, Ji-Soo; Kim, Seo-Eun; Son, Jin H

    2014-02-21

    Abnormal autophagy is frequently observed during dopaminergic neurodegeneration in Parkinson's disease (PD). However, it is not yet firmly established whether active autophagy is beneficial or pathogenic with respect to dopaminergic cell loss. Staurosporine, a common inducer of apoptosis, is often used in mechanistic studies of dopaminergic cell death. Here we report that staurosporine activates both autophagy and mitophagy simultaneously during dopaminergic neuronal cell death, and evaluate the physiological significance of these processes during cell death. First, staurosporine treatment resulted in induction of autophagy in more than 75% of apoptotic cells. Pharmacological inhibition of autophagy by bafilomycin A1 decreased significantly cell viability. In addition, staurosporine treatment resulted in activation of the PINK1-Parkin mitophagy pathway, of which deficit underlies some familial cases of PD, in the dopaminergic neuronal cell line, SN4741. The genetic blockade of this pathway by PINK1 null mutation also dramatically increased staurosporine-induced cell death. Taken together, our data suggest that staurosporine induces both mitophagy and autophagy, and that these pathways exert a significant neuroprotective effect, rather than a contribution to autophagic cell death. This model system may therefore be useful for elucidating the mechanisms underlying crosstalk between autophagy, mitophagy, and cell death in dopaminergic neurons. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  10. Sweet Taste and Nutrient Value Subdivide Rewarding Dopaminergic Neurons in Drosophila

    Science.gov (United States)

    Huetteroth, Wolf; Perisse, Emmanuel; Lin, Suewei; Klappenbach, Martín; Burke, Christopher; Waddell, Scott

    2015-01-01

    Summary Dopaminergic neurons provide reward learning signals in mammals and insects [1–4]. Recent work in Drosophila has demonstrated that water-reinforcing dopaminergic neurons are different to those for nutritious sugars [5]. Here, we tested whether the sweet taste and nutrient properties of sugar reinforcement further subdivide the fly reward system. We found that dopaminergic neurons expressing the OAMB octopamine receptor [6] specifically convey the short-term reinforcing effects of sweet taste [4]. These dopaminergic neurons project to the β′2 and γ4 regions of the mushroom body lobes. In contrast, nutrient-dependent long-term memory requires different dopaminergic neurons that project to the γ5b regions, and it can be artificially reinforced by those projecting to the β lobe and adjacent α1 region. Surprisingly, whereas artificial implantation and expression of short-term memory occur in satiated flies, formation and expression of artificial long-term memory require flies to be hungry. These studies suggest that short-term and long-term sugar memories have different physiological constraints. They also demonstrate further functional heterogeneity within the rewarding dopaminergic neuron population. PMID:25728694

  11. Evolution of visual art with dopaminergic therapy.

    Science.gov (United States)

    Walker, Ruth H

    2016-01-01

    A patient with right-side-predominant Parkinson's disease presented visual artwork which improved in resemblance to the model which he was copying with increasing doses of levodopa. I propose that increased dopaminergic replacement resulted in improved attention to detail, mediated by circuitry in the left hemisphere.

  12. Lower neighborhood quality in adolescence predicts higher mesolimbic sensitivity to reward anticipation in adulthood.

    Science.gov (United States)

    Gonzalez, Marlen Z; Allen, Joseph P; Coan, James A

    2016-12-01

    Life history theory suggests that adult reward sensitivity should be best explained by childhood, but not current, socioeconomic conditions. In this functional magnetic resonance imaging (fMRI) study, 83 participants from a larger longitudinal sample completed the monetary incentive delay (MID) task in adulthood (∼25 years old). Parent-reports of neighborhood quality and parental SES were collected when participants were 13 years of age. Current income level was collected concurrently with scanning. Lower adolescent neighborhood quality, but neither lower current income nor parental SES, was associated with heightened sensitivity to the anticipation of monetary gain in putative mesolimbic reward areas. Lower adolescent neighborhood quality was also associated with heightened sensitivity to the anticipation of monetary loss activation in visuo-motor areas. Lower current income was associated with heightened sensitivity to anticipated loss in occipital areas and the operculum. We tested whether externalizing behaviors in childhood or adulthood could better account for neighborhood quality findings, but they did not. Findings suggest that neighborhood ecology in adolescence is associated with greater neural reward sensitivity in adulthood above the influence of parental SES or current income and not mediated through impulsivity and externalizing behaviors. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  13. Dynamic mesolimbic dopamine signaling during action sequence learning and expectation violation

    Science.gov (United States)

    Collins, Anne L.; Greenfield, Venuz Y.; Bye, Jeffrey K.; Linker, Kay E.; Wang, Alice S.; Wassum, Kate M.

    2016-01-01

    Prolonged mesolimbic dopamine concentration changes have been detected during spatial navigation, but little is known about the conditions that engender this signaling profile or how it develops with learning. To address this, we monitored dopamine concentration changes in the nucleus accumbens core of rats throughout acquisition and performance of an instrumental action sequence task. Prolonged dopamine concentration changes were detected that ramped up as rats executed each action sequence and declined after earned reward collection. With learning, dopamine concentration began to rise increasingly earlier in the execution of the sequence and ultimately backpropagated away from stereotyped sequence actions, becoming only transiently elevated by the most distal and unexpected reward predictor. Action sequence-related dopamine signaling was reactivated in well-trained rats if they became disengaged in the task and in response to an unexpected change in the value, but not identity of the earned reward. Throughout training and test, dopamine signaling correlated with sequence performance. These results suggest that action sequences can engender a prolonged mode of dopamine signaling in the nucleus accumbens core and that such signaling relates to elements of the motivation underlying sequence execution and is dynamic with learning, overtraining and violations in reward expectation. PMID:26869075

  14. Prolactinergic and dopaminergic mechanisms underlying sexual arousal and orgasm in humans.

    Science.gov (United States)

    Krüger, Tillmann H C; Hartmann, Uwe; Schedlowski, Manfred

    2005-06-01

    Dopaminergic mechanisms play a major role in modulating sexual behavior in humans and animals. Animal data demonstrate important interactions between the dopaminergic and prolactinergic system. As recently demonstrated, dopamine agonists have facilitatory properties for penile erection but may also enhance sexual drive and orgasmic quality. In contrast, chronic elevations of prolactin inhibit appetitive as well as consummatory parameters of sexual behavior. Recent human studies show a marked increase in prolactin after orgasm in males and females. Concerning the biological relevance of acute prolactin alterations after orgasm, prolactin might serve as a neuroendocrine reproductive reflex for peripheral reproductive organs. Alternatively, prolactin may feedback to dopaminergic neurons in the central nervous system and thereby modulate sexual drive and satiation. Here, we provide a brief overview of the physiology of dopamine and prolactin in regulating sexual behavior. In addition, recent experimental and clinical evidence for a postulated feedback mechanism for prolactin and its implications for orgasmic disorders are discussed.

  15. The atypical homeoprotein Pbx1a participates in the axonal pathfinding of mesencephalic dopaminergic neurons

    Directory of Open Access Journals (Sweden)

    Sgadò Paola

    2012-07-01

    Full Text Available Abstract Background The pre B-cell leukemia transcription factor 1 (Pbx1 genes belong to the three amino acid loop extension family of homeodomain proteins that form hetero-oligomeric complexes with other homeodomain transcription factors, thereby modulating target specificity, DNA binding affinity and transcriptional activity of their molecular associates. Results Here, we provide evidence that Pbx1 is expressed in mesencephalic dopaminergic neurons from embryonic day 11 into adulthood and determines some of the cellular properties of this neuronal population. In Pbx1-deficient mice, the mesencephalic dopaminergic axons stall during mid-gestation at the border between di- and telencephalon before entering the ganglionic eminence, leading to a loose organization of the axonal bundle and partial misrouting. In Pbx1-deficient dopaminergic neurons, the high affinity netrin-1 receptor, deleted in colon cancer (DCC, is down-regulated. Interestingly, we found several conserved Pbx1 binding sites in the first intron of DCC, suggesting a direct regulation of DCC transcription by Pbx1. Conclusions The expression of Pbx1 in dopaminergic neurons and its regulation of DCC expression make it an important player in defining the axonal guidance of the midbrain dopaminergic neurons, with possible implications for the normal physiology of the nigro-striatal system as well as processes related to the degeneration of neurons during the course of Parkinson’s disease.

  16. Endogenous dopamine is involved in the herbicide paraquat-induced dopaminergic cell death.

    Science.gov (United States)

    Izumi, Yasuhiko; Ezumi, Masayuki; Takada-Takatori, Yuki; Akaike, Akinori; Kume, Toshiaki

    2014-06-01

    The herbicide paraquat is an environmental factor that may be involved in the etiology of Parkinson's disease (PD). Systemic exposure of mice to paraquat causes a selective loss of dopaminergic neurons in the substantia nigra pars compacta, although paraquat is not selectively incorporated in dopaminergic neurons. Here, we report a contribution of endogenous dopamine to paraquat-induced dopaminergic cell death. Exposure of PC12 cells to paraquat (50μM) caused delayed toxicity from 36 h onward. A decline in intracellular dopamine content achieved by inhibiting tyrosine hydroxylase (TH), an enzyme for dopamine synthesis, conferred resistance to paraquat toxicity on dopaminergic cells. Paraquat increased the levels of cytosolic and vesicular dopamine, accompanied by transiently increased TH activity. Quinone derived from cytosolic dopamine conjugates with cysteine residues in functional proteins to form quinoproteins. Formation of quinoprotein was transiently increased early during exposure to paraquat. Furthermore, pretreatment with ascorbic acid, which suppressed the elevations of intracellular dopamine and quinoprotein, almost completely prevented paraquat toxicity. These results suggest that the elevation of cytosolic dopamine induced by paraquat participates in the vulnerability of dopaminergic cells to delayed toxicity through the formation of quinoproteins.

  17. Creative cognition and dopaminergic modulation of fronto-striatal networks: Integrative review and research agenda.

    Science.gov (United States)

    Boot, Nathalie; Baas, Matthijs; van Gaal, Simon; Cools, Roshan; De Dreu, Carsten K W

    2017-07-01

    Creative cognition is key to human functioning yet the underlying neurobiological mechanisms are sparsely addressed and poorly understood. Here we address the possibility that creative cognition is a function of dopaminergic modulation in fronto-striatal brain circuitries. It is proposed that (i) creative cognition benefits from both flexible and persistent processing, (ii) striatal dopamine and the integrity of the nigrostriatal dopaminergic pathway is associated with flexible processing, while (iii) prefrontal dopamine and the integrity of the mesocortical dopaminergic pathway is associated with persistent processing. We examine this possibility in light of studies linking creative ideation, divergent thinking, and creative problem-solving to polymorphisms in dopamine receptor genes, indirect markers and manipulations of the dopaminergic system, and clinical populations with dysregulated dopaminergic activity. Combined, studies suggest a functional differentiation between striatal and prefrontal dopamine: moderate (but not low or high) levels of striatal dopamine benefit creative cognition by facilitating flexible processes, and moderate (but not low or high) levels of prefrontal dopamine enable persistence-driven creativity. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Prior stimulation of the endocannabinoid system prevents methamphetamine-induced dopaminergic neurotoxicity in the striatum through activation of CB2 receptors.

    Science.gov (United States)

    Nader, Joëlle; Rapino, Cinzia; Gennequin, Benjamin; Chavant, Francois; Francheteau, Maureen; Makriyannis, Alexandros; Duranti, Andrea; Maccarrone, Mauro; Solinas, Marcello; Thiriet, Nathalie

    2014-12-01

    Methamphetamine toxicity is associated with cell death and loss of dopamine neuron terminals in the striatum similar to what is found in some neurodegenerative diseases. Conversely, the endocannabinoid system (ECS) has been suggested to be neuroprotective in the brain, and new pharmacological tools have been developed to increase their endogenous tone. In this study, we evaluated whether ECS stimulation could reduce the neurotoxicity of high doses of methamphetamine on the dopamine system. We found that methamphetamine alters the levels of the major endocannabinoids, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) in the striatum, suggesting that the ECS participates in the brain responses to methamphetamine. Δ(9)-tetrahydrocannabinol (THC), a cannabis-derived agonist of both CB1 and CB2 cannabinoid receptors, or inhibitors of the main enzymes responsible for the degradation of AEA and 2-AG (URB597 and JZL184, respectively), blunted the decrease in striatal protein levels of tyrosine hydroxylase induced by methamphetamine. In addition, antagonists of CB2, but not of CB1, blocked the preventive effects of URB597 and JZL184, suggesting that only the former receptor subtype is engaged in neuroprotection exerted by ECS stimulation. Finally, we found that methamphetamine increases striatal levels of the cytokine tumor necrosis factor alpha, an effect that was blocked by ECS stimulation. Altogether, our results indicate that stimulation of ECS prior to the administration of an overdose of methamphetamine considerably reduces the neurotoxicity of the drug through CB2 receptor activation and highlight a protective function for the ECS against the toxicity induced by drugs and other external insults to the brain. This article is part of the Special Issue entitled 'CNS Stimulants'. Copyright © 2014 Elsevier Ltd. All rights reserved.

  19. New recreational drug 1-phenyl-2-(1-pyrrolidinyl)-1-pentanone (alpha-PVP) activates central nervous system via dopaminergic neuron.

    Science.gov (United States)

    Kaizaki, Asuka; Tanaka, Sachiko; Numazawa, Satoshi

    2014-02-01

    1-phenyl-2-(1-pyrrolidinyl)-1-pentanone (α-PVP) is a new designer drug of the cathinone type. People who have taken drugs containing α-PVP or other synthetic cathinone reportedly lose consciousness, develop difficulty breathing, and at worst case, die. However, the mechanism underlying α-PVP-induced neurotoxicity is unknown. The objective of the present study was to investigate the effect of α-PVP on the central nervous system (CNS) and compare its neurotoxicity with that of methamphetamine (METH) in mice. Balb/c male mice (8 weeks old) were orally administered α-PVP (25 mg/kg) or METH (5 mg/kg). α-PVP induced a significant increase in locomotor activity, which occurred earlier than locomotor activity induced by METH. This increase was inhibited by the D1 receptor antagonist SCH23990 (50 µg/kg, i.p.) and the D2 receptor antagonist sulpiride (50 mg/kg, i.m.). The extracellular concentration of dopamine (DA) in the striatum, determined by in vivo microdialysis increased immediately after α-PVP administration. These results suggest that α-PVP stimulates DA release, causing an increase in locomotor activity, and that this stimulatory effect of α-PVP on CNS is mediated, at least in part, by the D1 and D2 receptors.

  20. A translational systems biology approach in both animals and humans identifies a functionally related module of accumbal genes involved in the regulation of reward processing and binge drinking in males.

    Science.gov (United States)

    Stacey, David; Lourdusamy, Anbarasu; Ruggeri, Barbara; Maroteaux, Matthieu; Jia, Tianye; Cattrell, Anna; Nymberg, Charlotte; Banaschewski, Tobias; Bhattacharyya, Sohinee; Band, Hamid; Barker, Gareth; Bokde, Arun; Buchel, Christian; Carvalho, Fabiana; Conrod, Patricia; Desrivieres, Sylvane; Easton, Alanna; Fauth-Buehler, Mira; Fernandez-Medarde, Alberto; Flor, Herta; Frouin, Vincent; Gallinat, Jurgen; Garavanh, Hugh; Heinz, Andreas; Ittermann, Bernd; Lathrop, Mark; Lawrence, Claire; Loth, Eva; Mann, Karl; Martinot, Jean-Luc; Nees, Frauke; Paus, Tomas; Pausova, Zdenka; Rietschel, Marcella; Rotter, Andrea; Santos, Eugenio; Smolka, Michael; Sommer, Wolfgang; Mameli, Manuel; Spanagel, Rainer; Girault, Jean-Antoine; Mueller, Christian; Schumann, Gunter

    2016-04-01

    The mesolimbic dopamine system, composed primarily of dopaminergic neurons in the ventral tegmental area that project to striatal structures, is considered to be the key mediator of reinforcement-related mechanisms in the brain. Prompted by a genome-wide association meta-analysis implicating the Ras-specific guanine nucleotide-releasing factor 2 (RASGRF2) gene in the regulation of alcohol intake in men, we have recently shown that male Rasgrf2(-/-) mice exhibit reduced ethanol intake and preference accompanied by a perturbed mesolimbic dopamine system. We therefore propose that these mice represent a valid model to further elucidate the precise genes and mechanisms regulating mesolimbic dopamine functioning. Transcriptomic data from the nucleus accumbens (NAcc) of male Rasgrf2(-/-) mice and wild-type controls were analyzed by weighted gene coexpression network analysis (WGCNA). We performed follow-up genetic association tests in humans using a sample of male adolescents from the IMAGEN study characterized for binge drinking (n = 905) and ventral striatal activation during an fMRI reward task (n = 608). The WGCNA analyses using accumbal transcriptomic data revealed 37 distinct "modules," or functionally related groups of genes. Two of these modules were significantly associated with Rasgrf2 knockout status: M5 (p < 0.001) and M6 (p < 0.001). In follow-up translational analyses we found that human orthologues for the M5 module were significantly (p < 0.01) enriched with genetic association signals for binge drinking in male adolescents. Furthermore, the most significant locus, originating from the EH-domain containing 4 (EHD4) gene (p < 0.001), was also significantly associated with altered ventral striatal activity in male adolescents performing an fMRI reward task (pempirical < 0.001). It was not possible to determine the extent to which the M5 module was dysregulated in Rasgrf2(-/-) mice by perturbed mesolimbic dopamine signalling or by the loss of Rasgrf2

  1. Functional properties and synaptic integration of genetically labelled dopaminergic neurons in intrastriatal grafts

    DEFF Research Database (Denmark)

    Sørensen, Andreas Toft; Thompson, Lachlan; Kirik, Deniz

    2005-01-01

    , the electrophysiological properties grafted cells need to have in order to induce substantial functional recovery are poorly defined. It has not been possible to prospectively identify and record from dopaminergic neurons in fetal transplants. Here we used transgenic mice expressing green fluorescent protein under control...... of the rat tyrosine hydroxylase promoter for whole-cell patch-clamp recordings of endogenous and grafted dopaminergic neurons. We transplanted ventral mesencephalic tissue from E12.5 transgenic mice into striatum of neonatal rats with or without lesions of the nigrostriatal dopamine system. The transplanted...... in the dopamine-depleted striatum than of those in the intact striatum. Our findings define specific electrophysiological characteristics of transplanted fetal dopaminergic neurons, and we provide the first direct evidence of functional synaptic integration of these neurons into host neural circuitries....

  2. Expression and function of nr4a2, lmx1b, and pitx3 in zebrafish dopaminergic and noradrenergic neuronal development

    Directory of Open Access Journals (Sweden)

    Willaredt Marc

    2007-12-01

    Full Text Available Abstract Background: Dopaminergic neurons form in diverse areas of the vertebrate di- and mesencephalon to constitute several major neuromodulatory systems. While much is known about mammalian mesencephalic dopaminergic neuron development, little is known about the specification of the diencephalic dopaminergic groups. The transcription factors Pitx3 and Lmx1b play an important role in mammalian mesencephalic dopaminergic specification, and Nurr1/Nr4a2 has been shown to contribute to specification of the dopaminergic neurotransmitter phenotype. We use zebrafish to analyze potentially evolutionarily conserved roles of these transcription factors in a vertebrate brain that lacks a mesencephalic dopaminergic system, but has an ascending dopaminergic system in the ventral diencephalon. Results: We use a combination of fluorescent in situ hybridization and immunohistochemistry to determine whether nr4a2, lmx1b, and pitx3 genes are expressed in mature dopaminergic neurons or in potential precursor populations. We identify a second nr4a2 paralogue, nr4a2a, and find it co-expressed with Tyrosine hydroxylase in preoptic, pretectal and retinal amacrine dopaminergic neurons, while nr4a2b is only expressed in preoptic and retinal dopaminergic neurons. Both zebrafish nr4a2 paralogues are not expressed in ventral diencephalic dopaminergic neurons with ascending projections. Combined morpholino antisense oligo mediated knock-down of both nr4a2a and nr4a2b transcripts reveals that all zebrafish dopaminergic neurons expressing nr4a2a depend on Nr4a2 activity for tyrosine hydroxylase and dopamine transporter expression. Zebrafish lmx1b.1 is expressed in noradrenergic neurons of the locus coeruleus and medulla oblongata, but knock-down reveals that it is specifically required for tyrosine hydroxylase expression only in the medulla oblongata area postrema noradrenergic neurons. Both lmx1b genes and pitx3 are not expressed in dopaminergic neurons, but in a

  3. Distribution of serotonergic and dopaminergic nerve fibers in the salivary gland complex of the cockroach Periplaneta americana

    Directory of Open Access Journals (Sweden)

    Kühnel Dana

    2002-06-01

    Full Text Available Abstract Background The cockroach salivary gland consists of secretory acini with peripheral ion-transporting cells and central protein-producing cells, an extensive duct system, and a pair of reservoirs. Salivation is controled by serotonergic and dopaminergic innervation. Serotonin stimulates the secretion of a protein-rich saliva, dopamine causes the production of a saliva without proteins. These findings suggest a model in which serotonin acts on the central cells and possibly other cell types, and dopamine acts selectively on the ion-transporting cells. To examine this model, we have analyzed the spatial relationship of dopaminergic and serotonergic nerve fibers to the various cell types. Results The acinar tissue is entangled in a meshwork of serotonergic and dopaminergic varicose fibers. Dopaminergic fibers reside only at the surface of the acini next to the peripheral cells. Serotonergic fibers invade the acini and form a dense network between central cells. Salivary duct segments close to the acini are locally associated with dopaminergic and serotonergic fibers, whereas duct segments further downstream have only dopaminergic fibers on their surface and within the epithelium. In addition, the reservoirs have both a dopaminergic and a serotonergic innervation. Conclusion Our results suggest that dopamine is released on the acinar surface, close to peripheral cells, and along the entire duct system. Serotonin is probably released close to peripheral and central cells, and at initial segments of the duct system. Moreover, the presence of serotonergic and dopaminergic fiber terminals on the reservoir indicates that the functions of this structure are also regulated by dopamine and serotonin.

  4. Dopaminergic control of anxiety in young and aged zebrafish.

    Science.gov (United States)

    Kacprzak, Victoria; Patel, Neil A; Riley, Elizabeth; Yu, Lili; Yeh, Jing-Ruey J; Zhdanova, Irina V

    2017-06-01

    Changes in the expression of the dopamine transporter (DAT), or the sensitivity of dopamine receptors, are associated with aging and substance abuse and may underlie some of the symptoms common to both conditions. In this study, we explored the role of the dopaminergic system in the anxiogenic effects of aging and acute cocaine exposure by comparing the behavioral phenotypes of wild type (WT) and DAT knockout zebrafish (DAT-KO) of different ages. To determine the involvement of specific dopamine receptors in anxiety states, antagonists to D1 (SCH23390) and D2/D3 (sulpiride) were employed. We established that DAT-KO results in a chronic anxiety-like state, seen as an increase in bottom-dwelling and thigmotaxis. Similar effects were produced by aging and acute cocaine administration, both leading to reduction in DAT mRNA abundance (qPCR). Inhibition of D1 activity counteracted the anxiety-like effects associated with DAT deficit, independent of its origin. Inhibition of D2/D3 receptors reduced anxiety in young DAT-KO, and enhanced the anxiogenic effects of cocaine in WT, but did not affect aged WT or DAT-KO fish. These findings provide new evidence that the dopaminergic system plays a critical role in anxiety-like states, and suggest that adult zebrafish provide a sensitive diurnal vertebrate model for elucidating the molecular mechanisms of anxiety and a platform for anxiolytic drug screens. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Impaired cross-talk between mesolimbic food reward processing and metabolic signaling predicts body mass index

    Directory of Open Access Journals (Sweden)

    Joe J Simon

    2014-10-01

    Full Text Available The anticipation of the pleasure derived from food intake drives the motivation to eat, and hence facilitate overconsumption of food which ultimately results in obesity. Brain imaging studies provide evidence that mesolimbic brain regions underlie both general as well as food related anticipatory reward processing. In light of this knowledge, the present study examined the neural responsiveness of the ventral striatum in participants with a broad BMI spectrum. The study differentiated between general (i.e. monetary and food related anticipatory reward processing. We recruited a sample of volunteers with greatly varying body weights, ranging from a low BMI (below 20 kg/m² over a normal (20 to 25 kg/m² and overweight (25 to 30 kg/m² BMI, to class I (30 to 35 kg/m² and class II (35 to 40 kg/m² obesity. A total of 24 participants underwent functional magnetic resonance imaging whilst performing both a food and monetary incentive delay task, which allows to measure neural activation during the anticipation of rewards. After the presentation of a cue indicating the amount of food or money to be won, participants had to react correctly in order to earn snack points or money coins which could then be exchanged for real food or money, respectively, at the end of the experiment. During the anticipation of both types of rewards, participants displayed activity in the ventral striatum, a region that plays a pivotal role in the anticipation of rewards. Additionally, we observed that specifically anticipatory food reward processing predicted the individual BMI (current and maximum lifetime. This relation was found to be mediated by impaired hormonal satiety signaling, i.e. increased leptin levels and insulin resistance. These findings suggest that heightened food reward motivation contributes to obesity through impaired metabolic signaling.

  6. Habituation of the responsiveness of mesolimbic and mesocortical dopamine transmission to taste stimuli

    Directory of Open Access Journals (Sweden)

    Maria Antonietta eDe Luca

    2014-03-01

    Full Text Available The presentation of novel, remarkable and unpredictable tastes increases dopamine (DA transmission in different DA terminal areas such as the nucleus accumbens (NAc shell and core and the medial prefrontal cortex (mPFC, as estimated by in vivo microdialysis studies in rats. This effect undergoes adaptive regulation, as there is a decrease in DA responsiveness after a single pre-exposure to the same taste. This phenomenon termed habituation has been described as peculiar to NAc shell but not to NAc core and mPFC DA transmission. On this basis, it has been proposed that mPFC DA codes for generic motivational stimulus value and, together with the NAc core DA, is more consistent with a role in the expression of motivation. Conversely, NAc shell DA is specifically activated by unfamiliar or novel taste stimuli and rewards, and might serve to associate the sensory properties of the rewarding stimulus with its biological effect. Notably, habituation of the DA response to intraoral sweet or bitter tastes is not associated with a reduction in hedonic or aversive taste reactions, thus indicating that habituation is unrelated to satiety-induced hedonic devaluation and that it is not influenced by DA alteration or depletion. This mini-review describes specific circumstances of disruption of the habituation of NAc shell DA responsiveness (De Luca et al., 2011; Bimpisidis et al., 2013. In particular, we observed an abolishment of NAc shell DA habituation to chocolate (sweet taste by morphine sensitization and mPFC 6-OHDA lesion. Moreover, morphine sensitization was associated with the appearance of the habituation in the mPFC, and with an increased and delayed response of NAc core DA to taste in naive rats, but not in pre-exposed animals. The results here described shed light on the mechanism of the habituation phenomenon of mesolimbic and mesocortical DA transmission, and its putative role as a marker of cortical dysfunction in specific conditions such as

  7. Necrostatin-1 protection of dopaminergic neurons

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    Jing-ru Wu

    2015-01-01

    Full Text Available Necroptosis is characterized by programmed necrotic cell death and autophagic activation and might be involved in the death process of dopaminergic neurons in Parkinson′s disease. We hypothesized that necrostatin-1 could block necroptosis and give protection to dopaminergic neurons. There is likely to be crosstalk between necroptosis and other cell death pathways, such as apoptosis and autophagy. PC12 cells were pretreated with necroststin-1 1 hour before exposure to 6-hydroxydopamine. We examined cell viability, mitochondrial membrane potential and expression patterns of apoptotic and necroptotic death signaling proteins. The results showed that the autophagy/lysosomal pathway is involved in the 6-hydroxydopamine-induced death process of PC12 cells. Mitochondrial disability induced overactive autophagy, increased cathepsin B expression, and diminished Bcl-2 expression. Necrostatin-1 within a certain concentration range (5-30 μM elevated the viability of PC12 cells, stabilized mitochondrial membrane potential, inhibited excessive autophagy, reduced the expression of LC3-II and cathepsin B, and increased Bcl-2 expression. These findings suggest that necrostatin-1 exerted a protective effect against injury on dopaminergic neurons. Necrostatin-1 interacts with the apoptosis signaling pathway during this process. This pathway could be a new neuroprotective and therapeutic target in Parkinson′s disease.

  8. Ketogenic diet alters dopaminergic activity in the mouse cortex.

    Science.gov (United States)

    Church, William H; Adams, Ryan E; Wyss, Livia S

    2014-06-13

    The present study was conducted to determine if the ketogenic diet altered basal levels of monoamine neurotransmitters in mice. The catecholamines dopamine (DA) and norephinephrine (NE) and the indolamine serotonin (5HT) were quantified postmortem in six different brain regions of adult mice fed a ketogenic diet for 3 weeks. The dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and the serotonin metabolite 5-hydroxyindole acetic acid (5HIAA) were also measured. Tissue punches were collected bilaterally from the motor cortex, somatosensory cortex, nucleus accumbens, anterior caudate-putamen, posterior caudate-putamen and the midbrain. Dopaminergic activity, as measured by the dopamine metabolites to dopamine content ratio - ([DOPAC]+[HVA])/[DA] - was significantly increased in the motor and somatosensory cortex regions of mice fed the ketogenic diet when compared to those same areas in brains of mice fed a normal diet. These results indicate that the ketogenic diet alters the activity of the meso-cortical dopaminergic system, which may contribute to the diet's therapeutic effect in reducing epileptic seizure activity. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  9. Orexinergic input to dopaminergic neurons of the human ventral tegmental area.

    Directory of Open Access Journals (Sweden)

    Erik Hrabovszky

    Full Text Available The mesolimbic reward pathway arising from dopaminergic (DA neurons of the ventral tegmental area (VTA has been strongly implicated in reward processing and drug abuse. In rodents, behaviors associated with this projection are profoundly influenced by an orexinergic input from the lateral hypothalamus to the VTA. Because the existence and significance of an analogous orexigenic regulatory mechanism acting in the human VTA have been elusive, here we addressed the possibility that orexinergic neurons provide direct input to DA neurons of the human VTA. Dual-label immunohistochemistry was used and orexinergic projections to the VTA and to DA neurons of the neighboring substantia nigra (SN were analyzed comparatively in adult male humans and rats. Orexin B-immunoreactive (IR axons apposed to tyrosine hydroxylase (TH-IR DA and to non-DA neurons were scarce in the VTA and SN of both species. In the VTA, 15.0±2.8% of TH-IR perikarya in humans and 3.2±0.3% in rats received orexin B-IR afferent contacts. On average, 0.24±0.05 and 0.05±0.005 orexinergic appositions per TH-IR perikaryon were detected in humans and rats, respectively. The majority (86-88% of randomly encountered orexinergic contacts targeted the dendritic compartment of DA neurons. Finally, DA neurons of the SN also received orexinergic innervation in both species. Based on the observation of five times heavier orexinergic input to TH-IR neurons of the human, compared with the rat, VTA, we propose that orexinergic mechanism acting in the VTA may play just as important roles in reward processing and drug abuse in humans, as already established well in rodents.

  10. Dopaminergic and serotonergic agents : synthesis and pharmacological evaluation of 2-aminotetralins and related tricyclic compounds

    NARCIS (Netherlands)

    Dijkstra, Durk

    1992-01-01

    The main interest of our research group is the medicinal chemisq of agonists and antagonists of the neurotransmitters dopamine (DA) and serotonine (5-HT) and their modes of pharmacological interaction with dopaminergic and serotonergic neurotransmitter systems in the brain. The group is currently

  11. Phasic Dopaminergic Signaling and the Presymptomatic Phase of Parkinson's Disease

    National Research Council Canada - National Science Library

    Garris, Paul A; Schallert, Tim; Heldenreich, Byron A

    2005-01-01

    .... The overall hypothesis is that, in rats with partial dopamine lesions mimicking the preclinical phase of Parkinson's disease, deficits in phasic dopaminergic signaling are associated with behavioral deficits...

  12. Sexually dimorphic activation of dopaminergic areas depends on affiliation during courtship and pair formation

    Directory of Open Access Journals (Sweden)

    Mai eIwasaki

    2014-06-01

    Full Text Available For many species, dyadic interaction during courtship and pair bonding engage intense emotional states that control approach or avoidance behavior. Previous studies have shown that one component of a common social brain network (SBN, dopaminergic areas, are highly engaged during male songbird courtship of females. We tested whether the level of activity in dopaminergic systems of both females and males during courtship is related to their level of affiliation. In order to objectively quantify affiliative behaviors, we developed a system for tracking the position of both birds during free interaction sessions. During a third successive daily interaction session, there was a range of levels of affiliation among bird pairs, as quantified by several position and movement parameters. Because both positive and negative social interactions were present, we chose to characterize affiliation strength by pair valence. As a potential neural system involved in regulating pair valence, the level of activity of the dopaminergic group A11 (within the central gray was selectively reduced in females of positive valence pairs. Further, activation of non-dopaminergic neurons in VTA was negatively related to valence, with this relationship strongest in ventral VTA of females. Together, these results suggest that inhibition of fear or avoidance networks may be associated with development of close affiliation, and highlight the importance of negative as well as positive emotional states in the process of courtship, and in development of long-lasting social bonds.

  13. Maternal "junk-food" feeding of rat dams alters food choices and development of the mesolimbic reward pathway in the offspring.

    Science.gov (United States)

    Ong, Z Y; Muhlhausler, B S

    2011-07-01

    Individuals exposed to high-fat, high-sugar diets before birth have an increased risk of obesity in later life. Recent studies have shown that these offspring exhibit increased preference for fat, leading to suggestions that perinatal exposure to high-fat, high-sugar foods results in permanent changes within the central reward system that increase the subsequent drive to overconsume palatable foods. The present study has determined the effect of a maternal "junk-food" diet on the expression of key components of the mesolimbic reward pathway in the offspring of rat dams at 6 wk and 3 mo of age. We show that offspring of junk-food-fed (JF) dams exhibit higher fat intake from weaning until at least 3 mo of age (males: 16 ± 0.6 vs. 11 ± 0.8 g/kg/d; females: 19 ± 1.3 vs. 13 ± 0.4 g/kg/d; Pjunk-food intake in postnatal life.

  14. The mesolimbic system and eating addiction: what sugar does and does not do

    NARCIS (Netherlands)

    De Jong, Johannes; Adan, R.A.H.; Vanderschuren, L.J.M.J.

    2016-01-01

    Obesity and obesity-related disorders are a major threat to public health. It has been suggested that food addiction is a valid clinical concept and that food addiction is a contributing factor to the obesity epidemic. Research involving restricted access ‘binge’ diets has shown that rodents will

  15. The mesolimbic system and eating addiction : What sugar does and does not do

    NARCIS (Netherlands)

    De Jong, Johannes W.; Vanderschuren, Louk J M J; Adan, Roger A H

    2016-01-01

    Obesity and obesity-related disorders are a major threat to public health. It has been suggested that food addiction is a valid clinical concept and that food addiction is a contributing factor to the obesity epidemic. Research involving restricted access 'binge' diets has shown that rodents will

  16. A Tyrosine-Hydroxylase Characterization of Dopaminergic Neurons in the Honey Bee Brain

    Directory of Open Access Journals (Sweden)

    Stevanus R. Tedjakumala

    2017-07-01

    Full Text Available Dopamine (DA plays a fundamental role in insect behavior as it acts both as a general modulator of behavior and as a value system in associative learning where it mediates the reinforcing properties of unconditioned stimuli (US. Here we aimed at characterizing the dopaminergic neurons in the central nervous system of the honey bee, an insect that serves as an established model for the study of learning and memory. We used tyrosine hydroxylase (TH immunoreactivity (ir to ensure that the neurons detected synthesize DA endogenously. We found three main dopaminergic clusters, C1–C3, which had been previously described; the C1 cluster is located in a small region adjacent to the esophagus (ES and the antennal lobe (AL; the C2 cluster is situated above the C1 cluster, between the AL and the vertical lobe (VL of the mushroom body (MB; the C3 cluster is located below the calyces (CA of the MB. In addition, we found a novel dopaminergic cluster, C4, located above the dorsomedial border of the lobula, which innervates the visual neuropils of the bee brain. Additional smaller processes and clusters were found and are described. The profuse dopaminergic innervation of the entire bee brain and the specific connectivity of DA neurons, with visual, olfactory and gustatory circuits, provide a foundation for a deeper understanding of how these sensory modules are modulated by DA, and the DA-dependent value-based associations that occur during associative learning.

  17. Recent Advances in Imaging of Dopaminergic Neurons for Evaluation of Neuropsychiatric Disorders

    Directory of Open Access Journals (Sweden)

    Lie-Hang Shen

    2012-01-01

    Full Text Available Dopamine is the most intensely studied monoaminergic neurotransmitter. Dopaminergic neurotransmission plays an important role in regulating several aspects of basic brain function, including motor, behavior, motivation, and working memory. To date, there are numerous positron emission tomography (PET and single photon emission computed tomography (SPECT radiotracers available for targeting different steps in the process of dopaminergic neurotransmission, which permits us to quantify dopaminergic activity in the living human brain. Degeneration of the nigrostriatal dopamine system causes Parkinson’s disease (PD and related Parkinsonism. Dopamine is the neurotransmitter that has been classically associated with the reinforcing effects of drug abuse. Abnormalities within the dopamine system in the brain are involved in the pathophysiology of attention deficit hyperactivity disorder (ADHD. Dopamine receptors play an important role in schizophrenia and the effect of neuroleptics is through blockage of dopamine D2 receptors. This review will concentrate on the radiotracers that have been developed for imaging dopaminergic neurons, describe the clinical aspects in the assessment of neuropsychiatric disorders, and suggest future directions in the diagnosis and management of such disorders.

  18. Preserved dopaminergic homeostasis and dopamine-related behaviour in hemizygous TH-Cre mice.

    Science.gov (United States)

    Runegaard, Annika H; Jensen, Kathrine L; Fitzpatrick, Ciarán M; Dencker, Ditte; Weikop, Pia; Gether, Ulrik; Rickhag, Mattias

    2017-01-01

    Cre-driver mouse lines have been extensively used as genetic tools to target and manipulate genetically defined neuronal populations by expression of Cre recombinase under selected gene promoters. This approach has greatly advanced neuroscience but interpretations are hampered by the fact that most Cre-driver lines have not been thoroughly characterized. Thus, a phenotypic characterization is of major importance to reveal potential aberrant phenotypes prior to implementation and usage to selectively inactivate or induce transgene expression. Here, we present a biochemical and behavioural assessment of the dopaminergic system in hemizygous tyrosine hydroxylase (TH)-Cre mice in comparison to wild-type (WT) controls. Our data show that TH-Cre mice display preserved dopaminergic homeostasis with unaltered levels of TH and dopamine as well as unaffected dopamine turnover in striatum. TH-Cre mice also show preserved dopamine transporter expression and function supporting sustained dopaminergic transmission. In addition, TH-Cre mice demonstrate normal responses in basic behavioural paradigms related to dopaminergic signalling including locomotor activity, reward preference and anxiolytic behaviour. Our results suggest that TH-Cre mice represent a valid tool to study the dopamine system, though careful characterization must always be performed to prevent false interpretations following Cre-dependent transgene expression and manipulation of selected neuronal pathways. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  19. Dopaminergic modulation of the spectral characteristics in the rat brain oscillatory activity

    International Nuclear Information System (INIS)

    Valencia, Miguel; López-Azcárate, Jon; Nicolás, María Jesús; Alegre, Manuel; Artieda, Julio

    2012-01-01

    Highlights: ► The oscillatory activity recorded at different locations of the rat brain present a power law characteristic (PLC). ► Dopaminergic drugs are able to modify the power law spectral characteristic of the oscillatory activity. ► Drugs with opposite effects over the dopaminergic system (agonists/antagonists), induce opposite changes in the PLC. ► There is a fulcrum point for the modulation of the PLC around 20 Hz. ► The brain operates in a state of self-organized criticality (SOC) sensitive to dopaminergic modulation. - Abstract: Oscillatory activity can be widely recorded in the brain. It has been demonstrated to play an important role not only in the physiology of movement, perception and cognition, but also in the pathophysiology of a variety of diseases. In frequency domain, neurophysiological recordings show a power spectrum (PSD) following a log (PSD) ∝ log (f) −β , that reveals an intrinsic feature of many complex systems in nature: the presence of a scale-free dynamics characterized by a power-law component (PLC). Here we analyzed the influence of dopaminergic drugs over the PLC of the oscillatory activity recorded from different locations of the rat brain. Dopamine (DA) is a neurotransmitter that is required for a number of physiological functions like normal feeding, locomotion, posturing, grooming and reaction time. Alterations in the dopaminergic system cause vast effects in the dynamics of the brain activity, that may be crucial in the pathophysiology of neurological (like Parkinson’s disease) or psychiatric (like schizophrenia) diseases. Our results show that drugs with opposite effects over the dopaminergic system, induce opposite changes in the characteristics of the PLC: DA agonists/antagonists cause the PLC to swing around a fulcrum point in the range of 20 Hz. Changes in the harmonic component of the spectrum were also detected. However, differences between recordings are better explained by the modulation of the PLC

  20. The role of the MYD88-dependent pathway in MPTP-induced brain dopaminergic degeneration

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    Calon Frédéric

    2011-10-01

    Full Text Available Abstract Background Mounting evidence supports a significant role of inflammation in Parkinson's disease (PD pathophysiology, with several inflammatory pathways being suggested as playing a role in the dopaminergic degeneration seen in humans and animal models of the disease. These include tumor necrosis factor, prostaglandins and oxidative-related stress components. However, the role of innate immunity has not been established in PD. Methods Based on the fact that the myeloid differentiation primary response gene (88 (MyD88 is the most common adaptor protein implicated in toll-like receptor (TLR signaling, critical in the innate immune response, we undertook a study to investigate the potential contribution of this specific pathway to MPTP-induced brain dopaminergic degeneration using MyD88 knock out mice (MyD88-/-, following our observations that the MyD88-dependent pathway was critical for MPTP dopaminergic toxicity in the enteric nervous system. Post-mortem analyses assessing nigrostriatal dopaminergic degeneration and inflammation were performed using HPLC, western blots, autoradiography and immunofluorescence. Results Our results demonstrate that MyD88-/- mice are as vulnerable to MPTP-induced dopamine and DOPAC striatal depletion as wild type mice. Furthermore, MyD88-/- mice show similar striatal dopamine transporter and tyrosine hydroxylase loss, as well as dopaminergic cell loss in the substantia nigra pars compacta in response to MPTP. To evaluate the extent of the inflammatory response created by the MPTP regimen utilized, we further performed bioluminescence imaging using TLR2-luc/gfp transgenic mice and microglial density analysis, which revealed a modest brain microglial response following MPTP. This was accompanied by a significant astrocytic reaction in the striatum, which was of similar magnitude both in wild type and MyD88-/- mice. Conclusions Our results suggest that subacute MPTP-induced dopaminergic degeneration observed in

  1. Subthalamic nucleus stimulation, dopaminergic treatment and impulsivity in Parkinson's disease.

    Science.gov (United States)

    Fluchère, Frédérique; Burle, Borís; Vidal, Franck; van den Wildenberg, Wery; Witjas, Tatiana; Eusebio, Alexandre; Azulay, Jean-Philippe; Hasbroucq, Thierry

    2018-02-16

    Deep brain stimulation of the subthalamic nucleus (STN DBS) is known to increase response speed and lower response accuracy in Parkinson's disease (PD) patients. It has been proposed that this speed-accuracy tradeoff is due to enhanced sensitivity of the motor system to sensory information. An alternative possibility is that this effect is due to weakened suppressive processes. The two alternative interpretations can be tested by analyzing the electromyographic activity (EMG) of the response agonists when the patients perform conflict reaction time tasks. In those tasks, fast subthreshold muscle impulses often occur in the agonist of the incorrect response. These impulses are partial errors that are suppressed before being behaviourally committed. Here we analyzed the EMG of the response agonists recorded while sixteen PD patients performed a Simon task that elicits prepotent response tendencies so as to decipher (i) whether STN DBS affects the expression and/or suppression of subthreshold muscle impulses that are critical for action control and (ii) the interaction between dopaminergic treatment and STN DBS. The patients were tested On and Off STN DBS and On and Off dopaminergic medication in a full factorial design. STN DBS not only impaired the proficiency to suppress subliminal action impulses (p = 0.01) but also favoured the muscular expression of fast incorrect impulses (p<0.001). Dopaminergic treatment only affected the action impulses suppression (p = 0.02) and did not change the effect of STN DBS on impulsive action control. Contrary to a recent proposal, STN DBS impaired rather than improved action control by weakening erroneous impulse suppression, whether the patients were On or Off their usual medication. These findings are discussed in light of a recent proposal (Servant M, White C, Montagnini A, Burle B, 2015) that reconciles partial errors with accumulation-to-bound models of decision making. Our results suggest that medication specifically lowers

  2. Silicon surface biofunctionalization with dopaminergic tetrahydroisoquinoline derivatives

    Energy Technology Data Exchange (ETDEWEB)

    Lucena-Serrano, A.; Lucena-Serrano, C.; Contreras-Cáceres, R.; Díaz, A.; Valpuesta, M. [Dep. Química Orgánica, Facultad de Ciencias, Universidad de Málaga, 29071 Málaga (Spain); Cai, C. [Dep. Chemistry, University of Houston, Houston, TX 77204-5003 (United States); López-Romero, J.M., E-mail: jmromero@uma.es [Dep. Química Orgánica, Facultad de Ciencias, Universidad de Málaga, 29071 Málaga (Spain)

    2016-01-01

    Graphical abstract: - Highlights: • Two dopaminergic tetrahydroisoquinolines (THI) were synthesized. • Vinyl-terminated THI incorporated onto the H−Si(1 1 1) substrates via a hydrosilylation. • The highest yield in coverage was obtained in DMSO, at 4 h of irradiation and 0.1 mbar of vacuum. • Alkynyl-terminated Si surface was produced for incorporation of azide-THI by click reaction. • Best yields on grafted molecule were obtained by click reaction in absence of ascorbic acid. - Abstract: In this work we grafted vinyl- and azido-terminated tetrahydroisoquinolines (compounds 1 and 2, respectively) onto H−Si(1 1 1) silicon wafers obtaining highly stable modified surfaces. A double bond was incorporated into the tetrahydroisoquinoline structure of 1 to be immobilized by a light induced hydrosilylation reaction on hydrogen-terminated Si(1 1 1). The best results were obtained employing a polar solvent (DMSO), rather than a non-polar solvent (toluene). The azide derivative 2 was grafted onto alkenyl-terminated silicon substrates with copper-catalyzed azide-alkyne cycloaddition (CuAAC). Atomic force microscopy (AFM), contact angle goniometry (CA) and X-ray photoemission spectroscopy (XPS) were used to demonstrate the incorporation of 1 and 2 into the surfaces, study the morphology of the modified surfaces and to calculate the yield of grafting and surface coverage. CA measurements showed the increase in the surface hydrophobicity when 1 or 2 were incorporated into the surface. Moreover, compounds 1 and 2 were prepared starting from 1-(p-nitrophenyl)tetrahydroisoquinoline 3 under smooth conditions and in good yields. The structures of 1 and 2 were designed with a reduced A-ring, two substituents at positions C-6 and C-7, an N-methyl group and a phenyl moiety at C-1 in order to provide a high affinity against dopaminergic receptors. Moreover, O-demethylation of 1 was carried out once it was adsorbed onto the surface by treatment with BBr{sub 3}. The method

  3. Manganese nanoparticle activates mitochondrial dependent apoptotic signaling and autophagy in dopaminergic neuronal cells

    Energy Technology Data Exchange (ETDEWEB)

    Afeseh Ngwa, Hilary; Kanthasamy, Arthi [Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, IA 50011 (United States); Gu, Yan; Fang, Ning [Department of Chemistry, Iowa State University, Ames, IA 50011 (United States); Anantharam, Vellareddy [Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, IA 50011 (United States); Kanthasamy, Anumantha G., E-mail: akanthas@iastate.edu [Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, IA 50011 (United States)

    2011-11-15

    activate mitochondrial cell death signaling in dopaminergic neuron. Black-Right-Pointing-Pointer Mn nanoparticles activate caspase-mediated proteolytic cleavage of PKC{delta} cascade. Black-Right-Pointing-Pointer Mn nanoparticles induce autophagy in dopaminergic neuronal cells. Black-Right-Pointing-Pointer Mn nanoparticles induce loss of TH{sup +} neurons in primary mesencephalic cultures. Black-Right-Pointing-Pointer Study emphasizes neurotoxic risks of Mn nanoparticles to nigral dopaminergic system.

  4. Endogenous dynorphin protects against neurotoxin-elicited nigrostriatal dopaminergic neuron damage and motor deficits in mice

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    Wang Qingshan

    2012-06-01

    Full Text Available Abstract Background The striato-nigral projecting pathway contains the highest concentrations of dynorphin in the brain. The functional role of this opioid peptide in the regulation of mesencephalic dopaminergic (DAergic neurons is not clear. We reported previously that exogenous dynorphin exerts potent neuroprotective effects against inflammation-induced dopaminergic neurodegeneration in vitro. The present study was performed to investigate whether endogenous dynorphin has neuroprotective roles in vivo. Methods 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP and methamphetamine (MA, two commonly used neurotoxins in rodent models of Parkinson’s disease, were administered to wild-type (Dyn+/+ and prodynorphin-deficient mice (Dyn−/−. We examined dopaminergic neurotoxicity by using an automated video tracking system, HPLC, immunocytochemistry, and reverse transcription and polymerase chain reaction (RT-PCR. Results Treatment with MPTP resulted in behavioral impairments in both strains. However, these impairments were more pronounced in Dyn-l- than in Dyn+/+. Dyn−/− showed more severe MPTP-induced dopaminergic neuronal loss in the substantia nigra and striatum than Dyn+/+. Similarly, the levels of dopamine and its metabolites in the striatum were depleted to a greater extent in Dyn−/− than in Dyn+/+. Additional mechanistic studies revealed that MPTP treatment caused a higher degree of microglial activation and M1 phenotype differentiation in Dyn−/− than in Dyn+/+. Consistent with these observations, prodynorphin deficiency also exacerbated neurotoxic effects induced by MA, although this effect was less pronounced than that of MPTP. Conclusions The in vivo results presented here extend our previous in vitro findings and further indicate that endogenous dynorphin plays a critical role in protecting dopaminergic neurons through its anti-inflammatory effects.

  5. Influence of Dopaminergic Medication on Conditioned Pain Modulation in Parkinson's Disease Patients.

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    Wiebke Grashorn

    Full Text Available Pain is highly prevalent in patients with Parkinson's disease (PD, but little is known about the underlying pathophysiological mechanisms. The susceptibility to pain is known to depend on ascending and descending pathways. Because parts of the descending pain inhibitory system involve dopaminergic pathways, dysregulations in dopaminergic transmission might contribute to altered pain processing in PD. Deficits in endogenous pain inhibition can be assessed using conditioned pain modulation (CPM paradigms.Applying such a paradigm, we investigated i whether CPM responses differ between PD patients and healthy controls, ii whether they are influenced by dopaminergic medication and iii whether there are effects of disease-specific factors. 25 patients with idiopathic PD and 30 healthy age- and gender-matched controls underwent an established CPM paradigm combining heat pain test stimuli at the forearm and the cold pressor task on the contralateral foot as the conditioning stimulus. PD patients were tested under dopaminergic medication and after at least 12 hours of medication withdrawal.No significant differences between CPM responses of PD patients and healthy controls or between PD patients "on" and "off" medication were found. These findings suggest (i that CPM is insensitive to dopaminergic modulations and (ii that PD is not related to general deficits in descending pain inhibition beyond the known age-related decline. However, at a trend level, we found differences between PD subtypes (akinetic-rigid, tremor-dominant, mixed with the strongest impairment of pain inhibition in the akinetic-rigid subtype.There were no significant differences between CPM responses of patients compared to healthy controls or between patients "on" and "off" medication. Differences between PD subtypes at a trend level point towards different pathophysiological mechanisms underlying the three PD subtypes which warrant further investigation and potentially differential

  6. The roles of the reward system in sleep and dreaming.

    Science.gov (United States)

    Perogamvros, Lampros; Schwartz, Sophie

    2012-09-01

    The mesolimbic dopaminergic system (ML-DA) allows adapted interactions with the environment and is therefore of critical significance for the individual's survival. The ML-DA system is implicated in reward and emotional functions, and it is perturbed in schizophrenia, addiction, and depression. The ML-DA reward system is not only recruited during wakeful behaviors, it is also active during sleep. Here, we introduce the Reward Activation Model (RAM) for sleep and dreaming, according to which activation of the ML-DA reward system during sleep contributes to memory processes, to the regulation of rapid-eye movement (REM) sleep, and to the generation and motivational content of dreams. In particular, the engagement of ML-DA and associated limbic structures prioritizes information with high emotional or motivational relevance for (re)processing during sleep and dreaming. The RAM provides testable predictions and has clinical implications for our understanding of the pathogenesis of major depression and addiction. Copyright © 2012 Elsevier Ltd. All rights reserved.

  7. Dopaminergic innervation of human basal ganglia.

    Science.gov (United States)

    Prensa, L; Cossette, M; Parent, A

    2000-12-01

    This paper summarises the results of some of our recent tyrosine hydroxylase (TH) immunohistochemical studies of the dopaminergic innervation of the human basal ganglia. It also reports new findings on the presence of TH-immunoreactive (ir) neurons in the striatum. Our data show the existence of nigrostriatal TH-ir axons that provide collaterals arborizing in the globus pallidus and subthalamic nucleus. These thin and varicose collaterals emerge from thick and smooth axons that course along the main output pathways of the basal ganglia, including the ansa lenticularis, the lenticular fasciculus and Wilson's pencils. We postulate that this extrastriatal innervation, which allows nigral dopaminergic neurons to directly affect the pallidum and subthalamic nucleus, plays a critical role in the functional organisation of human basal ganglia. The TH-ir fibres that reach the striatum arborize according to a highly heterogeneous pattern. At rostral striatal levels, numerous small TH-poor zones embedded in a TH-rich matrix correspond to calbindin-poor striosomes and calbindin-rich extrastriosomal matrix, respectively. At caudal striatal levels, in contrast, striosomes display a TH immunostaining that is more intense than that of the matrix. A significant number of small, oval, aspiny TH-ir neurons scattered throughout the rostrocaudal extent of the caudate nucleus and putamen, together with a few larger, multipolar, spiny TH-ir neurons lying principally within the ventral portion of the putamen, were disclosed in human. This potential source of intrinsic striatal dopamine might play an important role in the functional organisation of the human striatum, particularly in case of Parkinson's disease.

  8. The significance of the adenosinergic system in morphine dependence

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    Lupina Malgorzata

    2015-09-01

    Full Text Available Addiction is a chronic and recurrent disease. In its pathology, neuroadaptive changes within the dopaminergic pathways inside the mesolimbic system play a predominant role. Of note, the manner in which various neurotransmitters act on their receptors, may modulate the addictive process. Adenosine, an important neuromodulator in the central nervous system, is able to modify the opioid dependence, doing so mainly by its activity on the adenosine A1 and A2A receptors. In the present manuscript, the actual state of knowledge on the relationships between adenosinergic receptors and opioid dependence has been described. Various literature data on the involvement of adenosine ligands, mainly in the signs of morphine withdrawal, as well as morphine-induced sensitization, were also collected. Additionally, in this paper, some important interactions between adenosine and other neurotransmitters (e.g. dopamine, glutamate are described. It is put forward that these connections are the major mechanism of involvement of the adenosinergic system in morphine addiction. The repeatedly confirmed effectiveness of adenosine ligands in morphine dependence, as seen in various experimental protocols, suggests that adenosine ligands may be useful tools for developing new strategies for attenuating morphine dependence.

  9. Dopaminergic and clinical correlates of pathological gambling in Parkinson's disease

    DEFF Research Database (Denmark)

    Callesen, Mette Buhl; Hansen, Kim Vang; Gjedde, Albert

    2013-01-01

    Dopaminergic medication for motor symptoms in Parkinson's disease (PD) recently has been linked with impulse control disorders, including pathological gambling (PG), which affects up to 8% of patients. PG often is considered a behavioral addiction associated with disinhibition, risky decision......-making, and altered striatal dopaminergic neurotransmission. Using [(11)C]raclopride with positron emission tomography, we assessed dopaminergic neurotransmission during Iowa Gambling Task performance. Here we present data from a single patient with PD and concomitant PG. We noted a marked decrease in [(11)C......]raclopride binding in the left ventral striatum upon gambling, indicating a gambling-induced dopamine release. The results imply that PG in PD is associated with a high dose of dopaminergic medication, pronounced motor symptomatology, young age at disease onset, high propensity for sensation seeking, and risky...

  10. In vitro study of dopaminergic central neurons radiosensitivity

    International Nuclear Information System (INIS)

    Multon, E.; Mallat, M.; Cadinu, J.; Court, L.

    1989-01-01

    An embryonic mesencephalic neuronal culture model was used to analyze the radiosensitivity of a dopaminergic neuronal population. Several criteria have allowed to evaluate the effects of a gamma irradiation. In the order of increasing sensitivity, a reduction of the dopamine uptake, a decrease of the number of differentiated dopaminergic neurons and some modifications of the size and the degree of branching or the neurites were noted. These results are preliminary and have to be confirmed [fr

  11. Central neurophysiology and dopaminergic control of ejaculation.

    Science.gov (United States)

    Peeters, Magali; Giuliano, François

    2008-01-01

    Although premature ejaculation (PE) represents the most common male sexual dysfunction, brain mechanisms controlling ejaculatory process remain poorly understood. Recently a group of neurons, identified in the lumbar spinal cord, has been proposed to constitute a spinal ejaculation generator. This key site in ejaculation control, relaying sensory inputs to the brain, is under supraspinal excitatory (medial preoptic area, paraventricular nucleus of the hypothalamus) and inhibitory (nucleus paragigantocellularis) controls. Activation of brain excitatory areas by dopamine (DA) or DA agonists being demonstrated to facilitate ejaculation, it seems particularly interesting to further understand the implication of central DA in the complex process leading to ejaculation. Moreover, the fact that dopaminergic pathways are involved in sexual behavior and that DA release in some brain regions is an important facilitator of male sexual behavior reinforces the crucial implication of DA. Clearly, a better understanding of DA incerto-hypothalamic pathways and targeting brain DA receptor subtypes mediating ejaculation (especially D(3) receptors) will benefit the development of new pharmacological strategies to treat ejaculatory dysfunction including PE.

  12. Potential environmental neurotoxins related to 1-methyl-4-phenylpyridinium: Selective toxicity of 1-methyl-4-(4'-acetamidophenyl)-pyridinium and 1-methyl-4-cyclohexylpyridinium for dopaminergic neurons in culture

    International Nuclear Information System (INIS)

    Michel, P.P.; Dandapani, B.K.; Efange, S.M.; Hefti, F.

    1990-01-01

    Mesencephalic cells in culture were exposed to various compounds which we hypothesized to be selective toxins for dopaminergic neurons. The culture system was previously shown suitable for assessing selective dopaminergic neurotoxicity, since 1-methyl-4-phenyl-pyridinium (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinium, destroyed dopaminergic neurons without affecting other cells. Some compounds tested were selected to fulfill two criteria believed to underly the selective dopaminergic neurotoxicity of MPP+, i.e., to be a potential substrate for the uptake carrier for dopamine and to possess a strong delocalized positive charge to inhibit the mitochondrial respiratory system. Other compounds were chosen on the basis of clinical or anecdotal evidence linking them to Parkinson's disease. Among the tested compounds two pyridinium analogs, 1-methyl-4-(4'-acetamidophenyl)pyridinium (MACPP+) and 1-methyl-4-cyclohexylpyridinium (MCP+) were found to be selectively toxic toward dopaminergic neurons. Incubation of cultures with both MACPP+ and MCP+ produced a dramatic reduction in the number of tyrosine hydroxylase-positive cells and the uptake of [3H]dopamine without reducing the number of cells visualized by phase-contrast microscopy or the uptake of [3H]aminobutyric acid. Besides MACPP+ and MCP+ none of the tested compounds exhibited any selective dopaminergic neurotoxicity. Together with earlier findings, these data suggest that the structural requirements are rather strict for a chemical to be a selective dopaminergic neurotoxin and make it unlikely that there is a wide spectrum of environmental dopaminergic toxins

  13. Drosophila divalent metal ion transporter Malvolio is required in dopaminergic neurons for feeding decisions.

    Science.gov (United States)

    Søvik, E; LaMora, A; Seehra, G; Barron, A B; Duncan, J G; Ben-Shahar, Y

    2017-06-01

    Members of the natural resistance-associated macrophage protein (NRAMP) family are evolutionarily conserved metal ion transporters that play an essential role in regulating intracellular divalent cation homeostasis in both prokaryotes and eukaryotes. Malvolio (Mvl), the sole NRAMP family member in insects, plays a role in food choice behaviors in Drosophila and other species. However, the specific physiological and cellular processes that require the action of Mvl for appropriate feeding decisions remain elusive. Here, we show that normal food choice requires Mvl function specifically in the dopaminergic system, and can be rescued by supplementing food with manganese. Collectively, our data indicate that the action of the Mvl transporter affects food choice behavior via the regulation of dopaminergic innervation of the mushroom bodies, a principle brain region associated with decision-making in insects. Our studies suggest that the homeostatic regulation of the intraneuronal levels of divalent cations plays an important role in the development and function of the dopaminergic system and associated behaviors. © 2017 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  14. Fibroblast growth factor-20 increases the yield of midbrain dopaminergic neurons derived from human embryonic stem cells

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    Ana Sofia Correia

    2007-12-01

    Full Text Available In the central nervous system, fibroblast growth factor (FGF-20 has been reported to act preferentially on midbrain dopaminergic neurons. It also promotes the dopaminergic differentiation of stem cells. We have analyzed the effects of FGF-20 on human embryonic stem cells (hESCs differentiation into dopaminergic neurons. We induced neuronal differentiation of hESCs by co-culturing those with PA6 mouse stromal cells for 3 weeks. When we supplemented the culture medium with FGF-20, the number of tyrosine hydroxylase (TH- expressing neurons increased fivefold, from 3% to 15% of the hESC-derived cells. The cultured cells also expressed other midbrain dopaminergic markers (PITX3, En1, Msx1, and Aldh1, suggesting that some had differentiated into midbrain dopaminergic neurons. We observed no effect of FGF-20 on the size of the soma area or neurite length of the TH-immunopositive neurons. Regardless of whether FGF-20 had been added or not, 17% of the hESC-derived cells expressed the pan-neuronal marker b-III-Tubulin. The proportion of proliferating cells positive for Ki-67 was also not affected by FGF-20 (7% of the hESC-derived cells. By contrast, after 3 weeks in culture FGF-20 significantly reduced the proportion of cells undergoing cell death, as revealed by immunoreactivity for cleaved caspase-8, Bcl-2 associated X protein (BAX and cleaved caspase-3 (2.5% to 1.2% of cleaved caspase-3-positive cells out of the hESC-derived cells. Taken together, our results indicate that FGF-20 specifically increases the yield of dopaminergic neurons from hESCs grown on PA6 feeder cells and at least part of this effect is due to a reduction in cell death.

  15. INTERACTION BETWEEN CHOLECYSTOKININ AND THE FIBROBLAST GROWTH FACTOR SYSTEM IN THE VENTRAL TEGMENTAL AREA OF SELECTIVELY BRED HIGH- AND LOW-RESPONDER RATS

    Science.gov (United States)

    Ballaz, Santiago J; Perez, Javier; Waselus, Maria; Akil, Huda; Watson, Stanley J

    2013-01-01

    Individual differences in the locomotor response to novelty have been linked to basal differences in dopaminergic neurotransmission. Mesolimbic dopaminergic outputs are regulated by cholecystokinin (CCK), a neuropeptide implicated in anxiety. In turn, CCK expression is regulated by fibroblast growth factor-2 (FGF2), which has recently been identified as an endogenous regulator of anxiety. FGF2 binds to the high-affinity fibroblast growth factor receptor-1 (FGF-R1) to regulate the development and maintenance of dopamine neurons in the ventral tegmental area (VTA). However, the relationship between the FGF and CCK systems in the VTA is not well understood. Therefore, we utilized the selectively-bred low-responder (bLR; high-anxiety) and high-responder (bHR; low-anxiety) rats to examine the effects of repeated (21-day) FGF2 treatment on CCK and FGF-R1 mRNA in the rostral VTA (VTAr). In vehicle-treated controls, both CCK and FGF-R1 mRNA levels were increased in the VTAr of bLR rats relative to bHR rats. Following FGF2 treatment, however, bHR-bLR differences in CCK and FGF-R1 mRNA expression were eliminated, due to decreased CCK mRNA levels in the VTAr of bLR rats and increased FGF-R1 expression in bHR rats. Differences after FGF2 treatment may denote distinct interactions between the CCK and FGF systems in the VTAr of bHR vs. bLR rats. Indeed, significant correlations between CCK and FGF-R1 mRNA expression were found in bHR, but not bLR rats. Colocalization studies suggest that CCK and FGF-R1 are coexpressed in some VTAr neurons. Taken together, our findings suggest that the FGF system is poised to modulate both CCK and FGF-R1 expression in the VTAr, which may be associated with individual differences in mesolimbic pathways associated with anxietylike behavior. PMID:24121132

  16. Physiological characterisation of human iPS-derived dopaminergic neurons.

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    Elizabeth M Hartfield

    Full Text Available Human induced pluripotent stem cells (hiPSCs offer the potential to study otherwise inaccessible cell types. Critical to this is the directed differentiation of hiPSCs into functional cell lineages. This is of particular relevance to research into neurological disease, such as Parkinson's disease (PD, in which midbrain dopaminergic neurons degenerate during disease progression but are unobtainable until post-mortem. Here we report a detailed study into the physiological maturation over time of human dopaminergic neurons in vitro. We first generated and differentiated hiPSC lines into midbrain dopaminergic neurons and performed a comprehensive characterisation to confirm dopaminergic functionality by demonstrating dopamine synthesis, release, and re-uptake. The neuronal cultures include cells positive for both tyrosine hydroxylase (TH and G protein-activated inward rectifier potassium channel 2 (Kir3.2, henceforth referred to as GIRK2, representative of the A9 population of substantia nigra pars compacta (SNc neurons vulnerable in PD. We observed for the first time the maturation of the slow autonomous pace-making (<10 Hz and spontaneous synaptic activity typical of mature SNc dopaminergic neurons using a combination of calcium imaging and electrophysiology. hiPSC-derived neurons exhibited inositol tri-phosphate (IP3 receptor-dependent release of intracellular calcium from the endoplasmic reticulum in neuronal processes as calcium waves propagating from apical and distal dendrites, and in the soma. Finally, neurons were susceptible to the dopamine neuron-specific toxin 1-methyl-4-phenylpyridinium (MPP+ which reduced mitochondrial membrane potential and altered mitochondrial morphology. Mature hiPSC-derived dopaminergic neurons provide a neurophysiologically-defined model of previously inaccessible vulnerable SNc dopaminergic neurons to bridge the gap between clinical PD and animal models.

  17. Hatching the behavioral addiction egg: Reward Deficiency Solution System (RDSS)™ as a function of dopaminergic neurogenetics and brain functional connectivity linking all addictions under a common rubric.

    Science.gov (United States)

    Blum, Kenneth; Febo, Marcelo; McLaughlin, Thomas; Cronjé, Frans J; Han, David; Gold, S Mark

    2014-09-01

    Following the first association between the dopamine D2 receptor gene polymorphism and severe alcoholism, there has been an explosion of research reports in the psychiatric and behavioral addiction literature and neurogenetics. With this increased knowledge, the field has been rife with controversy. Moreover, with the advent of Whole Genome-Wide Studies (GWAS) and Whole Exome Sequencing (WES), along with Functional Genome Convergence, the multiple-candidate gene approach still has merit and is considered by many as the most prudent approach. However, it is the combination of these two approaches that will ultimately define real, genetic allelic relationships, in terms of both risk and etiology. Since 1996, our laboratory has coined the umbrella term Reward Deficiency Syndrome (RDS) to explain the common neurochemical and genetic mechanisms involved with both substance and non-substance, addictive behaviors. This is a selective review of peer-reviewed papers primary listed in Pubmed and Medline. A review of the available evidence indicates the importance of dopaminergic pathways and resting-state, functional connectivity of brain reward circuits. Importantly, the proposal is that the real phenotype is RDS and impairments in the brain's reward cascade, either genetically or environmentally (epigenetically) induced, influence both substance and non-substance, addictive behaviors. Understanding shared common mechanisms will ultimately lead to better diagnosis, treatment and prevention of relapse. While, at this juncture, we cannot as yet state that we have "hatched the behavioral addiction egg", we are beginning to ask the correct questions and through an intense global effort will hopefully find a way of "redeeming joy" and permitting homo sapiens live a life, free of addiction and pain.

  18. Modeling fall propensity in Parkinson's disease: deficits in the attentional control of complex movements in rats with cortical-cholinergic and striatal-dopaminergic deafferentation.

    Science.gov (United States)

    Kucinski, Aaron; Paolone, Giovanna; Bradshaw, Marc; Albin, Roger L; Sarter, Martin

    2013-10-16

    Cognitive symptoms, complex movement deficits, and increased propensity for falls are interrelated and levodopa-unresponsive symptoms in patients with Parkinson's disease (PD). We developed a test system for the assessment of fall propensity in rats and tested the hypothesis that interactions between loss of cortical cholinergic and striatal dopaminergic afferents increase fall propensity. Rats were trained to traverse stationary and rotating rods, placed horizontally or at inclines, and while exposed to distractors. Rats also performed an operant Sustained Attention Task (SAT). Partial cortical cholinergic and/or caudate dopaminergic deafferentation were produced by bilateral infusions of 192 IgG-saporin (SAP) into the basal forebrain and/or 6-hydroxydopamine (6-OHDA) into the caudate nucleus, respectively, modeling the lesions seen in early PD. Rats with dual cholinergic-dopaminergic lesions (DL) fell more frequently than SAP or 6-OHDA rats. Falls in DL rats were associated with incomplete rebalancing after slips and low traversal speed. Ladder rung walking and pasta handling performance did not indicate sensorimotor deficits. SAT performance was impaired in DL and SAP rats; however, SAT performance and falls were correlated only in DL rats. Furthermore, in DL rats, but not in rats with only dopaminergic lesions, the placement and size of dopaminergic lesion correlated significantly with fall rates. The results support the hypothesis that after dual cholinergic-dopaminergic lesions, attentional resources can no longer be recruited to compensate for diminished striatal control of complex movement, thereby "unmasking" impaired striatal control of complex movements and yielding falls.

  19. Neuropsychiatric and metabolic aspects of dopaminergic therapy: perspectives from an endocrinologist and a psychiatrist

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    Anastasia P Athanasoulia-Kaspar

    2018-02-01

    Full Text Available The dopaminergic treatment represents the primary treatment in prolactinomas, which are the most common pituitary adenomas and account for about 40% of all pituitary tumours with an annual incidence of six to ten cases per million population. The dopaminergic treatment includes ergot and non-ergot derivatives with high affinity for the dopamine receptors D1 or/and D2. Through the activation of the dopaminergic pathway on pituitary lactotrophs, the dopamine agonists inhibit the prolactin synthesis and secretion, therefore normalizing the prolactin levels and restoring eugonadism, but they also lead to tumour shrinkage. Treatment with dopamine agonists has been associated – apart from the common side effects such as gastrointestinal symptoms, dizziness and hypotension – with neuropsychiatric side effects such as impulse control disorders (e.g. pathological gambling, compulsive shopping, hypersexuality and binge eating and also with behavioral changes from low mood, irritability and verbal aggressiveness up to psychotic and manic symptoms and paranoid delusions not only in patients with prolactinomas but also in patients with Parkinson’s disease and restless leg syndrome. They usually have de novo onset after initiation of the dopaminergic treatment and have been mainly reported in patients with Parkinson’s disease, who are being treated with higher doses of dopamine agonists. Moreover, dopamine and prolactin seem to play an essential role in the metabolic pathway. Patients with hyperprolactinemia tend to have increased body weight and an altered metabolic profile with hyperinsulinemia and increased prevalence of diabetes mellitus in comparison to healthy individuals and patients with non-functioning pituitary adenomas. Treatment with dopamine agonists in these patients in short-term studies seems to lead to weight loss and amelioration of the metabolic changes. Together these observations provide evidence that dopamine and prolactin have a

  20. Neuropsychiatric and metabolic aspects of dopaminergic therapy: perspectives from an endocrinologist and a psychiatrist.

    Science.gov (United States)

    Athanasoulia-Kaspar, Anastasia P; Popp, Kathrin H; Stalla, Gunter Karl

    2018-02-01

    The dopaminergic treatment represents the primary treatment in prolactinomas, which are the most common pituitary adenomas and account for about 40% of all pituitary tumours with an annual incidence of six to ten cases per million population. The dopaminergic treatment includes ergot and non-ergot derivatives with high affinity for the dopamine receptors D1 or/and D2. Through the activation of the dopaminergic pathway on pituitary lactotrophs, the dopamine agonists inhibit the prolactin synthesis and secretion, therefore normalizing the prolactin levels and restoring eugonadism, but they also lead to tumour shrinkage. Treatment with dopamine agonists has been associated - apart from the common side effects such as gastrointestinal symptoms, dizziness and hypotension - with neuropsychiatric side effects such as impulse control disorders (e.g. pathological gambling, compulsive shopping, hypersexuality and binge eating) and also with behavioral changes from low mood, irritability and verbal aggressiveness up to psychotic and manic symptoms and paranoid delusions not only in patients with prolactinomas but also in patients with Parkinson's disease and restless leg syndrome. They usually have de novo onset after initiation of the dopaminergic treatment and have been mainly reported in patients with Parkinson's disease, who are being treated with higher doses of dopamine agonists. Moreover, dopamine and prolactin seem to play an essential role in the metabolic pathway. Patients with hyperprolactinemia tend to have increased body weight and an altered metabolic profile with hyperinsulinemia and increased prevalence of diabetes mellitus in comparison to healthy individuals and patients with non-functioning pituitary adenomas. Treatment with dopamine agonists in these patients in short-term studies seems to lead to weight loss and amelioration of the metabolic changes. Together these observations provide evidence that dopamine and prolactin have a crucial role both in the

  1. Neuropsychiatric and metabolic aspects of dopaminergic therapy: perspectives from an endocrinologist and a psychiatrist

    Science.gov (United States)

    Athanasoulia-Kaspar, Anastasia P; Popp, Kathrin H; Stalla, Gunter Karl

    2018-01-01

    The dopaminergic treatment represents the primary treatment in prolactinomas, which are the most common pituitary adenomas and account for about 40% of all pituitary tumours with an annual incidence of six to ten cases per million population. The dopaminergic treatment includes ergot and non-ergot derivatives with high affinity for the dopamine receptors D1 or/and D2. Through the activation of the dopaminergic pathway on pituitary lactotrophs, the dopamine agonists inhibit the prolactin synthesis and secretion, therefore normalizing the prolactin levels and restoring eugonadism, but they also lead to tumour shrinkage. Treatment with dopamine agonists has been associated – apart from the common side effects such as gastrointestinal symptoms, dizziness and hypotension – with neuropsychiatric side effects such as impulse control disorders (e.g. pathological gambling, compulsive shopping, hypersexuality and binge eating) and also with behavioral changes from low mood, irritability and verbal aggressiveness up to psychotic and manic symptoms and paranoid delusions not only in patients with prolactinomas but also in patients with Parkinson’s disease and restless leg syndrome. They usually have de novo onset after initiation of the dopaminergic treatment and have been mainly reported in patients with Parkinson’s disease, who are being treated with higher doses of dopamine agonists. Moreover, dopamine and prolactin seem to play an essential role in the metabolic pathway. Patients with hyperprolactinemia tend to have increased body weight and an altered metabolic profile with hyperinsulinemia and increased prevalence of diabetes mellitus in comparison to healthy individuals and patients with non-functioning pituitary adenomas. Treatment with dopamine agonists in these patients in short-term studies seems to lead to weight loss and amelioration of the metabolic changes. Together these observations provide evidence that dopamine and prolactin have a crucial role both

  2. Abnormal striatal dopaminergic neurotransmission during rest and task production in spasmodic dysphonia.

    Science.gov (United States)

    Simonyan, Kristina; Berman, Brian D; Herscovitch, Peter; Hallett, Mark

    2013-09-11

    Spasmodic dysphonia is a primary focal dystonia characterized by involuntary spasms in the laryngeal muscles during speech production. The pathophysiology of spasmodic dysphonia is thought to involve structural and functional abnormalities in the basal ganglia-thalamo-cortical circuitry; however, neurochemical correlates underpinning these abnormalities as well as their relations to spasmodic dysphonia symptoms remain unknown. We used positron emission tomography with the radioligand [(11)C]raclopride (RAC) to study striatal dopaminergic neurotransmission at the resting state and during production of symptomatic sentences and asymptomatic finger tapping in spasmodic dysphonia patients. We found that patients, compared to healthy controls, had bilaterally decreased RAC binding potential (BP) to striatal dopamine D2/D3 receptors on average by 29.2%, which was associated with decreased RAC displacement (RAC ΔBP) in the left striatum during symptomatic speaking (group average difference 10.2%), but increased RAC ΔBP in the bilateral striatum during asymptomatic tapping (group average difference 10.1%). Patients with more severe voice symptoms and subclinically longer reaction time to initiate the tapping sequence had greater RAC ΔBP measures, while longer duration of spasmodic dysphonia was associated with a decrease in task-induced RAC ΔBP. Decreased dopaminergic transmission during symptomatic speech production may represent a disorder-specific pathophysiological trait involved in symptom generation, whereas increased dopaminergic function during unaffected task performance may be explained by a compensatory adaptation of the nigrostriatal dopaminergic system possibly due to decreased striatal D2/D3 receptor availability. These changes can be linked to the clinical and subclinical features of spasmodic dysphonia and may represent the neurochemical basis of basal ganglia alterations in this disorder.

  3. Alteration to Dopaminergic Synapses Following Exposure to Perfluorooctane Sulfonate (PFOS, in Vitro and in Vivo

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    Rahul Patel

    2016-08-01

    Full Text Available Our understanding of the contribution exposure to environmental toxicants has on neurological disease continues to evolve. Of these, Parkinson’s disease (PD has been shown to have a strong environmental component to its etiopathogenesis. However, work is still needed to identify and characterize environmental chemicals that could alter the expression and function of the nigrostriatal dopamine system. Of particular interest is the neurotoxicological effect of perfluorinated compounds, such as perfluorooctane sulfonate (PFOS, which has been demonstrated to alter aspects of dopamine signaling. Using in vitro approaches, we have elaborated these initial findings to demonstrate the neurotoxicity of PFOS to the SH-SY5Y neuroblastoma cell line and dopaminergic primary cultured neurons. Using an in vivo model, we did not observe a deficit to dopaminergic terminals in the striatum of mice exposed to 10 mg/kg PFOS for 14 days. However, subsequent exposure to the selective dopaminergic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP significantly reduced the expression of dopamine transporter (DAT and tyrosine hydroxylase (TH, and resulted in an even greater reduction in DAT expression in animals previously exposed to PFOS. These findings suggest that PFOS is neurotoxic to the nigrostriatal dopamine circuit and this neurotoxicity could prime the dopamine terminal to more extensive damage following additional toxicological insults.

  4. Constitutive Ret signaling leads to long-lasting expression of amphetamine-induced place conditioning via elevation of mesolimbic dopamine.

    Science.gov (United States)

    Kopra, Jaakko; Villarta-Aguilera, Marian; Savolainen, Mari; Weingerl, Samo; Myöhänen, Timo T; Rannanpää, Saara; Salvatore, Michael F; Andressoo, Jaan-Olle; Piepponen, T Petteri

    2018-01-01

    Addictive drugs enhance dopamine release in the striatum, which can lead to compulsive drug-seeking after repeated exposure. Glial cell line-derived neurotrophic factor (GDNF) is an important regulator of midbrain dopamine neurons, and may play a mechanistic role in addiction-related behaviors. To elucidate the components of GDNF-signaling that contribute to addiction-related behaviors of place preference and its extinction, we utilized two genetically modified GDNF mouse models in an amphetamine-induced conditioned place preference (CPP) paradigm and evaluated how the behavioral findings correlate with dopamine signaling in the dorsal and ventral striatum. We utilized two knock-in mouse strains to delineate contributions of GDNF and Ret signaling using MEN2B mice (constitutively active GDNF receptor Ret), and GDNF hypermorphic mice (enhanced endogenous GDNF expression). The duration of amphetamine-induced CPP was greatly enhanced in MEN2B mice, but not in the GDNF hypermorphic mice. The enhanced duration of CPP was correlated with increased tyrosine hydroxylase (TH) expression and dopamine content in the ventral striatum. Together, our results suggest that downstream components of GDNF signaling, in this case Ret, may mediate persistent drug-seeking behavior through increased TH expression and dopamine levels in the mesolimbic dopamine neurons. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Cellular manganese content is developmentally regulated in human dopaminergic neurons

    Science.gov (United States)

    Kumar, Kevin K.; Lowe, Edward W., Jr.; Aboud, Asad A.; Neely, M. Diana; Redha, Rey; Bauer, Joshua A.; Odak, Mihir; Weaver, C. David; Meiler, Jens; Aschner, Michael; Bowman, Aaron B.

    2014-10-01

    Manganese (Mn) is both an essential biological cofactor and neurotoxicant. Disruption of Mn biology in the basal ganglia has been implicated in the pathogenesis of neurodegenerative disorders, such as parkinsonism and Huntington's disease. Handling of other essential metals (e.g. iron and zinc) occurs via complex intracellular signaling networks that link metal detection and transport systems. However, beyond several non-selective transporters, little is known about the intracellular processes regulating neuronal Mn homeostasis. We hypothesized that small molecules that modulate intracellular Mn could provide insight into cell-level Mn regulatory mechanisms. We performed a high throughput screen of 40,167 small molecules for modifiers of cellular Mn content in a mouse striatal neuron cell line. Following stringent validation assays and chemical informatics, we obtained a chemical `toolbox' of 41 small molecules with diverse structure-activity relationships that can alter intracellular Mn levels under biologically relevant Mn exposures. We utilized this toolbox to test for differential regulation of Mn handling in human floor-plate lineage dopaminergic neurons, a lineage especially vulnerable to environmental Mn exposure. We report differential Mn accumulation between developmental stages and stage-specific differences in the Mn-altering activity of individual small molecules. This work demonstrates cell-level regulation of Mn content across neuronal differentiation.

  6. An optimized method for counting dopaminergic neurons in zebrafish.

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    Hideaki Matsui

    Full Text Available In recent years, considerable effort has been devoted to the development of a fish model for Parkinson's disease (PD to examine the pathological mechanisms of neurodegeneration. To effectively evaluate PD pathology, the ability to accurately and reliably count dopaminergic neurons is important. However, there is currently no such standardized method. Due to the relatively small number of dopaminergic neurons in fish, stereological estimation would not be suitable. In addition, serial sectioning requires proficiency to not lose any sections, and it permits double counting due to the large size of some of the dopaminergic neurons. In this study, we report an optimized protocol for staining dopaminergic neurons in zebrafish and provide a reliable counting method. Finally, using our optimized protocol, we confirmed that administration of 6-hydroxydopamine (a neurotoxin or the deletion of the PINK1 gene (one of the causative genes of familiar PD in zebrafish caused significant reduction in the number of dopaminergic and noradrenergic neurons. In summary, this method will serve as an important tool for the appropriate evaluation and establishment of fish PD models.

  7. Dopaminergic Medication in Parkinson's Disease and Problem Gambling.

    Science.gov (United States)

    Olley, Jacqueline; Blaszczynski, Alex; Lewis, Simon

    2015-09-01

    Studies on Parkinson's disease patients on dopaminergic medication report elevated rates of problem gambling. Results suggest changes in gambling behaviour are associated with the commencement and termination of dopaminergic medication implying a direct causal relationship. However, previous reports have not controlled for possible factors independent of dopamine medication contributing to the onset of problem gambling. This study aimed to explore the temporal relationships between problem gambling and dopamine medication taking into account premorbid gambling risk factors in a sample of Parkinson's disease patients. Twenty patients with Parkinson's disease meeting criteria for moderate risk or problem gambling were compared to twenty patients with Parkinson's disease who did not meet such criteria. The cross-sectional research design compared between group qualitative and quantitative differences. Participants completed an in-depth interview and timeline follow back, and battery of psychometric measures assessing impulsivity, gambling status, affective states, and obsessionality. Results revealed a complex and varied temporal relationship between dopaminergic medication onset and gambling. A small number of participants manifested excessive gambling following dopaminergic medication, with some ceasing on reduction in dosage or change in agonist class. Many demonstrated a range of individual and situational characteristic similar to problem gamblers in the general population, and in older adults with gambling problems. The obtained results provide a better understanding of the role of dopaminergic medication in problem gambling. Such findings have theoretical relevance to the reward deficiency model of gambling and have implications for the treatment of pathological gambling in PD and the general community.

  8. Dopaminergic Dysregulation, Artistic Expressiveness, and Parkinson’s Disease

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    S. López-Pousa

    2012-11-01

    Full Text Available Background: The most frequent behavioral manifestations in Parkinson’s disease (PD are attributed to the dopaminergic dysregulation syndrome (DDS, which is considered to be secondary to the iatrogenic effects of the drugs that replace dopamine. Over the past few years some cases of patients improving their creative abilities after starting treatment with dopaminergic pharmaceuticals have been reported. These effects have not been clearly associated to DDS, but a relationship has been pointed out. Methods: Case study of a patient with PD. The evolution of her paintings along medication changes and disease advance has been analyzed. Results: The patient showed a compulsive increase of pictorial production after the diagnosis of PD was made. She made her best paintings when treated with cabergolide, and while painting, she reported a feeling of well-being, with loss of awareness of the disease and reduction of physical limitations. Conclusions: Dopaminergic antagonists (DA trigger a dopaminergic dysfunction that alters artistic creativity in patients having a predisposition for it. The development of these skills might be due to the dopaminergic overstimulation due to the therapy with DA, which causes a neurophysiological alteration that globally determines DDS.

  9. Environmental enrichment has no effect on the development of dopaminergic and GABAergic fibers during methylphenidate treatment of early traumatized gerbils

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    Teuchert-Noodt Gertraud

    2008-05-01

    Full Text Available Abstract It is widely believed, that environmental factors play a crucial role in the etiology and outcome of psychiatric diseases such as Attention-Deficit/Hyperactivity Disorder (ADHD. A former study from our laboratory has shown that both methylphenidate (MP and handling have a positive effect on the dopaminergic fiber density in the prefrontal cortex (PFC of early traumatized gerbils (Meriones unguiculatus. The current study was performed to investigate if enriched environment during MP application has an additional influence on the dopaminergic and GABAergic fiber densities in the PFC and amygdala in this animal model. Animals received a single early dose of methamphetamine (MA; 50 mg/kg; i.p. on postnatal day (PD 14, which is known to cause multiple changes in the subsequent development of several neurotransmitter systems including the dopaminergic systems, and were then treated with oral daily applications of MP (5 mg/kg from PD30–60. Animals treated this way were either transferred to an enriched environment after weaning (on PD30 or were kept under impoverished rearing conditions. There was no effect of an enriched environment on the dopaminergic or GABAergic fiber density neither in the PFC nor in the amygdala. With regard to former studies these results underline the particular impact of MP in the treatment of ADHD.

  10. Convergent dysregulation of frontal cortical cognitive and reward systems in eating disorders.

    Science.gov (United States)

    Stefano, George B; Ptáček, Radek; Kuželová, Hana; Mantione, Kirk J; Raboch, Jiří; Papezova, Hana; Kream, Richard M

    2013-05-10

    A substantive literature has drawn a compelling case for the functional involvement of mesolimbic/prefrontal cortical neural reward systems in normative control of eating and in the etiology and persistence of severe eating disorders that affect diverse human populations. Presently, we provide a short review that develops an equally compelling case for the importance of dysregulated frontal cortical cognitive neural networks acting in concert with regional reward systems in the regulation of complex eating behaviors and in the presentation of complex pathophysiological symptoms associated with major eating disorders. Our goal is to highlight working models of major eating disorders that incorporate complementary approaches to elucidate functionally interactive neural circuits defined by their regulatory neurochemical phenotypes. Importantly, we also review evidence-based linkages between widely studied psychiatric and neurodegenerative syndromes (e.g., autism spectrum disorders and Parkinson's disease) and co-morbid eating disorders to elucidate basic mechanisms involving dopaminergic transmission and its regulation by endogenously expressed morphine in these same cortical regions.

  11. Increased dopaminergic signaling impairs aversive olfactory memory retention in Drosophila.

    Science.gov (United States)

    Zhang, Shixing; Yin, Yan; Lu, Huimin; Guo, Aike

    2008-05-23

    Dopamine is necessary for the aversive olfactory associative memory formation in Drosophila, but its effect on other stages of memory is not known. Herein, we studied the effect of enhanced dopaminergic signaling on aversive olfactory memory retention in flies. We used l-3,4-dihydroxyphenylalanine (l-DOPA) to elevate dopamine levels: l-DOPA-treated flies exhibited a normal learning performance, but a decrease in 1-h memory. Dopamine transporter (DAT) mutant flies or flies treated with the DAT inhibitor desipramine exhibited poor memory retention. Flies subjected to heat stress after training exhibited a decrease in memory. Memory was restored by blocking dopaminergic neuronal output during heat stress, suggesting that dopamine is involved in heat stress-induced memory impairment in flies. Taken together, our findings suggest that increased dopaminergic signaling impairs aversive olfactory memory retention in flies.

  12. Influence of dopaminergically mediated reward on somatosensory decision-making.

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    Burkhard Pleger

    2009-07-01

    Full Text Available Reward-related dopaminergic influences on learning and overt behaviour are well established, but any influence on sensory decision-making is largely unknown. We used functional magnetic resonance imaging (fMRI while participants judged electric somatosensory stimuli on one hand or other, before being rewarded for correct performance at trial end via a visual signal, at one of four anticipated financial levels. Prior to the procedure, participants received either placebo (saline, a dopamine agonist (levodopa, or an antagonist (haloperidol.higher anticipated reward improved tactile decisions. Visually signalled reward reactivated primary somatosensory cortex for the judged hand, more strongly for higher reward. After receiving a higher reward on one trial, somatosensory activations and decisions were enhanced on the next trial. These behavioural and neural effects were all enhanced by levodopa and attenuated by haloperidol, indicating dopaminergic dependency. Dopaminergic reward-related influences extend even to early somatosensory cortex and sensory decision-making.

  13. Dopaminergic profile of new heterocyclic N-phenylpiperazine derivatives

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    Neves G.

    2003-01-01

    Full Text Available Dopamine constitutes about 80% of the content of central catecholamines and has a crucial role in the etiology of several neuropsychiatric disorders, including Parkinson's disease, depression and schizophrenia. Several dopaminergic drugs are used to treat these pathologies, but many problems are attributed to these therapies. Within this context, the search for new more efficient dopaminergic agents with less adverse effects represents a vast research field. The aim of the present study was to report the structural design of two N-phenylpiperazine derivatives, compound 4: 1-[1-(4-chlorophenyl-1H-4-pyrazolylmethyl]-4-phenylhexahydropyrazine and compound 5: 1-[1-(4-chlorophenyl-1H-1,2,3-triazol-4-ylmethyl]-4-phenylhexahydropyrazine, planned to be dopamine ligands, and their dopaminergic action profile. The two compounds were assayed (dose range of 15-40 mg/kg in three experimental models: 1 blockade of amphetamine (30 mg/kg, ip-induced stereotypy in rats; 2 the catalepsy test in mice, and 3 apomorphine (1 mg/kg, ip-induced hypothermia in mice. Both derivatives induced cataleptic behavior (40 mg/kg, ip and a hypothermic response (30 mg/kg, ip which was not prevented by haloperidol (0.5 mg/kg, ip. Compound 5 (30 mg/kg, ip also presented a synergistic hypothermic effect with apomorphine (1 mg/kg, ip. Only compound 4 (30 mg/kg, ip significantly blocked the amphetamine-induced stereotypy in rats. The N-phenylpiperazine derivatives 4 and 5 seem to have a peculiar profile of action on dopaminergic functions. On the basis of the results of catalepsy and amphetamine-induced stereotypy, the compounds demonstrated an inhibitory effect on dopaminergic behaviors. However, their hypothermic effect is compatible with the stimulation of dopaminergic function which seems not to be mediated by D2/D3 receptors.

  14. Cholinergic modulation of dopaminergic reward areas: upstream and downstream targets of nicotine addiction

    NARCIS (Netherlands)

    Mansvelder, H.D.; de Rover, M.; McGehee, D.S.; Brussaard, A.B.

    2003-01-01

    Nicotine reinforces smoking behaviour by activating nicotinic acetylcholine receptors in the midbrain dopaminergic reward centres. Upstream of the dopaminergic neurons nicotine induces long-term potentiation of the excitatory input to dopamine cells in the ventral tegmental area, and depresses

  15. Effect of inhibition of fatty acid amide hydrolase on MPTP-induced dopaminergic neuronal damage.

    Science.gov (United States)

    Viveros-Paredes, J M; Gonzalez-Castañeda, R E; Escalante-Castañeda, A; Tejeda-Martínez, A R; Castañeda-Achutiguí, F; Flores-Soto, M E

    2017-01-16

    Parkinson's disease (PD) is a neurodegenerative disorder characterised by balance problems, muscle rigidity, and slow movement due to low dopamine levels and loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The endocannabinoid system is known to modulate the nigrostriatal pathway through endogenous ligands such as anandamide (AEA), which is hydrolysed by fatty acid amide hydrolase (FAAH). The purpose of this study was to increase AEA levels using FAAH inhibitor URB597 to evaluate the modulatory effect of AEA on dopaminergic neuronal death induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Our study included 4 experimental groups (n = 6 mice per group): a control group receiving no treatment, a group receiving URB597 (0.2mg/kg) every 3 days for 30 days, a group treated with MPTP (30mg/kg) for 5 days, and a group receiving URB597 and subsequently MPTP injections. Three days after the last dose, we conducted a series of behavioural tests (beam test, pole test, and stride length test) to compare motor coordination between groups. We subsequently analysed immunoreactivity of dopaminergic cells and microglia in the SNpc and striatum. Mice treated with URB597 plus MPTP were found to perform better on behavioural tests than mice receiving MPTP only. According to the immunohistochemistry study, mice receiving MPTP showed fewer dopaminergic cells and fibres in the SNpc and striatum. Animals treated with URB597 plus MPTP displayed increased tyrosine hydroxylase immunoreactivity compared to those treated with MPTP only. Regarding microglial immunoreactivity, the group receiving MPTP showed higher Iba1 immunoreactivity in the striatum and SNpc than did the group treated with URB597 plus MPTP. Our results show that URB597 exerts a protective effect since it inhibits dopaminergic neuronal death, decreases microglial immunoreactivity, and improves MPTP-induced motor alterations. Copyright © 2016 Sociedad Española de Neurología. Publicado

  16. Dopaminergic Receptors on CD4+ T Naive and Memory Lymphocytes Correlate with Motor Impairment in Patients with Parkinson's Disease.

    Science.gov (United States)

    Kustrimovic, Natasa; Rasini, Emanuela; Legnaro, Massimiliano; Bombelli, Raffaella; Aleksic, Iva; Blandini, Fabio; Comi, Cristoforo; Mauri, Marco; Minafra, Brigida; Riboldazzi, Giulio; Sanchez-Guajardo, Vanesa; Marino, Franca; Cosentino, Marco

    2016-09-22

    Parkinson's disease (PD) is characterized by loss of dopaminergic neurons in substantia nigra pars compacta, α-synuclein (α-syn)-rich intraneuronal inclusions (Lewy bodies), and microglial activation. Emerging evidence suggests that CD4+ T lymphocytes contribute to neuroinflammation in PD. Since the mainstay of PD treatment is dopaminergic substitution therapy and dopamine is an established transmitter connecting nervous and immune systems, we examined CD4+ T naive and memory lymphocytes in PD patients and in healthy subjects (HS), with specific regard to dopaminergic receptor (DR) expression. In addition, the in vitro effects of α-syn were assessed on CD4+ T naive and memory cells. Results showed extensive association between DR expression in T lymphocytes and motor dysfunction, as assessed by UPDRS Part III score. In total and CD4+ T naive cells expression of D 1 -like DR decrease, while in T memory cells D 2 -like DR increase with increasing score. In vitro, α-syn increased CD4+ T memory cells, possibly to a different extent in PD patients and in HS, and affected DR expression with cell subset-specific patterns. The present results support the involvement of peripheral adaptive immunity in PD, and may contribute to develop novel immunotherapies for PD, as well as to better use of current dopaminergic antiparkinson drugs.

  17. Dopaminergic expression of the Parkinsonian gene LRRK2-G2019S leads to non-autonomous visual neurodegeneration, accelerated by increased neural demands for energy

    Science.gov (United States)

    Hindle, Samantha; Afsari, Farinaz; Stark, Meg; Middleton, C. Adam; Evans, Gareth J.O.; Sweeney, Sean T.; Elliott, Christopher J.H.

    2013-01-01

    Parkinson's disease (PD) is associated with loss of dopaminergic signalling, and affects not just movement, but also vision. As both mammalian and fly visual systems contain dopaminergic neurons, we investigated the effect of LRRK2 mutations (the most common cause of inherited PD) on Drosophila electroretinograms (ERGs). We reveal progressive loss of photoreceptor function in flies expressing LRRK2-G2019S in dopaminergic neurons. The photoreceptors showed elevated autophagy, apoptosis and mitochondrial disorganization. Head sections confirmed extensive neurodegeneration throughout the visual system, including regions not directly innervated by dopaminergic neurons. Other PD-related mutations did not affect photoreceptor function, and no loss of vision was seen with kinase-dead transgenics. Manipulations of the level of Drosophila dLRRK suggest G2019S is acting as a gain-of-function, rather than dominant negative mutation. Increasing activity of the visual system, or of just the dopaminergic neurons, accelerated the G2019S-induced deterioration of vision. The fly visual system provides an excellent, tractable model of a non-autonomous deficit reminiscent of that seen in PD, and suggests that increased energy demand may contribute to the mechanism by which LRRK2-G2019S causes neurodegeneration. PMID:23396536

  18. The effects of dopaminergic/serotonergic reuptake inhibition on maternal behavior, maternal aggression, and oxytocin in the rat☆

    OpenAIRE

    Johns, J.M.; Joyner, P.W.; McMurray, M.S.; Elliott, D.L.; Hofler, V.E.; Middleton, C.L.; Knupp, K.; Greenhill, K.W.; Lomas, L.M.; Walker, C.H.

    2005-01-01

    Studies using dopaminergic and serotonergic agonists or antagonists implicate involvement of these systems in various aspects of early maternal behavior and postpartum aggression towards an intruder in rats, both of which are associated with the presence of oxytocin in specific brain regions. It is unclear however, if or how long-term uptake inhibition of either neurotransmitter system alone or in combination, affects oxytocin system dynamics or maternal behavior/aggression. Pregnant women fr...

  19. The zebrafish mutation m865 affects formation of dopaminergic neurons and neuronal survival, and maps to a genetic interval containing the sepiapterin reductase locus.

    Science.gov (United States)

    Ettl, Anne-Kathrin; Holzschuh, Jochen; Driever, Wolfgang

    2006-12-01

    The zebrafish mutation m865 was isolated during a large-scale mutagenesis screen aimed at identifying genes involved in the development and maintenance of subgroups of neurons in the zebrafish central nervous system. The phenotype of m865 mutant embryos shows defects in the development of dopaminergic neurons in the pretectum and of retinal amacrine cells, as well as abnormal caudal dopaminergic cluster in the diencephalon. The effects of the mutation appear not to be restricted to dopaminergic neurons, as development of other neurotransmitter systems (serotonergic and cholinergic) is impaired as well. Furthermore, increased apoptosis is localized to the m865 mutant retina and in the optic tectum starting at 24hpf, and may lead to the observed reduced size of the mutant head and eye. Early patterning is not affected in m865 mutant embryos, and expression of genes known to play a role in dopaminergic cell differentiation is normal except for reduced expression of nurr1 in the mutant retina. Thus the m865 mutation does not specifically affect dopaminergic neuron development. m865 was genetically mapped to linkage group 5, and the critical genomic interval could be narrowed down to a region of 110 kb, containing four candidate genes. For one of these candidate genes, sepiapterin reductase (spr), a requirement for neuronal survival has previously been implicated, including dopaminergic neurons. Identification of the mutated gene should lead to a more detailed understanding of the defects observed in m865 mutant embryos, and potentially could enhance the understanding of the development and maintenance of specific dopaminergic neuronal populations.

  20. Effects of dopaminergic treatment on functional cortico-cortical connectivity in Parkinson's disease

    DEFF Research Database (Denmark)

    Zittel, S; Heinbokel, C; van der Vegt, J P M

    2015-01-01

    dopaminergic therapy on these interactions in PD. Twelve untreated PD patients were studied before and after their first-ever intake of levodopa. The effects of chronic dopaminergic medication were evaluated in 11 patients who had received regular dopaminergic medication for approximately 3 years. Nine...

  1. Exposure to mitochondrial genotoxins and dopaminergic neurodegeneration in Caenorhabditis elegans.

    Directory of Open Access Journals (Sweden)

    Claudia P González-Hunt

    Full Text Available Neurodegeneration has been correlated with mitochondrial DNA (mtDNA damage and exposure to environmental toxins, but causation is unclear. We investigated the ability of several known environmental genotoxins and neurotoxins to cause mtDNA damage, mtDNA depletion, and neurodegeneration in Caenorhabditis elegans. We found that paraquat, cadmium chloride and aflatoxin B1 caused more mitochondrial than nuclear DNA damage, and paraquat and aflatoxin B1 also caused dopaminergic neurodegeneration. 6-hydroxydopamine (6-OHDA caused similar levels of mitochondrial and nuclear DNA damage. To further test whether the neurodegeneration could be attributed to the observed mtDNA damage, C. elegans were exposed to repeated low-dose ultraviolet C radiation (UVC that resulted in persistent mtDNA damage; this exposure also resulted in dopaminergic neurodegeneration. Damage to GABAergic neurons and pharyngeal muscle cells was not detected. We also found that fasting at the first larval stage was protective in dopaminergic neurons against 6-OHDA-induced neurodegeneration. Finally, we found that dopaminergic neurons in C. elegans are capable of regeneration after laser surgery. Our findings are consistent with a causal role for mitochondrial DNA damage in neurodegeneration, but also support non mtDNA-mediated mechanisms.

  2. Dopaminergic agents and nutritional status in Parkinson's disease.

    Science.gov (United States)

    Laudisio, Alice; Vetrano, Davide L; Meloni, Eleonora; Ricciardi, Diego; Franceschi, Francesco; Bentivoglio, Anna Rita; Bernabei, Roberto; Zuccalà, Giuseppe

    2014-10-01

    Malnutrition has been found in up to 24% of patients with Parkinson's disease; dopaminergic drugs might impair nutritional status. We evaluated the association of nutritional status with the use of dopaminergic agents. We analyzed data from 75 elderly patients with Parkinson's disease attending a geriatric day hospital. Nutritional status was assessed by the Mini Nutritional Assessment (MNA). Dopaminergic drugs were normalized for weight. In linear regression, total levodopa (l-dopa) equivalent daily dose (LEDD) was associated with worse MNA (B = -0.14, 95% CI = -0.26--0.02; P = 0.019). This association remained significant only for l-dopa (B = -0.19, 95% CI = -0.32--0.52; P = 0.007), but not dopaminergic agent dosages. Increasing l-dopa dosages were associated with increasing probability of risk of malnutrition (P for trend = 0.049). In our population, LEDD was associated with worse nutritional status and risk of malnutrition; this association was limited to use of l-dopa. © 2014 International Parkinson and Movement Disorder Society.

  3. Dopaminergic medication alters auditory distractor processing in Parkinson's disease.

    Science.gov (United States)

    Georgiev, Dejan; Jahanshahi, Marjan; Dreo, Jurij; Čuš, Anja; Pirtošek, Zvezdan; Repovš, Grega

    2015-03-01

    Parkinson's disease (PD) patients show signs of cognitive impairment, such as executive dysfunction, working memory problems and attentional disturbances, even in the early stages of the disease. Though motor symptoms of the disease are often successfully addressed by dopaminergic medication, it still remains unclear, how dopaminergic therapy affects cognitive function. The main objective of this study was to assess the effect of dopaminergic medication on visual and auditory attentional processing. 14 PD patients and 13 matched healthy controls performed a three-stimulus auditory and visual oddball task while their EEG was recorded. The patients performed the task twice, once on- and once off-medication. While the results showed no significant differences between PD patients and controls, they did reveal a significant increase in P3 amplitude on- vs. off-medication specific to processing of auditory distractors and no other stimuli. These results indicate significant effect of dopaminergic therapy on processing of distracting auditory stimuli. With a lack of between group differences the effect could reflect either 1) improved recruitment of attentional resources to auditory distractors; 2) reduced ability for cognitive inhibition of auditory distractors; 3) increased response to distractor stimuli resulting in impaired cognitive performance; or 4) hindered ability to discriminate between auditory distractors and targets. Further studies are needed to differentiate between these possibilities. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Dopaminergic medication affects choice bias in Parkinson's disease

    NARCIS (Netherlands)

    Nuland, A.J.M. van; Helmich, R.C.G.; Dirkx, M.F.M.; Zach, H.; Bloem, B.R.; Toni, I.; Cools, R.; Ouden, H.E.M. den

    2016-01-01

    Objective: Assess dopaminergic effects on choice bias in Parkinson's disease (PD). Background: Bradykinesia, rigidity and resting tremor are the core symptoms of PD, but many patients also suffer from cognitive dysfunction. For instance, PD patients have an increased tendency to learn from aversive

  5. Pathological gambling secondary to dopaminergic therapy in Parkinson's disease.

    Science.gov (United States)

    Drapier, Dominique; Drapier, Sophie; Sauleau, Paul; Derkinderen, Pascal; Damier, Philippe; Allain, Herve; Vérin, Marc; Millet, Bruno

    2006-11-15

    We describe six patients with Parkinson's disease (PD) and pathological gambling. All patients started gambling after the onset of PD and initiation or increase of treatment with dopaminergic therapy. The fact that pathological behaviour disappeared as medication was ended or decreased suggests that an elaborate behavioural manifestation could be related to dopamine tone in patients with Parkinson's disease.

  6. Epigenetic mechanisms in the development and maintenance of dopaminergic neurons

    NARCIS (Netherlands)

    van Heesbeen, H.J.; Mesman, S.; Veenvliet, J.V.; Smidt, M.P.

    2013-01-01

    Mesodiencephalic dopaminergic (mdDA) neurons are located in the ventral mesodiencephalon and are involved in psychiatric disorders and severely affected in neurodegenerative diseases such as Parkinson's disease. mdDA neuronal development has received much attention in the last 15 years and many

  7. A dopaminergic projection to the rat mammillary nuclei demonstrated by retrograde transport of wheat germ agglutinin-horseradish peroxidase and tyrosine hydroxylase immunohistochemistry

    Science.gov (United States)

    Gonzalo-Ruiz, A.; Alonso, A.; Sanz, J. M.; Llinas, R. R.

    1992-01-01

    The presence and distribution of dopaminergic neurons and terminals in the hypothalamus of the rat were studied by tyrosine hydroxylase (TH) immunohistochemistry. Strongly labelled TH-immunoreactive neurons were seen in the dorsomedial hypothalamic nucleus, periventricular region, zona incerta, arcuate nucleus, and supramammillary nucleus. A few TH-positive neurons were also identified in the dorsal and ventral premammillary nucleus, as well as the lateral hypothalamic area. TH-immunoreactive fibres and terminals were unevenly distributed in the mammillary nuclei; small, weakly labelled terminals were scattered in the medial mammillary nucleus, while large, strongly labelled, varicose terminals were densely concentrated in the internal part of the lateral mammillary nucleus. A few dorsoventrally oriented TH-positive axon bundles were also identified in the lateral mammillary nucleus. A dopaminergic projection to the mammillary nuclei from the supramammillary nucleus and lateral hypothalamic area was identified by double labelling with retrograde transport of wheat germ agglutinin-horseradish peroxidase and TH-immunohistochemistry. The lateral mammillary nucleus receives a weak dopaminergic projection from the medial, and stronger projections from the lateral, caudal supramammillary nucleus. The double-labelled neurons in the lateral supramammillary nucleus appear to encapsulate the caudal end of the mammillary nuclei. The medial mammillary nucleus receives a very light dopaminergic projection from the caudal lateral hypothalamic area. These results suggest that the supramammillary nucleus is the principal source of the dopaminergic input to the mammillary nuclei, establishing a local TH-pathway in the mammillary complex. The supramammillary cell groups are able to modulate the limbic system through its dopaminergic input to the mammillary nuclei as well as through its extensive dopaminergic projection to the lateral septal nucleus.

  8. Associations between visual perception accuracy and confidence in a dopaminergic manipulation study

    Directory of Open Access Journals (Sweden)

    Christina eAndreou

    2015-04-01

    Full Text Available Delusions are defined as fixed erroneous beliefs that are based on misinterpretation of events or perception, and cannot be corrected by argumentation to the opposite. Cognitive theories of delusions regard this symptom as resulting from specific distorted thinking styles that lead to biased integration and interpretation of perceived stimuli (i.e., reasoning biases. In previous studies, we were able to show that one of these reasoning biases, overconfidence in errors, can be modulated by drugs that act on the dopamine system, a major neurotransmitter system implicated in the pathogenesis of delusions and other psychotic symptoms. Another processing domain suggested to involve the dopamine system and to be abnormal in psychotic disorders is sensory perception. The present study aimed to investigate whether (lower-order sensory perception and (higher-order overconfidence in errors are similarly affected by dopaminergic modulation in healthy subjects. Thirty-four healthy individuals were assessed upon administration of L-dopa, placebo, or haloperidol within a randomized, double-blind, cross-over design. Variables of interest were hits and false alarms in an illusory perception paradigm requiring speeded detection of pictures over a noisy background, and subjective confidence ratings for correct and incorrect responses. There was a significant linear increase of false alarm rates from haloperidol to placebo to L-dopa, whereas hit rates were not affected by dopaminergic manipulation. As hypothesized, confidence in error responses was significantly higher with L-dopa compared to placebo. Moreover, confidence in erroneous responses significantly correlated with false alarm rates. These findings suggest that overconfidence in errors and aberrant sensory processing might be both interdependent and related to dopaminergic transmission abnormalities in patients with psychosis.

  9. Tp53 gene mediates distinct dopaminergic neuronal damage in different dopaminergic neurotoxicant models

    Directory of Open Access Journals (Sweden)

    Tao Lu

    2017-01-01

    Full Text Available Tp53, a stress response gene, is involved in diverse cell death pathways and its activation is implicated in the pathogenesis of Parkinson's disease. However, whether the neuronal Tp53 protein plays a direct role in regulating dopaminergic (DA neuronal cell death or neuronal terminal damage in different neurotoxicant models is unknown. In our recent studies, in contrast to the global inhibition of Tp53 function by pharmacological inhibitors and in traditional Tp53 knock-out mice, we examined the effects of DA-specific Tp53 gene deletion after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and methamphetamine exposure. Our data suggests that the Tp53 gene might be involved in both neuronal apoptosis and neuronal terminal damage caused by different neurotoxicants. Additional results from other studies also suggest that as a master regulator of many pathways that regulate apoptosis and synaptic terminal damage, it is possible that Tp53 may function as a signaling hub to integrate different signaling pathways to mediate distinctive target pathways. Tp53 protein as a signaling hub might be able to evaluate the microenvironment of neurons, assess the forms and severities of injury incurred, and determine whether apoptotic cell death or neuronal terminal degeneration occurs. Identification of the precise mechanisms activated in distinct neuronal damage caused by different forms and severities of injuries might allow for development of specific Tp53 inhibitors or ways to modulate distinct downstream target pathways involved.

  10. Do CSF levels of t-Tau, p-Tau and β{sub 1-42} amyloid correlate with dopaminergic system impairment in patients with a clinical diagnosis of Parkinson disease? A {sup 123}I-FP-CIT study in the early stages of the disease

    Energy Technology Data Exchange (ETDEWEB)

    Chiaravalloti, Agostino; Fiorentini, Alessandro; Lacanfora, Annamaria [University Tor Vergata, Department of Biomedicine and Prevention, Rome (Italy); Stefani, Alessandro [University Tor Vergata, Department of Neurosciences, Rome (Italy); IRCCS Santa Lucia, Rome (Italy); Stanzione, Paolo [University Tor Vergata, Department of Neurosciences, Rome (Italy); Schillaci, Orazio [University Tor Vergata, Department of Biomedicine and Prevention, Rome (Italy); IRCCS Neuromed, Pozzilli (Italy)

    2014-11-15

    To investigate the relationships among cerebrospinal fluid (CSF) levels of t-Tau, p-Tau and Aβ{sub 1-42} amyloid peptide and {sup 123}I-FP-CIT uptake. The study included 58 subjects (31 men and 27 women, age 67 ± 9 years) with a clinical diagnosis of Parkinson disease diagnosed according to the United Kingdom Parkinson Disease Society Brain Bank criteria. All subjects underwent a CSF assay 28 ± 3 days before {sup 123}I-FP-CIT SPECT scanning. The relationships were evaluated by means of linear regression analysis and Pearson correlation. Striatal {sup 123}I-FP-CIT was positively related to both t-Tau and p-Tau CSF values with low levels of t-Tau and p-Tau being related to a low uptake of {sup 123}I-FP-CIT. In particular, differences with higher statistical significance were found for the striatum between the contralateral side and the side mainly affected on clinical examination (P < 0.001). No significant relationships were found between Aβ{sub 1-42} amyloid peptide and {sup 123}I-FP-CIT binding. The results of our study suggest that the presynaptic dopaminergic system is more involved in Parkinson disease patients with lower t-Tau and p-Tau CSF values while values of Aβ{sub 1-42} amyloid peptide seems not to be related to nigrostriatal degeneration in our series. (orig.)

  11. Do CSF levels of t-Tau, p-Tau and β1-42 amyloid correlate with dopaminergic system impairment in patients with a clinical diagnosis of Parkinson disease? A 123I-FP-CIT study in the early stages of the disease

    International Nuclear Information System (INIS)

    Chiaravalloti, Agostino; Fiorentini, Alessandro; Lacanfora, Annamaria; Stefani, Alessandro; Stanzione, Paolo; Schillaci, Orazio

    2014-01-01

    To investigate the relationships among cerebrospinal fluid (CSF) levels of t-Tau, p-Tau and Aβ 1-42 amyloid peptide and 123 I-FP-CIT uptake. The study included 58 subjects (31 men and 27 women, age 67 ± 9 years) with a clinical diagnosis of Parkinson disease diagnosed according to the United Kingdom Parkinson Disease Society Brain Bank criteria. All subjects underwent a CSF assay 28 ± 3 days before 123 I-FP-CIT SPECT scanning. The relationships were evaluated by means of linear regression analysis and Pearson correlation. Striatal 123 I-FP-CIT was positively related to both t-Tau and p-Tau CSF values with low levels of t-Tau and p-Tau being related to a low uptake of 123 I-FP-CIT. In particular, differences with higher statistical significance were found for the striatum between the contralateral side and the side mainly affected on clinical examination (P 1-42 amyloid peptide and 123 I-FP-CIT binding. The results of our study suggest that the presynaptic dopaminergic system is more involved in Parkinson disease patients with lower t-Tau and p-Tau CSF values while values of Aβ 1-42 amyloid peptide seems not to be related to nigrostriatal degeneration in our series. (orig.)

  12. Dopamine D2L receptor-interacting proteins regulate dopaminergic signaling

    Directory of Open Access Journals (Sweden)

    Norifumi Shioda

    2017-10-01

    Full Text Available Dopamine receptor family proteins include seven transmembrane and trimeric GTP-binding protein-coupled receptors (GPCRs. Among them, the dopamine D2 receptor (D2R is most extensively studied. All clinically used antipsychotic drugs serve as D2R antagonists in the mesolimbic dopamine system, and their ability to block D2R signaling is positively correlated with antipsychotic efficiency. Human genetic studies also show a significant association of DRD2 polymorphisms with disorders including schizophrenia and Parkinson's disease. D2R exists as two alternatively spliced isoforms, the long isoform (D2LR and the short isoform (D2SR, which differ in a 29-amino acid (AA insert in the third cytoplasmic loop. Importantly, previous reports demonstrate functional diversity between the two isoforms in humans. In this review, we focus on binding proteins that specifically interact with the D2LR 29AA insert. We discuss how D2R activities are mediated not only by heterotrimeric G proteins but by D2LR-interacting proteins, which in part regulate diverse D2R activities. Keywords: Dopamine D2L receptor, Antipsychotic drugs, DRD2 polymorphisms, Alternatively spliced isoforms, D2LR-interacting proteins

  13. Differences in the time course of haloperidol-induced up-regulation of rat striatal and mesolimbic dopamine receptors

    International Nuclear Information System (INIS)

    Prosser, E.S.; Csernansky, J.G.; Hollister, L.E.

    1988-01-01

    Regional differences in the onset and persistence of increased dopamine D2 receptor density in rat brain were studied following daily injections of haloperidol for 3, 7, 14, or 28 days. Striatal [ 3 H]-spiroperidol Bmax values were significantly increased following 3 - 28 days of haloperidol treatment, as compared to saline controls. Olfactory tubercle Bmax values were significantly increased only after 14 or 28 days of haloperidol treatment. Nucleus accumbens Bmax values were significantly increased only in the 14-day drug treatment group, suggesting that dopamine D2 receptor up-regulation in nucleus accumbens may reverse during ongoing neuroleptic treatment. These findings suggest that important differences in adaptive responses to chronic dopamine blockade may exist between dopaminergic synapses located in various rat brain regions

  14. Neither Cholinergic Nor Dopaminergic Enhancement Improve Spatial Working Memory Precision in Humans.

    Science.gov (United States)

    Harewood Smith, Adeola N; Challa, Jnana Aditya; Silver, Michael A

    2017-01-01

    Acetylcholine and dopamine are neurotransmitters that play multiple important roles in perception and cognition. Pharmacological cholinergic enhancement reduces excitatory receptive field size of neurons in marmoset primary visual cortex and sharpens the spatial tuning of visual perception and visual cortical fMRI responses in humans. Moreover, previous studies show that manipulation of cholinergic or dopaminergic signaling alters the spatial tuning of macaque prefrontal cortical neurons during the delay period of a spatial working memory (SWM) task and can improve SWM performance in macaque monkeys and human subjects. Here, we investigated the effects of systemic cholinergic and dopaminergic enhancement on the precision of SWM, as measured behaviorally in human subjects. Cholinergic transmission was increased by oral administration of 5 mg of the cholinesterase inhibitor donepezil, and dopaminergic signaling was enhanced with 100 mg levodopa/10 mg carbidopa. Each neurotransmitter system was separately investigated in double-blind placebo-controlled studies. On each trial of the SWM task, a square was presented for 150 ms at a random location along an invisible circle with a radius of 12 degrees of visual angle, followed by a 900 ms delay period with no stimulus shown on the screen. Then, the square was presented at new location, displaced in either a clockwise (CW) or counterclockwise (CCW) direction along the circle. Subjects used their memory of the location of the original square to report the direction of displacement. SWM precision was defined as the amount of displacement corresponding to 75% correct performance. We observed no significant effect on SWM precision for either donepezil or levodopa/carbidopa. There was also no significant effect on performance on the SWM task (percent correct across all trials) for either donepezil or levodopa/carbidopa. Thus, despite evidence that acetylcholine and dopamine regulate spatial tuning of individual neurons and can

  15. Compensatory weight gain due to dopaminergic hypofunction: new evidence and own incidental observations

    Directory of Open Access Journals (Sweden)

    Bohr Iwo

    2008-12-01

    Full Text Available Abstract There is increasing evidence for a role of dopamine in the development of obesity. More specifically, dopaminergic hypofunction might lead to (overcompensatory food intake. Overeating and resulting weight gain may be induced by genetic predisposition for lower dopaminergic activity, but might also be a behavioral mechanism of compensating for decreased dopamine signaling after dopaminergic overstimulation, for example after smoking cessation or overconsumption of high palatable food. This hypothesis is in line with our incidental finding of increased weight gain after discontinuation of pharmaceutical dopaminergic overstimulation in rats. These findings support the crucial role of dopaminergic signaling for eating behaviors and offer an explanation for weight-gain after cessation of activities associated with high dopaminergic signaling. They further support the possibility that dopaminergic medication could be used to moderate food intake.

  16. Can the dopaminergic-related effects of general anesthetics be linked to mechanisms involved in drug abuse and addiction?

    Science.gov (United States)

    Melo, A; Tavares, I; Sousa, N; Pêgo, J M

    2015-08-01

    General anesthetics (GA) are well known for the ability to induce a state of reversible loss of consciousness and unresponsiveness to painful stimuli. However, evidence from animal models and clinical studies show that GA exposure may induce behavioral changes beyond acute effects. Most research and concerns are focused on changes in cognition and memory. We will look at effects of GA on behavior that is mediated by the dopaminergic system. Pharmacological resemblance of GA with drugs of abuse, and the complexity and importance of dopaminergic systems in both reward seeking and addictive illnesses make us believe that it deserves an overview about what is already known and what matters to us as healthcare workers and specifically as anesthesiologists. A review of available evidence strongly suggests that there may be a link between the effects of GA on the brain and substance abuse, partly explained by their influence on the dopaminergic system. © 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

  17. Rapid signaling in distinct dopaminergic axons during locomotion and reward

    Science.gov (United States)

    Howe, MW; Dombeck, DA

    2016-01-01

    Summary Dopaminergic projections from the midbrain to striatum are critical for motor control, as their degeneration in Parkinson’s disease results in profound movement deficits. Paradoxically, most recording methods report rapid phasic dopamine signaling (~100ms bursts) to unpredicted rewards, with little evidence for movement-related signaling. The leading model posits that phasic signaling in striatum targeting dopamine neurons drive reward-based learning, while slow variations in firing (tens of seconds to minutes) in these same neurons bias animals towards or away from movement. However, despite widespread acceptance of this model, current methods have provided little evidence to support or refute it. Here, using new optical recording methods, we report the discovery of rapid phasic signaling in striatum-targeting dopaminergic axons that was associated with, and capable of triggering, locomotion in mice. Axons expressing these signals were largely distinct from those signaling during unexpected rewards. These results suggest that dopaminergic neuromodulation can differentially impact motor control and reward learning with sub-second precision and suggest that both precise signal timing and neuronal subtype are important parameters to consider in the treatment of dopamine-related disorders. PMID:27398617

  18. Neurturin overexpression in dopaminergic neurons induces presynaptic and postsynaptic structural changes in rats with chronic 6-hydroxydopamine lesion.

    Directory of Open Access Journals (Sweden)

    David Reyes-Corona

    Full Text Available The structural effect of neurturin (NRTN on the nigrostriatal dopaminergic system in animals remains unknown, although NRTN has been shown to be effective in Parkinson's disease animal models. Herein, we aimed to demonstrate that NRTN overexpression in dopaminergic neurons stimulates both neurite outgrowths in the nigrostriatal pathway and striatal dendritic spines in aging rats with chronic 6-hydroxydopamine (6-OHDA lesion. At week 12 after lesion, pTracer-mNRTN-His or pGreenLantern-1 plasmids were intranigrally transfected using the NTS-polyplex nanoparticles system. We showed that the transgenic expression in dopaminergic neurons remained until the end of the study (12 weeks. Only animals expressing NRTN-His showed recovery of tyrosine hydroxylase (TH+ cells (28 ± 2%, their neurites (32 ± 2% and the neuron-specific cytoskeletal marker β-III-tubulin in the substantia nigra; striatal TH(+ fibers were also recovered (52 ± 3%, when compared to the healthy condition. Neurotensin receptor type 1 levels were also significantly recovered in the substantia nigra and striatum. Dopamine recovery was 70 ± 4% in the striatum and complete in the substantia nigra. The number of dendritic spines of striatal medium spiny neurons was also significantly increased, but the recovery was not complete. Drug-activated circling behavior decreased by 73 ± 2% (methamphetamine and 89 ± 1% (apomorphine. Similar decrease was observed in the spontaneous motor behavior. Our results demonstrate that NRTN causes presynaptic and postsynaptic restoration of the nigrostriatal dopaminergic system after a 6-OHDA-induced chronic lesion. However, those improvements did not reach the healthy condition, suggesting that NRTN exerts lesser neurotrophic effects than other neurotrophic approaches.

  19. Enduring, Sexually Dimorphic Impact of In Utero Exposure to Elevated Levels of Glucocorticoids on Midbrain Dopaminergic Populations

    Directory of Open Access Journals (Sweden)

    Glenda E. Gillies

    2016-12-01

    Full Text Available Glucocorticoid hormones (GCs released from the fetal/maternal glands during late gestation are required for normal development of mammalian organs and tissues. Accordingly, synthetic glucocorticoids have proven to be invaluable in perinatal medicine where they are widely used to accelerate fetal lung maturation when there is risk of pre-term birth and to promote infant survival. However, clinical and pre-clinical studies have demonstrated that inappropriate exposure of the developing brain to elevated levels of GCs, either as a result of clinical over-use or after stress-induced activation of the fetal/maternal adrenal cortex, is linked with significant effects on brain structure, neurological function and behaviour in later life. In order to understand the underlying neural processes, particular interest has focused on the midbrain dopaminergic systems, which are critical regulators of normal adaptive behaviours, cognitive and sensorimotor functions. Specifically, using a rodent model of GC exposure in late gestation (approximating human brain development at late second/early third trimester, we demonstrated enduring effects on the shape and volume of the ventral tegmental area (VTA and substantia nigra pars compacta (SNc (origins of the mesocorticolimbic and nigrostriatal dopaminergic pathways on the topographical organisation and size of the dopaminergic neuronal populations and astrocytes within these nuclei and on target innervation density and neurochemical markers of dopaminergic transmission (receptors, transporters, basal and amphetamine-stimulated dopamine release at striatal and prefrontal cortical sites that impact on the adult brain. The effects of antenatal GC treatment (AGT were both profound and sexually-dimorphic, not only in terms of quantitative change but also qualitatively, with several parameters affected in the opposite direction in males and females. Although such substantial neurobiological changes might presage marked

  20. Selected therapeutic advances beyond the dopaminergic etiologies

    African Journals Online (AJOL)

    Abdelaziz Ghanemi

    2013-04-04

    Apr 4, 2013 ... tive stress14,15 and therefore modify the bioavailability of the neurons.16. To find out more lines of ... including olfactory and memory impairments, sleep abnormal- ities, anxiety and depression, as well ... gic input to the amygdala51,52 and it has been shown that nor- adrenergic and serotonergic systems ...

  1. Subthalamic deep brain stimulation and dopaminergic medication in Parkinson's disease: Impact on inter-limb coupling.

    Science.gov (United States)

    Daneault, Jean-François; Carignan, Benoit; Sadikot, Abbas F; Duval, Christian

    2016-10-29

    Patients with Parkinson's disease (PD) often present with bimanual coordination deficits whose exact origins remain unclear. One aspect of bimanual coordination is inter-limb coupling. This is characterized by the harmonization of movement parameters between limbs. We assessed different aspects of bimanual coordination in patients with PD, including inter-limb coupling, and determined whether they are altered by subthalamic (STN) deep brain stimulation (DBS) or dopaminergic medication. Twenty PD patients were tested before STN DBS surgery; with and without medication. Post- surgery, patients were tested with their stimulators on and off as well as with and without medication. Patients were asked to perform a unimanual and bimanual rapid repetitive diadochokinesis task. The difference in mean amplitude and mean duration of cycles between hands was computed in order to assess inter-limb coupling. Also, mean angular velocity of both hands and structural coupling were computed for the bimanual task. There was a positive effect of medication and stimulation on mean angular velocity, which relates to clinical improvement. PD patients exhibited temporal inter-limb coupling that was not altered by either medication or STN stimulation. However, PD patients did not exhibit spatial inter-limb coupling. Again, this was not altered by medication or stimulation. Collectively, the results suggest that structures independent of the dopaminergic system and basal ganglia may mediate temporal and spatial inter-limb coupling. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  2. Impulse control disorders associated with dopaminergic medication in patients with pituitary adenomas.

    Science.gov (United States)

    Martinkova, Jana; Trejbalova, Ludmila; Sasikova, Michaela; Benetin, Jan; Valkovic, Peter

    2011-01-01

    Impulse control disorders (ICDs) such as pathological gambling, compulsive shopping, compulsive eating, and hypersexuality are a matter of growing interest, especially in patients with Parkinson disease who are on dopamine replacement therapy. It was recently reported that ICDs are associated with other disorders also treated with dopaminergic drugs (dopamine agonists) such as restless legs syndrome, multiple system atrophy, progressive supranuclear palsy, and fibromyalgia. The aim of this study was to determine the prevalence of ICDs in patients with pituitary adenomas who take dopamine agonists (DAs). Twenty consecutive patients with pituitary adenomas (mostly prolactinomas) taking DAs were assessed. All participated in a structured interview focused on ICDs, which was conducted by a physician. Two (10%) of 20 subjects had a condition diagnosed as ICD. The first patient is a 35-year-old man with giant macroprolactinoma who was alternately treated with different types of DAs (cabergoline, bromocriptine, and quinagolide). He developed compulsive eating and pathological gambling. The second patient is a 53-year-old man with macroprolactinoma who suffered from severe hypersexuality after cabergoline was begun. This study demonstrates the importance of systematic screening for ICDs in patients taking dopaminergic medication regardless of their primary condition.

  3. Colour vision in ADHD: part 1--testing the retinal dopaminergic hypothesis.

    Science.gov (United States)

    Kim, Soyeon; Al-Haj, Mohamed; Chen, Samantha; Fuller, Stuart; Jain, Umesh; Carrasco, Marisa; Tannock, Rosemary

    2014-10-24

    To test the retinal dopaminergic hypothesis, which posits deficient blue color perception in ADHD, resulting from hypofunctioning CNS and retinal dopamine, to which blue cones are exquisitely sensitive. Also, purported sex differences in red color perception were explored. 30 young adults diagnosed with ADHD and 30 healthy young adults, matched on age and gender, performed a psychophysical task to measure blue and red color saturation and contrast discrimination ability. Visual function measures, such as the Visual Activities Questionnaire (VAQ) and Farnsworth-Munsell 100 hue test (FMT), were also administered. Females with ADHD were less accurate in discriminating blue and red color saturation relative to controls but did not differ in contrast sensitivity. Female control participants were better at discriminating red saturation than males, but no sex difference was present within the ADHD group. Poorer discrimination of red as well as blue color saturation in the female ADHD group may be partly attributable to a hypo-dopaminergic state in the retina, given that color perception (blue-yellow and red-green) is based on input from S-cones (short wavelength cone system) early in the visual pathway. The origin of female superiority in red perception may be rooted in sex-specific functional specialization in hunter-gather societies. The absence of this sexual dimorphism for red colour perception in ADHD females warrants further investigation.

  4. Imbalanced Dopaminergic Transmission Mediated by Serotonergic Neurons in L-DOPA-Induced Dyskinesia

    Directory of Open Access Journals (Sweden)

    Sylvia Navailles

    2012-01-01

    Full Text Available L-DOPA-induced dyskinesias (LIDs are one of the main motor side effects of L-DOPA therapy in Parkinson's disease. The review will consider the biochemical evidence indicating that the serotonergic neurons are involved in the dopaminergic effects of L-DOPA in the brain. The consequences are an ectopic and aberrant release of dopamine that follows the serotonergic innervation of the brain. After mid- to long-term treatment with L-DOPA, the pattern of L-DOPA-induced dopamine release is modified. In several brain regions, its effect is dramatically reduced while, in the striatum, its effect is quite preserved. LIDs could appear when the dopaminergic effects of L-DOPA fall in brain areas such as the cortex, enhancing the subcortical impact of dopamine and promoting aberrant motor responses. The consideration of the serotonergic system in the core mechanism of action of L-DOPA opens an important reserve of possible strategies to limit LIDs.

  5. Representation of spontaneous movement by dopaminergic neurons is cell-type selective and disrupted in parkinsonism

    DEFF Research Database (Denmark)

    Dodson, Paul D.; Dreyer, Jakob K.; Jennings, Katie Ann

    2016-01-01

    receptor expressed by striatal neurons. Importantly, in aged mice harboring a genetic burden relevant for human Parkinson's disease, the precise movement-related firing of SNc dopaminergic neurons and the resultant striatal dopamine signaling were lost. These data show that distinct dopaminergic cell types......Midbrain dopaminergic neurons are essential for appropriate voluntary movement, as epitomized by the cardinal motor impairments arising in Parkinson's disease. Understanding the basis of such motor control requires understanding how the firing of different types of dopaminergic neuron relates...... of these dopaminergic neurons can manifest as rapid and robust fluctuations in striatal dopamine concentration and receptor activity. The exact nature of the movement-related signaling in the striatum depended on the type of dopaminergic neuron providing inputs, the striatal region innervated, and the type of dopamine...

  6. The rise and fall of mesodiencephalic dopaminergic neurons : Molecular programming by transcription factors Engrailed 1, Pitx3, and Nkx2.9 during the development of mesodiencephalic neurons

    NARCIS (Netherlands)

    Kouwenhoven, W.M.

    2016-01-01

    The mid- and hindbrain harbor two essential monoaminergic neuronal populations: the mesodiencephalic dopaminergic (mdDA) neurons in the midbrain and the serotonergic (5HT) neurons in the hindbrain. Both systems innervate multiple regions in the forebrain and are involved in the guidance of our mood,

  7. Molecular Programming of Mesodiencephalic Dopaminergic Neuronal Subsets

    Directory of Open Access Journals (Sweden)

    Marten P. Smidt

    2017-07-01

    Full Text Available Dopamine neurons of the substantia nigra compacta (SNc and ventral tegmental area (VTA are critical components of the neuronal machinery to control emotion and movement in mammals. The slow and gradual death of these neurons as seen in Parkinson's disease has triggered a large investment in research toward unraveling the molecular determinants that are used to generate these neurons and to get an insight in their apparent selective vulnerability. Here, I set out to summarize the current view on the molecular distinctions that exist within this mesodiencephalic dopamine (mdDA system and elaborate on the molecular programming that is responsible for creating such diversity.

  8. Dopaminergic and Clinical Correlates of Pathological Gambling in Parkinson’s Disease: A Case Report

    OpenAIRE

    Callesen, Mette Buhl; Hansen, K. V.; Gjedde, A.; Linnet, J.; Møller, A.

    2013-01-01

    Dopaminergic medication for motor symptoms in Parkinson’s disease (PD) recently has been linked with impulse control disorders, including pathological gambling (PG), which affects up to 8% of patients. PG often is considered a behavioral addiction associated with disinhibition, risky decision-making, and altered striatal dopaminergic neurotransmission. Using [11C]raclopride with positron emission tomography, we assessed dopaminergic neurotransmission during Iowa Gambling Task performance. Her...

  9. Dopaminergic and clinical correlates of pathological gambling in Parkinson's disease: A case report

    OpenAIRE

    Mette Buhl Callesen; Mette Buhl Callesen; Kim Vang Hansen; Albert eGjedde; Albert eGjedde; Jakob eLinnet; Jakob eLinnet; Arne eMøller; Arne eMøller

    2013-01-01

    Dopaminergic medication for motor symptoms in Parkinson’s disease recently has been linked with impulse control disorders, including pathological gambling, which affects up to 8% of patients. Pathological gambling often is considered a behavioral addiction associated with disinhibition, risky decision-making, and altered striatal dopaminergic neurotransmission. Using [11C]raclopride with positron emission tomography, we assessed dopaminergic neurotransmission during Iowa Gambling Task perform...

  10. Dopaminergic Immunofluorescence Studies in Kidney Tissue.

    Science.gov (United States)

    Gildea, J J; Van Sciver, R E; McGrath, H E; Kemp, B A; Jose, P A; Carey, R M; Felder, R A

    2017-01-01

    The kidney is a highly integrated system of specialized differentiated cells that are responsible for fluid and electrolyte balance in the body. While much of today's research focuses on isolated nephron segments or cells from nephron segments grown in tissue culture, an often overlooked technique that can provide a unique view of many cell types in the kidney is slice culture. Here, we describe techniques that use freshly excised kidney tissue from rats to perform a variety of experiments shortly after isolating the tissue. By slicing the rat kidney in a "bread loaf" format, multiple studies can be performed on slices from the same tissue in parallel. Cryosectioning and staining of the tissue allow for the evaluation of physiological or biochemical responses in a wide variety of specific nephron segments. The procedures described within this chapter can also be extended to human or mouse kidney tissue.

  11. A new digitized method of the compulsive gnawing test revealed dopaminergic activity of salvinorin A in vivo.

    Science.gov (United States)

    Phipps, Stephen M; Butterweck, Veronika

    2010-09-01

    The compulsive gnawing (CG) test has been used for numerous years as an assay to determine the dopaminergic activity of various compounds. We developed a new method of quantification via a digitization step which allowed a more precise measurement of the gnawing activity. It was the aim of the present study to explore possible dopaminergic effects of salvinorin A (SA), the major active compound of Salvia divinorum, using the new digitized CG test. A group of experiments using male C57BL/6 mice were performed to validate the new method of quantification showing only significant increases of gnawing when the dopamine reuptake inhibitors buproprion (20 mg/kg, p.0.) and nomifensine (10 mg/kg, i.p.) were given concomitantly with apomorphine (10 mg/kg, i.p.). Different concentrations of the SA (1.0, 2.5, 5, and 10 mg/kg, i.p.) were tested with positive dopaminergic activity when administered with apomorphine which differed from the semisynthetic counterpart U-69593. Furthermore, the activity observed with SA was unsuccessfully antagonized by the κ-opioid receptor antagonist norbinaltorphimine (NorBNI; 10 and 20 mg/kg, i.p.), while the dopamine antagonist haloperidol did successfully block (0.06 mg/kg, i.p.) the gnawing activity seen with SA. Our data further strengthen the argument that salvinorin A is not a selective κ-opioid receptor agonist and is the first in vivo study that veers from salvinorin A acting solely like its synthetic counterparts. Furthermore, the digitized CG test system used in this study provides a new computational method to accurately detect behavior associated with dopaminergic neurotransmission. © Georg Thieme Verlag KG Stuttgart-New York.

  12. Thyrotoxic and dopaminergic effects of polychlorinated biphenyls

    Energy Technology Data Exchange (ETDEWEB)

    Ness, D.K.

    1994-01-01

    Perturbations in the developing nervous system have been associated with perinatal exposures to polychlorinated biphenyls (PCBs). To determine which PCBs accumulate in brain following perinatal exposure, Sprague-Dawley rats were exposed by gavage to Aroclor 1242 (4 or 16 mg/kg/day) during days 10-16 of gestation. At weaning (day 21), analysis of pup brain (frontal cortex, hippocampus, and caudate putamen) by gas chromatography revealed ten peaks representing 10-14 congeners in PCB-exposed animals. Brain PCB concentrations were greatest in high-dose pups for all congeners except for 2,4,4[prime]-trichlorobiphenyl (PCB 28) which had a higher concentration in the low-dose group. Congeners differed significantly in their degree of bioaccumulation, but no significant differences among brain regions were found. A lack of regionalization of PCB residues in the brain was also demonstrated by autoradiography in weanling rats treated iv with [[sup 14]C]-3,3[prime],4,4[prime]-tetrachlorobiphenyl or [[sup 14]C]-2,2[prime],4,4[prime]-tetrachlorobiphenyl. Time-mated Sprague-Dawley rats were exposed on days 10-16 of gestation to three environmentally-relevant PCBs: 2,4,4[prime]-trichlorobiphenyl (PCB 28), 8 or 32 mg/kg/day; 2,3[prime],4,4[prime],5-pentachlorobiphenyl (PCB 118), 4 or 16 mg/kg/day; or 2,2[prime],4,4[prime],5,5[prime]-hexachlorobiphenyl (PCB 153), 16 or 64 mg/kg/day. At weaning, serum total thyroxin, but not triiodothyronine, was markedly depressed in pups exposed perinatally to PCB 118 or 153; and thyroid glands from PCB 118-treated pups revealed histologic changes suggestive of sustained TSH stimulation. No significant PCB-induced changes were detected in the activity of the rate limiting enzyme in the synthesis of catecholamines, tyrosine hydroxylase, in the caudate putamen at weaning or in adulthood. Likewise no significant changes were detected in dopamine receptor (D1 and D2) concentrations in several regions in the mesocortical and nigrostriatal pathways.

  13. Dopaminergic Neurogenetics of Sleep Disorders in Reward Deficiency Syndrome (RDS).

    Science.gov (United States)

    Blum, Kenneth; Oscar-Berman, Marlene; Badgaiyan, Rajendra D; Khurshid, Khurshid A; Gold, Mark S

    2014-02-18

    It is well-known that sleep has a vital function especially as it relates to prevention of substance-related disorders as discussed in the DSM-V. We are cognizant that certain dopaminergic gene polymorphisms have been associated with various sleep disorders. The importance of "normal dopamine homeostasis" is tantamount for quality of life especially for the recovering addict. Since it is now know that sleep per se has been linked with metabolic clearance of neurotoxins in the brain, it is parsonomiuos to encourage continued research in sleep science, which should ultimately result in attenuation of sleep deprivation especially associated with substance related disorders.

  14. Adolescent Traumatic Brain Injury Induces Chronic Mesolimbic Neuroinflammation with Concurrent Enhancement in the Rewarding Effects of Cocaine in Mice during Adulthood.

    Science.gov (United States)

    Merkel, Steven F; Razmpour, Roshanak; Lutton, Evan M; Tallarida, Christopher S; Heldt, Nathan A; Cannella, Lee Anne; Persidsky, Yuri; Rawls, Scott M; Ramirez, Servio H

    2017-01-01

    Clinical psychiatric disorders of depression, anxiety, and substance abuse are most prevalent after traumatic brain injury (TBI). Pre-clinical research has focused on depression and anxiety post-injury; however, virtually no data exist examining whether the preference for illicit drugs is affected by traumatic injury in the developing adolescent brain. Using the controlled cortical impact (CCI) model of TBI and the conditioned place preference (CPP) assay, we tested the underlying hypothesis that brain injury during adolescence exacerbates the rewarding properties of cocaine in adulthood possibly through an active inflammatory status in the mesolimbic pathway. Six-week old, C57BL/6 mice sustained a single CCI-TBI to the right somatosensory cortex. CPP experiments with cocaine began 2 weeks post-TBI. Animals receiving cocaine displayed significant place preference shifts compared to saline controls. Further, within the cocaine-experienced cohort, moderate CCI-TBI during adolescence significantly increased the preference shift in adulthood when compared to naïve controls. Additionally, persistent neuroinflammatory responses were observed in the cortex, nucleus accumbens (NAc), and ventral tegmental area post-CCI-TBI. Significant increases in both astrocytic, glial fibrillary acidic protein, and microglial, ionization basic acid 1, markers were observed in the NAc at the end of CPP testing. Moreover, analysis using focused array gene expression panels identified the upregulation of numerous inflammatory genes in moderate CCI-TBI animals, compared to naïve controls, both in the cortex and NAc at 2 weeks post-TBI, before onset of cocaine administration. These results suggest that sustaining moderate TBI during adolescence may augment the rewarding effects of psychostimulants in adulthood, possibly by induction of chronic mesolimbic neuroinflammation.

  15. Glial cell line-derived neurotrophic factor up-regulates GTP-cyclohydrolase I activity and tetrahydrobiopterin levels in primary dopaminergic neurones

    DEFF Research Database (Denmark)

    Bauer, M; Suppmann, S; Meyer, M

    2002-01-01

    Glial cell line-derived neurotrophic factor (GDNF) protects dopaminergic neurones against toxic and physical damage. In addition, GDNF promotes differentiation and structural integrity of dopaminergic neurones. Here we show that GDNF can support the function of primary dopaminergic neurones...

  16. Advances in non-dopaminergic pharmacological treatments of Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Sandy eStayte

    2014-05-01

    Full Text Available Since the 1960’s treatments for Parkinson's disease (PD have traditionally been directed to effectively restore or replace dopamine, with L-Dopa the gold standard. However, chronic L-Dopa use is associated with debilitating dyskinesias, limiting its effectiveness. This has created a need to develop new therapies that work in ways other than restoring or replacing dopamine. We provide a comprehensive overview of the emerging non-dopaminergic pharmacological treatments including drugs targeting adenosine, glutamate, adrenergic, and serotonin receptors, as well as GLP-1 agonists, calcium channel blockers, iron chelators, anti-inflammatories, neurotrophic factors and gene therapy, with a detailed overview of their success in animal models and their translation to human clinical trials. We suggest that further developments in the identification of novel therapeutics, particularly those offering disease-modifying effects, will consistently be met with challenges until improvements in clinical trial design and advances in understanding the basic science of PD are made. We consider how developments in genetics, the possibility that PD may consist of multiple disease states, and potential etiology in non-dopaminergic regions will influence drug development. We conclude that despite the challenges ahead patients have much cause for optimism that novel therapeutics that offer better disease management and/or which slow disease progression are inevitable.

  17. Dopaminergic influence on disturbed spatial discrimination in Parkinson's disease.

    Science.gov (United States)

    Shin, Hae-Won; Kang, Suk Y; Sohn, Young H

    2005-12-01

    Various sensory symptoms and disturbed sensory perception are often observed in patients with idiopathic Parkinson's disease (PD). The basis of sensory disturbance in PD is unknown but possibly reflects a role for the basal ganglia in sensory processing. To investigate the relationship between the sensory dysfunction and dopaminergic deficiency in PD, we measured spatial discrimination using the Grating Orientation Task in 21 drug-naive patients with PD, before and after long-term antiparkinson therapy, and 25 age-matched healthy controls. The grating orientation threshold was significantly higher in patients (3.03 +/- 0.84) than controls (2.03 +/- 0.79). After 3 to 10 months of antiparkinson therapy, the grating orientation threshold was significantly lowered (2.66 +/- 0.84), although it was still higher than that in controls. Improvement in the patients' sensory function was significantly correlated with motor improvement (r = 0.44). These results suggest that sensory dysfunction in Parkinson's disease is related at least in part to the dopaminergic deficit.

  18. Quetiapine and clozapine in parkinsonian patients with dopaminergic psychosis.

    Science.gov (United States)

    Morgante, Letterio; Epifanio, Antonio; Spina, Edoardo; Zappia, Mario; Di Rosa, Antonio E; Marconi, Roberto; Basile, Giorgio; Di Raimondo, Giorgio; La Spina, Paolo; Quattrone, Aldo

    2004-01-01

    This study aimed to compare the efficacy and safety of quetiapine and clozapine in parkinsonian patients with dopaminergic psychosis in a randomized, open-label, blinded-rater, parallel group trial. Forty-five patients with Parkinson disease (PD) and psychosis induced by antiparkinsonian drugs were randomly assigned to receive either quetiapine or clozapine. The duration of the trial was 12 weeks. Forty patients, 20 in each treatment group, completed the study. The final dose of quetiapine (mean +/- SD) was 91 +/- 47 mg/d and that of clozapine 26 +/- 12 mg/d. The severity of psychosis was assessed using the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impression Scale-Severity Subscale (CGI-S). The Unified Parkinson's Disease Rating Scale (UPDRS) III was used to assess motor conditions during the study period. The Abnormal Involuntary Movement Scale (AIMS) was performed to evaluate dyskinesias. Forty patients, 20 on clozapine and 20 on quetiapine, completed the study. The psychopathologic state improved significantly (P clozapine and quetiapine at any assessment time. Motor conditions remained unchanged after clozapine and quetiapine. Dyskinesias decreased significantly (P clozapine appear equally efficacious for treatment of dopaminergic psychosis in patients with PD.

  19. [Molecular mechanism of brain regeneration and reconstruction of dopaminergic neural network in planarians].

    Science.gov (United States)

    Nishimura, Kaneyasu; Kitamura, Yoshihisa; Agata, Kiyokazu

    2008-04-01

    Recently, planarians have received much attention because of their contributions to research on the basic science of stem cell systems, neural regeneration, and regenerative medicine. Planarians can regenerate complete organs, including a well-organized central nervous system (CNS), within about 7 days. This high regenerative capacity is supported by pluripotent stem cells present in the mesenchymal space throughout the body. Interestingly, planarians can regenerate their brain via a molecular mechanism similar to that of mammalian brain development. The regeneration process of the planarian brain can be divided into five steps: (1) anterior blastema formation, (2) brain rudiment formation, (3) brain pattern formation, (4) neural network formation, and (5) functional recovery, with several kinds of genes and molecular cascades acting at each step. Recently, we have identified a planarian tyrosine hydroxylase (TH) gene, a rate-limiting enzyme for dopamine (DA) biosynthesis, and produced TH-knockdown planarians by the RNA interference technique. Studies of TH-knockdown planarians showed that DA has an important role of the modification in behavioral movement in planarians. Using monoclonal anti-planarian TH antibody, we also found that dopaminergic neurons are mainly localized in the planarian brain. When the planarian body was amputated, newly generated TH-immunopositive neurons were detected in the anterior region at day 3 of regeneration (i.e., the period of neural network formation), and the TH-immunopositive axonal and dendritic neural network in the CNS was reconstructed during day 5-7 of regeneration. In this article, recent advances in elucidating the molecular mechanism of planarian brain regeneration and dopaminergic neurons are reviewed, and its future prospects for contribution of this system to basic science and medical science research are described.

  20. Pathological gambling: Relation of skin conductance response to dopaminergic neurotransmission and sensation-seeking

    DEFF Research Database (Denmark)

    Peterson, Ericka Ann; Møller, Arne; Doudet, Doris J.

    2010-01-01

    Absent Skin Conductance Response (SCR) in pathological gambling (PG) may relate to dopaminergic mechanisms. We recruited equal numbers of PG subjects and healthy control (HC) subjects, and then tested the claim that SCR is less conditioned by dopaminergic activity in PG subjects. During active...... gambling, SCR differed in PG and HC subjects (P

  1. Ascending Midbrain Dopaminergic Axons Require Descending GAD65 Axon Fascicles for Normal Pathfinding

    Directory of Open Access Journals (Sweden)

    Claudia Marcela Garcia-Peña

    2014-06-01

    Full Text Available The Nigrostriatal pathway (NSP is formed by dopaminergic axons that project from the ventral midbrain to the dorsolateral striatum as part of the medial forebrain bundle. Previous studies have implicated chemotropic proteins in the formation of the NSP during development but little is known of the role of substrate-anchored signals in this process. We observed in mouse and rat embryos that midbrain dopaminergic axons ascend in close apposition to descending GAD65-positive axon bundles throughout their trajectory to the striatum. To test whether such interaction is important for dopaminergic axon pathfinding, we analyzed transgenic mouse embryos in which the GAD65 axon bundle was reduced by the conditional expression of the diphtheria toxin. In these embryos we observed dopaminergic misprojection into the hypothalamic region and abnormal projection in the striatum. In addition, analysis of Robo1/2 and Slit1/2 knockout embryos revealed that the previously described dopaminergic misprojection in these embryos is accompanied by severe alterations in the GAD65 axon scaffold. Additional studies with cultured dopaminergic neurons and whole embryos suggest that NCAM and Robo proteins are involved in the interaction of GAD65 and dopaminergic axons. These results indicate that the fasciculation between descending GAD65 axon bundles and ascending dopaminergic axons is required for the stereotypical NSP formation during brain development and that known guidance cues may determine this projection indirectly by instructing the pathfinding of the axons that are part of the GAD65 axon scaffold.

  2. Neurofunctional dopaminergic impairment in elderly after lifetime exposure to manganese.

    Science.gov (United States)

    Lucchini, Roberto G; Guazzetti, Stefano; Zoni, Silvia; Benedetti, Chiara; Fedrighi, Chiara; Peli, Marco; Donna, Filippo; Bontempi, Elza; Borgese, Laura; Micheletti, Serena; Ferri, Roberta; Marchetti, Serena; Smith, Donald R

    2014-12-01

    interval of 22.7 ng/m(3) (median 26.4). For the odor identification score of the Sniffin Stick test, an association was observed with soil Mn (p=0.0006) and with a significant interaction with blood Pb (p=0.0856). Significant dose-responses resulted also for the Raven's Colored Progressive Matrices with the distance from exposure point source (p=0.0025) and Mn in soil (p=0.09), and for the Trail Making test, with urinary Mn (p=0.0074). Serum prolactin (PRL) levels were associated with air (p=0.061) and urinary (p=0.003) Mn, and with blood Pb (p=0.0303). In most of these associations age played a significant role as an effect modifier. Lifelong exposure to Mn was significantly associated with changes in odor discrimination, motor coordination, cognitive abilities and serum PRL levels. These effects are consistent with the hypothesis of a specific mechanism of toxicity of Mn on the dopaminergic system. Lead co-exposure, even at very low levels, can further enhance Mn toxicity. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. Neurophysiological evidence of impaired self-monitoring in schizotypal personality disorder and its reversal by dopaminergic antagonism

    Directory of Open Access Journals (Sweden)

    Mireia Rabella

    2016-01-01

    Conclusions: These results indicate that SPD individuals show deficits in self-monitoring analogous to those in schizophrenia. These deficits can be evidenced by neurophysiological measures, suggest a dopaminergic imbalance, and can be reverted by dopaminergic antagonists.

  4. A simple algorithm for subregional striatal uptake analysis with partial volume correction in dopaminergic PET imaging

    International Nuclear Information System (INIS)

    Lue Kunhan; Lin Hsinhon; Chuang Kehshih; Kao Chihhao, K.; Hsieh Hungjen; Liu Shuhsin

    2014-01-01

    In positron emission tomography (PET) of the dopaminergic system, quantitative measurements of nigrostriatal dopamine function are useful for differential diagnosis. A subregional analysis of striatal uptake enables the diagnostic performance to be more powerful. However, the partial volume effect (PVE) induces an underestimation of the true radioactivity concentration in small structures. This work proposes a simple algorithm for subregional analysis of striatal uptake with partial volume correction (PVC) in dopaminergic PET imaging. The PVC algorithm analyzes the separate striatal subregions and takes into account the PVE based on the recovery coefficient (RC). The RC is defined as the ratio of the PVE-uncorrected to PVE-corrected radioactivity concentration, and is derived from a combination of the traditional volume of interest (VOI) analysis and the large VOI technique. The clinical studies, comprising 11 patients with Parkinson's disease (PD) and 6 healthy subjects, were used to assess the impact of PVC on the quantitative measurements. Simulations on a numerical phantom that mimicked realistic healthy and neurodegenerative situations were used to evaluate the performance of the proposed PVC algorithm. In both the clinical and the simulation studies, the striatal-to-occipital ratio (SOR) values for the entire striatum and its subregions were calculated with and without PVC. In the clinical studies, the SOR values in each structure (caudate, anterior putamen, posterior putamen, putamen, and striatum) were significantly higher by using PVC in contrast to those without. Among the PD patients, the SOR values in each structure and quantitative disease severity ratings were shown to be significantly related only when PVC was used. For the simulation studies, the average absolute percentage error of the SOR estimates before and after PVC were 22.74% and 1.54% in the healthy situation, respectively; those in the neurodegenerative situation were 20.69% and 2

  5. Cognitive judgment bias interacts with risk based decision making and sensitivity to dopaminergic challenge in rats

    Directory of Open Access Journals (Sweden)

    Robert Drozd

    2016-08-01

    Full Text Available Although cognitive theory has implicated judgement bias in various psychopathologies, its role in decision making under risk remains relatively unexplored. In the present study we assessed the effects of cognitive judgment bias on risky choices in rats. First, we trained and tested the animals on the rat version of the probability-discounting task. During discrete trials, the rats chose between two levers; a press on the ‘small/certain’ lever always resulted in the delivery of one reward pellet, whereas a press on the ‘large/risky’ lever resulted in the delivery of four pellets. However, the probability of receiving a reward from the ‘large/risky’ lever gradually decreased over the four trial blocks. Subsequently, the rats were re-trained and evaluated on a series of ambiguous-cue interpretation tests, which permitted their classification according to the display of ‘optimistic’ or ‘pessimistic’ traits. Because dopamine has been implicated in both: risky choices and optimism, in the last experiment, we compared the reactivity of the dopaminergic system in the ‘optimistic’ and ‘pessimistic’ animals using the apomorphine (2mg/kg s.c. sensitivity test. We demonstrated that as risk increased, the proportion of risky lever choices decreased significantly slower in ‘optimists’ compared with ‘pessimists’ and that these differences between the two groups of rats were associated with different levels of dopaminergic system reactivity. Our findings suggest that cognitive judgement bias, risky decision-making and dopamine are linked, and they provide a foundation for further investigation of the behavioural traits and cognitive processes that influence risky choices in animal models.

  6. Dopaminergic influences on changes in human tactile acuity induced by tactile coactivation.

    Science.gov (United States)

    Bliem, Barbara; Frombach, Elke; Ragert, Patrick; Knossalla, Frauke; Woitalla, Dirk; Tegenthoff, Martin; Dinse, Hubert R

    2007-07-01

    As shown in animal experiments, dopaminergic mechanisms participate in N-methyl-D-aspartate (NMDA) receptor-dependent neuroplasticity. Dopamine is thought to play a similar role in humans, where it influences learning and memory. Here, we tested the dopaminergic action on learning in the tactile domain. To induce tactile non-associative learning, we applied a tactile coactivation protocol, which is known to improve tactile two-point discrimination of the stimulated finger. We studied the influence of a single oral dose of levodopa (25, 50, 100, 250 or 350 mg) administered preceding the coactivation protocol on changes in tactile performance in different groups of subjects. In addition, 3 x 100 mg levodopa was administered over a time period of 3 h in another group. Under placebo conditions, tactile two-point discrimination was improved on the coactivated index finger. Similar improvement was found when 25, 50 and 250 mg levodopa was applied. On the contrary, tactile improvement was completely eliminated by 1 x 100 and 3 x 100 mg levodopa. No drug effects were found on the left index finger indicating that the drug had no effect on performance per se. In contrast to previous findings in the motor and speech domain, we found that the administration of levodopa exerts either no or even negative effects on non-associative learning in the human somatosensory system. Whenever levodopa is used in neurorehabilitative context, it has to be kept in mind that beneficial effects in the motor or speech domain cannot be easily generalized to other systems.

  7. [The endocannabinoid system role in the pathogenesis of obesity and depression].

    Science.gov (United States)

    Zdanowicz, Anna; Kaźmierczak, Wieńczysław; Wierzbiński, Piotr

    2015-07-01

    Excessive consumption and obesity do not always have to be strictly pathological. The adjustment of food intake as well as the pleasure of eating are the results of the circulation of neurotransmitters, hormones and glucocorticoids which have an ability to regulate the activity of many receptors connected with G protein, including endocannabinoid receptors. The key role of endocannabinoids in pathogenesis of obesity is their overproduction by adipose cells. Endocannabinoids (eCBs) affect CB1 receptors and increase hunger, willingness to intake food, decrease peristalsis and delay stomach emptying. In obese people increased levels of both central and peripheral endocannabinoids are observed. It may be connected with higher availability of endocannabinoid precursors to synthesis from adipose tissue and lipids. Raised concentration of eCBs in the body may be the consequence of their catabolism dysfunction. There is a positive correlation between amount the number of receptors in the peripheral tissues and obesity increase. It is thought that expression of CB1 receptors in mesolimbic system is connected with motivation to consume food in response to rewarding factor. The appetite increase after cannabinoids use is probably caused by rewarding action of the consumed food and it results from excessive dopaminergic transmission in award system. The pharmacological inhibition of endocannabinoids activity leads to weight loss, but may also have negative consequences such as decreased mood, reduced tolerance of pain, intensified anxiety, anhedonia, depressive symptoms, even suicidal thoughts. In post mortem examinations a decrease in CB1 receptor density in grey matter of glial cells in patients with major depression was identified. The pleiotropic and extensive activity of endocannabinoid system can influence a range of neurotransmitters thereby modulating the psychiatric life phenomena, simultaneously being involved in metabolism control and energetic system of human body

  8. Dopaminergic mediation of the discriminative stimulus functions of modafinil in rats.

    Science.gov (United States)

    Quisenberry, Amanda J; Baker, Lisa E

    2015-12-01

    Modafinil is a wake-promoting drug with FDA approval for the treatment of excessive daytime sleepiness that has been prescribed for ADHD and recently assessed as a potential treatment for psychostimulant dependence. Previous research indicates that modafinil modestly increases locomotor activity and produces similar discriminative stimulus effects to psychostimulants in rodents, although the subjective effects of modafinil are reportedly distinct from those of cocaine or amphetamine in humans with a history of psychostimulant abuse. The current study employed drug discrimination procedures in rats to examine the pharmacological actions contributing to modafinil's discriminative stimulus functions. Eight male Sprague-Dawley rats were trained to discriminate intragastric administration of 256 mg/kg modafinil from vehicle (5% arabic gum) under a FR 20 schedule of food reinforcement. Substitution tests were conducted with various dopaminergic agents (d-amphetamine, cocaine, PNU-91356A, GBR 12909, methylphenidate) and nondopaminergic agents (nicotine, ethanol). Antagonist tests were conducted with the selective D1 antagonist, SCH 39166, and the nonselective D2 antagonist, haloperidol. Rats trained to discriminate modafinil displayed complete stimulus generalization to cocaine, methylphenidate, and GBR 12909 and the discrimination was completely blocked by both SCH 39166 and haloperidol. Evidence for significant partial substitution was obtained with d-amphetamine, PNU-91356A, and nicotine. Results strongly support the role of dopaminergic mechanisms in the discriminative stimulus functions of modafinil, although further evaluation regarding the contribution of other neurotransmitter systems to these effects should be continued. The findings are discussed in light of clinical research efforts with modafinil as a treatment for psychostimulant dependence.

  9. Antidepressant-like effect of modafinil in mice: Evidence for the involvement of the dopaminergic neurotransmission.

    Science.gov (United States)

    Mahmoudi, Javad; Farhoudi, Mehdi; Talebi, Mahnaz; Sabermarouf, Babak; Sadigh-Eteghad, Saeed

    2015-06-01

    Modafinil is a wake-promoting agent that provides wide ranges of neurological effects. There is evidence that it can produce antidepressant effects. This study investigated the antidepressant effect of modafinil in the tail suspension (TST) in mice. Different doses of modafinil was intraperitoneally (ip) administrated and then animals were subjected to TST and/or open field test (OFT). Moreover, the implication of the dopaminergic neurotransmission in modafinil's antidepressant effect was studied. For this purpose, animals were pretreated with haloperidol (non-selective dopamine receptor antagonist), or SCH23390 and sulpiride (the dopamine D1 and D2 receptor antagonist, respectively), then were assessed by TST. The possible effect of sub-effective dose of modafinil in combination with sub-therapeutic doses of standard antidepressants was also evaluated in separate groups. Modafinil (75 mg/kg, ip) produced antidepressant effect in TST, as compared to a control group, without any alterations in ambulation in OFT. Pretreatment of mice with haloperidol (0.2mg/kg, ip) and sulpride (50mg/kg, ip) blocked the anti-immobility effect of modafinil (75 mg/kg, ip). We also found that the administration of SCH23390 (0.05 mg/kg, sc) couldn't antagonize the antidepressant effects of modafinil. In addition, a sub-effective dose of modafinil (50mg/kg, ip) potentiated the sub-effective doses of standard antidepressants including of bupropion (1mg/kg, ip), fluoxetine (1mg/kg, ip) and imipramine (0.1mg/kg, ip) and reduced immobility time in TST. Results show that modafinil induced an antidepressant property in TST and this effect apparently was mediated through interaction with the dopaminergic (D2 receptors) system. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  10. Alpha-synuclein cell-to-cell transfer and seeding in grafted dopaminergic neurons in vivo.

    Directory of Open Access Journals (Sweden)

    Elodie Angot

    Full Text Available Several people with Parkinson's disease have been treated with intrastriatal grafts of fetal dopaminergic neurons. Following autopsy, 10-22 years after surgery, some of the grafted neurons contained Lewy bodies similar to those observed in the host brain. Numerous studies have attempted to explain these findings in cell and animal models. In cell culture, α-synuclein has been found to transfer from one cell to another, via mechanisms that include exosomal transport and endocytosis, and in certain cases seed aggregation in the recipient cell. In animal models, transfer of α-synuclein from host brain cells to grafted neurons has been shown, but the reported frequency of the event has been relatively low and little is known about the underlying mechanisms as well as the fate of the transferred α-synuclein. We now demonstrate frequent transfer of α-synuclein from a rat brain engineered to overexpress human α-synuclein to grafted dopaminergic neurons. Further, we show that this model can be used to explore mechanisms underlying cell-to-cell transfer of α-synuclein. Thus, we present evidence both for the involvement of endocytosis in α-synuclein uptake in vivo, and for seeding of aggregation of endogenous α-synuclein in the recipient neuron by the transferred α-synuclein. Finally, we show that, at least in a subset of the studied cells, the transmitted α-synuclein is sensitive to proteinase K. Our new model system could be used to test compounds that inhibit cell-to-cell transfer of α-synuclein and therefore might retard progression of Parkinson neuropathology.

  11. Developmental Deltamethrin Exposure Causes Persistent Changes in Dopaminergic Gene Expression, Neurochemistry, and Locomotor Activity in Zebrafish

    Science.gov (United States)

    Kung, Tiffany S.; Richardson, Jason R.; Cooper, Keith R.; White, Lori A.

    2015-01-01

    Pyrethroids are commonly used insecticides that are considered to pose little risk to human health. However, there is an increasing concern that children are more susceptible to the adverse effects of pesticides. We used the zebrafish model to test the hypothesis that developmental exposure to low doses of the pyrethroid deltamethrin results in persistent alterations in dopaminergic gene expression, neurochemistry, and locomotor activity. Zebrafish embryos were treated with deltamethrin (0.25–0.50 μg/l), at concentrations below the LOAEL, during the embryonic period [3–72 h postfertilization (hpf)], after which transferred to fresh water until the larval stage (2-weeks postfertilization). Deltamethrin exposure resulted in decreased transcript levels of the D1 dopamine (DA) receptor (drd1) and increased levels of tyrosine hydroxylase at 72 hpf. The reduction in drd1 transcripts persisted to the larval stage and was associated with decreased D2 dopamine receptor transcripts. Larval fish, exposed developmentally to deltamethrin, had increased levels of homovanillic acid, a DA metabolite. Since the DA system is involved in locomotor activity, we measured the swim activity of larval fish following a transition to darkness. Developmental exposure to deltamethrin significantly increased larval swim activity which was attenuated by concomitant knockdown of the DA transporter. Acute exposure to methylphenidate, a DA transporter inhibitor, increased swim activity in control larva, while reducing swim activity in larva developmentally exposed to deltamethrin. Developmental exposure to deltamethrin causes locomotor deficits in larval zebrafish, which is likely mediated by dopaminergic dysfunction. This highlights the need to understand the persistent effects of low-dose neurotoxicant exposure during development. PMID:25912032

  12. Orexin-A Suppresses Signal Transmission to Dopaminergic Amacrine Cells From Outer and Inner Retinal Photoreceptors.

    Science.gov (United States)

    Qiao, Sheng-Nan; Zhou, Wei; Liu, Lei-Lei; Zhang, Dao-Qi; Zhong, Yong-Mei

    2017-09-01

    The neuropeptides orexin-A and orexin-B are widely expressed in the vertebrate retina; however, their role in visual function is unclear. This study investigates whether and how orexins modulate signal transmission to dopaminergic amacrine cells (DACs) from both outer retinal photoreceptors (rods and cones) and inner retinal photoreceptors (melanopsin-expressing intrinsically photosensitive retinal ganglion cells [ipRGCs]). A whole-cell voltage-clamp technique was used to record light-induced responses from genetically labeled DACs in flat-mount mouse retinas. Rod and cone signaling to DACs was confirmed pharmacologically (in wild-type retinas), whereas retrograde melanopsin signaling to DACs was isolated either pharmacologically (in wild-type retinas) or by genetic deletion of rod and cone function (in transgenic mice). Orexin-A attenuated rod/cone-mediated light responses in the majority of DACs and inhibited all DACs that exhibited melanopsin-based light responses, suggesting that exogenous orexin suppresses signal transmission from rods, cones, and ipRGCs to DACs. In addition, orexin receptor 1 antagonist SB334867 and orexin receptor 2 antagonist TCS OX229 enhanced melanopsin-based DAC responses, indicating that endogenous orexins inhibit signal transmission from ipRGCs to DACs. We further found that orexin-A inhibits melanopsin-based DAC responses via orexin receptors on DACs, whereas orexin-A may modulate signal transmission from rods and cones to DACs through activation of orexin receptors on DACs and their upstream neurons. Our results suggest that orexins could influence visual function via the dopaminergic system in the mammalian retina.

  13. Predicting abuse potential of stimulants and other dopaminergic drugs: overview and recommendations.

    Science.gov (United States)

    Huskinson, Sally L; Naylor, Jennifer E; Rowlett, James K; Freeman, Kevin B

    2014-12-01

    Examination of a drug's abuse potential at multiple levels of analysis (molecular/cellular action, whole-organism behavior, epidemiological data) is an essential component to regulating controlled substances under the Controlled Substances Act (CSA). We reviewed studies that examined several central nervous system (CNS) stimulants, focusing on those with primarily dopaminergic actions, in drug self-administration, drug discrimination, and physical dependence. For drug self-administration and drug discrimination, we distinguished between experiments conducted with rats and nonhuman primates (NHP) to highlight the common and unique attributes of each model in the assessment of abuse potential. Our review of drug self-administration studies suggests that this procedure is important in predicting abuse potential of dopaminergic compounds, but there were many false positives. We recommended that tests to determine how reinforcing a drug is relative to a known drug of abuse may be more predictive of abuse potential than tests that yield a binary, yes-or-no classification. Several false positives also occurred with drug discrimination. With this procedure, we recommended that future research follow a standard decision-tree approach that may require examining the drug being tested for abuse potential as the training stimulus. This approach would also allow several known drugs of abuse to be tested for substitution, and this may reduce false positives. Finally, we reviewed evidence of physical dependence with stimulants and discussed the feasibility of modeling these phenomena in nonhuman animals in a rational and practical fashion. This article is part of the Special Issue entitled 'CNS Stimulants'. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Oxytocin gene polymorphisms influence human dopaminergic function in a sex-dependent manner.

    Science.gov (United States)

    Love, Tiffany M; Enoch, Mary-Anne; Hodgkinson, Colin A; Peciña, Marta; Mickey, Brian; Koeppe, Robert A; Stohler, Christian S; Goldman, David; Zubieta, Jon-Kar

    2012-08-01

    Oxytocin, classically involved in social and reproductive activities, is increasingly recognized as an antinociceptive and anxiolytic agent, effects which may be mediated via oxytocin's interactions with the dopamine system. Thus, genetic variation within the oxytocin gene (OXT) is likely to explain variability in dopamine-related stress responses. As such, we examined how OXT variation is associated with stress-induced dopaminergic neurotransmission in a healthy human sample. Fifty-five young healthy volunteers were scanned using [¹¹C]raclopride positron emission tomography while they underwent a standardized physical and emotional stressor that consisted of moderate levels of experimental sustained deep muscle pain, and a baseline, control state. Four haplotype tagging single nucleotide polymorphisms located in regions near OXT were genotyped. Measures of pain, affect, anxiety, well-being and interpersonal attachment were also assessed. Female rs4813625 C allele carriers demonstrated greater stress-induced dopamine release, measured as reductions in receptor availability from baseline to the pain-stress condition relative to female GG homozygotes. No significant differences were detected among males. We also observed that female rs4813625 C allele carriers exhibited higher attachment anxiety, higher trait anxiety and lower emotional well-being scores. In addition, greater stress-induced dopamine release was associated with lower emotional well-being scores in female rs4813625 C allele carriers. Our results suggest that variability within the oxytocin gene appear to explain interindividual differences in dopaminergic responses to stress, which are shown to be associated with anxiety traits, including those linked to attachment style, as well as emotional well-being in women. Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  15. Dopaminergic control of cognitive flexibility in humans and animals

    Directory of Open Access Journals (Sweden)

    Marianne eKlanker

    2013-11-01

    Full Text Available Striatal dopamine is thought to code for learned associations between cues and reinforcers and to mediate approach behavior towards a reward. Less is known about the contribution of dopamine to cognitive flexibility – the ability to adapt behavior in response to changes in the environment. Altered reward processing and impairments in cognitive flexibility are observed in psychiatric disorders such as obsessive compulsive disorder. Patients with this disorder show a disruption of functioning in the frontostriatal circuit and alterations in dopamine signaling. In this review we summarize findings from animal and human studies that have investigated the involvement of striatal dopamine in cognitive flexibility. These findings may provide a better understanding of the role of dopaminergic dysfunction in cognitive inflexibility in psychiatric disorders, such as OCD.

  16. Mazindol anorexia is mediated by activation of dopaminergic mechanisms.

    Science.gov (United States)

    Kruk, Z L; Zarrindast, M R

    1976-01-01

    1 Anorexia in rats following injections of mazindol (0.1-8 mg/kg i.p.) could be antagonized by pretreatment with a dopamine receptor blocker (primozide) but not by pretreatment with an alpha-adrenoceptor blocker (phenoxybenzamine), a beta-adrenoceptor blocker ((-)-propranolol), or a 5-hydroxytryptamine receptor blocker (methergoline). 2 In rats with a unilateral lesion in the substantia nigra made by stereotaxic injection of 6-hydroxydopamine, mazindol caused a dose-dependent turning towards the lesioned side, indicating an indirect mechanism of action. This effect could be antagonized by pretreatment with a dopamine receptor blocker. 3 In rats pretreated with reserpine and alpha-methyl-p-tyrosine, mazindol did not have any motor stimulant action. 4 In vitro studies with synaptosomes prepared from rat brain, indicated that mazindol blocks uptake and causes release of dopamine. 5 It is concluded that the anorectic action of mazindol is mediated by a dopaminergic mechanism. PMID:990591

  17. A Case of Painless Legs and Moving Toes Syndrome in Parkinson’s Disease Responsive to Dopaminergic Therapy

    Directory of Open Access Journals (Sweden)

    Sumihiro Kawajiri

    2016-01-01

    Full Text Available Painless Legs and Moving Toes Syndrome (PoLMT is a rare movement disorder characterized by flexion, extension, abduction, adduction, and torsion of toes without pain. It is considered a variant of Painful Legs and Moving Toes Syndrome (PLMT, which is characterized by similar movements but with pain. Although neuropathy and several central nervous system (CNS involvements have been reported to be associated with PoLMT, the actual cause and mechanism remain unclear. Here we describe the first case of PoLMT in Parkinson’s Disease (PD, parallel to parkinsonism in severity, who demonstrated a good response to dopaminergic therapy.

  18. ELECTROPHYSIOLOGICAL CHARACTERIZATION OF DOPAMINERGIC AND NONDOPAMINERGIC NEURONS IN ORGANOTYPIC SLICE CULTURES OF THE RAT VENTRAL MESENCEPHALON

    DEFF Research Database (Denmark)

    STEENSEN, BH; NEDERGAARD, S; OSTERGAARD, K

    1995-01-01

    -old organotypic slice cultures of the ventral mesencephalon prepared from newborn rats. Dopaminergic neurones were distinguished from non-dopaminergic neurones by staining with the autofluorescent serotonin analogue 5,7-dihydroxytryptamine and briefly viewing the preparation with short exposures to ultraviolet...... 81 M Omega), were silent or fired spontaneously at a low frequency (0-9 Hz), and no spontaneous GABA(A)-ergic inhibitory postsynaptic potentials or inward rectification were present. In contrast, non-dopaminergic neurones had fast action potentials (0.6-3.2 ms), low input resistance (mean 32 M Omega...

  19. The Effects of Age, from Young to Middle Adulthood, and Gender on Resting State Functional Connectivity of the Dopaminergic Midbrain.

    Science.gov (United States)

    Peterson, Andrew C; Zhang, Sheng; Hu, Sien; Chao, Herta H; Li, Chiang-Shan R

    2017-01-01

    Dysfunction of the dopaminergic ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) is implicated in psychiatric disorders including attention-deficit/ hyperactivity disorder (ADHD), addiction, schizophrenia and movement disorders such as Parkinson's disease (PD). Although the prevalence of these disorders varies by age and sex, the underlying neural mechanism is not well understood. The objective of this study was to delineate the distinct resting state functional connectivity (rsFC) of the VTA and SNc and examine the effects of age, from young to middle-adulthood, and sex on the rsFC of these two dopaminergic structures in a data set of 250 healthy adults (18-49 years of age, 104 men). Using blood oxygenation level dependent (BOLD) signals, we correlated the time course of the VTA and SNc to the time courses of all other brain voxels. At a corrected threshold, paired t -test showed stronger VTA connectivity to bilateral angular gyrus and superior/middle and orbital frontal regions and stronger SNc connectivity to the insula, thalamus, parahippocampal gyrus (PHG) and amygdala. Compared to women, men showed a stronger VTA/SNc connectivity to the left posterior orbital gyrus. In linear regressions, men but not women showed age-related changes in VTA/SNc connectivity to a number of cortical and cerebellar regions. Supporting shared but also distinct cerebral rsFC of the VTA and SNc and gender differences in age-related changes from young and middle adulthood in VTA/SNc connectivity, these new findings help advance our understanding of the neural bases of many neuropsychiatric illnesses that implicate the dopaminergic systems.

  20. Meta-type analysis of dopaminergic effects on gene expression in the neuroendocrine brain of female goldfish

    Directory of Open Access Journals (Sweden)

    Jason T Popesku

    2012-11-01

    Full Text Available Dopamine (DA is a major neurotransmitter important for neuroendocrine control and recent studies have described genomic signalling pathways activated and inhibited by DA agonists and antagonists in the goldfish brain. Here we perform a meta-type analysis using microarray datasets from experiments conducted with female goldfish to characterize the gene expression responses that underlie dopaminergic signalling. Sexually mature, pre-spawning (GSI 4.5 ± 1.3% or sexually regressing ( GSI 3 ± 0.4% female goldfish (15-40 g injected intraperitoneally with either SKF 38393, LY 171555, SCH 23390, sulpiride, or a combination of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and α-methyl-p-tyrosine. Microarray meta-type analysis identified 268 genes in the telencephalon and hypothalamus as having reciprocal (i.e. opposite between agonism and antagonism/depletion fold change responses, suggesting that these transcripts are likely targets for DA-mediated regulation. Noteworthy genes included ependymin, vimentin, and aromatase, genes that support the significance of DA in neuronal plasticity and tissue remodelling. Sub-network enrichment analysis (SNEA was used to identify common gene regulators and binding proteins associated with the differentially expressed genes mediated by DA. SNEA analysis identified gene expression targets that were related to three major categories that included cell signalling (STAT3, SP1, SMAD, Jun/Fos, immune response (IL6, IL1β, TNFs, cytokine, NF-κB, and cell proliferation and growth (IGF1, TGFβ1. These gene networks are also known to be associated with neurodegenerative disorders such as Parkinsons’ disease, well-known to be associated with loss of dopaminergic neurons. This study identifies genes and networks that underlie DA signalling in the vertebrate CNS and provides targets that may be key neuroendocrine regulators. The results provide a foundation for future work on dopaminergic regulation of gene expression in fish

  1. Cell therapy for Parkinson's disease: Functional role of the host immune response on survival and differentiation of dopaminergic neuroblasts.

    Science.gov (United States)

    Wenker, Shirley D; Leal, María Celeste; Farías, María Isabel; Zeng, Xianmin; Pitossi, Fernando J

    2016-05-01

    Parkinson's disease (PD) is a neurodegenerative disorder, whose cardinal pathology is the loss of dopaminergic neurons in the substantia nigra. Current treatments for PD have side effects in the long term and do not halt disease progression or regenerate dopaminergic cell loss. Attempts to compensate neuronal cell loss by transplantation of dopamine-producing cells started more than 30 years ago, leading to several clinical trials. These trials showed safety and variable efficacy among patients. In addition to variability in efficacy, several patients developed graft-induced dyskinesia. Nevertheless, they have provided a proof of concept that motor symptoms could be improved by cell transplantation. Cell transplantation in the brain presents several immunological challenges. The adaptive immune response should be abolished to avoid graft rejection by the host. In addition, the innate immune response will always be present after transplanting cells into the brain. Remarkably, the innate immune response can have dramatic effects on the survival, differentiation and proliferation of the transplanted cells, but has been hardly investigated. In this review, we analyze data on the functional effects of signals from the innate immune system on dopaminergic differentiation, survival and proliferation. Then, we discussed efforts on cell transplantation in animal models and PD patients, highlighting the immune response and the immunomodulatory treatment strategies performed. The analysis of the available data lead us to conclude that the modulation of the innate immune response after transplantation can increase the success of future clinical trials in PD by enhancing cell differentiation and survival. This article is part of a Special Issue entitled SI: PSC and the brain. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Effects of Forskolin on Trefoil factor 1 expression in cultured ventral mesencephalic dopaminergic neurons

    DEFF Research Database (Denmark)

    Jensen, Pia; Ducray, A D; Widmer, H R

    2015-01-01

    , suggesting that Forskolin induced TFF1 expression through diverse signaling pathways. In conclusion, distinct populations of cultured dopaminergic neurons express TFF1, and their numbers can be increased by factors known to influence survival and differentiation of dopaminergic cells....... shown that TFF1 is expressed in developing and adult rat ventral mesencephalic tyrosine hydroxylase-immunoreactive (TH-ir) dopaminergic neurons. Here, we investigated the expression of TFF1 in rat ventral mesencephalic dopaminergic neurons (embryonic day 14) grown in culture for 5, 7 or 10days...... to neuronal cells, and the percentage of TH/TFF1 co-expressing cells was increased to the same extent in GDNF and Forskolin-treated cultures (4-fold) as compared to controls. Interestingly, the combination of GDNF and Forskolin resulted in a significantly increased co-expression (8-fold) of TH/TFF1, which...

  3. Cognitive executive impairment and dopaminergic deficits in de novo Parkinson's disease

    NARCIS (Netherlands)

    Siepel, Françoise J.; Brønnick, Kolbjørn S.; Booij, Jan; Ravina, Bernard M.; Lebedev, Alexander V.; Pereira, Joana B.; Grüner, Renate; Aarsland, Dag

    2014-01-01

    Cognitive impairment in Parkinson's disease (PD) is common and does directly impact patients' everyday functioning. However, the underlying mechanisms of early cognitive decline are not known. This study explored the association between striatal dopaminergic deficits and cognitive impairment within

  4. No association between 12 dopaminergic genes and schizophrenia in a large Dutch sample

    NARCIS (Netherlands)

    Hoogendoorn, Mechteld L C; Bakker, Steven C; Schnack, Hugo G; Selten, Jean-Paul C; Otten, Henny G; Verduijn, Willem; van der Heijden, Frank M M A; Pearson, Peter L; Kahn, René S; Sinke, Richard J

    2005-01-01

    It has been suggested that genes involved in dopamine neurotransmission contribute to the pathogenesis of schizophrenia. However, reported associations of the disorder with genetic markers in dopaminergic genes have yielded inconsistent results. Possible explanations are differences in phenotyping,

  5. Effects of combined BDNF and GDNF treatment on cultured dopaminergic midbrain neurons

    DEFF Research Database (Denmark)

    Sautter, J; Meyer, Morten; Spenger, C

    1998-01-01

    Neural transplantation is an experimental therapy for Parkinson's disease. Pretreatment of fetal donor tissue with neurotrophic factors may improve survival of grafted dopaminergic neurons. Free-floating roller tube cultures of fetal rat ventral mesencephalon were treated with brain...

  6. Psychotic Symptoms Associated with the use of Dopaminergic Drugs, in Patients with Cocaine Dependence or Abuse

    OpenAIRE

    Roncero, Carlos; Abad, Alfonso C.; Padilla-Mata, Antonio; Ros-Cucurull, Elena; Barral, Carmen; Casas, Miquel; Grau-L?pez, Lara

    2017-01-01

    Background In the field of dual diagnosis, physicians are frequently presented with pharmacological questions. Questions about the risk of developing psychotic symptoms in cocaine users who need treatment with dopaminergic drugs could lead to an undertreatment. Objective Review the presence of psychotic symptoms in patients with cocaine abuse/dependence, in treatment with dopaminergic drugs. Methods Systematic PubMed searches were conducted including December 2014, using the keywords: ?cocain...

  7. Diversity matters - heterogeneity of dopaminergic neurons in the ventral mesencephalon and its relation to Parkinson's Disease.

    Science.gov (United States)

    Vogt Weisenhorn, Daniela Maria; Giesert, Florian; Wurst, Wolfgang

    2016-10-01

    Dopaminergic neurons in the ventral mesencephalon (the ventral mesencephalic dopaminergic complex) are known for their role in a multitude of behaviors, including cognition, reward, addiction and voluntary movement. Dysfunctions of these neurons are the underlying cause of various neuropsychiatric disorders, such as depression, addiction and schizophrenia. In addition, Parkinson's disease (PD), which is the second most common degenerative disease in developed countries, is characterized by the degeneration of dopaminergic neurons, leading to the core motor symptoms of the disease. However, only a subset of dopaminergic neurons in the ventral mesencephalon is highly vulnerable to the disease process. Indeed, research over several decades revealed that the neurons in the ventral mesencephalic dopaminergic complex do not form a homogeneous group with respect to anatomy, physiology, function, molecular identity or vulnerability/dysfunction in different diseases. Here, we review how the concept of dopaminergic neuron diversity, assisted by the advent and application of new technologies, evolved and was refined over time and how it shaped our understanding of PD pathogenesis. Understanding this diversity of neurons in the ventral mesencephalic dopaminergic complex at all levels is imperative for the development of new and more selective drugs for both PD and various other neuropsychiatric diseases. Several decades of research revealed that the neurons in the ventral mesencephalic dopaminergic complex do not form a homogeneous group in respect to anatomy, physiology, function, molecular identity or vulnerability/dysfunction in diseases like Parkinson's disease (PD). Here, we review how this concept evolved and was refined over time and how it shaped our understanding of the pathogenesis of PD. Source of the midbrain image: www.wikimd.org/wiki/index.php/The_Midbrain_or_Mesencephalon; downloaded 28.01.2016. See also Figures and of the paper. This article is part of a

  8. Dopaminergic modulation of performance monitoring in Parkinson's disease: An event-related potential study.

    Science.gov (United States)

    Seer, Caroline; Lange, Florian; Loens, Sebastian; Wegner, Florian; Schrader, Christoph; Dressler, Dirk; Dengler, Reinhard; Kopp, Bruno

    2017-01-24

    Monitoring one's actions is essential for goal-directed performance. In the event-related potential (ERP), errors are followed by fronto-centrally distributed negativities. These error(-related) negativity (N e /ERN) amplitudes are often found to be attenuated in patients with Parkinson's disease (PD) compared to healthy controls (HC). Although N e /ERN has been proposed to be related to dopaminergic neuronal activity, previous research did not find evidence for effects of dopaminergic medication on N e /ERN amplitudes in PD. We examined 13 PD patients "on" and "off" dopaminergic medication. Their response-locked ERP amplitudes (obtained on correct [N c /CRN] and error [N e /ERN] trials of a flanker task) were compared to those of 13 HC who were tested twice as well, without receiving dopaminergic medication. While PD patients committed more errors than HC, error rates were not significantly modulated by dopaminergic medication. PD patients showed reduced N e /ERN amplitudes relative to HC; however, this attenuation of response-locked ERP amplitudes was not specific to errors in this study. PD-related attenuation of response-locked ERP amplitudes was most pronounced when PD patients were on medication. These results suggest overdosing of dopaminergic pathways that are relatively spared in PD, but that are related to the generation of the N e /ERN, notably pathways targeted on the medial prefrontal cortex.

  9. Human iPS cell-derived dopaminergic neurons function in a primate Parkinson's disease model.

    Science.gov (United States)

    Kikuchi, Tetsuhiro; Morizane, Asuka; Doi, Daisuke; Magotani, Hiroaki; Onoe, Hirotaka; Hayashi, Takuya; Mizuma, Hiroshi; Takara, Sayuki; Takahashi, Ryosuke; Inoue, Haruhisa; Morita, Satoshi; Yamamoto, Michio; Okita, Keisuke; Nakagawa, Masato; Parmar, Malin; Takahashi, Jun

    2017-08-30

    Induced pluripotent stem cells (iPS cells) are a promising source for a cell-based therapy to treat Parkinson's disease (PD), in which midbrain dopaminergic neurons progressively degenerate. However, long-term analysis of human iPS cell-derived dopaminergic neurons in primate PD models has never been performed to our knowledge. Here we show that human iPS cell-derived dopaminergic progenitor cells survived and functioned as midbrain dopaminergic neurons in a primate model of PD (Macaca fascicularis) treated with the neurotoxin MPTP. Score-based and video-recording analyses revealed an increase in spontaneous movement of the monkeys after transplantation. Histological studies showed that the mature dopaminergic neurons extended dense neurites into the host striatum; this effect was consistent regardless of whether the cells were derived from patients with PD or from healthy individuals. Cells sorted by the floor plate marker CORIN did not form any tumours in the brains for at least two years. Finally, magnetic resonance imaging and positron emission tomography were used to monitor the survival, expansion and function of the grafted cells as well as the immune response in the host brain. Thus, this preclinical study using a primate model indicates that human iPS cell-derived dopaminergic progenitors are clinically applicable for the treatment of patients with PD.

  10. Protective effect of sulforaphane against dopaminergic cell death.

    Science.gov (United States)

    Han, Ji Man; Lee, Yong Jin; Lee, So Yeon; Kim, Eun Mee; Moon, Younghye; Kim, Ha Won; Hwang, Onyou

    2007-04-01

    Parkinson's disease (PD) is a progressive neurodegenerative disorder with a selective loss of dopaminergic neurons in the substantia nigra. Evidence suggests oxidation of dopamine (DA) to DA quinone and consequent oxidative stress as a major factor contributing to this vulnerability. We have previously observed that exposure to or induction of NAD(P)H:quinone reductase (QR1), the enzyme that catalyzes the reduction of quinone, effectively protects DA cells. Sulforaphane (SF) is a drug identified as a potent inducer of QR1 in various non-neuronal cells. In the present study, we show that SF protects against compounds known to induce DA quinone production (6-hydroxydopamine and tetrahydrobiopterin) in DAergic cell lines CATH.a and SK-N-BE(2)C as well as in mesencephalic DAergic neurons. SF leads to attenuation of the increase in protein-bound quinone in tetrahydrobiopterin-treated cells, but this does not occur in cells that have been depleted of DA, suggesting involvement of DA quinone. SF pretreatment prevents membrane damage, DNA fragmentation, and accumulation of reactive oxygen species. SF causes increases in mRNA levels and enzymatic activity of QR1 in a dose-dependent manner. Taken together, these results indicate that SF causes induction of QR1 gene expression, removal of intracellular DA quinone, and protection against toxicity in DAergic cells. Thus, this major isothiocyanate found in cruciferous vegetables may serve as a potential candidate for development of treatment and/or prevention of PD.

  11. Neuroprotective effects of phytochemicals on dopaminergic neuron cultures.

    Science.gov (United States)

    Sandoval-Avila, S; Diaz, N F; Gómez-Pinedo, U; Canales-Aguirre, A A; Gutiérrez-Mercado, Y K; Padilla-Camberos, E; Marquez-Aguirre, A L; Díaz-Martínez, N E

    2016-06-21

    Parkinson's disease is a progressive neurodegenerative disorder characterised by a loss of dopaminergic neurons in the substantia nigra pars compacta, which results in a significant decrease in dopamine levels and consequent functional motor impairment. Although its aetiology is not fully understood, several pathogenic mechanisms, including oxidative stress, have been proposed. Current therapeutic approaches are based on dopamine replacement drugs; these agents, however, are not able to stop or even slow disease progression. Novel therapeutic approaches aimed at acting on the pathways leading to neuronal dysfunction and death are under investigation. In recent years, such natural molecules as polyphenols, alkaloids, and saponins have been shown to have a neuroprotective effect due to their antioxidant and anti-inflammatory properties. The aim of our review is to analyse the most relevant studies worldwide addressing the benefits of some phytochemicals used in in vitro models of Parkinson's disease. Copyright © 2016 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.

  12. Intra-accumbens Raclopride Administration Prevents Behavioral Changes Induced by Intermittent Access to Sucrose Solution

    OpenAIRE

    Josué O. Suárez-Ortiz; Felipe Cortés-Salazar; Ariadna L. Malagón-Carrillo; Verónica E. López-Alonso; Juan M. Mancilla-Díaz; Juan G. Tejas-Juárez; Rodrigo E. Escartín-Pérez

    2018-01-01

    Overeating is one of the most relevant clinical features in Binge Eating Disorder and in some obesity patients. According to several studies, alterations in the mesolimbic dopaminergic transmission produced by non-homeostatic feeding behavior may be associated with changes in the reward system similar to those produced by drugs of abuse. Although it is known that binge-eating is related with changes in dopaminergic transmission mediated by D2 receptors in the nucleus accumbens shell (NAcS), i...

  13. Interactions between cannabidiol and Δ9-THC following acute and repeated dosing: Rebound hyperactivity, sensorimotor gating and epigenetic and neuroadaptive changes in the mesolimbic pathway.

    Science.gov (United States)

    Todd, Stephanie M; Zhou, Cilla; Clarke, David J; Chohan, Tariq W; Bahceci, Dilara; Arnold, Jonathon C

    2017-02-01

    The evidence base for the use of medical cannabis preparations containing specific ratios of cannabidiol (CBD) and Δ 9 -tetrahydrocannabinol (THC) is limited. While there is abundant data on acute interactions between CBD and THC, few studies have assessed the impact of their repeated co-administration. We previously reported that CBD inhibited or potentiated the acute effects of THC dependent on the measure being examined at a 1:1 CBD:THC dose ratio. Further, CBD decreased THC effects on brain regions involved in memory, anxiety and body temperature regulation. Here we extend on these finding by examining over 15 days of treatment whether CBD modulated the repeated effects of THC on behaviour and neuroadaption markers in the mesolimbic dopamine pathway. After acute locomotor suppression, repeated THC caused rebound locomotor hyperactivity that was modestly inhibited by CBD. CBD also slightly reduced the acute effects of THC on sensorimotor gating. These subtle effects were found at a 1:1 CBD:THC dose ratio but were not accentuated by a 5:1 dose ratio. CBD did not alter the trajectory of enduring THC-induced anxiety nor tolerance to the pharmacological effects of THC. There was no evidence of CBD potentiating the behavioural effects of THC. However we demonstrated for the first time that repeated co-administration of CBD and THC increased histone 3 acetylation (H3K9/14ac) in the VTA and ΔFosB expression in the nucleus accumbens. These changes suggest that while CBD may have protective effects acutely, its long-term molecular actions on the brain are more complex and may be supradditive. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

  14. Oxytocin receptors are expressed on dopamine and glutamate neurons in the mouse ventral tegmental area that project to nucleus accumbens and other mesolimbic targets.

    Science.gov (United States)

    Peris, Joanna; MacFadyen, Kaley; Smith, Justin A; de Kloet, Annette D; Wang, Lei; Krause, Eric G

    2017-04-01

    The mesolimbic dopamine (DA) circuitry determines which behaviors are positively reinforcing and therefore should be encoded in the memory to become a part of the behavioral repertoire. Natural reinforcers, like food and sex, activate this pathway, thereby increasing the likelihood of further consummatory, social, and sexual behaviors. Oxytocin (OT) has been implicated in mediating natural reward and OT-synthesizing neurons project to the ventral tegmental area (VTA) and nucleus accumbens (NAc); however, direct neuroanatomical evidence of OT regulation of DA neurons within the VTA is sparse. To phenotype OT-receptor (OTR) expressing neurons originating within the VTA, we delivered Cre-inducible adeno-associated virus that drives the expression of fluorescent marker into the VTA of male mice that had Cre-recombinase driven by OTR gene expression. OTR-expressing VTA neurons project to NAc, prefrontal cortex, the extended amygdala, and other forebrain regions but less than 10% of these OTR-expressing neurons were identified as DA neurons (defined by tyrosine hydroxylase colocalization). Instead, almost 50% of OTR-expressing cells in the VTA were glutamate (GLU) neurons, as indicated by expression of mRNA for the vesicular GLU transporter (vGluT). About one-third of OTR-expressing VTA neurons did not colocalize with either DA or GLU phenotypic markers. Thus, OTR expression by VTA neurons implicates that OT regulation of reward circuitry is more complex than a direct action on DA neurotransmission. J. Comp. Neurol. 525:1094-1108, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  15. Functional effects of cannabinoids during dopaminergic specification of human neural precursors derived from induced pluripotent stem cells.

    Science.gov (United States)

    Stanslowsky, Nancy; Jahn, Kirsten; Venneri, Anna; Naujock, Maximilian; Haase, Alexandra; Martin, Ulrich; Frieling, Helge; Wegner, Florian

    2017-09-01

    Among adolescents cannabis is one of the most widely used illicit drugs. In adolescence brain development continues, characterized by neuronal maturation and synaptic plasticity. The endocannabinoid system plays an important role during brain development by modulating neuronal function and neurogenesis. Changes in endocannabinoid signaling by Δ 9 -tetrahydrocannabinol (THC), the psychoactive component of cannabis, might therefore lead to neurobiological changes influencing brain function and behavior. We investigated the functional maturation and dopaminergic specification of human cord blood-derived induced pluripotent stem cell (hCBiPSC)-derived small molecule neural precursor cells (smNPCs) after cultivation with the endogenous cannabinoid anandamide (AEA) and the exogenous THC, both potent agonists at the cannabinoid 1 receptor (CB 1 R). Higher dosages of 10-μM AEA or THC significantly decreased functionality of neurons, indicated by reduced ion currents and synaptic activity. A lower concentration of 1-μM THC had no marked effect on neuronal and dopaminergic maturation, while 1-μM AEA significantly enhanced the frequency of synaptic activity. As there were no significant effects on DNA methylation in promotor regions of genes important for neuronal function, these cannabinoid actions seem to be mediated by another than this epigenetic mechanism. Our data suggest that there are concentration-dependent actions of cannabinoids on neuronal function in vitro indicating neurotoxic, dysfunctional effects of 10-μM AEA and THC during human neurogenesis. © 2016 Society for the Study of Addiction.

  16. N-Acetyl Cysteine Protects against Methamphetamine-Induced Dopaminergic Neurodegeneration via Modulation of Redox Status and Autophagy in Dopaminergic Cells

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    Prashanth Chandramani Shivalingappa

    2012-01-01

    Full Text Available Methamphetamine- (MA- induced neurotoxicity is associated with mitochondrial dysfunction and enhanced oxidative stress. Our previous study demonstrated that MA induces autophagy in a dopaminergic neuronal cell model (N27 cells. The cellular mechanisms underlying MA-induced autophagy and apoptosis remain poorly characterized. In the present study we sought to investigate the importance of GSH redox status in MA-induced neurotoxicity using a thiol antioxidant, N-acetylcysteine (NAC. Morphological and biochemical analysis revealed that MA-induced autophagy in N27 dopaminergic cells was associated with pronounced depletion of GSH levels. Moreover, pretreatment with NAC reduced MA-induced GSH depletion and autophagy, while depletion of GSH using L-buthionine sulfoximine (L-BSO enhanced autophagy. Furthermore, treatment with NAC significantly attenuated MA-induced apoptotic cell death as well as oxidative stress markers, namely, 3-nitrotyrosine (3-NT and 4-hydroxynonenal (4-HNE. Together, these results suggest that NAC exhibits significant protective effects against MA-induced dopaminergic cell death, presumably via modulation of the GSH level and autophagy. Collectively, our data provide mechanistic insights into the role of cellular GSH redox status in MA-induced autophagy and apoptotic cell death, and additional studies are needed to determine the therapeutic effectiveness of cellular redox modifiers in attenuating dopaminergic neurodegeneration in vivo.

  17. Cholinergic and dopaminergic mechanisms involved in the recovery of circadian anticipation by aniracetam in aged rats.

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    Tanaka, Yushiro; Kurasawa, Mitsue; Nakamura, Kazuo

    2002-05-01

    We have reported that repeated administration of aniracetam (100 mg/kg p.o.) for 7 consecutive days recovers mealtime-associated circadian anticipatory behavior diminished in aged rats. The present study examines the mode of action underlying the restoration by aniracetam with various types of receptor antagonists. Coadministration of scopolamine (0.1 mg/kg i.p.) or haloperidol (0.1 mg/kg i.p.) for the last 3 days significantly reduced the restorative effects of aniracetam without affecting the timed feeding-induced anticipatory behavior by each receptor antagonist itself. The other receptor antagonists, mecamylamine (3 mg/kg i.p.), 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX, 1 microg/rat i.c.v.) had no effect on either the basal or aniracetam-elicited circadian anticipation. In contrast, ketanserin (1 mg/kg i.p.) itself recovered the diminished anticipatory behavior as aniracetam did, but it did not alter the restorative effects of aniracetam. Among the receptor antagonists tested, NBQX reduced appetite and haloperidol induced circadian hypoactivity. These results suggest that the food-entrainable circadian oscillations or the temporal regulatory system of behavior is modulated by cholinergic, dopaminergic and serotonergic systems. Furthermore, aniracetam may restore the aging-diminished behavioral anticipation by activating muscarinic acetylcholine (ACh) and/or dopamine (DA) D2 receptors through the enhanced release of ACh and/or DA in the brain.

  18. Nucleus accumbens deep brain stimulation as treatment option for binge eating disorder?

    NARCIS (Netherlands)

    Lok, R.; Verhagen, M.; Staal, L.; Van Dijk, J.; Van Beek, A.; Temel, Y.; Jahanshahi, A.; Staal, M.; Van Dijk, G.

    2014-01-01

    Introduction: Binge eating disorder (BED) has been postulated to arise from mesolimbic dopaminergic system changes, presumably homologous to those seen in drug addiction. Deep Brain Stimulation (DBS) is regarded as a relatively novel but promising surgical treatment of addiction. Because of

  19. Novel Method To Differentiate Human Embryonic Stem Cells Into Dopaminergic Nerve Cells | NCI Technology Transfer Center | TTC

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    The National Institute on Drug Abuse's Development and Plasticity Section is seeking statements of capability or interest from parties interested in licensing opportunities to further develop, evaluate, or commercialize novel methods to differentiate human embryonic stem cells into dopaminergic nerve cells. The invention described here is a novel method of differentiating human embryonic stem cells (hESCs) into dopaminergic nerve cells, which is preferable to the currently available dopaminergic differentiation techniques.

  20. Sorbus alnifolia protects dopaminergic neurodegeneration in Caenorhabditis elegans.

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    Cheon, Se-Myeong; Jang, Insoo; Lee, Myon-Hee; Kim, Dae Keun; Jeon, Hoon; Cha, Dong Seok

    2017-12-01

    The twigs of Sorbus alnifolia (Sieb. et Zucc.) K. Koch (Rosaceae) have been used to treat neurological disorders as a traditional medicine in Korea. However, there are limited data describing the efficacy of S. alnifolia in Parkinson's disease (PD). This study was conducted to identify the protective effects of the methanol extracts of S. alnifolia (MESA) on the dopaminergic (DA) neurodegeneration in Caenorhabditis elegans. To test the neuroprotective action of MESA, viability assay was performed after 48 h exposure to 1-methyl-4-phenylpyridine (MMP + ) in PC12 cells and C. elegans (400 μM and 2 mM of MMP + , respectively). Fluorescence intensity was quantified using transgenic mutants such as BZ555 (Pdat-1::GFP) and and UA57 (Pdat-1::GFP and Pdat-1::CAT-2) to determine MESA's effects on DA neurodegeneration in C. elegans. Aggregation of α-synuclein was observed using NL5901 strain (unc-54p::α-synuclein::YFP). MESA's protective effects on the DA neuronal functions were examined by food-sensing assay. Lifespan assay was conducted to test the effects of MESA on the longevity. MESA restored MPP + -induced loss of viability in both PC12 cells and C. elegans (85.8% and 54.9%, respectively). In C. elegans, MESA provided protection against chemically and genetically-induced DA neurodegeneration, respectively. Moreover, food-sensing functions were increased 58.4% by MESA in the DA neuron degraded worms. MESA also prolonged the average lifespan by 25.6%. However, MESA failed to alter α-synuclein aggregation. These results revealed that MESA protects DA neurodegeneration and recovers diminished DA neuronal functions, thereby can be a valuable candidate for the treatment of PD.

  1. Electrophysiological effects of trace amines on mesencephalic dopaminergic neurons

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    Ada eLedonne

    2011-07-01

    Full Text Available Trace amines (TAs are a class of endogenous compounds strictly related to classic monoamine neurotransmitters with regard to their structure, metabolism and tissue distribution. Although the presence of TAs in mammalian brain has been recognized for decades, until recently they were considered to be by-products of amino acid metabolism or as ‘false’ neurotransmitters. The discovery in 2001 of a new family of G protein-coupled receptors (GPCRs, namely trace amines receptors, has re-ignited interest in TAs. In particular, two members of the family, trace amine receptor 1 (TA1 and trace amine receptor 2 (TA2, were shown to be highly sensitive to these endogenous compounds. Experimental evidence suggests that TAs modulate the activity of catecholaminergic neurons and that TA dysregulation may contribute to neuropsychiatric disorders, including schizophrenia, attention deficit hyperactivity disorder, depression and Parkinson’s disease, all of which are characterised by altered monoaminergic networks. Here we review recent data concerning the electrophysiological effects of TAs on the activity of mesencephalic dopaminergic neurons. In the context of recent data obtained with TA1 receptor knockout mice, we also discuss the mechanisms by which the activation of these receptors modulates the activity of these neurons. Three important new aspects of TAs action have recently emerged: (a inhibition of firing due to increased release of dopamine; (b reduction of D2 and GABAB receptor-mediated inhibitory responses (excitatory effects due to dysinhibition; and (c a direct TA1 receptor-mediated activation of GIRK channels which produce cell membrane hyperpolarization. While the first two effects have been well documented in our laboratory, the direct activation of GIRK channels by TA1 receptors has been reported by others, but has not been seen in our laboratory (Geracitano et al., 2004. Further research is needed to address this point, and to further

  2. Alterations in Lipid and Inositol Metabolisms in Two Dopaminergic Disorders.

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    Eva C Schulte

    Full Text Available Serum metabolite profiling can be used to identify pathways involved in the pathogenesis of and potential biomarkers for a given disease. Both restless legs syndrome (RLS and Parkinson`s disease (PD represent movement disorders for which currently no blood-based biomarkers are available and whose pathogenesis has not been uncovered conclusively. We performed unbiased serum metabolite profiling in search of signature metabolic changes for both diseases.456 metabolites were quantified in serum samples of 1272 general population controls belonging to the KORA cohort, 82 PD cases and 95 RLS cases by liquid-phase chromatography and gas chromatography separation coupled with tandem mass spectrometry. Genetically determined metabotypes were calculated using genome-wide genotyping data for the 1272 general population controls.After stringent quality control, we identified decreased levels of long-chain (polyunsaturated fatty acids of individuals with PD compared to both RLS (PD vs. RLS: p = 0.0001 to 5.80x10-9 and general population controls (PD vs. KORA: p = 6.09x10-5 to 3.45x10-32. In RLS, inositol metabolites were increased specifically (RLS vs. KORA: p = 1.35x10-6 to 3.96x10-7. The impact of dopaminergic drugs was reflected in changes in the phenylalanine/tyrosine/dopamine metabolism observed in both individuals with RLS and PD.A first discovery approach using serum metabolite profiling in two dopamine-related movement disorders compared to a large general population sample identified significant alterations in the polyunsaturated fatty acid metabolism in PD and implicated the inositol metabolism in RLS. These results provide a starting point for further studies investigating new perspectives on factors involved in the pathogenesis of the two diseases as well as possible points of therapeutic intervention.

  3. Increased L-DOPA-derived dopamine following selective MAO-A or-B inhibition in rat striatum depleted of dopaminergic and serotonergic innervation

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    Sader-Mazbar, O; Loboda, Y; Rabey, M J; Finberg, J P M

    2013-01-01

    Background and Purpose Selective MAO type B (MAO-B) inhibitors are effective in potentiation of the clinical effect of L-DOPA in Parkinson's disease, but dopamine (DA) is deaminated mainly by MAO type A (MAO-A) in rat brain. We sought to clarify the roles of MAO-A and MAO-B in deamination of DA formed from exogenous L-DOPA in rat striatum depleted of dopaminergic, or both dopaminergic and serotonergic innervations. We also studied the effect of organic cation transporter-3 (OCT-3) inhibition by decinium-22 on extracellular DA levels following L-DOPA. Experimental Approach Striatal dopaminergic and/or serotonergic neuronal innervations were lesioned by 6-hydroxydopamine or 5,7-dihydroxytryptamine respectively. Microdialysate DA levels after systemic L-DOPA were measured after inhibition of MAO-A or MAO-B by clorgyline or rasagiline respectively. MAO subtype localization in the striatum was determined by immunofluorescence. Key Results Rasagiline increased DA extracellular levels following L-DOPA to a greater extent in double-than in single-lesioned rats (2.8-and 1.8-fold increase, respectively, relative to saline treatment); however, clorgyline elevated DA levels in both models over 10-fold. MAO-A was strongly expressed in medium spiny neurons (MSNs) in intact and lesioned striata, while MAO-B was localized in glia and to a small extent in MSNs. Inhibition of OCT-3 increased DA levels in the double-more than the single-lesion animals. Conclusions and Implications In striatum devoid of dopaminergic and serotonergic inputs, most deamination of L-DOPA-derived DA is mediated by MAO-A in MSN and a smaller amount by MAO-B in both MSN and glia. OCT-3 plays a significant role in uptake of DA from extracellular space. Inhibitors of OCT-3 are potential future targets for anti-Parkinsonian treatments. PMID:23992249

  4. Identification of the endogenous key substrates of the human organic cation transporter OCT2 and their implication in function of dopaminergic neurons.

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    Dirk Taubert

    Full Text Available BACKGROUND: The etiology of neurodegenerative disorders, such as the accelerated loss of dopaminergic neurons in Parkinson's disease, is unclear. Current hypotheses suggest an abnormal function of the neuronal sodium-dependent dopamine transporter DAT to contribute to cell death in the dopaminergic system, but it has not been investigated whether sodium-independent amine transporters are implicated in the pathogenesis of Parkinson's disease. METHODOLOGY/PRINCIPAL FINDINGS: By the use of a novel tandem-mass spectrometry-based substrate search technique, we have shown that the dopaminergic neuromodulators histidyl-proline diketopiperazine (cyclo(his-pro and salsolinol were the endogenous key substrates of the sodium-independent organic cation transporter OCT2. Quantitative real-time mRNA expression analysis revealed that OCT2 in contrast to its related transporters was preferentially expressed in the dopaminergic regions of the substantia nigra where it colocalized with DAT and tyrosine hydroxylase. By assessing cell viability with the MTT reduction assay, we found that salsolinol exhibited a selective toxicity toward OCT2-expressing cells that was prevented by cyclo(his-pro. A frequent genetic variant of OCT2 with the amino acid substitution R400C reduced the transport efficiency for the cytoprotective cyclo(his-pro and thereby increased the susceptibility to salsolinol-induced cell death. CONCLUSIONS/SIGNIFICANCE: Our findings indicate that the OCT2-regulated interplay between cyclo(his-pro and salsolinol is crucial for nigral cell integrity and that a shift in transport efficiency may impact the risk of Parkinson's disease.

  5. Overexpression of alpha-synuclein at non-toxic levels increases dopaminergic cell death induced by copper exposure via modulation of protein degradation pathways.

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    Anandhan, Annadurai; Rodriguez-Rocha, Humberto; Bohovych, Iryna; Griggs, Amy M; Zavala-Flores, Laura; Reyes-Reyes, Elsa M; Seravalli, Javier; Stanciu, Lia A; Lee, Jaekwon; Rochet, Jean-Christophe; Khalimonchuk, Oleh; Franco, Rodrigo

    2015-09-01

    Gene multiplications or point mutations in alpha (α)-synuclein are associated with familial and sporadic Parkinson's disease (PD). An increase in copper (Cu) levels has been reported in the cerebrospinal fluid and blood of PD patients, while occupational exposure to Cu has been suggested to augment the risk to develop PD. We aimed to elucidate the mechanisms by which α-synuclein and Cu regulate dopaminergic cell death. Short-term overexpression of wild type (WT) or mutant A53T α-synuclein had no toxic effect in human dopaminergic cells and primary midbrain cultures, but it exerted a synergistic effect on Cu-induced cell death. Cell death induced by Cu was potentiated by overexpression of the Cu transporter protein 1 (Ctr1) and depletion of intracellular glutathione (GSH) indicating that the toxic effects of Cu are linked to alterations in its intracellular homeostasis. Using the redox sensor roGFP, we demonstrated that Cu-induced oxidative stress was primarily localized in the cytosol and not in the mitochondria. However, α-synuclein overexpression had no effect on Cu-induced oxidative stress. WT or A53T α-synuclein overexpression exacerbated Cu toxicity in dopaminergic and yeast cells in the absence of α-synuclein aggregation. Cu increased autophagic flux and protein ubiquitination. Impairment of autophagy by overexpression of a dominant negative Atg5 form or inhibition of the ubiquitin/proteasome system (UPS) with MG132 enhanced Cu-induced cell death. However, only inhibition of the UPS stimulated the synergistic toxic effects of Cu and α-synuclein overexpression. Our results demonstrate that α-synuclein stimulates Cu toxicity in dopaminergic cells independent from its aggregation via modulation of protein degradation pathways. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Neuron-derived IgG protects dopaminergic neurons from insult by 6-OHDA and activates microglia through the FcγR I and TLR4 pathways.

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    Zhang, Jie; Niu, Na; Wang, Mingyu; McNutt, Michael A; Zhang, Donghong; Zhang, Baogang; Lu, Shijun; Liu, Yuqing; Liu, Zhihui

    2013-08-01

    Oxidative and immune attacks from the environment or microglia have been implicated in the loss of dopaminergic neurons of Parkinson's disease. The role of IgG which is an important immunologic molecule in the process of Parkinson's disease has been unclear. Evidence suggests that IgG can be produced by neurons in addition to its traditionally recognized source B lymphocytes, but its function in neurons is poorly understood. In this study, extensive expression of neuron-derived IgG was demonstrated in dopaminergic neurons of human and rat mesencephalon. With an in vitro Parkinson's disease model, we found that neuron-derived IgG can improve the survival and reduce apoptosis of dopaminergic neurons induced by 6-hydroxydopamine toxicity, and also depress the release of NO from microglia triggered by 6-hydroxydopamine. Expression of TNF-α and IL-10 in microglia was elevated to protective levels by neuron-derived IgG at a physiologic level via the FcγR I and TLR4 pathways and microglial activation could be attenuated by IgG blocking. All these data suggested that neuron-derived IgG may exert a self-protective function by activating microglia properly, and IgG may be involved in maintaining immunity homeostasis in the central nervous system and serve as an active factor under pathological conditions such as Parkinson's disease. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.

  7. Asymmetric cell division and Notch signaling specify dopaminergic neurons in Drosophila.

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    Murni Tio

    Full Text Available In Drosophila, dopaminergic (DA neurons can be found from mid embryonic stages of development till adulthood. Despite their functional involvement in learning and memory, not much is known about the developmental as well as molecular mechanisms involved in the events of DA neuronal specification, differentiation and maturation. In this report we demonstrate that most larval DA neurons are generated during embryonic development. Furthermore, we show that loss of function (l-o-f mutations of genes of the apical complex proteins in the asymmetric cell division (ACD machinery, such as inscuteable and bazooka result in supernumerary DA neurons, whereas l-o-f mutations of genes of the basal complex proteins such as numb result in loss or reduction of DA neurons. In addition, when Notch signaling is reduced or abolished, additional DA neurons are formed and conversely, when Notch signaling is activated, less DA neurons are generated. Our data demonstrate that both ACD and Notch signaling are crucial mechanisms for DA neuronal specification. We propose a model in which ACD results in differential Notch activation in direct siblings and in this context Notch acts as a repressor for DA neuronal specification in the sibling that receives active Notch signaling. Our study provides the first link of ACD and Notch signaling in the specification of a neurotransmitter phenotype in Drosophila. Given the high degree of conservation between Drosophila and vertebrate systems, this study could be of significance to mechanisms of DA neuronal differentiation not limited to flies.

  8. Pro-survival role for Parkinson's associated gene DJ-1 revealed in trophically impaired dopaminergic neurons.

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    Liviu Aron

    2010-04-01

    Full Text Available The mechanisms underlying the selective death of substantia nigra (SN neurons in Parkinson disease (PD remain elusive. While inactivation of DJ-1, an oxidative stress suppressor, causes PD, animal models lacking DJ-1 show no overt dopaminergic (DA neuron degeneration in the SN. Here, we show that aging mice lacking DJ-1 and the GDNF-receptor Ret in the DA system display an accelerated loss of SN cell bodies, but not axons, compared to mice that only lack Ret signaling. The survival requirement for DJ-1 is specific for the GIRK2-positive subpopulation in the SN which projects exclusively to the striatum and is more vulnerable in PD. Using Drosophila genetics, we show that constitutively active Ret and associated Ras/ERK, but not PI3K/Akt, signaling components interact genetically with DJ-1. Double loss-of-function experiments indicate that DJ-1 interacts with ERK signaling to control eye and wing development. Our study uncovers a conserved interaction between DJ-1 and Ret-mediated signaling and a novel cell survival role for DJ-1 in the mouse. A better understanding of the molecular connections between trophic signaling, cellular stress and aging could uncover new targets for drug development in PD.

  9. The Shh coreceptor Cdo is required for differentiation of midbrain dopaminergic neurons

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    Yu-Rim Kwon

    2014-09-01

    Full Text Available Sonic hedgehog (Shh signaling is required for numerous developmental processes including specification of ventral cell types in the central nervous system such as midbrain dopaminergic (DA neurons. The multifunctional coreceptor Cdo increases the signaling activity of Shh which is crucial for development of forebrain and neural tube. In this study, we investigated the role of Cdo in midbrain DA neurogenesis. Cdo and Shh signaling components are induced during neurogenesis of embryonic stem (ES cells. Cdo−/− ES cells show reduced neuronal differentiation accompanied by increased cell death upon neuronal induction. In addition, Cdo−/− ES cells form fewer tyrosine hydroxylase (TH and microtubule associated protein 2 (MAP2-positive DA neurons correlating with the decreased expression of key regulators of DA neurogenesis, such as Shh, Neurogenin2, Mash1, Foxa2, Lmx1a, Nurr1 and Pitx3, relative to the Cdo+/+ ES cells. Consistently, the Cdo−/− embryonic midbrain displays a reduction in expression of TH and Nurr1. Furthermore, activation of Shh signaling by treatment with Purmorphamine (Pur restores the DA neurogenesis of Cdo−/− ES cells, suggesting that Cdo is required for the full Shh signaling activation to induce efficient DA neurogenesis.

  10. Enhancement of Dopaminergic Differentiation in Proliferating Midbrain Neuroblasts by Sonic Hedgehog and Ascorbic Acid

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    Volpicelli, Floriana; Consales, Claudia; Caiazzo, Massimiliano; Colucci-D'Amato, Luca; Perrone-Capano, Carla; di Porzio, Umberto

    2004-01-01

    We analyzed the molecular mechanisms involved in the acquisition and maturation of dopaminergic (DA) neurons generated in vitro from rat ventral mesencephalon (MES) cells in the presence of mitogens or specific signaling molecules. The addition of basic fibroblast growth factor (bFGF) to MES cells in serum-free medium stimulates the proliferation of neuroblasts but delays DA differentiation. Recombinant Sonic hedgehog (SHH) protein increases up to three fold the number of tyrosine hydroxylase (TH)-positive cells and their differentiation, an effect abolished by anti-SHH antibodies. The expanded cultures are rich in nestin-positive neurons, glial cells are rare, all TH+ neurons are DA, and all DA and GABAergic markers analyzed are expressed. Adding ascorbic acid to bFGF/SHH-treated cultures resulted in a further five- to seven-fold enhancement of viable DA neurons. This experimental system also provides a powerful tool to generate DA neurons from single embryos. Our strategy provides an enriched source of MES DA neurons that are useful for analyzing molecular mechanisms controlling their function and for experimental regenerative approaches in DA dysfunction. PMID:15303305

  11. FoxO1 in dopaminergic neurons regulates energy homeostasis and targets tyrosine hydroxylase

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    Doan, Khanh V.; Kinyua, Ann W.; Yang, Dong Joo; Ko, Chang Mann; Moh, Sang Hyun; Shong, Ko Eun; Kim, Hail; Park, Sang-Kyu; Kim, Dong-Hoon; Kim, Inki; Paik, Ji-Hye; DePinho, Ronald A.; Yoon, Seul Gi; Kim, Il Yong; Seong, Je Kyung; Choi, Yun-Hee; Kim, Ki Woo

    2016-01-01

    Dopaminergic (DA) neurons are involved in the integration of neuronal and hormonal signals to regulate food consumption and energy balance. Forkhead transcriptional factor O1 (FoxO1) in the hypothalamus plays a crucial role in mediation of leptin and insulin function. However, the homoeostatic role of FoxO1 in DA system has not been investigated. Here we report that FoxO1 is highly expressed in DA neurons and mice lacking FoxO1 specifically in the DA neurons (FoxO1 KODAT) show markedly increased energy expenditure and interscapular brown adipose tissue (iBAT) thermogenesis accompanied by reduced fat mass and improved glucose/insulin homoeostasis. Moreover, FoxO1 KODAT mice exhibit an increased sucrose preference in concomitance with higher dopamine and norepinephrine levels. Finally, we found that FoxO1 directly targets and negatively regulates tyrosine hydroxylase (TH) expression, the rate-limiting enzyme of the catecholamine synthesis, delineating a mechanism for the KO phenotypes. Collectively, these results suggest that FoxO1 in DA neurons is an important transcriptional factor that directs the coordinated control of energy balance, thermogenesis and glucose homoeostasis. PMID:27681312

  12. Blocking Dopaminergic Signaling Soon after Learning Impairs Memory Consolidation in Guinea Pigs.

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    Kiera-Nicole Lee

    Full Text Available Formation of episodic memories (i.e. remembered experiences requires a process called consolidation which involves communication between the neocortex and hippocampus. However, the neuromodulatory mechanisms underlying this neocortico-hippocampal communication are poorly understood. Here, we examined the involvement of dopamine D1 receptors (D1R and D2 receptors (D2R mediated signaling on memory consolidation using the Novel Object Recognition (NOR test. We conducted the tests in male Hartley guinea pigs and cognitive behaviors were assessed in customized Phenotyper home cages utilizing Ethovision XT software from Noldus enabled for the 3-point detection system (nose, center of the body, and rear. We found that acute intraperitoneal injections of either 0.25 mg/kg SCH23390 to block D1Rs or 1.0 mg/kg sulpiride to block D2Rs soon after acquisition (which involved familiarization to two similar objects attenuated subsequent discrimination for novel objects when tested after 5-hours in the NOR test. By contrast guinea pigs treated with saline showed robust discrimination for novel objects indicating normal operational processes undergirding memory consolidation. The data suggests that involvement of dopaminergic signaling is a key post-acquisition factor in modulating memory consolidation in guinea pigs.

  13. Music improves dopaminergic neurotransmission: demonstration based on the effect of music on blood pressure regulation.

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    Sutoo, Den'etsu; Akiyama, Kayo

    2004-08-06

    The mechanism by which music modifies brain function is not clear. Clinical findings indicate that music reduces blood pressure in various patients. We investigated the effect of music on blood pressure in spontaneously hypertensive rats (SHR). Previous studies indicated that calcium increases brain dopamine (DA) synthesis through a calmodulin (CaM)-dependent system. Increased DA levels reduce blood pressure in SHR. In this study, we examined the effects of music on this pathway. Systolic blood pressure in SHR was reduced by exposure to Mozart's music (K.205), and the effect vanished when this pathway was inhibited. Exposure to music also significantly increased serum calcium levels and neostriatal DA levels. These results suggest that music leads to increased calcium/CaM-dependent DA synthesis in the brain, thus causing a reduction in blood pressure. Music might regulate and/or affect various brain functions through dopaminergic neurotransmission, and might therefore be effective for rectification of symptoms in various diseases that involve DA dysfunction.

  14. Effect of incubation temperature and androgens on dopaminergic activity in the leopard gecko, Eublepharis macularius.

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    Dias, Brian George; Ataya, Ramona Sousan; Rushworth, David; Zhao, Jun; Crews, David

    2007-04-01

    Male leopard geckos that hatch from eggs incubated at a female-biased temperature (Tf) behave differently when compared with males hatching at a temperature which produces a male-biased sex ratio (Tm). We investigated the effect of incubation temperature and androgen implantation on aspects of the dopaminergic system of Tf and Tm males. Our data suggest that more dopamine (DA) is stored in the nucleus accumbens of naive Tf males compared with naïve Tm males when they encounter a receptive female conspecific across a barrier. No difference was measured in the preoptic area and the ventral tegmental area (VTA). This difference in intracellular DA levels in a motivation-related brain nucleus might be correlated with differences in sociosexual behavior observed between the two morphs. There were no differences in tyrosine hydroxylase (TH) expressing cell numbers in the VTA of cholesterol (CH)-implanted naive castrated Tf and Tm males. Only Tf males implanted with testosterone had significantly higher TH immunopositive cell numbers in the VTA compared with CH- and dihydrotestosterone-implanted Tf males. These data indicate that both the embryonic environment as well as the circulating hormonal milieu can modulate neurochemistry, which might in turn be a basis for individual variation in behavior. Copyright (c) 2007 Wiley Periodicals, Inc.

  15. Spinal dopaminergic involvement in the antihyperalgesic effect of antidepressants in a rat model of neuropathic pain.

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    Chen, Mi; Hoshino, Hajime; Saito, Shigeru; Yang, Yang; Obata, Hideaki

    2017-05-10

    Antidepressants such as tricyclic antidepressants, and serotonin noradrenaline reuptake inhibitors are a first-line treatment for neuropathic pain. Here, we aimed to determine the involvement of the spinal dopaminergic system in the antihyperalgesic effects of antidepressants in a rat model of neuropathic pain induced by spinal nerve ligation (SNL). The right L5 spinal nerve of male Sprague-Dawley rats was ligated under inhalation anesthesia to induce hyperalgesia. Behavioral testing was performed by measuring ipsilateral hindpaw withdrawal thresholds after intraperitoneal injection of amitriptyline, duloxetine, milnacipran, and fluoxetine. D2-like receptors were blocked by intrathecal administration of sulpiride. We also determined the concentrations of dopamine in the spinal cord using microdialysis after injection of antidepressants. The dopamine contents in the spinal dorsal horn were also measured in normal and SNL rats at 2, 3, 4, and 8 weeks after SNL surgery. Intraperitoneal injection of amitriptyline, duloxetine, milnacipran, and fluoxetine (3-30mg/kg) produced antihyperalgesic effects, and prevented by intrathecal pre-injection of sulpiride (30μg). Microdialysis revealed the dopamine levels in the spinal cord were increased after intraperitoneal injection of each antidepressant (10mg/kg). Furthermore, the dopamine content in homogenized spinal cord tissue were increased at 2 weeks after SNL and then subsequently declined. Our results suggest that the effect of antidepressants against neuropathic pain is related to modulation of not only noradrenalin and serotonin but also dopamine levels in the spinal cord. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Redundant dopaminergic activity may enable compensatory axonal sprouting in Parkinson disease.

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    Arkadir, David; Bergman, Hagai; Fahn, Stanley

    2014-03-25

    Neurodegenerative diseases become clinically apparent only after a substantial population of neurons is lost. This raises the possibility of compensatory mechanisms in the early phase of these diseases. The importance of understanding these mechanisms cannot be underestimated because it may guide future disease-modifying strategies. Because the anatomy and physiology of the nigrostriatal dopaminergic pathways have been well described, the study of Parkinson disease can offer insight into these early compensatory mechanisms. Collateral axonal sprouting of dopaminergic terminals into the denervated striatum is the most studied compensatory mechanism in animal (almost exclusively rodent) models of Parkinson disease and is correlated with behavioral recovery after partial lesions. This sprouting, however, does not respect the normal anatomy of the original nigrostriatal pathways and leads to aberrant neuronal networks. We suggest here that the unique physiologic property of the dopaminergic innervation of the striatum, namely redundancy of information encoding, is crucial to the efficacy of compensatory axonal sprouting in the presence of aberrant anatomical connections. Redundant information encoding results from the similarity of representation of salient and rewarding events by many dopaminergic neurons, from the wide axonal field of a single dopaminergic neuron in the striatum, and from the nonspecific spatial effect of dopamine on striatal neurons (volume conductance). Finally, we discuss the relevance of these findings in animal models to human patients with Parkinson disease.

  17. Predictive value of the smell identification test for nigrostriatal dopaminergic depletion in Korean tremor patients.

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    Hong, Jin Yong; Chung, Seok Jong; Lee, Ji E; Sunwoo, Mun Kyung; Lee, Phil Hyu; Sohn, Young H

    2013-11-01

    The predictive value of Cross-Cultural Smell Identification Test for nigrostriatal dopaminergic depletion in Korean tremor patients has yet to be assessed. Three hundred nineteen drug-naive patients who visited our clinic for the diagnosis of their tremor, and took both Cross-Cultural Smell Identification Test and dopamine transporter PET were included in the data analysis. Visual grading of each PET image was performed by two independent neurologists. Smell test scores were significantly correlated to the striatal dopaminergic activity (Kendall's τb = -0.291, p smell test score alone appeared to have relatively weak power for predicting dopaminergic depletion (area under the curve = 0.693). Multivariate logistic regression model with inclusion of the patient's age and symptom duration as independent variables enhanced predictive power for dopaminergic depletion (area under the curve = 0.812). These results demonstrated that Cross-Cultural Smell Identification Test measurements alone may be insufficient to predict striatal dopaminergic depletion in Korean tremor patients. Copyright © 2013 Elsevier Ltd. All rights reserved.

  18. Neural Progenitor Cells Derived from Human Embryonic Stem Cells as an Origin of Dopaminergic Neurons

    Directory of Open Access Journals (Sweden)

    Parinya Noisa

    2015-01-01

    Full Text Available Human embryonic stem cells (hESCs are able to proliferate in vitro indefinitely without losing their ability to differentiate into multiple cell types upon exposure to appropriate signals. Particularly, the ability of hESCs to differentiate into neuronal subtypes is fundamental to develop cell-based therapies for several neurodegenerative disorders, such as Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease. In this study, we differentiated hESCs to dopaminergic neurons via an intermediate stage, neural progenitor cells (NPCs. hESCs were induced to neural progenitor cells by Dorsomorphin, a small molecule that inhibits BMP signalling. The resulting neural progenitor cells exhibited neural bipolarity with high expression of neural progenitor genes and possessed multipotential differentiation ability. CBF1 and bFGF responsiveness of these hES-NP cells suggested their similarity to embryonic neural progenitor cells. A substantial number of dopaminergic neurons were derived from hES-NP cells upon supplementation of FGF8 and SHH, key dopaminergic neuron inducers. Importantly, multiple markers of midbrain neurons were detected, including NURR1, PITX3, and EN1, suggesting that hESC-derived dopaminergic neurons attained the midbrain identity. Altogether, this work underscored the generation of neural progenitor cells that retain the properties of embryonic neural progenitor cells. These cells will serve as an unlimited source for the derivation of dopaminergic neurons, which might be applicable for treating patients with Parkinson’s disease.

  19. Mesolimbic dopamine in desire and dread: enabling motivation to be generated by localized glutamate disruptions in nucleus accumbens.

    Science.gov (United States)

    Faure, Alexis; Reynolds, Sheila M; Richard, Jocelyn M; Berridge, Kent C

    2008-07-09

    An important issue in affective neuroscience concerns the role of mesocorticolimbic dopamine systems in positive-valenced motivation (e.g., reward) versus negative-valenced motivation (e.g., fear). Here, we assessed whether endogenous dopamine receptor stimulation in nucleus accumbens contributes to both appetitive behavior and fearful behavior that is generated in keyboard manner by local glutamate disruptions at different sites in medial shell. 6,7-Dinitroquinoxaline-2,3(1H,4H)-dione (DNQX) microinjections (450 ng) locally disrupt glutamate signals in <4 mm(3) of nucleus accumbens, and generate either desire or fear (or both) depending on precise rostrocaudal location in medial shell. At rostral shell sites, local AMPA/kainate blockade generates positive ingestive behavior, but the elicited motivated behavior becomes incrementally more fearful as the same microinjection is moved caudally. A dopamine-blocking mixture of D(1) and D(2) antagonists (raclopride and SCH-23390 [R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5,-tetrahydro-1H-3-benzazepine hydrochloride]) was combined here in the same microinjection with DNQX to assess the role of endogenous local dopamine in mediating the DNQX-motivated behaviors. We report that local dopamine blockade prevented DNQX microinjections from generating appetitive behavior (eating) in rostral shell, and equally prevented DNQX from generating fearful behavior (defensive treading) in caudal shell. We conclude that local dopamine is needed to enable disruptions of corticolimbic glutamate signals in shell to generate either positive incentive salience or negative fearful salience (valence depending on site and other conditions). Thus, dopamine interacts with localization of valence-biased glutamate circuits in medial shell to facilitate keyboard stimulation of both appetitive and fearful motivations.

  20. Assessment of Dopaminergic Homeostasis in Mice by Use of High-performance Liquid Chromatography Analysis and Synaptosomal Dopamine Uptake

    DEFF Research Database (Denmark)

    Jensen, Kathrine L; Runegaard, Annika H; Weikop, Pia

    2017-01-01

    Dopamine (DA) is a modulatory neurotransmitter controlling motor activity, reward processes and cognitive function. Impairment of dopaminergic (DAergic) neurotransmission is strongly associated with several central nervous system-associated diseases such as Parkinson's disease, attention......-deficit-hyperactivity disorder and drug addiction(1)(,)(2)(,)(3)(,)(4). Delineating disease mechanisms involving DA imbalance is critically dependent on animal models to mimic aspects of the diseases, and thus protocols that assess specific parts of the DA homeostasis are important to provide novel insights and possible...... therapeutic targets for these diseases. Here, we present two useful experimental protocols that when combined provide a functional read-out of the DAergic system in mice. Biochemical and functional parameters on DA homeostasis are obtained through assessment of DA levels and dopamine transporter (DAT...

  1. A novel dopamine transporter transgenic mouse line for identification and purification of midbrain dopaminergic neurons reveals midbrain heterogeneity

    DEFF Research Database (Denmark)

    Christiansen, Mia Apuschkin; Stilling, Sara; Rahbek-Clemmensen, Troels

    2015-01-01

    Midbrain dopaminergic (DAergic) neurons are a heterogeneous cell group, composed of functionally distinct cell populations projecting to the basal ganglia, prefrontal cortex and limbic system. Despite their functional significance, the midbrain population of DAergic neurons is sparse, constituting...... in synaptosomal DA uptake nor altered levels of DAT and TH in both striatum and midbrain. No behavioural difference between Dat1-eGFP and wild-type was found, suggesting that the strain is not aberrant. Finally, cell populations highly enriched in DAergic neurons can be obtained from postnatal mice...... only 20 000-30 000 neurons in mice, and development of novel tools to identify these cells is warranted. Here, a bacterial artificial chromosome mouse line [Dat1-enhanced green fluorescent protein (eGFP)] from the Gene Expression Nervous System Atlas (GENSAT) that expresses eGFP under control...

  2. Effects on prolactin secretion and binding to dopaminergic receptors in sleep-deprived lupus-prone mice

    Directory of Open Access Journals (Sweden)

    B.D. Palma

    2009-03-01

    Full Text Available Sleep disturbances have far-reaching effects on the neuroendocrine and immune systems and may be linked to disease manifestation. Sleep deprivation can accelerate the onset of lupus in NZB/NZWF1 mice, an animal model of severe systemic lupus erythematosus. High prolactin (PRL concentrations are involved in the pathogenesis of systemic lupus erythematosus in human beings, as well as in NZB/NZWF1 mice. We hypothesized that PRL could be involved in the earlier onset of the disease in sleep-deprived NZB/NZWF1 mice. We also investigated its binding to dopaminergic receptors, since PRL secretion is mainly controlled by dopamine. Female NZB/NZWF1 mice aged 9 weeks were deprived of sleep using the multiple platform method. Blood samples were taken for the determination of PRL concentrations and quantitative receptor autoradiography was used to map binding of the tritiated dopaminergic receptor ligands [³H]-SCH23390, [³H]-raclopride and [³H]-WIN35,428 to D1 and D2 dopaminergic receptors and dopamine transporter sites throughout the brain, respectively. Sleep deprivation induced a significant decrease in plasma PRL secretion (2.58 ± 0.95 ng/mL compared with the control group (25.25 ± 9.18 ng/mL. The binding to D1 and D2 binding sites was not significantly affected by sleep deprivation; however, dopamine transporter binding was significantly increased in subdivisions of the caudate-putamen - posterior (16.52 ± 0.5 vs 14.44 ± 0.6, dorsolateral (18.84 ± 0.7 vs 15.97 ± 0.7 and ventrolateral (24.99 ± 0.5 vs 22.54 ± 0.7 µCi/g, in the sleep-deprived mice when compared to the control group. These results suggest that PRL is not the main mechanism involved in the earlier onset of the disease observed in sleep-deprived NZB/NZWF1 mice and the reduction of PRL concentrations after sleep deprivation may be mediated by modifications in the dopamine transporter sites of the caudate-putamen.

  3. Differential Somatic Ca2+ Channel Profile in Midbrain Dopaminergic Neurons.

    Science.gov (United States)

    Philippart, Fabian; Destreel, Geoffrey; Merino-Sepúlveda, Paulina; Henny, Pablo; Engel, Dominique; Seutin, Vincent

    2016-07-06

    Dopaminergic (DA) neurons located in the ventral midbrain continuously generate a slow endogenous pacemaker activity, the mechanism of which is still debated. It has been suggested that, in the substantia nigra pars compacta (SNc), the pacemaking relies more on Ca(2+) channels and that the density of L-type Ca(2+) channels is higher in these DA neurons than in those located in the ventral tegmental area (VTA). This might lead to a higher Ca(2+) load in SNc DA neurons and explain their higher susceptibility to degeneration. However, direct evidence for this hypothesis is lacking. We found that the L-type current and channel density are indeed higher in the somata of rat SNc DA neurons and that this current undergoes less inactivation in this region. Nonstationary fluctuation analysis measurements showed a much higher number of L-type channels in the soma of SNc DA neurons, as well as a smaller single-channel conductance, pointing to a possible different molecular identity of L-type channels in DA neurons from the two areas. A major consequence of this is that pacemaking and, even more so, bursting are associated with a larger Ca(2+) entry through L-type channels in SNc DA neurons than in their VTA counterparts. Our results establish a molecular and functional difference between two populations of midbrain DA neurons that may contribute to their differential sensitivity to neurodegeneration. Dopamine neurons from the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) are involved in various brain functions, such as movement initiation and goal directed behavior, respectively. This work shows that, although both neurons fire in a similar regular and slow pacemaker mode, this firing activity is supported by different calcium channel landscapes. Indeed, the L-type calcium current is larger in the soma of dopamine neurons of the SNc, leading to a higher charge transfer through L-type channels during pacemaking and bursting. Therefore, these neurons may

  4. CALBINDIN CONTENT AND DIFFERENTIAL VULNERABILITY OF MIDBRAIN EFFERENT DOPAMINERGIC NEURONS IN MACAQUES

    Directory of Open Access Journals (Sweden)

    Iria G Dopeso-Reyes

    2014-12-01

    Full Text Available Calbindin (CB is a calcium binding protein reported to protect dopaminergic neurons from degeneration. Although a direct link between CB content and differential vulnerability of dopaminergic neurons has long been accepted, factors other than CB have also been suggested, particularly those related to the dopamine transporter. Indeed, several studies have reported that CB levels are not causally related to the differential vulnerability of dopaminergic neurons against neurotoxins. Here we have used dual stains for tyrosine hydroxylase (TH and CB in 3 control and 3 MPTP-treated monkeys to visualize dopaminergic neurons in the ventral tegmental area (VTA and in the dorsal and ventral tiers of the substantia nigra pars compacta (SNcd and SNcv co-expressing TH and CB. In control animals, the highest percentages of co-localization were found in VTA (58.2%, followed by neurons located in the SNcd (34.7%. As expected, SNcv neurons lacked CB expression. In MPTP-treated animals, the percentage of CB-ir/TH-ir neurons in the VTA was similar to control monkeys (62.1%, whereas most of the few surviving neurons in the SNcd were CB-ir/TH-ir (88.6%. Next, we have elucidated the presence of CB within identified nigrostriatal and nigroextrastriatal midbrain dopaminergic projection neurons. For this purpose, two control monkeys received one injection of Fluoro-Gold into the caudate nucleus and one injection of cholera toxin (CTB into the postcommissural putamen, whereas two more monkeys were injected with CTB into the internal division of the globus pallidus. As expected, all the nigrocaudate- and nigroputamen-projecting neurons were TH-ir, although surprisingly, all of these nigrostriatal-projecting neurons were negative for CB. Furthermore, all the nigropallidal-projecting neurons co-expressed both TH and CB. In summary, although CB-ir dopaminergic neurons seem to be less prone to MPTP-induced degeneration, our data clearly demonstrated that these neurons are not

  5. Intermittent, low dose carbon monoxide exposure enhances survival and dopaminergic differentiation of human neural stem cells

    DEFF Research Database (Denmark)

    Dreyer-Andersen, Nanna; Almeida, Ana Sofia; Jensen, Pia

    2018-01-01

    Exploratory studies using human fetal tissue have suggested that intrastriatal transplantation of dopaminergic neurons may become a future treatment for patients with Parkinson's disease. However, the use of human fetal tissue is compromised by ethical, regulatory and practical concerns. Human stem...... cells constitute an alternative source of cells for transplantation in Parkinson's disease, but efficient protocols for controlled dopaminergic differentiation need to be developed. Short-term, low-level carbon monoxide (CO) exposure has been shown to affect signaling in several tissues, resulting...... in Parkinson's disease....

  6. Dopaminergic differentiation of human neural stem cells mediated by co-cultured rat striatal brain slices

    DEFF Research Database (Denmark)

    Anwar, Mohammad Raffaqat; Andreasen, Christian Maaløv; Lippert, Solvej Kølvraa

    2008-01-01

    differentiation, we co-cultured cells from a human neural forebrain-derived stem cell line (hNS1) with rat striatal brain slices. In brief, coronal slices of neonatal rat striatum were cultured on semiporous membrane inserts placed in six-well trays overlying monolayers of hNS1 cells. After 12 days of co......Properly committed neural stem cells constitute a promising source of cells for transplantation in Parkinson's disease, but a protocol for controlled dopaminergic differentiation is not yet available. To establish a setting for identification of secreted neural compounds promoting dopaminergic...

  7. Pathological gambling: Relation of skin conductance response to dopaminergic neurotransmission and sensation-seeking

    DEFF Research Database (Denmark)

    Peterson, Ericka; Møller, Arne; Doudet, Doris

    2010-01-01

    Absent Skin Conductance Response (SCR) in pathological gambling (PG) may relate to dopaminergic mechanisms. We recruited equal numbers of PG subjects and healthy control (HC) subjects, and then tested the claim that SCR is less conditioned by dopaminergic activity in PG subjects. During active...... gambling, SCR differed in PG and HC subjects (Pb0.05), but positron emission tomography revealed the same dopamine receptor availability. However, highly sensation-seeking (HS) PG subjects had lower dopamine receptor availability (Pb0.0001) in the baseline, compared to normal sensation-seeking (NS) PG...

  8. THE PARABRACHIAL NUCLEUS IS A CRITICAL LINK IN THE TRANSMISSION OF SHORT LATENCY NOCICEPTIVE INFORMATION TO MIDBRAIN DOPAMINERGIC NEURONS

    NARCIS (Netherlands)

    Coizet, V.; Dommett, E. J.; Klop, E. M.; Redgrave, P.; Overton, P. G.

    2010-01-01

    Many dopaminergic neurons exhibit a short-latency response to noxious stimuli, the source of which is unknown. Here we report that the nociceptive-recipient parabrachial nucleus appears to be a critical link in the transmission of pain related information to dopaminergic neurons. Injections of

  9. Effect of long-term estrogen therapy on dopaminergic responsivity in post-menopausal women--a preliminary study

    NARCIS (Netherlands)

    Craig, M. C.; Cutter, W. J.; Wickham, H.; van Amelsvoort, T. A. M. J.; Rymer, J.; Whitehead, M.; Murphy, D. G. M.

    2004-01-01

    Females have a higher prevalence than men of neuropsychiatric disorders in which dopaminergic abnormalities play a prominent role, e.g. very late-onset schizophrenia and Parkinson's disease (PD). The biological basis of these sex differences is unknown but may include modulation of the dopaminergic

  10. Does cannabis affect dopaminergic signaling in the human brain? A systematic review of evidence to date.

    Science.gov (United States)

    Sami, Musa Basser; Rabiner, Eugenii A; Bhattacharyya, Sagnik

    2015-08-01

    A significant body of epidemiological evidence has linked psychotic symptoms with both acute and chronic use of cannabis. Precisely how these effects of THC are mediated at the neurochemical level is unclear. While abnormalities in multiple pathways may lead to schizophrenia, an abnormality in dopamine neurotransmission is considered to be the final common abnormality. One would thus expect cannabis use to be associated with dopamine signaling alterations. This is the first systematic review of all studies, both observational as well as experimental, examining the acute as well as chronic effect of cannabis or its main psychoactive ingredient, THC, on the dopamine system in man. We aimed to review all studies conducted in man, with any reported neurochemical outcomes related to the dopamine system after cannabis, cannabinoid or endocannabinoid administration or use. We identified 25 studies reporting outcomes on over 568 participants, of which 244 participants belonged to the cannabis/cannabinoid exposure group. In man, there is as yet little direct evidence to suggest that cannabis use affects acute striatal dopamine release or affects chronic dopamine receptor status in healthy human volunteers. However some work has suggested that acute cannabis exposure increases dopamine release in striatal and pre-frontal areas in those genetically predisposed for, or at clinical high risk of psychosis. Furthermore, recent studies are suggesting that chronic cannabis use blunts dopamine synthesis and dopamine release capacity. Further well-designed studies are required to definitively delineate the effects of cannabis use on the dopaminergic system in man. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  11. Enantiomeric analogues of SCH 23390 as new probes for behavioral interactions between D-1 and D-2 dopaminergic function

    International Nuclear Information System (INIS)

    Waddington, J.L.; Mashurano, M.; Molloy, A.G.; O'Boyle, K.M.

    1986-01-01

    The purposes of this article are to describe the properties of some newer selective D 1 agents, and to characterize behavioral responses to a D 1 agonist in the intact adult rat. R- and S-SKandF 83566 and other new 1-phenyl-1H-3-benzazephines as selective D 1 agents are discussed. The displacement of 3 H-SCH 23390 from human brain D 1 receptors, in comparison with displacement of 3 H-piflutixol and 3 H-spiperone is shown. Enantiomeric induction of grooming and other behaviors by R- and S-SKandF 38393 is examined. Sections are also devoted to pharmacological characterization of behavioral responses to SKandF 38393 and to D 1 : D 2 receptor systems and the regulation of dopaminergic behaviors

  12. Dopaminergic Neuronal Loss and Dopamine-Dependent Locomotor Defects in Fbxo7-Deficient Zebrafish

    NARCIS (Netherlands)

    T. Zhao (Tianna); H. Zondervan-van der Linde (Herma); E.A.W.F.M. Severijnen (Lies-Anne); B.A. Oostra (Ben); R. Willemsen (Rob); V. Bonifati (Vincenzo)

    2012-01-01

    textabstractRecessive mutations in the F-box only protein 7 gene (FBXO7) cause PARK15, a Mendelian form of early-onset, levodopa-responsive parkinsonism with severe loss of nigrostriatal dopaminergic neurons. However, the function of the protein encoded by FBXO7, and the pathogenesis of PARK15

  13. Nigral dopaminergic neuron replenishment in adult mice through VE-cadherin-expressing neural progenitor cells

    Directory of Open Access Journals (Sweden)

    Abir A Rahman

    2017-01-01

    Full Text Available The function of dopaminergic neurons in the substantia nigra is of central importance to the coordination of movement by the brain's basal ganglia circuitry. This is evidenced by the loss of these neurons, resulting in the cardinal motor deficits associated with Parkinson's disease. In order to fully understand the physiology of these key neurons and develop potential therapies for their loss, it is essential to determine if and how dopaminergic neurons are replenished in the adult brain. Recent work has presented evidence for adult neurogenesis of these neurons by Nestin+/Sox2– neural progenitor cells. We sought to further validate this finding and explore a potential atypical origin for these progenitor cells. Since neural progenitor cells have a proximal association with the vasculature of the brain and subsets of endothelial cells are Nestin+, we hypothesized that dopaminergic neural progenitors might share a common cell lineage. Therefore, we employed a VE-cadherin promoter-driven CREERT2:THlox/THlox transgenic mouse line to ablate the tyrosine hydroxylase gene from endothelial cells in adult animals. After 26 weeks, but not 13 weeks, following the genetic blockade of tyrosine hydroxylase expression in VE-cadherin+ cells, we observed a significant reduction in tyrosine hydroxylase+ neurons in the substantia nigra. The results from this genetic lineage tracing study suggest that dopaminergic neurons are replenished in adult mice by a VE-cadherin+ progenitor cell population potentially arising from an endothelial lineage.

  14. Wnt/beta-catenin signaling blockade promotes neuronal induction and dopaminergic differentiation in embryonic stem cells

    Czech Academy of Sciences Publication Activity Database

    Čajánek, L.; Ribeiro, D.; Liste, I.; Parish, C.L.; Bryja, Vítězslav; Arenas, E.

    2009-01-01

    Roč. 27, č. 12 (2009), s. 2917-2927 ISSN 1066-5099 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : embryonic stem cells * Wnt pathway * dopaminergic neurons Subject RIV: BO - Biophysics Impact factor: 7.747, year: 2009

  15. Dopaminergic and clinical correlates of pathological gambling in Parkinson's disease: A case report

    Directory of Open Access Journals (Sweden)

    Mette Buhl Callesen

    2013-07-01

    Full Text Available Dopaminergic medication for motor symptoms in Parkinson’s disease recently has been linked with impulse control disorders, including pathological gambling, which affects up to 8% of patients. Pathological gambling often is considered a behavioral addiction associated with disinhibition, risky decision-making, and altered striatal dopaminergic neurotransmission. Using [11C]raclopride with positron emission tomography, we assessed dopaminergic neurotransmission during Iowa Gambling Task performance. Here we present data from a single patient with Parkinson’s disease and concomitant pathological gambling. We noted a marked decrease in [11C]raclopride binding in the left ventral striatum upon gambling, indicating a gambling-induced dopamine release. The results imply that pathological gambling in Parkinson’s disease is associated with a high dose of dopaminergic medication, pronounced motor symptomatology, young age at disease onset, high propensity for sensation seeking, and risky decision-making. Overall, the findings are consistent with the hypothesis of medication-related pathological gambling in Parkinson’s disease and underscore the importance of taking clinical variables, such as age and personality, into account when patients with Parkinson’s disease are medicated, to reduce the risk of pathological gambling.

  16. Postendocytic sorting of constitutively internalized dopamine transporter in cell lines and dopaminergic neurons

    DEFF Research Database (Denmark)

    Eriksen, Jacob; Bjørn-Yoshimoto, Walden Emil; Jørgensen, Trine Nygaard

    2010-01-01

    the same co-localization pattern as TacDAT in 1Rb3An27 cells and in cultured midbrain dopaminergic neurons. We conclude that DAT is constitutively internalized and sorted in a ubiquitination-independent manner to late endosomes/lysosomes and in part to a Rab4 positive short loop recycling pathway....

  17. Dopaminergic and clinical correlates of pathological gambling in Parkinson's disease: a case report.

    Science.gov (United States)

    Callesen, Mette Buhl; Hansen, K V; Gjedde, A; Linnet, J; Møller, A

    2013-01-01

    Dopaminergic medication for motor symptoms in Parkinson's disease (PD) recently has been linked with impulse control disorders, including pathological gambling (PG), which affects up to 8% of patients. PG often is considered a behavioral addiction associated with disinhibition, risky decision-making, and altered striatal dopaminergic neurotransmission. Using [(11)C]raclopride with positron emission tomography, we assessed dopaminergic neurotransmission during Iowa Gambling Task performance. Here we present data from a single patient with PD and concomitant PG. We noted a marked decrease in [(11)C]raclopride binding in the left ventral striatum upon gambling, indicating a gambling-induced dopamine release. The results imply that PG in PD is associated with a high dose of dopaminergic medication, pronounced motor symptomatology, young age at disease onset, high propensity for sensation seeking, and risky decision-making. Overall, the findings are consistent with the hypothesis of medication-related PG in PD and underscore the importance of taking clinical variables, such as age and personality, into account when patients with PD are medicated, to reduce the risk of PG.

  18. Dopaminergic and Clinical Correlates of Pathological Gambling in Parkinson’s Disease: A Case Report

    Science.gov (United States)

    Callesen, Mette Buhl; Hansen, K. V.; Gjedde, A.; Linnet, J.; Møller, A.

    2013-01-01

    Dopaminergic medication for motor symptoms in Parkinson’s disease (PD) recently has been linked with impulse control disorders, including pathological gambling (PG), which affects up to 8% of patients. PG often is considered a behavioral addiction associated with disinhibition, risky decision-making, and altered striatal dopaminergic neurotransmission. Using [11C]raclopride with positron emission tomography, we assessed dopaminergic neurotransmission during Iowa Gambling Task performance. Here we present data from a single patient with PD and concomitant PG. We noted a marked decrease in [11C]raclopride binding in the left ventral striatum upon gambling, indicating a gambling-induced dopamine release. The results imply that PG in PD is associated with a high dose of dopaminergic medication, pronounced motor symptomatology, young age at disease onset, high propensity for sensation seeking, and risky decision-making. Overall, the findings are consistent with the hypothesis of medication-related PG in PD and underscore the importance of taking clinical variables, such as age and personality, into account when patients with PD are medicated, to reduce the risk of PG. PMID:23908610

  19. DIFFERENTIATION OF NON-MESENCEPHALIC NEURAL STEM CELLS TOWARDS DOPAMINERGIC NEURONS

    NARCIS (Netherlands)

    Rossler, R.; Boddeke, E.; Copray, S.

    2010-01-01

    Neural stem cells (NSCs), either isolated from fetal or adult human brain or derived from induced pluripotent stem cells, are now considered major candidates for in vitro generation of transplantable dopaminergic (DA) neurons and modeling of Parkinson's disease. It is generally thought that in vitro

  20. Intermittent, low dose carbon monoxide exposure enhances survival and dopaminergic differentiation of human neural stem cells

    DEFF Research Database (Denmark)

    Dreyer-Andersen, Nanna; Almeida, Ana Sofia; Jensen, Pia

    2018-01-01

    Exploratory studies using human fetal tissue have suggested that intrastriatal transplantation of dopaminergic neurons may become a future treatment for patients with Parkinson's disease. However, the use of human fetal tissue is compromised by ethical, regulatory and practical concerns. Human st...

  1. Pathological gambling and hypersexuality due to dopaminergic treatment in Parkinson' disease.

    Science.gov (United States)

    Martín Fernández, F; Martín González, T

    2009-01-01

    Prevalence of psychiatric disorders in patients suffering from Parkinson's disease varies from 12 to 90%. The most common disorder in the natural evolution of Parkinson's disease is depression. However, episodes of psychosis and hypomania are related to treatment with L-dopa and dopaminergic agents. Other recognized, although less frequent, psychiatric disorders are hypersexuality and development of certain addictive behaviors, which is compulsive gambling and overdosing of anti-Parkinson agents. A case is presented of a male patient diagnosed with Parkinson's Disease at an early age who was treated with L-dopa and a combination of dopaminergic agents. During the course of his evolution he manifested symptoms of hypersexuality and pathological gambling which were unrelated to psychotic or mood changes. A number of hospital admissions were needed into order to detect a pattern of abusive consumption of L-dopa as the main factor behind his behavior changes. The possibility of overdosage of L-dopa and dopaminergic drugs should be considered when there is pathological gambling conduct and/or hypersexuality, without psychotic or accompanying affective symptoms, in a male who develops Parkinson's disease at an early age and who undergoes treatment with these drugs and manifests motor fluctuations and dyskinesias. Early detection of the presence of these alterations, included within those described as "dopaminergic dysregulation syndrome", would allow for an early intervention on the cause behind them and would hence avoid the possible medical and social complications.

  2. Prolonged Dysfunction of Astrocytes and Activation of Microglia Accelerate Degeneration of Dopaminergic Neurons in the Rat Substantia Nigra and Block Compensation of Early Motor Dysfunction Induced by 6-OHDA.

    Science.gov (United States)

    Kuter, Katarzyna; Olech, Łukasz; Głowacka, Urszula

    2018-04-01

    Progressive degeneration of dopaminergic neurons in the substantia nigra (SN) is the underlying cause of Parkinson's disease (PD). The disease in early stages is difficult to diagnose, because behavioral deficits are masked by compensatory processes. Astrocytic and microglial pathology precedes motor symptoms. Besides supportive functions of astrocytes in the brain, their role in PD is unrecognized. Prolonged dysfunction of astrocytes could increase the vulnerability of dopaminergic neurons and advance their degeneration during aging. The aim of our studies was to find out whether prolonged dysfunction of astrocytes in the SN is deleterious for neuronal functioning and if it influences their survival after toxic insult or changes the compensatory potential of the remaining neurons. In Wistar rat model, we induced activation, prolonged dysfunction, and death of astrocytes by chronic infusion of fluorocitrate (FC) into the SN, without causing dopaminergic neuron degeneration. Strongly enhanced dopamine turnover in the SN after 7 days of FC infusion was induced probably by microglia activated in response to astrocyte stress. The FC effect was reversible, and astrocyte pool was replenished 3 weeks after the end of infusion. Importantly, the prolonged astrocyte dysfunction and microglia activation accelerated degeneration of dopaminergic neurons induced by 6-hydroxydopamine and blocked the behavioral compensation normally observed after moderate neurodegeneration. Impaired astrocyte functioning, activation of microglia, diminishing compensatory capability of the dopaminergic system, and increasing neuronal vulnerability to external insults could be the underlying causes of PD. This animal model of prolonged astrocyte dysfunction can be useful for in vivo studies of glia-microglia-neuron interaction.

  3. sigma receptor ligands attenuate N-methyl-D-aspartate cytotoxicity in dopaminergic neurons of mesencephalic slice cultures.

    Science.gov (United States)

    Shimazu, S; Katsuki, H; Takenaka, C; Tomita, M; Kume, T; Kaneko, S; Akaike, A

    2000-01-28

    We investigated the potential neuroprotective effects of several sigma receptor ligands in organotypic midbrain slice cultures as an excitotoxicity model system. When challenged with 100-microM N-methyl-D-aspartate (NMDA) for 24 h, dopaminergic neurons in midbrain slice cultures degenerated, and this was prevented by (5R, 10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,b]-cyclohepten-5, 10-imine (MK-801; 1-10 microM). Concomitant application of ifenprodil (1-10 microM) or haloperidol (1-10 microM), both of which are high-affinity sigma receptor ligands, significantly attenuated the neurotoxicity of 100 microM NMDA. The sigma(1) receptor-selective ligand (+)-N-allylnormetazocine ((+)-SKF 10047; 1-10 microM) was also effective in attenuating the toxicity of NMDA. The effect of R(-)-N-(3-phenyl-1-propyl)-1-phenyl-2-aminopropane hydrochloride ((-)-PPAP), a sigma receptor ligand with negligible affinity for the phencyclidine site of NMDA receptors, was also examined. (-)-PPAP (3-100 microM) caused a concentration-dependent reduction of NMDA cytotoxicity, with significant protection at concentrations of 30 and 100 microM. In contrast, (+)-SKF 10047 (10 microM) and (-)-PPAP (100 microM) showed no protective effects against cell death induced by the Ca(2+) ionophore ionomycin (1-3 microM). These results indicate that sigma receptor ligands attenuate the cytotoxic effects of NMDA on midbrain dopaminergic neurons, possibly via inhibition of NMDA receptor functions.

  4. Dopaminergic Receptors and Tyrosine Hydroxylase Expression in Peripheral Blood Mononuclear Cells: A Distinct Pattern in Central Obesity.

    Science.gov (United States)

    Leite, Fernanda; Lima, Margarida; Marino, Franca; Cosentino, Marco; Ribeiro, Laura

    2016-01-01

    Dopamine (DA) may be involved in central obesity (CO), an inflammatory condition, through its role in the central nervous system and in periphery, where it may affect immune cell function through five different DA receptors (DR). Whether dopaminergic pathways in peripheral immune cells are implicated in the inflammatory condition linked to CO is however unknown. In a cohort of blood donors with and without CO, categorized by waist circumference (WC) (CO: WC ≥ 0.80 m in women and ≥ 0.94 m in men), we studied the expression of DR and tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of DA, in peripheral blood mononuclear cells (PBMCs) and their relation with anthropometric and metabolic/endocrine and inflammatory parameters. DR D1-5 and TH expression was assessed by semi quantitative real-time PCR. As inflammatory markers we investigated the immunophenotype of monocyte subsets by flow cytometry, staining for CD14, CD16, CD11b and CD36. CO individuals showed higher plasma levels of leptin and higher inflammatory pattern of monocytes compared with non-CO. PBMC expression of DR D2, DR D4 and DR D5 as well as of TH were lower in CO in comparison with non-CO. DR D2, and DR D5 expression correlated with lower WC and weight, and with lower inflammatory pattern of monocytes, and TH expression correlated with lower WC. DR D4 expression correlated with lower plasma levels of glycosylated hemoglobin, and DR D2 expression correlated with lower CO. Results show that CO is associated with peripheral inflammation and downregulation of dopaminergic pathways in PBMCs, possibly suggesting DR expressed on immune cells as pharmacological targets in obesity for better metabolic outcome.

  5. AF-6 Protects Against Dopaminergic Dysfunction and Mitochondrial Abnormalities in Drosophila Models of Parkinson’s Disease

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    Adeline H. Basil

    2017-08-01

    Full Text Available Afadin 6 (AF-6 is an F-actin binding multidomain-containing scaffolding protein that is known for its function in cell-cell adhesion. Interestingly, besides this well documented role, we recently found that AF-6 is a Parkin-interacting protein that augments Parkin/PINK1-mediated mitophagy. Notably, mutations in Parkin and PINK1 are causative of recessively inherited forms of Parkinson’s disease (PD and aberrant mitochondrial homeostasis is thought to underlie PD pathogenesis. Given the novel role of AF-6 in mitochondrial quality control (QC, we hypothesized that AF-6 overexpression may be beneficial to PD. Using the Drosophila melanogaster as a model system, we demonstrate in this study that transgenic overexpression of human AF-6 in parkin and also pink1 null flies rescues their mitochondrial pathology and associated locomotion deficit, which results in their improved survival over time. Similarly, AF-6 overexpression also ameliorates the pathological phenotypes in flies expressing the Leucine Rich Repeat Kinase 2 (LRRK2 G2019S mutant, a mutation that is associated with dominantly-inherited PD cases in humans. Conversely, when endogenous AF-6 expression is silenced, it aggravates the disease phenotypes of LRRK2 mutant flies. Aside from these genetic models, we also found that AF-6 overexpression is protective against the loss of dopaminergic neurons in flies treated with rotenone, a mitochondrial complex I inhibitor commonly used to generate animal models of PD. Taken together, our results demonstrate that AF-6 protects against dopaminergic dysfunction and mitochondrial abnormalities in multiple Drosophila models of PD, and suggest the therapeutic value of AF-6-related pathways in mitigating PD pathogenesis.

  6. Large-scale resting state network correlates of cognitive impairment in Parkinson's disease and related dopaminergic deficits.

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    Lebedev, Alexander V; Westman, Eric; Simmons, Andrew; Lebedeva, Aleksandra; Siepel, Françoise J; Pereira, Joana B; Aarsland, Dag

    2014-01-01

    Cognitive impairment is a common non-motor feature of Parkinson's disease (PD). Understanding the neural mechanisms of this deficit is crucial for the development of efficient methods for treatment monitoring and augmentation of cognitive functions in PD patients. The current study aimed to investigate resting state fMRI correlates of cognitive impairment in PD from a large-scale network perspective, and to assess the impact of dopamine deficiency on these networks. Thirty PD patients with resting state fMRI were included from the Parkinson's Progression Marker Initiative (PPMI) database. Eighteen patients from this sample were also scanned with (123)I-FP-CIT SPECT. A standardized neuropsychological battery was administered, evaluating verbal memory, visuospatial, and executive cognitive domains. Image preprocessing was performed using an SPM8-based workflow, obtaining time-series from 90 regions-of-interest (ROIs) defined from the AAL brain atlas. The Brain Connectivity Toolbox (BCT) was used to extract nodal strength from all ROIs, and modularity of the cognitive circuitry determined using the meta-analytical software Neurosynth. Brain-behavior covariance patterns between cognitive functions and nodal strength were estimated using Partial Least Squares. Extracted latent variable (LV) scores were matched with the performances in the three cognitive domains (memory, visuospatial, and executive) and striatal dopamine transporter binding ratios (SBR) using linear modeling. Finally, influence of nigrostriatal dopaminergic deficiency on the modularity of the "cognitive network" was analyzed. For the range of deficits studied, better executive performance was associated with increased dorsal fronto-parietal cortical processing and inhibited subcortical and primary sensory involvement. This profile was also characterized by a relative preservation of nigrostriatal dopaminergic function. The profile associated with better memory performance correlated with increased

  7. Lateralization and gender differences in the dopaminergic response to unpredictable reward in the human ventral striatum.

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    Martin-Soelch, Chantal; Szczepanik, Joanna; Nugent, Allison; Barhaghi, Krystle; Rallis, Denise; Herscovitch, Peter; Carson, Richard E; Drevets, Wayne C

    2011-05-01

    Electrophysiological studies have shown that mesostriatal dopamine (DA) neurons increase activity in response to unpredicted rewards. With respect to other functions of the mesostriatal dopaminergic system, dopamine's actions show prominent laterality effects. Whether changes in DA transmission elicited by rewards also are lateralized, however, has not been investigated. Using [¹¹C]raclopride-PET to assess the striatal DA response to unpredictable monetary rewards, we hypothesized that such rewards would induce an asymmetric reduction in [¹¹C]raclopride binding in the ventral striatum, reflecting lateralization of endogenous dopamine release. In 24 healthy volunteers, differences in the regional D₂/₃ receptor binding potential (ΔBP) between an unpredictable reward condition and a sensorimotor control condition were measured using the bolus-plus-constant-infusion [¹¹C]raclopride method. During the reward condition subjects randomly received monetary awards while performing a 'slot-machine' task. The ΔBP between conditions was assessed in striatal regions-of-interest and compared between left and right sides. We found a significant condition × lateralization interaction in the ventral striatum. A significant reduction in binding potential (BP(ND) ) in the reward condition vs. the control condition was found only in the right ventral striatum, and the ΔBP was greater in the right than the left ventral striatum. Unexpectedly, these laterality effects appeared to be partly accounted for by gender differences, as our data showed a significant bilateral BP(ND) reduction in women while in men the reduction reached significance only in the right ventral striatum. These data suggest that DA release in response to unpredictable reward is lateralized in the human ventral striatum, particularly in males. © 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  8. Investigating bacterial sources of toxicity as an environmental contributor to dopaminergic neurodegeneration.

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    Kim A Caldwell

    2009-10-01

    Full Text Available Parkinson disease (PD involves progressive neurodegeneration, including loss of dopamine (DA neurons from the substantia nigra. Select genes associated with rare familial forms of PD function in cellular pathways, such as the ubiquitin-proteasome system (UPS, involved in protein degradation. The misfolding and accumulation of proteins, such as alpha-synuclein, into inclusions termed Lewy Bodies represents a clinical hallmark of PD. Given the predominance of sporadic PD among patient populations, environmental toxins may induce the disease, although their nature is largely unknown. Thus, an unmet challenge surrounds the discovery of causal or contributory neurotoxic factors that could account for the prevalence of sporadic PD. Bacteria within the order Actinomycetales are renowned for their robust production of secondary metabolites and might represent unidentified sources of environmental exposures. Among these, the aerobic genera, Streptomyces, produce natural proteasome inhibitors that block protein degradation and may potentially damage DA neurons. Here we demonstrate that a metabolite produced by a common soil bacterium, S. venezuelae, caused DA neurodegeneration in the nematode, Caenorhabditis elegans, which increased as animals aged. This metabolite, which disrupts UPS function, caused gradual degeneration of all neuronal classes examined, however DA neurons were particularly vulnerable to exposure. The presence of DA exacerbated toxicity because neurodegeneration was attenuated in mutant nematodes depleted for tyrosine hydroxylase (TH, the rate-limiting enzyme in DA production. Strikingly, this factor caused dose-dependent death of human SH-SY5Y neuroblastoma cells, a dopaminergic line. Efforts to purify the toxic activity revealed that it is a highly stable, lipophilic, and chemically unique small molecule. Evidence of a robust neurotoxic factor that selectively impacts neuronal survival in a progressive yet moderate manner is consistent

  9. Simvastatin prevents dopaminergic neurodegeneration in experimental parkinsonian models: the association with anti-inflammatory responses.

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    Junqiang Yan

    Full Text Available BACKGROUND: In addition to their original applications to lowering cholesterol, statins display multiple neuroprotective effects. N-methyl-D-aspartate (NMDA receptors interact closely with the dopaminergic system and are strongly implicated in therapeutic paradigms of Parkinson's disease (PD. This study aims to investigate how simvastatin impacts on experimental parkinsonian models via regulating NMDA receptors. METHODOLOGY/PRINCIPAL FINDINGS: Regional changes in NMDA receptors in the rat brain and anxiolytic-like activity were examined after unilateral medial forebrain bundle lesion by 6-hydroxydopamine via a 3-week administration of simvastatin. NMDA receptor alterations in the post-mortem rat brain were detected by [³H]MK-801(Dizocilpine binding autoradiography. 6-hydroxydopamine treated PC12 was applied to investigate the neuroprotection of simvastatin, the association with NMDA receptors, and the anti-inflammation. 6-hydroxydopamine induced anxiety and the downregulation of NMDA receptors in the hippocampus, CA1(Cornu Ammonis 1 Area, amygdala and caudate putamen was observed in 6-OHDA(6-hydroxydopamine lesioned rats whereas simvastatin significantly ameliorated the anxiety-like activity and restored the expression of NMDA receptors in examined brain regions. Significant positive correlations were identified between anxiolytic-like activity and the restoration of expression of NMDA receptors in the hippocampus, amygdala and CA1 following simvastatin administration. Simvastatin exerted neuroprotection in 6-hydroxydopamine-lesioned rat brain and 6-hydroxydopamine treated PC12, partially by regulating NMDA receptors, MMP9 (matrix metalloproteinase-9, and TNF-a (tumour necrosis factor-alpha. CONCLUSIONS/SIGNIFICANCE: Our results provide strong evidence that NMDA receptor modulation after simvastatin treatment could partially explain its anxiolytic-like activity and anti-inflammatory mechanisms in experimental parkinsonian models. These findings

  10. Interaction of NMDA receptor and pacemaking mechanisms in the midbrain dopaminergic neuron.

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    Joon Ha

    Full Text Available Dopamine neurotransmission has been found to play a role in addictive behavior and is altered in psychiatric disorders. Dopaminergic (DA neurons display two functionally distinct modes of electrophysiological activity: low- and high-frequency firing. A puzzling feature of the DA neuron is the following combination of its responses: N-methyl-D-aspartate receptor (NMDAR activation evokes high-frequency firing, whereas other tonic excitatory stimuli (α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate receptor (AMPAR activation or applied depolarization block firing instead. We suggest a new computational model that reproduces this combination of responses and explains recent experimental data. Namely, somatic NMDAR stimulation evokes high-frequency firing and is more effective than distal dendritic stimulation. We further reduce the model to a single compartment and analyze the mechanism of the distinct high-frequency response to NMDAR activation vs. other stimuli. Standard nullcline analysis shows that the mechanism is based on a decrease in the amplitude of calcium oscillations. The analysis confirms that the nonlinear voltage dependence provided by the magnesium block of the NMDAR determine its capacity to elevate the firing frequency. We further predict that the moderate slope of the voltage dependence plays the central role in the frequency elevation. Additionally, we suggest a repolarizing current that sustains calcium-independent firing or firing in the absence of calcium-dependent repolarizing currents. We predict that the ether-a-go-go current (ERG, which has been observed in the DA neuron, is the best fit for this critical role. We show that a calcium-dependent and a calcium-independent oscillatory mechanisms form a structure of interlocked negative feedback loops in the DA neuron. The structure connects research of DA neuron firing with circadian biology and determines common minimal models for investigation of robustness of oscillations

  11. Dopaminergic influences on executive function and impulsive behaviour in impulse control disorders in Parkinson's disease.

    Science.gov (United States)

    Leroi, Iracema; Barraclough, Michelle; McKie, Shane; Hinvest, Neal; Evans, Jonathan; Elliott, Rebecca; McDonald, Kathryn

    2013-09-01

    The development of impulse control disorders (ICDs) in Parkinson's disease (PD) may arise from an interaction among cognitive impairment, impulsive responding and dopaminergic state. Dopaminergic state may be influenced by pharmacologic or genotypic (catechol-O-methyltransferase; COMT) factors. We sought to investigate this interaction further by comparing those with (n = 35) and without (n = 55) ICDs on delay-discounting in different pharmacologic conditions (ON or OFF dopaminergic medication) and on response inhibition as well as aspects of executive functioning in the ON state. We then undertook an exploratory sub-group analysis of these same tasks when the overall PD group was divided into different allelic variants of COMT (val/val vs. met/met). A healthy control group (HC; n = 20) was also included. We found that in those with PD and ICDs, 'cognitive flexibility' (set shifting, verbal fluency, and attention) in the ON medication state was not impaired compared with those without ICDs. In contrast, our working memory, or 'cognitive focus', task was impaired in both PD groups compared with the HC group when ON. During the delay-discounting task, the PD with ICDs group expressed greater impulsive choice compared with the PD group without ICDs, when in the ON, but not the OFF, medication state. However, no group difference on the response inhibition task was seen when ON. Finally, the met homozygous group performed differently on tests of executive function compared with the val homozygous group. We concluded that the disparity in levels of impairment among different domains of executive function and impulsive decision-making distinguishes those with ICD in PD from those without ICD, and may in part be affected by dopaminergic status. Both pharmacologic and genotypic influences on dopaminergic state may be important in ICD. © 2013 The British Psychological Society.

  12. Psychotic Symptoms Associated with the use of Dopaminergic Drugs, in Patients with Cocaine Dependence or Abuse.

    Science.gov (United States)

    Roncero, Carlos; Abad, Alfonso C; Padilla-Mata, Antonio; Ros-Cucurull, Elena; Barral, Carmen; Casas, Miquel; Grau-López, Lara

    2017-01-01

    In the field of dual diagnosis, physicians are frequently presented with pharmacological questions. Questions about the risk of developing psychotic symptoms in cocaine users who need treatment with dopaminergic drugs could lead to an undertreatment. Review the presence of psychotic symptoms in patients with cocaine abuse/dependence, in treatment with dopaminergic drugs. Systematic PubMed searches were conducted including December 2014, using the keywords: "cocaine", dopaminergic drug ("disulfuram-methylphenidate-bupropion-bromocriptine-sibutramineapomorphine- caffeine") and ("psychosis-psychotic symptoms-delusional-paranoia"). Articles in English, Spanish, Portuguese, French, and Italian were included. Articles in which there was no history of cocaine abuse/dependence, absence of psychotic symptoms, systematic reviews, and animal studies, were excluded. 313 papers were reviewed. 7 articles fulfilled the inclusion-exclusion criteria. There is a clinical trial including 8 cocaine-dependent patients using disulfiram in which 3 of them presented psychotic symptoms and 6 case-reports: disulfuram (1), methylphenidate (1), disulfiram with methylphenidate (2), and bupropion (2), reporting psychotic symptoms, especially delusions of reference and persecutory ideation. Few cases have been described, which suggests that the appearance of these symptoms is infrequent. The synergy of dopaminergic effects or the dopaminergic sensitization in chronic consumption are the explanatory theories proposed by the authors. In these cases, a relationship was found between taking these drugs and the appearance of psychotic symptoms. Given the low number of studies found, further research is required. The risk of psychotic symptoms seems to be acceptable if we compare it with the benefits for the patients but a closer monitoring seems to be advisable.

  13. Effects of dopaminergic therapy on locomotor adaptation and adaptive learning in persons with Parkinson's disease

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    Roemmich, Ryan T.; Hack, Nawaz; Akbar, Umer; Hass, Chris J.

    2014-01-01

    Persons with Parkinson’s disease (PD) are characterized by multifactorial gait deficits, though the factors which influence the abilities of persons with PD to adapt and store new gait patterns are unclear. The purpose of this study was to investigate the effects of dopaminergic therapy on the abilities of persons with PD to adapt and store gait parameters during split-belt treadmill (SBT) walking. Ten participants with idiopathic PD who were being treated with stable doses of orally-administered dopaminergic therapy participated. All participants performed two randomized testing sessions on separate days: once while optimally-medicated (ON meds) and once after 12-hour withdrawal from dopaminergic medication (OFF meds). During each session, locomotor adaptation was investigated as the participants walked on a SBT for ten minutes while the belts moved at a 2:1 speed ratio. We assessed locomotor adaptive learning by quantifying: 1) aftereffects during de-adaptation (once the belts returned to tied speeds immediately following SBT walking) and 2) savings during re-adaptation (as the participants repeated the same SBT walking task after washout of aftereffects following the initial SBT task). The withholding of dopaminergic medication diminished step length aftereffects significantly during de-adaptation. However, both locomotor adaptation and savings were unaffected by levodopa. These findings suggest that dopaminergic pathways influence aftereffect storage but do not influence locomotor adaptation or savings within a single session of SBT walking. It appears important that persons with PD should be optimally-medicated if walking on the SBT as gait rehabilitation. PMID:24698798

  14. Histamine impairs midbrain dopaminergic development in vivo by activating histamine type 1 receptors.

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    Escobedo-Avila, Itzel; Vargas-Romero, Fernanda; Molina-Hernández, Anayansi; López-González, Rodrigo; Cortés, Daniel; De Carlos, Juan A; Velasco, Iván

    2014-08-12

    Histamine (HA) regulates the sleep-wake cycle, synaptic plasticity and memory in adult mammals. Dopaminergic specification in the embryonic ventral midbrain (VM) coincides with increased HA brain levels. To study the effect of HA receptor stimulation on dopamine neuron generation, we administered HA to dopamine progenitors, both in vitro and in vivo. Cultured embryonic day 12 (E12) VM neural stem/progenitor cells expressed transcripts for HA receptors H1R, H2R and H3R. These undifferentiated progenitors increased intracellular calcium upon HA addition. In HA-treated cultures, dopamine neurons significantly decreased after activation of H1R. We performed intrauterine injections in the developing VM to investigate HA effects in vivo. HA administration to E12 rat embryos notably reduced VM Tyrosine Hydroxylase (TH) staining 2 days later, without affecting GABA neurons in the midbrain, or serotonin neurons in the mid-hindbrain boundary. qRT-PCR and Western blot analyses confirmed that several markers important for the generation and maintenance of dopaminergic lineage such as TH, Lmx1a and Lmx1b were significantly diminished. To identify the cell type susceptible to HA action, we injected embryos of different developmental stages, and found that neural progenitors (E10 and E12) were responsive, whereas differentiated dopaminergic neurons (E14 and E16) were not susceptible to HA actions. Proliferation was significantly diminished, whereas neuronal death was not increased in the VM after HA administration. We injected H1R or H2R antagonists to identify the receptor responsible for the detrimental effect of HA on dopaminergic lineage and found that activation of H1R was required. These results reveal a novel action of HA affecting dopaminergic lineage during VM development.

  15. Destruction of midbrain dopaminergic neurons by using immunotoxin to dopamine transporter.

    Science.gov (United States)

    Wiley, R G; Harrison, M B; Levey, A I; Lappi, D A

    2003-10-01

    1. The ability to target specific neurons can be used to produce selective neural lesions and potentially to deliver therapeutically useful moieties for treatment of disease. In the present study, we sought to determine if a monoclonal antibody to the dopamine transporter (anti-DAT) could be used to target midbrain dopaminergic neurons. 2. The monoclonal antibody recognizes the second, large extracellular loop of DAT. The antibody was conjugated to the "ribosome-inactivating protein"; saporin, and stereotactically pressure microinjected into either the center of the striatum or the left lateral ventricle of adult, male Sprague-Dawley rats. 3. Local intrastriatal injections produced destruction of dopaminergic neurons in the ipsilateral substantia nigra consistent with suicide transport of the immunotoxin. Intraventricular injections (i.c.v.) produced significant loss of dopaminergic neurons in the substantia nigra and ventral tegmental area bilaterally without evident damage to any other aminergic structures such as the locus coeruleus and raphe nuclei. To confirm the anatomic findings, binding of [3-H]mazindol to DAT in the striatum and midbrain was assessed using densitometric analysis of autoradiograms. Anti-DAT-saporin injected i.c.v. at a dose of 21 microg, but not 8 microg, produced highly significant decreases in mazindol binding consistent with loss of the dopaminergic neurons. 4. These results show that anti-DAT can be used to target midbrain dopaminergic neurons and that anti-DAT-saporin may be useful for producing a lesion very similar to the naturally occurring neural degeneration seen in Parkinson's disease. Anti-DAT-saporin joins the growing list of neural lesioning agents based on targeted cytotoxins.

  16. Iowa gambling task impairment in Parkinson's disease can be normalised by reduction of dopaminergic medication after subthalamic stimulation.

    Science.gov (United States)

    Castrioto, Anna; Funkiewiez, Aurélie; Debû, Bettina; Cools, Roshan; Lhommée, Eugénie; Ardouin, Claire; Fraix, Valérie; Chabardès, Stephan; Robbins, Trevor W; Pollak, Pierre; Krack, Paul

    2015-02-01

    Impulse control disorders (ICD), including pathological gambling, are common in Parkinson's disease (PD) and tend to improve after subthalamic (STN) stimulation after a marked reduction of dopaminergic medication. In order to investigate the effect of STN stimulation on impulsive decision making, we used the Iowa Gambling task (IGT). We investigated IGT performance in 20 patients with PD before STN surgery with and without dopaminergic treatment and in 24 age-matched controls. All patients underwent an extensive neuropsychological interview screening for behavioural disorders. Assessment in patients was repeated 3 months after surgery without dopaminergic treatment with and without stimulation. Chronic antiparkinsonian treatment was drastically reduced after surgery (-74%). At baseline, on high chronic dopaminergic treatment 8/20 patients with PD presented with pathological hyperdopaminergic behaviours, which had resolved in 7/8 patients 3 months after surgery on low chronic dopaminergic treatment. Preoperative performance on the IGT was significantly impaired compared to after surgery. Dopaminergic medication likely contributes to the impairment in decision making underlying ICDs. Deep brain stimulation allows drastic reduction of dopaminergic medication and, thus, concomitant remediation of medication-induced impairment in decision making. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  17. Regulation of differentiation flux by Notch signalling influences the number of dopaminergic neurons in the adult brain

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    Niurka Trujillo-Paredes

    2016-03-01

    Full Text Available Notch signalling is a well-established pathway that regulates neurogenesis. However, little is known about the role of Notch signalling in specific neuronal differentiation. Using Dll1 null mice, we found that Notch signalling has no function in the specification of mesencephalic dopaminergic neural precursor cells (NPCs, but plays an important role in regulating their expansion and differentiation into neurons. Premature neuronal differentiation was observed in mesencephalons of Dll1-deficient mice or after treatment with a Notch signalling inhibitor. Coupling between neurogenesis and dopaminergic differentiation was indicated from the coincident emergence of neuronal and dopaminergic markers. Early in differentiation, decreasing Notch signalling caused a reduction in NPCs and an increase in dopaminergic neurons in association with dynamic changes in the proportion of sequentially-linked dopaminergic NPCs (Msx1/2+, Ngn2+, Nurr1+. These effects in differentiation caused a significant reduction in the number of dopaminergic neurons produced. Accordingly, Dll1 haploinsufficient adult mice, in comparison with their wild-type littermates, have a consistent reduction in neuronal density that was particularly evident in the substantia nigra pars compacta. Our results are in agreement with a mathematical model based on a Dll1-mediated regulatory feedback loop between early progenitors and their dividing precursors that controls the emergence and number of dopaminergic neurons.

  18. Circadian Rhythms and Substance Abuse: Chronobiological Considerations for the Treatment of Addiction.

    Science.gov (United States)

    Webb, Ian C

    2017-02-01

    Reward-related learning, including that associated with drugs of abuse, is largely mediated by the dopaminergic mesolimbic pathway. Mesolimbic neurophysiology and motivated behavior, in turn, are modulated by the circadian timing system which generates ∼24-h rhythms in cellular activity. Both drug taking and seeking and mesolimbic dopaminergic neurotransmission can vary widely over the day. Moreover, circadian clock genes are expressed in ventral tegmental area dopaminergic cells and in mesolimbic target regions where they can directly modulate reward-related neurophysiology and behavior. There also exists a reciprocal influence between drug taking and circadian timing as the administration of drugs of abuse can alter behavioral rhythms and circadian clock gene expression in mesocorticolimbic structures. These interactions suggest that manipulations of the circadian timing system may have some utility in the treatment of substance abuse disorders. Here, the literature on bidirectional interactions between the circadian timing system and drug taking is briefly reviewed, and potential chronotherapeutic considerations for the treatment of addiction are discussed.

  19. Dopaminergic neuronal loss and dopamine-dependent locomotor defects in Fbxo7-deficient zebrafish.

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    Tianna Zhao

    Full Text Available Recessive mutations in the F-box only protein 7 gene (FBXO7 cause PARK15, a mendelian form of early-onset, levodopa-responsive parkinsonism with severe loss of nigrostriatal dopaminergic neurons. However, the function of the protein encoded by FBXO7, and the pathogenesis of PARK15 remain unknown. No animal models of this disease exist. Here, we report the generation of a vertebrate model of PARK15 in zebrafish. We first show that the zebrafish Fbxo7 homolog protein (zFbxo7 is expressed abundantly in the normal zebrafish brain. Next, we used two zFbxo7-specific morpholinos (targeting protein translation and mRNA splicing, respectively, to knock down the zFbxo7 expression. The injection of either of these zFbxo7-specific morpholinos in the fish embryos induced a marked decrease in the zFbxo7 protein expression, and a range of developmental defects. Furthermore, whole-mount in situ mRNA hybridization showed abnormal patterning and significant decrease in the number of diencephalic tyrosine hydroxylase-expressing neurons, corresponding to the human nigrostriatal or ventral tegmental dopaminergic neurons. Of note, the number of the dopamine transporter-expressing neurons was much more severely depleted, suggesting dopaminergic dysfunctions earlier and larger than those due to neuronal loss. Last, the zFbxo7 morphants displayed severe locomotor disturbances (bradykinesia, which were dramatically improved by the dopaminergic agonist apomorphine. The severity of these morphological and behavioral abnormalities correlated with the severity of zFbxo7 protein deficiency. Moreover, the effects of the co-injection of zFbxo7- and p53-specific morpholinos were similar to those obtained with zFbxo7-specific morpholinos alone, supporting further the contention that the observed phenotypes were specifically due to the knock down of zFbxo7. In conclusion, this novel vertebrate model reproduces pathologic and behavioral hallmarks of human parkinsonism (dopaminergic

  20. Human FGF1 promoter is active in ependymal cells and dopaminergic neurons in the brains of F1B-GFP transgenic mice.

    Science.gov (United States)

    Chen, Mei-Shu; Lin, Hua-Kuo; Chiu, Hsun; Lee, Don-Ching; Chung, Yu-Fen; Chiu, Ing-Ming

    2015-03-01

    FGF1 is involved in multiple biological functions and exhibits the importance in neuroprotective effects. Our previous studies indicated that, in human brain and retina, the FGF1B promoter controlled the expression of FGF1. However, the exact function and regulation of FGF1 in brain is still unclear. Here, we generated F1B-GFP transgenic mice that expressed the GFP reporter gene under the control of human FGF1B promoter (-540 to +31). Using the fresh brain sections of F1B-GFP transgenic mice, we found that the F1B-GFP cells expressed strong fluorescent signals in the ventricular system throughout the brain. The results of immunohistochemistry further showed that two distinct populations of F1B-GFP(+) cells existed in the brains of F1B-GFP transgenic mice. We demonstrated that one population of F1B-GFP(+) cells was ependymal cells, which distributed along the entire ventricles, and the second population of F1B-GFP(+) cells was neuronal cells that projected their long processes into multiple directions in specific areas of the brain. The double labeling of F1B-GFP(+) cells and tyrosine hydroxylase indicated that a subpopulation of F1B-GFP(+) -neuronal cells was dopaminergic neurons. Importantly, these F1B-GFP(+) /TH(+) cells were distributed in the main dopaminergic neuronal groups including hypothalamus, ventral tegmental area, and raphe nuclei. These results suggested that human FGF1B promoter was active in ependymal cells, neurons, and a portion of dopaminergic neurons. Thus, the F1B-GFP transgenic mice provide an animal model not only for studying FGF1 gene expression in vivo but also for understanding the role of FGF1 contribution in neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. © 2014 The Authors Developmental Neurobiology Published by Wiley Periodicals, Inc.

  1. Nucleus Accumbens and Dopamine-Mediated Turning Behavior of the Rat: Role of Accumbal Non-dopaminergic Receptors

    NARCIS (Netherlands)

    Ikeda, H.; Kamei, J.; Koshikawa, N.; Cools, A.R.

    2012-01-01

    Accumbal dopamine plays an important role in physiological responses and diseases such as schizophrenia, Parkinson's disease, and depression. Since the nucleus accumbens contains different neurotransmitters, it is important to know how they interact with dopaminergic function: this is because

  2. Iowa gambling task impairment in Parkinson's disease can be normalised by reduction of dopaminergic medication after subthalamic stimulation

    NARCIS (Netherlands)

    Castrioto, A.; Funkiewiez, A.; Debu, B.; Cools, R.; Lhommee, E.; Ardouin, C.; Fraix, V.; Chabardes, S.; Robbins, T.W.; Pollak, P.; Krack, P.

    2015-01-01

    BACKGROUND: Impulse control disorders (ICD), including pathological gambling, are common in Parkinson's disease (PD) and tend to improve after subthalamic (STN) stimulation after a marked reduction of dopaminergic medication. In order to investigate the effect of STN stimulation on impulsive

  3. Does the cerebral cortex exacerbate dopaminergic cell death in the substantia nigra of 6OHDA-lesioned rats?

    Science.gov (United States)

    Luquin, Natasha; Mitrofanis, John

    2008-01-01

    We have explored the survival of dopaminergic cells of the substantia nigra pars compacta (SNc) in 6 hydroxydopamine (6OHDA)-lesioned rats with prior cortical removal. There were approximately 35% more dopaminergic cells in the ventral sector of SNc (vSNc) of 6OHDA-lesioned rats that had prior cortical removal compared to those that did not. By contrast, there were no differences in dopaminergic cell number between these experimental groups in the ventral tegmental area (VTA) and the dorsal sector of SNc (dSNc). Hence, prior cortical removal in 6OHDA-lesioned rats neuroprotected vSNc--but not VTA or dSNc--dopaminergic cells from death.

  4. Spread of neuronal degeneration in a dopaminergic, Lrrk-G2019S model of Parkinson disease

    Science.gov (United States)

    Hindle, Samantha J.; Elliott, Christopher J.H.

    2013-01-01

    Flies expressing the most common Parkinson disease (PD)-related mutation, LRRK2-G2019S, in their dopaminergic neurons show loss of visual function and degeneration of the retina, including mitochondrial abnormalities, apoptosis and autophagy. Since the photoreceptors that degenerate are not dopaminergic, this demonstrates nonautonomous degeneration, and a spread of pathology. This provides a model consistent with Braak’s hypothesis on progressive PD. The loss of visual function is specific for the G2019S mutation, implying the cause is its increased kinase activity, and is enhanced by increased neuronal activity. These data suggest novel explanations for the variability in animal models of PD. The specificity of visual loss to G2019S, coupled with the differences in neural firing rate, provide an explanation for the variability between people with PD in visual tests. PMID:23529190

  5. Abnormal dopaminergic modulation of striato-cortical networks underlies levodopa-induced dyskinesias in humans

    DEFF Research Database (Denmark)

    Herz, Damian M.; Haagensen, Brian N.; Christensen, Mark S.

    2015-01-01

    Dopaminergic signalling in the striatum contributes to reinforcement of actions and motivational enhancement of motor vigour. Parkinson's disease leads to progressive dopaminergic denervation of the striatum, impairing the function of cortico-basal ganglia networks. While levodopa therapy...... alleviates basal ganglia dysfunction in Parkinson's disease, it often elicits involuntary movements, referred to as levodopa-induced peak-of-dose dyskinesias. Here, we used a novel pharmacodynamic neuroimaging approach to identify the changes in cortico-basal ganglia connectivity that herald the emergence...... of levodopa-induced dyskinesias. Twenty-six patients with Parkinson's disease (age range: 51–84 years; 11 females) received a single dose of levodopa and then performed a task in which they had to produce or suppress a movement in response to visual cues. Task-related activity was continuously mapped...

  6. Control of sleep by dopaminergic inputs to the Drosophila mushroom body

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    Divya eSitaraman

    2015-11-01

    Full Text Available The Drosophila mushroom body (MB is an associative learning network that is important for the control of sleep. We have recently identified particular intrinsic MB Kenyon cell (KC classes that regulate sleep through synaptic activation of particular MB output neurons (MBONs whose axons convey sleep control signals out of the MB to downstream target regions. Specifically, we found that sleep-promoting KCs increase sleep by preferentially activating cholinergic sleep-promoting MBONs, while wake-promoting KCs decrease sleep by preferentially activating glutamatergic wake-promoting MBONs. Here we use a combination of genetic and physiological approaches to identify wake-promoting dopaminergic neurons (DANs that innervate the MB, and show that they activate wake-promoting MBONs. These studies reveal a dopaminergic sleep control mechanism that likely operates by modulation of KC-MBON microcircuits.

  7. Deficits in Sustained Attention and Changes in Dopaminergic Protein Levels following Exposure to Proton Radiation Are Related to Basal Dopaminergic Function.

    Directory of Open Access Journals (Sweden)

    Catherine M Davis

    Full Text Available The current report assessed the effects of low-level proton irradiation in inbred adult male Fischer 344 and Lewis rats performing an analog of the human Psychomotor Vigilance Test (PVT, commonly utilized as an object risk assessment tool to quantify fatigue and sustained attention in laboratory, clinical, and operational settings. These strains were used to determine if genetic differences in dopaminergic function would impact radiation-induced deficits in sustained attention. Exposure to head-only proton irradiation (25 or 100 cGy disrupted rPVT performance in a strain-specific manner, with 25 cGy-exposed Fischer 344 rats displaying the most severe deficits in sustained attention (i.e., decreased accuracy and increased premature responding; Lewis rats did not display behavioral deficits following radiation. Fischer 344 rats displayed greater tyrosine hydroxylase and dopamine transporter levels in the frontal cortex compared to the Lewis rats, even though radiation exposure increased both of these proteins in the Lewis rats only. Tyrosine hydroxylase was decreased in the parietal cortex of both rat strains following radiation exposure, regardless of proton dose. Strain-specific cytokine changes were also found in the frontal cortex, with the Lewis rats displaying increased levels of putative neurotrophic cytokines (e.g., CNTF. These data support the hypothesis that basal dopaminergic function impacts the severity of radiation-induced deficits in sustained attention.

  8. The h-current in periglomerular dopaminergic neurons of the mouse olfactory bulb.

    Science.gov (United States)

    Pignatelli, Angela; Borin, Mirta; Fogli Iseppe, Alex; Gambardella, Cristina; Belluzzi, Ottorino

    2013-01-01

    The properties of the hyperpolarization-activated cation current (I(h)) were investigated in rat periglomerular dopaminergic neurons using patch-clamp recordings in thin slices. A reliable identification of single dopaminergic neurons was made possible by use of a transgenic line of mice expressing eGFP under the tyrosine hydroxylase promoter. At 37 °C and minimizing the disturbance of the intracellular milieu with perforated patches, this current shows a midpoint of activation around -82.7 mV, with a significant level of opening already at rest, thereby giving a substantial contribution to the resting potential, and ultimately playing a relevant function in the control of the cell excitability. The blockage of I(h) has a profound influence on the spontaneous firing of these neurons, which result as strongly depressed. However the effect is not due to a direct role of the current in the pacemaker process, but to the I(h) influence on the resting membrane potential. I(h) kinetics is sensitive to the intracellular levels of cAMP, whose increase promotes a shift of the activation curve towards more positive potentials. The direct application of DA and 5-HT neurotransmitters, physiologically released onto bulbar dopaminergic neurons and known to act on metabotropic receptors coupled to the cAMP pathway, do not modifythe I(h) amplitude. On the contrary, noradrenaline almost halves the I(h) amplitude. Our data indicate that the HCN channels do not participate directly to the pacemaker activity of periglomerular dopaminergic neurons, but influence their resting membrane potential by controlling the excitability profile of these cells, and possibly affecting the processing of sensory information taking place at the entry of the bulbar circuitry.

  9. The h-current in periglomerular dopaminergic neurons of the mouse olfactory bulb.

    Directory of Open Access Journals (Sweden)

    Angela Pignatelli

    Full Text Available The properties of the hyperpolarization-activated cation current (I(h were investigated in rat periglomerular dopaminergic neurons using patch-clamp recordings in thin slices. A reliable identification of single dopaminergic neurons was made possible by use of a transgenic line of mice expressing eGFP under the tyrosine hydroxylase promoter. At 37 °C and minimizing the disturbance of the intracellular milieu with perforated patches, this current shows a midpoint of activation around -82.7 mV, with a significant level of opening already at rest, thereby giving a substantial contribution to the resting potential, and ultimately playing a relevant function in the control of the cell excitability. The blockage of I(h has a profound influence on the spontaneous firing of these neurons, which result as strongly depressed. However the effect is not due to a direct role of the current in the pacemaker process, but to the I(h influence on the resting membrane potential. I(h kinetics is sensitive to the intracellular levels of cAMP, whose increase promotes a shift of the activation curve towards more positive potentials. The direct application of DA and 5-HT neurotransmitters, physiologically released onto bulbar dopaminergic neurons and known to act on metabotropic receptors coupled to the cAMP pathway, do not modifythe I(h amplitude. On the contrary, noradrenaline almost halves the I(h amplitude. Our data indicate that the HCN channels do not participate directly to the pacemaker activity of periglomerular dopaminergic neurons, but influence their resting membrane potential by controlling the excitability profile of these cells, and possibly affecting the processing of sensory information taking place at the entry of the bulbar circuitry.

  10. COUP-TFI controls activity-dependent tyrosine hydroxylase expression in adult dopaminergic olfactory bulb interneurons.

    Science.gov (United States)

    Bovetti, Serena; Bonzano, Sara; Garzotto, Donatella; Giannelli, Serena Gea; Iannielli, Angelo; Armentano, Maria; Studer, Michèle; De Marchis, Silvia

    2013-12-01

    COUP-TFI is an orphan nuclear receptor acting as a strong transcriptional regulator in different aspects of forebrain embryonic development. In this study, we investigated COUP-TFI expression and function in the mouse olfactory bulb (OB), a highly plastic telencephalic region in which continuous integration of newly generated inhibitory interneurons occurs throughout life. OB interneurons belong to different populations that originate from distinct progenitor lineages. Here, we show that COUP-TFI is highly expressed in tyrosine hydroxylase (TH)-positive dopaminergic interneurons in the adult OB glomerular layer (GL). We found that odour deprivation, which is known to downregulate TH expression in the OB, also downregulates COUP-TFI in dopaminergic cells, indicating a possible correlation between TH- and COUP-TFI-activity-dependent action. Moreover, we demonstrate that conditional inactivation of COUP-TFI in the EMX1 lineage results in a significant reduction of both TH and ZIF268 expression in the GL. Finally, lentiviral vector-mediated COUP-TFI deletion in adult-generated interneurons confirmed that COUP-TFI acts cell-autonomously in the control of TH and ZIF268 expression. These data indicate that COUP-TFI regulates TH expression in OB cells through an activity-dependent mechanism involving ZIF268 induction and strongly argue for a maintenance rather than establishment function of COUP-TFI in dopaminergic commitment. Our study reveals a previously unknown role for COUP-TFI in the adult brain as a key regulator in the control of sensory-dependent plasticity in olfactory dopaminergic neurons.

  11. Effects of Feeder Cells on Dopaminergic Differentiation of Human Embryonic Stem Cells

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    Zhenqiang Zhao

    2016-12-01

    Full Text Available Mouse embryonic fibroblasts (MEFs and human foreskin fibroblasts (HFFs are used for the culture of human embryonic stem cells (hESCs. MEFs and HFFs differed in their capacity to support the proliferation and pluripotency of hESCs and could affect cardiac differentiation potential of hESCs. The aim of this study was to evaluate the effect of MEFs and HFFs feeders on dopaminergic differentiation of hESCs lines. To minimize the impact of culture condition variation, two hESCs lines were cultured on mixed feeder cells (MFCs, MEFs: HFFs =1:1 and HFFs feeder respectively, and then were differentiated into DA neurons under the identical protocol. Dopaminergic differentiation was evaluated by immunocytochemistry, quantitative fluorescent real-time PCR (qRT-PCR, transmission and scanning electron microscopy, and patch clamp. Our results demonstrated that these hESCs-derived neurons were genuine and functional DA neurons. However, compared to hESCs line on MFCs feeder, hESCs line on HFFs feeder had a higher proportion of TH positive cells and expressed higher levels of FOXA2, PITX3, NURR1 and TH genes. In addition, the values of threshold intensity and threshold membrane potential of DA neurons from hESCs line on HFFs feeder were lower than those of DA neurons from hESCs line on the MFCs feeder. In conclusion, HFFs feeder not only facilitated the differentiation of hESCs cells into dopaminergic neurons, but also induced hESCs-derived DA neurons to express higher electrophysiological excitability. Therefore, feeder cells could affect not only dopaminergic differentiation potential of different hESCs lines, but also electrophysiological properties of hESCs-derived DA neurons.

  12. Graphene derivatives as scaffold for ex vivo survival and maturation of dopaminergic SN4741 cells.

    OpenAIRE

    Rodriguez-Losada, Noela; Wendelbo, Rune; Garcia-Fernandez, Maria; Pavia, Jose; Martin-Montañez, Elisa; Lara-Muñoz, José Pablo; Arenas, Ernest; Aguirre-Gomez, Jose Angel

    2014-01-01

    Carbon nanomaterial Graphene (G) can form a three-dimensional porous structure with efficient bioconjugation and cell differentiation properties, providing a promising scaffold for neural regeneration. Aims: To study this putative new application of G, we cultured a clonal substantia nigra dopaminergic neuronal progenitor cell line (SN4741) in presence of G as scaffold. Methods: Cells were cultured in DMEM/10% FCS to about 80% confluence and incubated with different concentrations (0.001 to 1...

  13. Ceftriaxone attenuates acute cocaine-evoked dopaminergic neurotransmission in the nucleus accumbens of the rat.

    Science.gov (United States)

    Barr, J L; Rasmussen, B A; Tallarida, C S; Scholl, J L; Forster, G L; Unterwald, E M; Rawls, S M

    2015-11-01

    Ceftriaxone is a β-lactam antibiotic and glutamate transporter activator that reduces the reinforcing effects of psychostimulants. Ceftriaxone also reduces locomotor activation following acute psychostimulant exposure, suggesting that alterations in dopamine transmission in the nucleus accumbens contribute to its mechanism of action. In the present studies we tested the hypothesis that pretreatment with ceftriaxone disrupts acute cocaine-evoked dopaminergic neurotransmission in the nucleus accumbens. Adult male Sprague-Dawley rats were pretreated with saline or ceftriaxone (200 mg kg(-1) , i.p. × 10 days) and then challenged with cocaine (15 mg kg(-1) , i.p.). Motor activity, dopamine efflux (via in vivo microdialysis) and protein levels of tyrosine hydroxylase (TH), the dopamine transporter and organic cation transporter as well as α-synuclein, Akt and GSK3β were analysed in the nucleus accumbens. Ceftriaxone-pretreated rats challenged with cocaine displayed reduced locomotor activity and accumbal dopamine efflux compared with saline-pretreated controls challenged with cocaine. The reduction in cocaine-evoked dopamine levels was not counteracted by excitatory amino acid transporter 2 blockade in the nucleus accumbens. Pretreatment with ceftriaxone increased Akt/GSK3β signalling in the nucleus accumbens and reduced levels of dopamine transporter, TH and phosphorylated α-synuclein, indicating that ceftriaxone affects numerous proteins involved in dopaminergic transmission. These results are the first evidence that ceftriaxone affects cocaine-evoked dopaminergic transmission, in addition to its well-described effects on glutamate, and suggest that its ability to attenuate cocaine-induced behaviours, such as psychomotor activity, is due in part to reduced dopaminergic neurotransmission in the nucleus accumbens. © 2015 The British Pharmacological Society.

  14. Neuroprotective Effects of β-Caryophyllene against Dopaminergic Neuron Injury in a Murine Model of Parkinson’s Disease Induced by MPTP

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    Juan M. Viveros-Paredes

    2017-07-01

    Full Text Available Parkinson’s disease (PD is one of the most common neurodegenerative disorders and is characterized by the loss of dopaminergic neurons in the substantia nigra (SN. Although the causes of PD are not understood, evidence suggests that its pathogenesis is associated with oxidative stress and inflammation. Recent studies have suggested a protective role of the cannabinoid signalling system in PD. β-caryophyllene (BCP is a natural bicyclic sesquiterpene that is an agonist of the cannabinoid type 2 receptor (CB2R. Previous studies have suggested that BCP exerts prophylactic and/or curative effects against inflammatory bowel disease through its antioxidative and/or anti-inflammatory action. The present study describes the neuroprotective effects of BCP in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP-induced murine model of PD, and we report the results of our investigation of its neuroprotective mechanism in neurons and glial cells. In the murine model, BCP pretreatment ameliorated motor dysfunction, protected against dopaminergic neuronal losses in the SN and striatum, and alleviated MPTP-induced glia activation. Additionally, BCP inhibited the levels of inflammatory cytokines in the nigrostriatal system. The observed neuroprotection and inhibited glia activation were reversed upon treatment with the CB2R selective antagonist AM630, confirming the involvement of the CB2R. These results indicate that BCP acts via multiple neuroprotective mechanisms in our murine model and suggest that BCP may be viewed as a potential treatment and/or preventative agent for PD.

  15. Activation of CNTF/CNTFRα signaling pathway by hRheb(S16H transduction of dopaminergic neurons in vivo.

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    Kyoung Hoon Jeong

    Full Text Available Ciliary neurotrophic factor (CNTF is one of representative neurotrophic factors for the survival of dopaminergic neurons. Its effects are primarily mediated via CNTF receptor α (CNTFRα. It is still unclear whether the levels of CNTFRα change in the substantia nigra of Parkinson's disease (PD patients, but CNTF expression shows the remarkable decrease in dopaminergic neurons in the substantia nigra pars compacta (SNpc, suggesting that the support of CNTF/CNTFRα signaling pathway may be a useful neuroprotective strategy for the nigrostriatal dopaminergic projection in the adult brain. Here, we report that transduction of rat SNpc dopaminergic neurons by adeno-associated virus with a gene encoding human ras homolog enriched in brain (hRheb, with an S16H mutation [hRheb(S16H], significantly upregulated the levels of both CNTF and CNTFRα in dopaminergic neurons. Moreover, the hRheb(S16H-activated CNTF/CNTFRα signaling pathway was protective against 1-methyl-4-phenylpyridinium-induced neurotoxicity in the nigrostriatal dopaminergic projections. These results suggest that activation of CNTF/CNTFRα signaling pathway by specific gene delivery such as hRheb(S16H may have therapeutic potential in the treatment of PD.

  16. Activation of CNTF/CNTFRα Signaling Pathway by hRheb(S16H) Transduction of Dopaminergic Neurons In Vivo

    Science.gov (United States)

    Jeong, Kyoung Hoon; Nam, Jin Han; Jin, Byung Kwan; Kim, Sang Ryong

    2015-01-01

    Ciliary neurotrophic factor (CNTF) is one of representative neurotrophic factors for the survival of dopaminergic neurons. Its effects are primarily mediated via CNTF receptor α (CNTFRα). It is still unclear whether the levels of CNTFRα change in the substantia nigra of Parkinson’s disease (PD) patients, but CNTF expression shows the remarkable decrease in dopaminergic neurons in the substantia nigra pars compacta (SNpc), suggesting that the support of CNTF/CNTFRα signaling pathway may be a useful neuroprotective strategy for the nigrostriatal dopaminergic projection in the adult brain. Here, we report that transduction of rat SNpc dopaminergic neurons by adeno-associated virus with a gene encoding human ras homolog enriched in brain (hRheb), with an S16H mutation [hRheb(S16H)], significantly upregulated the levels of both CNTF and CNTFRα in dopaminergic neurons. Moreover, the hRheb(S16H)-activated CNTF/CNTFRα signaling pathway was protective against 1-methyl-4-phenylpyridinium-induced neurotoxicity in the nigrostriatal dopaminergic projections. These results suggest that activation of CNTF/CNTFRα signaling pathway by specific gene delivery such as hRheb(S16H) may have therapeutic potential in the treatment of PD. PMID:25799580

  17. Subthalamic nucleus stimulation and compulsive use of dopaminergic medication in Parkinson's disease.

    Science.gov (United States)

    Eusebio, Alexandre; Witjas, Tatiana; Cohen, Julien; Fluchère, Frédérique; Jouve, Elisabeth; Régis, Jean; Azulay, Jean-Philippe

    2013-08-01

    Behavioural disorders associated with compulsive use of dopaminergic drugs for Parkinson's disease (PD) such as dopamine dysregulation syndrome (DDS) and impulse control disorders (ICDs) may have devastating consequences and are challenging to manage. Whether or not such patients should undergo subthalamic nucleus (STN) deep brain stimulation (DBS) is controversial. A few case reports and small series have reported contrasting effects of STN DBS on dopamine misuse and ICDs, while a recent prospective study found clear beneficial effects of STN DBS on these disorders. We conducted an observational study on 110 consecutive parkinsonian patients scheduled for STN DBS surgery. Patients were assessed preoperatively through extensive behavioural and psychiatric evaluations and divided into two groups: with or without compulsive dopaminergic medication use. Evaluations were repeated 1 year after surgery in both groups. Before surgery 18 patients (16.3%) were compulsive dopamine users of whom 12 (10.9%) fulfilled all criteria for DDS. 90% of these patients also had at least one ICD compared to 20% in the group without compulsive dopamine use. One year after surgery, one patient had persistent compulsive dopamine use, while no new occurrences were reported in the group without the condition before surgery. STN DBS did not provoke any major psychiatric complications and ICDs were reduced in all patients. Our results suggest that STN DBS may reduce compulsive use of dopaminergic medication and its behavioural consequences. Whether this improvement is the result of STN DBS or the consequence of better treatment management remains to be established.

  18. Brain metabolic correlates of dopaminergic degeneration in de novo idiopathic Parkinson's disease

    International Nuclear Information System (INIS)

    Berti, Valentina; Polito, Cristina; Vanzi, Eleonora; Cristofaro, Maria Teresa de; Pellicano, Giannantonio; Mungai, Francesco; Formiconi, Andreas Robert; Pupi, Alberto; Ramat, Silvia; Marini, Paolo; Sorbi, Sandro

    2010-01-01

    The aim of the present study was to evaluate the reciprocal relationships between motor impairment, dopaminergic dysfunction, and cerebral metabolism (rCMRglc) in de novo Parkinson's disease (PD) patients. Twenty-six de novo untreated PD patients were scanned with 123 I-FP-CIT SPECT and 18 F-FDG PET. The dopaminergic impairment was measured with putaminal 123 I-FP-CIT binding potential (BP), estimated with two different techniques: an iterative reconstruction algorithm (BP OSEM ) and the least-squares (LS) method (BP LS ). Statistical parametric mapping (SPM) multiple regression analyses were performed to determine the specific brain regions in which UPDRS III scores and putaminal BP values correlated with rCMRglc. The SPM results showed a negative correlation between UPDRS III and rCMRglc in premotor cortex, and a positive correlation between BP OSEM and rCMRglc in premotor and dorsolateral prefrontal cortex, not surviving at multiple comparison correction. Instead, there was a positive significant correlation between putaminal BP LS and rCMRglc in premotor, dorsolateral prefrontal, anterior prefrontal, and orbitofrontal cortex (p LS is an efficient parameter for exploring the correlations between PD severity and rCMRglc cortical changes. The correlation between dopaminergic degeneration and rCMRglc in several prefrontal regions likely represents the cortical functional correlate of the dysfunction in the motor basal ganglia-cortical circuit in PD. This finding suggests focusing on the metabolic course of these areas to follow PD progression and to analyze treatment effects. (orig.)

  19. PINK1 Primes Parkin-Mediated Ubiquitination of PARIS in Dopaminergic Neuronal Survival

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    Yunjong Lee

    2017-01-01

    Full Text Available Mutations in PTEN-induced putative kinase 1 (PINK1 and parkin cause autosomal-recessive Parkinson’s disease through a common pathway involving mitochondrial quality control. Parkin inactivation leads to accumulation of the parkin interacting substrate (PARIS, ZNF746 that plays an important role in dopamine cell loss through repression of proliferator-activated receptor gamma coactivator-1-alpha (PGC-1α promoter activity. Here, we show that PARIS links PINK1 and parkin in a common pathway that regulates dopaminergic neuron survival. PINK1 interacts with and phosphorylates serines 322 and 613 of PARIS to control its ubiquitination and clearance by parkin. PINK1 phosphorylation of PARIS alleviates PARIS toxicity, as well as repression of PGC-1α promoter activity. Conditional knockdown of PINK1 in adult mouse brains leads to a progressive loss of dopaminergic neurons in the substantia nigra that is dependent on PARIS. Altogether, these results uncover a function of PINK1 to direct parkin-PARIS-regulated PGC-1α expression and dopaminergic neuronal survival.

  20. Pathological Gambling in Parkinson's disease patients: Dopaminergic medication or personality traits fault?

    Science.gov (United States)

    Brusa, L; Pavino, V; Massimetti, M C; Ceravolo, R; Stefani, S; Stanzione, P

    2016-07-15

    Impulse control disorders (ICDs) are clinically relevant in Parkinson disease (PD) patients, with an established association with PD medication. Aim of our study was to study whether the increased frequency of pathological gambling (PG), reported in subgroups of PD patients, is related to specific personality tracts additional to dopaminergic medications. Thirty-seven PD patients with a personal history of PG where enrolled. Twenty one PD patients, matched for disease and dopaminergic therapy, never experiencing PG, were enrolled as controls. All subjects were tested with the Minnesota Multiphasic Inventory Personality scales (MMPI-2). Our data showed that PD group with PG exhibited significantly higher mean values of the three validity scales in comparison to the non-PG-PD group, demonstrating an higher tendency to lie. Content scales showed a significant increase of cynicism and bizarre ideation scales score in the PG-PD group, not exhibiting pathological values at the validity scales, (p: 0.02) in comparison to non-PG PD patients. According to our results, PG seems to be associated with precise personality tracts. Personality profiles of cluster A personality disturbances - Axys 2 according with DSM-5 TR (paranoid type) at MMPI-2 might be a warning index helpful in selecting dopaminergic treatment, to avoid subsequent ICDs appearance. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Detection of tyrosine hydroxylase in dopaminergic neuron cell using gold nanoparticles-based barcode DNA.

    Science.gov (United States)

    An, Jeung Hee; Oh, Byung-Keun; Choi, Jeong Woo

    2013-04-01

    Tyrosine hydroxylase, the rate-limiting enzyme of catecholamine biosysthesis, is predominantly expressed in several cell groups within the brain, including the dopaminergic neurons of the substantia nigra and ventral tegmental area. We evaluated the efficacy of this protein-detection method in detecting tyrosine hydroxylase in normal and oxidative stress damaged dopaminergic cells. In this study, a coupling of DNA barcode and bead-based immnunoassay for detecting tyrosine hydroxylaser with PCR-like sensitivity is reported. The method relies on magnetic nanoparticles with antibodies and nanoparticles that are encoded with DNA and antibodies that can sandwich the target protein captured by the nanoparticle-bound antibodies. The aggregate sandwich structures are magnetically separated from solution, and treated to remove the conjugated barcode DNA. The DNA barcodes were identified by PCR analysis. The concentration of tyrosine hydroxylase in dopaminergic cell can be easily and rapidly detected using bio-barcode assay. The bio-barcode assay is a rapid and high-throughput screening tool to detect of neurotransmitter such as dopamine.

  2. Eight different types of dopaminergic neurons innervate the Drosophila mushroom body neuropil: anatomical and physiological heterogeneity

    Directory of Open Access Journals (Sweden)

    Zhengmei Mao

    2009-07-01

    Full Text Available We examined tyrosine hydroxylase (TH-GAL4 expression and anti-TH immunoreactivity in the Drosophila protocerebrum and characterized single cell clones of the TH-GAL4 neurons. Eight clusters of putative dopaminergic neurons were characterized. Neurons in three of the clusters project to the mushroom body neuropil: PAM neurons project to the medial portion of the horizontal lobes; PPL1 neurons project to the vertical lobes, the junction area, the heel and distal peduncle; and PPL2ab neurons project to the calyx. Five types of PPL1 neurons were discovered that innervate different zones of the mushroom body lobes. Functional imaging experiments showed that the dopaminergic processes in four of the zones differ in response properties to odor, electric shock, or following the pairing of odor and electric shock. These results indicate that distinct dopaminergic neurons define separate zones of the mushroom body lobes and are probably involved in different functions. Differences in functional response properties of these neurons suggest that they are involved in different behavioral processes.

  3. Oleuropein Prevents Neuronal Death, Mitigates Mitochondrial Superoxide Production and Modulates Autophagy in a Dopaminergic Cellular Model

    Directory of Open Access Journals (Sweden)

    Imène Achour

    2016-08-01

    Full Text Available Parkinson’s disease (PD is a progressive neurodegenerative disorder, primarily affecting dopaminergic neurons in the substantia nigra. There is currently no cure for PD and present medications aim to alleviate clinical symptoms, thus prevention remains the ideal strategy to reduce the prevalence of this disease. The goal of this study was to investigate whether oleuropein (OLE, the major phenolic compound in olive derivatives, may prevent neuronal degeneration in a cellular dopaminergic model of PD, differentiated PC12 cells exposed to the potent parkinsonian toxin 6-hydroxydopamine (6-OHDA. We also investigated OLE’s ability to mitigate mitochondrial oxidative stress and modulate the autophagic flux. Our results obtained by measuring cytotoxicity and apoptotic events demonstrate that OLE significantly decreases neuronal death. OLE could also reduce mitochondrial production of reactive oxygen species resulting from blocking superoxide dismutase activity. Moreover, quantification of autophagic and acidic vesicles in the cytoplasm alongside expression of specific autophagic markers uncovered a regulatory role for OLE against autophagic flux impairment induced by bafilomycin A1. Altogether, our results define OLE as a neuroprotective, anti-oxidative and autophagy-regulating molecule, in a neuronal dopaminergic cellular model.

  4. Efficient induction of dopaminergic neuron differentiation from induced pluripotent stem cells reveals impaired mitophagy in PARK2 neurons.

    Science.gov (United States)

    Suzuki, Sadafumi; Akamatsu, Wado; Kisa, Fumihiko; Sone, Takefumi; Ishikawa, Kei-Ichi; Kuzumaki, Naoko; Katayama, Hiroyuki; Miyawaki, Atsushi; Hattori, Nobutaka; Okano, Hideyuki

    2017-01-29

    Patient-specific induced pluripotent stem cells (iPSCs) show promise for use as tools for in vitro modeling of Parkinson's disease. We sought to improve the efficiency of dopaminergic (DA) neuron induction from iPSCs by the using surface markers expressed in DA progenitors to increase the significance of the phenotypic analysis. By sorting for a CD184 high /CD44 - fraction during neural differentiation, we obtained a population of cells that were enriched in DA neuron precursor cells and achieved higher differentiation efficiencies than those obtained through the same protocol without sorting. This high efficiency method of DA neuronal induction enabled reliable detection of reactive oxygen species (ROS) accumulation and vulnerable phenotypes in PARK2 iPSCs-derived DA neurons. We additionally established a quantitative system using the mt-mKeima reporter system to monitor mitophagy in which mitochondria fuse with lysosomes and, by combining this system with the method of DA neuronal induction described above, determined that mitophagy is impaired in PARK2 neurons. These findings suggest that the efficiency of DA neuron induction is important for the precise detection of cellular phenotypes in modeling Parkinson's disease. Copyright © 2016. Published by Elsevier Inc.

  5. The influence of dopaminergic gene variants on decision making in the ultimatum game.

    Science.gov (United States)

    Reuter, Martin; Felten, Andrea; Penz, Sabrina; Mainzer, Anna; Markett, Sebastian; Montag, Christian

    2013-01-01

    One of the most prominent paradigms in neuroeconomics is the ultimatum game (UG) that provides a framework for the study of pro-social behavior in two players interacting anonymously with each other: Player 1 has to split an endowment with player 2. Player 2 can either accept or reject the offer from player 1. If player 2 accepts the offer then the money is split as proposed by player 1. In case of rejection both players get nothing. Until now only one twin study investigated the heritability of the behavior in the UG. Results indicated a strong heritability for the decision behavior of player 2 whereas no genetic influence on player 1 behavior could be detected. Further studies are mandatory to validate these heritability estimates. However, a first candidate polymorphism, the DRD4 exon III, constituting the biological basis of the heritability in the responder behavior has already been identified in a Chinese sample (Zhong et al., 2010). Until now genetic studies in Caucasians on the UG are lacking. The present study wants to fill this gap by investigating the UG in a healthy German sample. Moreover, we intend to find candidate genes that are associated with the first-mover-behavior. In a sample of N = 130 healthy participants an online version of the UG was conducted and polymorphisms of the dopamine D2 receptor gene (DRD2) and the DRD4 exon III VNTR were genotyped. We could confirm the DRD4 exon III effect on the responder behavior and the absence of an effect on the proposer behavior reported before. In line with Zhong et al. (2010) carriers of the 4/4 genotype showed a significant higher minimal acceptable offer (p = 0.023) than subjects with any other genotype. Furthermore, a DRD2-haplotype-block containing the single nucleotide polymorphisms rs1800497 and rs2283265 was significantly associated with the amount player1 offered (p = 0.005) but not with the decision of player 2. Results support the importance of the dopaminergic system for pro-social behavior.

  6. The influence of dopaminergic gene variants on decision making in the ultimatum game

    Directory of Open Access Journals (Sweden)

    Martin eReuter

    2013-06-01

    Full Text Available One of the most prominent paradigms in neuroeconomics is the Ultimatum Game (UG that provides a framework for the study of pro-social behavior in two players interacting anonymously with each other: Player 1 has to split an endowment with player 2. Player 2 can either accept or reject the offer from player 1. If player 2 accepts the offer then the money is split as proposed by player 1. In case of rejection both players get nothing. Until now only one twin study investigated the heritability of the behavior in the UG. Results indicated a strong heritability for the decision behavior of player 2 whereas no genetic influence on player 1 behavior could be detected. Further studies are mandatory to validate these heritability estimates. However, a first candidate polymorphism, the DRD4 exon III, constituting the biological basis of the heritability in the responder behavior has already been identified in a Chinese sample (Zhong et al., 2010. Until now genetic studies in Caucasians on the UG are lacking. The present study wants to fill this gap by investigating the UG in a healthy German sample. Moreover, we intend to find candidate genes that are associated with the first-mover-behavior. In a sample of N=130 healthy participants an online version of the UG was conducted and polymorphisms of the dopamine D2 receptor gene (DRD2 and the DRD4 exon III VNTR were genotyped. We could confirm the DRD4 exon III effect on the responder behavior and the absence of an effect on the proposer behavior reported before. In line with Zhong et al. (2010 carriers of the 4/4 genotype showed a significant higher minimal acceptable offer (p=0.023 than subjects with any other genotype. Furthermore, a DRD2-haplotype-block containing the single nucleotide polymorphisms rs1800497 and rs2283265 was significantly associated with the amount player1 offered (p=.005 but not with the decision of player 2. Results support the importance of the dopaminergic system for pro

  7. Histamine induces microglia activation and dopaminergic neuronal toxicity via H1 receptor activation.

    Science.gov (United States)

    Rocha, Sandra M; Saraiva, Tatiana; Cristóvão, Ana C; Ferreira, Raquel; Santos, Tiago; Esteves, Marta; Saraiva, Cláudia; Je, Goun; Cortes, Luísa; Valero, Jorge; Alves, Gilberto; Klibanov, Alexander; Kim, Yoon-Seong; Bernardino, Liliana

    2016-06-04

    Histamine is an amine widely known as a peripheral inflammatory mediator and as a neurotransmitter in the central nervous system. Recently, it has been suggested that histamine acts as an innate modulator of microglial activity. Herein, we aimed to disclose the role of histamine in microglial phagocytic activity and reactive oxygen species (ROS) production and to explore the consequences of histamine-induced neuroinflammation in dopaminergic (DA) neuronal survival. The effect of histamine on phagocytosis was assessed both in vitro by using a murine N9 microglial cell line and primary microglial cell cultures and in vivo. Cells were exposed to IgG-opsonized latex beads or phosphatidylserine (PS) liposomes to evaluate Fcγ or PS receptor-mediated microglial phagocytosis, respectively. ROS production and protein levels of NADPH oxidases and Rac1 were assessed as a measure of oxidative stress. DA neuronal survival was evaluated in vivo by counting the number of tyrosine hydroxylase-positive neurons in the substantia nigra (SN) of mice. We found that histamine triggers microglial phagocytosis via histamine receptor 1 (H1R) activation and ROS production via H1R and H4R activation. By using apocynin, a broad NADPH oxidase (Nox) inhibitor, and Nox1 knockout mice, we found that the Nox1 signaling pathway is involved in both phagocytosis and ROS production induced by histamine in vitro. Interestingly, both apocynin and annexin V (used as inhibitor of PS-induced phagocytosis) fully abolished the DA neurotoxicity induced by the injection of histamine in the SN of adult mice in vivo. Blockade of H1R protected against histamine-induced Nox1 expression and death of DA neurons in vivo. Overall, our results highlight the relevance of histamine in the modulation of microglial activity that ultimately may interfere with neuronal survival in the context of Parkinson's disease (PD) and, eventually, other neurodegenerative diseases which are accompanied by microglia

  8. Neurotoxicity of cerebro-spinal fluid from patients with Parkinson's disease on mesencephalic primary cultures as an in vitro model of dopaminergic neurons.

    Science.gov (United States)

    Kong, Ping; Zhang, Ben-Shu; Lei, Ping; Kong, Xiao-Dong; Zhang, Shi-Shuang; Li, Dai; Zhang, Yun

    2015-08-01

    Parkinson's disease is a degenerative disorder of the central nervous system. In spite of extensive research, neither the cause nor the mechanisms have been firmly established thus far. One assumption is that certain toxic substances may exist in the cerebro-spinal fluid (CSF) of Parkinson's disease patients. To confirm the neurotoxicity of CSF and study the potential correlation between neurotoxicity and the severity of Parkinson's disease, CSF was added to cultured cells. By observation of cell morphology, changes in the levels of lactate dehydrogenase, the ratio of tyrosine hydroxylase-positive cells, and the expression of tyrosine hydroxylase mRNA and protein, the differences between the two groups were shown. The created in vitro model of dopaminergic neurons using primary culture of mouse embryonic mesencephalic tissue is suitable for the study of neurotoxicity. The observations of the present study indicated that CSF from Parkinson's disease patients contains factors that can cause specific injury to cultured dopaminergic neurons. However, no obvious correlation was found between the neurotoxicity of CSF and the severity of Parkinson's disease.

  9. Increased dopaminergic activity in socially isolated rats: an electrophysiological study

    DEFF Research Database (Denmark)

    Fabricius, Katrine; Helboe, Lone; Fink-Jensen, Anders

    2010-01-01

    The development of animal models mimicking symptoms associated with schizophrenia has been a critical step in understanding the neurobiological mechanisms underlying the disease. Long-term social isolation from weaning in rodents, a model based on the neurodevelopmental hypothesis of schizophrenia......, and a change of firing activity towards a more irregular and bursting firing pattern. Taken together, our findings suggest that the behavioral phenotype induced by social isolation may be driven by an overactive dopamine system....

  10. Role of Inflammation in MPTP-Induced Dopaminergic Degeneration

    Science.gov (United States)

    2005-12-01

    Stern, G , Wilkin, GP, et al. Inflammatory regulators in Parkinson’s disease: iNOS, lipocortin-1 and cyclooxygenase 1 and 2. Mol Cell Neurosci, 16:724...INTRODUCTION profound deficit in brain dopamine (15). Another pathologi- cal hallmark of PD is the eosinophilic intraneuronal proteina -p ARKINSON’S...killing of SNpc dopamninergic ates HI202, as illustrated above. In biological systems, the pro-the a efimtion el t i ~p pain g duction of H 0 results

  11. Fluorodopa is a Promising Fluorine-19 MRI Probe for Evaluating Striatal Dopaminergic Function in a Rat Model of Parkinson's Disease.

    Science.gov (United States)

    Yanagisawa, Daijiro; Oda, Keisuke; Inden, Masatoshi; Morikawa, Shigehiro; Inubushi, Toshiro; Taniguchi, Takashi; Hijioka, Masanori; Kitamura, Yoshihisa; Tooyama, Ikuo

    2017-07-01

    Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra projecting to the striatum. It has been estimated that approximately 80% of the striatal dopamine and 50% of nigral dopaminergic neurons are lost before the onset of typical motor symptoms, indicating that early diagnosis of PD using noninvasive imaging is feasible. Fluorine-19 ( 19 F) magnetic resonance imaging (MRI) represents a highly sensitive, easily available, low-background, and cost-effective approach to evaluate dopaminergic function using non-radioactive fluorine-containing dopaminergic agents. The aim of this study was to find a potent 19 F MRI probe to evaluate dopaminergic presynaptic function in the striatum. To select candidates for 19 F MRI probes, we investigated the following eight non-radioactive fluorine-containing dopaminergic agents: fluorodopa (F-DOPA), F-tyrosine, haloperidol, GBR13069 duhydrochloride, GBR12909 duhydrochloride, 3-bis-(4-fluorophenyl) methoxytropane hydrochloride, flupenthixol, and fenfluramine. In 19 F nuclear magnetic resonance measurements, F-tyrosine and F-DOPA displayed a relatively higher signal-to-noise ratio value in brain homogenates than in others. F-DOPA, but not F-tyrosine, induced the rotational behavior in a 6-hydroxydopamine (6-OHDA)-induced hemiparkinsonian rat model. In addition, a significantly high amount of F-DOPA accumulated in the ipsilateral striatum of hemiparkinsonian rats after the injection. We performed 19 F MRI in PC12 cells and isolated rat brain using a 7T MR scanner. Our findings suggest that F-DOPA is a promising 19 F MRI probe for evaluating dopaminergic presynaptic function in the striatum of hemiparkinsonian rats. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  12. Effect of crowding, temperature and age on glia activation and dopaminergic neurotoxicity induced by MDMA in the mouse brain.

    Science.gov (United States)

    Frau, Lucia; Simola, Nicola; Porceddu, Pier Francesca; Morelli, Micaela

    2016-09-01

    3,4-methylenedyoxymethamphetamine (MDMA or "ecstasy"), a recreational drug of abuse, can induce glia activation and dopaminergic neurotoxicity. Since MDMA is often consumed in crowded environments featuring high temperatures, we studied how these factors influenced glia activation and dopaminergic neurotoxicity induced by MDMA. C57BL/6J adolescent (4 weeks old) and adult (12 weeks old) mice received MDMA (4×20mg/kg) in different conditions: 1) while kept 1, 5, or 10×cage at room temperature (21°C); 2) while kept 5×cage at either room (21°C) or high (27°C) temperature. After the last MDMA administration, immunohistochemistry was performed in the caudate-putamen for CD11b and GFAP, to mark microglia and astroglia, and in the substantia nigra pars compacta for tyrosine hydroxylase, to mark dopaminergic neurons. MDMA induced glia activation and dopaminergic neurotoxicity, compared with vehicle administration. Crowding (5 or 10 mice×cage) amplified MDMA-induced glia activation (in adult and adolescent mice) and dopaminergic neurotoxicity (in adolescent mice). Conversely, exposure to a high environmental temperature (27°C) potentiated MDMA-induced glia activation in adult and adolescent mice kept 5×cage, but not dopaminergic neurotoxicity. Crowding and exposure to a high environmental temperature amplified MDMA-induced hyperthermia, and a positive correlation between body temperature and activation of either microglia or astroglia was found in adult and adolescent mice. These results provide further evidence that the administration setting influences the noxious effects of MDMA in the mouse brain. However, while crowding amplifies both glia activation and dopaminergic neurotoxicity, a high environmental temperature exacerbates glia activation only. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Dopaminergic Therapy Increases Go Timeouts in the Go/No-Go Task in Patients with Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Xue Q. Yang

    2018-01-01

    Full Text Available Parkinson’s disease (PD is characterized by resting tremor, rigidity and bradykinesia. Dopaminergic medications such as L-dopa treat these motor symptoms, but can have complex effects on cognition. Impulse control is an essential cognitive function. Impulsivity is multifaceted in nature. Motor impulsivity involves the inability to withhold pre-potent, automatic, erroneous responses. In contrast, cognitive impulsivity refers to improper risk-reward assessment guiding behavior. Informed by our previous research, we anticipated that dopaminergic therapy would decrease motor impulsivity though it is well known to enhance cognitive impulsivity. We employed the Go/No-go paradigm to assess motor impulsivity in PD. Patients with PD were tested using a Go/No-go task on and off their normal dopaminergic medication. Participants completed cognitive, mood, and physiological measures. PD patients on medication had a significantly higher proportion of Go trial Timeouts (i.e., trials in which Go responses were not completed prior to a deadline of 750 ms compared to off medication (p = 0.01. No significant ON-OFF differences were found for Go trial or No-go trial response times (RTs, or for number of No-go errors. We interpret that dopaminergic therapy induces a more conservative response set, reflected in Go trial Timeouts in PD patients. In this way, dopaminergic therapy decreased motor impulsivity in PD patients. This is in contrast to the widely recognized effects of dopaminergic therapy on cognitive impulsivity leading in some patients to impulse control disorders. Understanding the nuanced effects of dopaminergic treatment in PD on cognitive functions such as impulse control will clarify therapeutic decisions.

  14. Traumatic Brain Injury in Adult Rats Causes Progressive Nigrostriatal Dopaminergic Cell Loss and Enhanced Vulnerability to the Pesticide Paraquat

    Science.gov (United States)

    Hutson, Che Brown; Lazo, Carlos R.; Mortazavi, Farzad; Giza, Christopher C.; Hovda, David

    2011-01-01

    Abstract Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of nigrostriatal dopaminergic neurons and the accumulation of alpha-synuclein. Both traumatic brain injury (TBI) and pesticides are risk factors for PD, but whether TBI causes nigrostriatal dopaminergic cell loss in experimental models and whether it acts synergistically with pesticides is unknown. We have examined the acute and long-term effects of TBI and exposure to low doses of the pesticide paraquat, separately and in combination, on nigrostriatal dopaminergic neurons in adult male rats. In an acute study, rats received moderate TBI by lateral fluid percussion (LFP) injury, were injected with saline or paraquat (10 mg/kg IP) 3 and 6 days after LFP, were sacrificed 5 days later, and their brains processed for immunohistochemistry. TBI alone increased microglial activation in the substantia nigra, and caused a 15% loss of dopaminergic neurons ipsilaterally. Paraquat increased the TBI effect, causing a 30% bilateral loss of dopaminergic neurons, reduced striatal tyrosine hydroxylase (TH) immunoreactivity more than TBI alone, and induced alpha-synuclein accumulation in the substantia nigra pars compacta. In a long-term study, rats received moderate LFP, were injected with saline or paraquat at 21 and 22 weeks post-injury, and were sacrificed 4 weeks later. At 26 weeks post injury, TBI alone induced a 30% bilateral loss of dopaminergic neurons that was not exacerbated by paraquat. These data suggest that TBI is sufficient to induce a progressive degeneration of nigrostriatal dopaminergic neurons. Furthermore, TBI and pesticide exposure, when occurring within a defined time frame, could combine to increase the PD risk. PMID:21644813

  15. Enhanced dopaminergic differentiation of human neural stem cells by synergistic effect of Bcl-xL and reduced oxygen tension

    DEFF Research Database (Denmark)

    Krabbe, Christina; Courtois, Elise; Jensen, Pia

    2009-01-01

    Neural stem cells constitute a promising source of cells for transplantation in Parkinson's disease, but a protocol for controlled dopaminergic differentiation is not yet available. Here we investigated the effect of the anti-apoptotic protein Bcl-x(L) and oxygen tension on dopaminergic different......Neural stem cells constitute a promising source of cells for transplantation in Parkinson's disease, but a protocol for controlled dopaminergic differentiation is not yet available. Here we investigated the effect of the anti-apoptotic protein Bcl-x(L) and oxygen tension on dopaminergic...... differentiation and survival of a human ventral mesencephalic stem cell line (hVM1). hVM1 cells and a Bcl-x(L) over-expressing subline (hVMbcl-x(L)) were differentiated by sequential treatment with fibroblast growth factor-8, forskolin, sonic hedgehog, and glial cell line-derived neurotrophic factor. After 10......-PCR-analysis revealed expression of several dopaminergic markers besides of TH just as dopamine was detected in the culture medium by HPLC analysis. Although Bcl-x(L)-over-expression reduced cell death in the cultures, it did not alter the relative content of GABAergic, neurons, while the content of astroglial cells...

  16. Rapid dopaminergic and GABAergic modulation of calcium and voltage transients in dendrites of prefrontal cortex pyramidal neurons

    Science.gov (United States)

    Zhou, Wen-Liang; Antic, Srdjan D

    2012-01-01

    The physiological responses of dendrites to dopaminergic inputs are poorly understood and controversial. We applied dopamine on one dendritic branch while simultaneously monitoring action potentials (APs) from multiple dendrites using either calcium-sensitive dye, voltage-sensitive dye or both. Dopaminergic suppression of dendritic calcium transients was rapid (calcium signals, as determined by dual voltage and calcium imaging. The dopamine effects on dendritic calcium transients were fully mimicked by D1 agonists, partially reduced by D1 antagonist and completely insensitive to protein kinase blockade; consistent with a membrane delimited mechanism. This dopamine effect was unaltered in the presence of L-, R- and T-type calcium channel blockers. The somatic excitability (i.e. AP firing) was not affected by strong dopaminergic stimulation of dendrites. Dopamine and GABA were then sequentially applied on the same dendrite. In contrast to dopamine, the pulses of GABA prohibited AP backpropagation distally from the application site, even in neurons with natural Cl− concentration (patch pipette removed). Thus, the neocortex employs at least two distinct mechanisms (dopamine and GABA) for rapid modulation of dendritic calcium influx. The spatio-temporal pattern of dendritic calcium suppression described in this paper is expected to occur during phasic dopaminergic signalling, when midbrain dopaminergic neurons generate a transient (0.5 s) burst of APs in response to a salient event. PMID:22641784

  17. Electrophysiological and pharmacological evidence for the existence of distinct subpopulations of nigrostriatal dopaminergic neuron in the rat.

    Science.gov (United States)

    Shepard, P D; German, D C

    1988-11-01

    The electrophysiological and pharmacological properties of dopaminergic neurons were systematically examined throughout the anterior-posterior extent of the substantia nigra zona compacta in the rat. Cells were characterized in terms of their (1) firing pattern, (2) firing rate, (3) antidromic response properties, and (4) inhibition in firing rate following dopaminergic agonist administration. These properties were then related to the cell's position within one of four anterior-posterior segments of the nucleus. There were three types of neuronal discharge pattern encountered; irregular, burst and regular. Cells which exhibited different firing patterns exhibited different firing rates and anatomical locations within the substantia nigra zona compacta. All neurons were antidromically activated from the striatum, however, the burst- and regular-firing cells exhibited significantly faster estimated conduction velocities than irregular-firing cells. The irregular-firing cells were most sensitive to dopaminergic autoreceptor agonists whereas the burst-firing cells were most sensitive to an indirect-acting dopaminergic agonist. These experiments provide both electrophysiological and pharmacological evidence to indicate that nigrostriatal dopaminergic neurons are composed of distinct subpopulations which are characterized by their firing pattern.

  18. Glucose-rich diet aggravates monocrotophos-induced dopaminergic neuronal dysfunction in Caenorhabditis elegans.

    Science.gov (United States)

    Salim, Chinnu; Rajini, P S

    2017-06-01

    The present study aimed to obtain insights into the mechanism(s) by which glucose-rich diet aggravates monocrotophos (MCP)-induced dopaminergic neuronal dysfunction in Caenorhabditis elegans. In this study, we exposed three different strains of worms (wild-type N2, CB1112 (cat-2(e1112)II, tyrosine hydroxylase-deficient mutant, catecholamine absent) and the transgenic BZ555 (egls1-dat-1p::green fluorescent protein [GFP]) (in which bright GFP is tagged to the dopamine neuronal soma and processes) grown and maintained in normal nematode growth medium or 2% glucose enriched-nematode growth medium to MCP (0.75 mm) for 48 h. After the exposure, dopamine-mediated behaviors such as repulsion to nonanone, chemotaxis index and basal slowing response were determined in worms. Dopamine, 3,4-dihydroxy phenyl acetic acid and homovanillic acid content were quantified in N2 worms. The extent of neurodegeneration was visualized and quantified in dat-1::GFP worms. Basal slowing response study clearly indicated that cat-2 worms exposed to MCP and glucose were less affected compared to N2 of the same treatment. Learning and memory were affected by MCP and glucose. While MCP-treated worms showed lesser repulsion to nonanone compared to control worms, MCP-treated, glucose-fed worms showed a greater reduction in repulsion to nonanone. Further, MCP-treated, glucose-fed worms exhibited a marked reduction in dopamine content and an increase in 3,4-dihydroxy phenyl acetic acid and homovanillic acid levels compared to that in control. Dat-1::GFP showed a significant degeneration of dopaminergic neurons when exposed to glucose and MCP. Thus, our results clearly demonstrate that glucose-rich diet aggravates the dopaminergic neuronal dysfunction induced by MCP in C. elegans. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  19. Vitamin D regulation of GDNF/Ret signaling in dopaminergic neurons.

    Science.gov (United States)

    Pertile, Renata A N; Cui, Xiaoying; Hammond, Luke; Eyles, Darryl W

    2018-02-01

    1,25(OH) 2 D 3 (vitamin D) appears essential for the normal development of dopaminergic neurons. Vitamin D affects dopamine synthesis and metabolism as well as expression of glial cell line-derived neurotrophic factor (GDNF), which is crucial for the survival of dopaminergic neurons. We investigated the role of vitamin D on GDNF and its receptors protooncogene tyrosine-protein kinase receptor Ret (C-Ret) and GDNF family receptor alpha 1 (GFRα1) signaling. To this end, we used a developmental vitamin D-deficient rat model and SH-SY5Y cells transfected with vitamin D receptor (VDR). The absence of vitamin D ligand in gestation reduces C-Ret expression, but not GDNF and GFRα1, in embryo forebrains. Overexpression of VDR in SH-SY5Y in the absence of ligand (mimicking in vivo developmental vitamin D deficiency) also suppressed C-Ret mRNA levels. In the presence of vitamin D, C-Ret mRNA and protein expression were increased. The chromatin immunoprecipitation results suggested that C-Ret is directly regulated by vitamin D via VDR. GDNF was also increased by vitamin D in these cells. Our small interfering RNA studies showed that knocking down VDR leads to an increase in C-Ret in the absence of ligand. Finally, we confirmed the inverse relationship between GFRα1 and C-Ret, as knocking down C-Ret led to increases in GFRα1 expression. These data extend our knowledge of the diverse and important roles played by vitamin D in dopamine physiology.-Pertile, R. A. N., Cui, X., Hammond, L., Eyles, D. W. Vitamin D regulation of GDNF/Ret signaling in dopaminergic neurons.

  20. The effects of long-term dopaminergic treatment on locomotor behavior in rats

    Science.gov (United States)

    Oliveira de Almeida, Welinton Alessandro; Maculano Esteves, Andrea; Leite de Almeida-Júnior, Canuto; Lee, Kil Sun; Kannebley Frank, Miriam; Oliveira Mariano, Melise; Frussa-Filho, Roberto; Tufik, Sergio; Tulio de Mello, Marco

    2014-01-01

    Long-term treatments with dopaminergic agents are associated with adverse effects, including augmentation. Augmentation consists of an exacerbation of restless legs syndrome (a sleep-related movement disorder) symptoms during treatment compared to those experienced during the period before therapy was initiated. The objective of this study was to examine locomotor activity in rats after long-term dopaminergic treatment and its relationship with expression of the D2 receptor, in addition to demonstrating possible evidence of augmentation. The rats were divided into control (CTRL) and drug (Pramipexole—PPX) groups that received daily saline vehicle and PPX treatments, respectively, for 71 days. The locomotor behavior of the animals was evaluated weekly in the Open Field test for 71 days. The expression of the dopamine D2 receptor was evaluated by Western Blot analysis. The animals that received the PPX demonstrated a significant reduction in locomotor activity from day 1 to day 57 and a significant increase in immobility time from day 1 to day 64 relative to baseline values, but these values had returned to baseline levels at 71 days. No changes in the expression of the D2 receptor were demonstrated after treatment with a dopaminergic agonist. This study suggests changes in locomotor activity in rats after long-term PPX treatment that include an immediate reduction of locomotion and an increase in immobilization, and after 64 days, these values returned to baseline levels without evidence of augmentation. In addition, it was not possible to demonstrate a relationship between locomotor activity and the expression of D2 receptors under these conditions. PMID:26483930

  1. The effects of long-term dopaminergic treatment on locomotor behavior in rats

    Directory of Open Access Journals (Sweden)

    Welinton Alessandro Oliveira de Almeida

    2014-12-01

    Full Text Available Long-term treatments with dopaminergic agents are associated with adverse effects, including augmentation. Augmentation consists of an exacerbation of restless legs syndrome (a sleep-related movement disorder symptoms during treatment compared to those experienced during the period before therapy was initiated. The objective of this study was to examine locomotor activity in rats after long-term dopaminergic treatment and its relationship with expression of the D2 receptor, in addition to demonstrating possible evidence of augmentation. The rats were divided into control (CTRL and drug (Pramipexole—PPX groups that received daily saline vehicle and PPX treatments, respectively, for 71 days. The locomotor behavior of the animals was evaluated weekly in the Open Field test for 71 days. The expression of the dopamine D2 receptor was evaluated by Western Blot analysis. The animals that received the PPX demonstrated a significant reduction in locomotor activity from day 1 to day 57 and a significant increase in immobility time from day 1 to day 64 relative to baseline values, but these values had returned to baseline levels at 71 days. No changes in the expression of the D2 receptor were demonstrated after treatment with a dopaminergic agonist. This study suggests changes in locomotor activity in rats after long-term PPX treatment that include an immediate reduction of locomotion and an increase in immobilization, and after 64 days, these values returned to baseline levels without evidence of augmentation. In addition, it was not possible to demonstrate a relationship between locomotor activity and the expression of D2 receptors under these conditions.

  2. Brain metabolic correlates of dopaminergic degeneration in de novo idiopathic Parkinson's disease

    Energy Technology Data Exchange (ETDEWEB)

    Berti, Valentina; Polito, Cristina; Vanzi, Eleonora; Cristofaro, Maria Teresa de; Pellicano, Giannantonio; Mungai, Francesco; Formiconi, Andreas Robert; Pupi, Alberto [University of Florence, Department of Clinical Pathophysiology, Florence (Italy); Ramat, Silvia; Marini, Paolo; Sorbi, Sandro [University of Florence, Department of Psychiatric and Neurological Sciences, Florence (Italy)

    2010-03-15

    The aim of the present study was to evaluate the reciprocal relationships between motor impairment, dopaminergic dysfunction, and cerebral metabolism (rCMRglc) in de novo Parkinson's disease (PD) patients. Twenty-six de novo untreated PD patients were scanned with {sup 123}I-FP-CIT SPECT and {sup 18}F-FDG PET. The dopaminergic impairment was measured with putaminal {sup 123}I-FP-CIT binding potential (BP), estimated with two different techniques: an iterative reconstruction algorithm (BP{sub OSEM}) and the least-squares (LS) method (BP{sub LS}). Statistical parametric mapping (SPM) multiple regression analyses were performed to determine the specific brain regions in which UPDRS III scores and putaminal BP values correlated with rCMRglc. The SPM results showed a negative correlation between UPDRS III and rCMRglc in premotor cortex, and a positive correlation between BP{sub OSEM} and rCMRglc in premotor and dorsolateral prefrontal cortex, not surviving at multiple comparison correction. Instead, there was a positive significant correlation between putaminal BP{sub LS} and rCMRglc in premotor, dorsolateral prefrontal, anterior prefrontal, and orbitofrontal cortex (p < 0.05, corrected for multiple comparison). Putaminal BP{sub LS} is an efficient parameter for exploring the correlations between PD severity and rCMRglc cortical changes. The correlation between dopaminergic degeneration and rCMRglc in several prefrontal regions likely represents the cortical functional correlate of the dysfunction in the motor basal ganglia-cortical circuit in PD. This finding suggests focusing on the metabolic course of these areas to follow PD progression and to analyze treatment effects. (orig.)

  3. Dopaminergic function in cannabis users and its relationship to cannabis-induced psychotic symptoms.

    Science.gov (United States)

    Bloomfield, Michael A P; Morgan, Celia J A; Egerton, Alice; Kapur, Shitij; Curran, H Valerie; Howes, Oliver D

    2014-03-15

    Cannabis is the most widely used illicit drug globally, and users are at increased risk of mental illnesses including psychotic disorders such as schizophrenia. Substance dependence and schizophrenia are both associated with dopaminergic dysfunction. It has been proposed, although never directly tested, that the link between cannabis use and schizophrenia is mediated by altered dopaminergic function. We compared dopamine synthesis capacity in 19 regular cannabis users who experienced psychotic-like symptoms when they consumed cannabis with 19 nonuser sex- and age-matched control subjects. Dopamine synthesis capacity (indexed as the influx rate constant [Formula: see text] ) was measured with positron emission tomography and 3,4-dihydroxy-6-[(18)F]-fluoro-l-phenylalanine ([(18)F]-DOPA). Cannabis users had reduced dopamine synthesis capacity in the striatum (effect size: .85; t36 = 2.54, p = .016) and its associative (effect size: .85; t36 = 2.54, p = .015) and limbic subdivisions (effect size: .74; t36 = 2.23, p = .032) compared with control subjects. The group difference in dopamine synthesis capacity in cannabis users compared with control subjects was driven by those users meeting cannabis abuse or dependence criteria. Dopamine synthesis capacity was negatively associated with higher levels of cannabis use (r = -.77, p cannabis use (r = .51, p = .027) but was not associated with cannabis-induced psychotic-like symptoms (r = .32, p = .19). These findings indicate that chronic cannabis use is associated with reduced dopamine synthesis capacity and question the hypothesis that cannabis increases the risk of psychotic disorders by inducing the same dopaminergic alterations seen in schizophrenia. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  4. Effect of basal ganglia calcification on its glucose metabolism and dopaminergic function in idiopathic hypoparathyroidism.

    Science.gov (United States)

    Modi, Sagar; Arora, Geetanjali; Bal, Chandra Shekhar; Sreenivas, Vishnubhatla; Kailash, Suparna; Sagar, Rajesh; Goswami, Ravinder

    2015-10-01

    The functional significance of basal ganglia calcification (BGC) in idiopathic hypoparathyroidism (IH) is not clear. To assess the effect of BGC on glucose metabolism and dopaminergic function in IH. (18) F-FDG and (99m) Tc-TRODAT-1 nuclear imaging were performed in 35 IH patients with (n = 26) and without (n = 9) BGC. Controls were subjects without hypoparathyroidism or BGC (nine for (18) F-FDG and 12 for (99m) Tc-TRODAT-1). Relationship of the glucose metabolism and dopaminergic function was assessed with the neuropsychological and biochemical abnormalities. (18) F-FDG uptake in IH patients with calcification at caudate and striatum was less than that of IH patients without calcification (1·06 ± 0·13 vs 1·24 ± 0·09, P = basal ganglia was comparable between IH with and without BGC and between IH without BGC and controls. Serum calcium-phosphorus ratio maintained by the patients correlated with (18) F-FDG uptake at striatum (r = 0·57, P = 0·001). For every 0·1 unit reduction in calcium-phosphorus ratio, (18) F-FDG uptake decreased by 2·5 ± 0·68% (P = 0·001). BGC was associated with modest reduction (15%) in (18) F-FDG uptake at basal ganglia in IH but did not affect dopaminergic function. (18) F-FDG uptake did not correlate with neuropsychological dysfunctions. Interestingly, chronic hypocalcaemia-hyperphosphataemia also contributed to reduction in (18) F-FDG uptake which was independent of BGC. © 2014 John Wiley & Sons Ltd.

  5. Dopaminergic stimulation enhances confidence and accuracy in seeing rapidly presented words

    DEFF Research Database (Denmark)

    Lou, Hans Olav Christensen; Skewes, Joshua; Thomsen, Kristine Rømer

    2011-01-01

    Liberal acceptance, overconfidence, and increased activity of the neurotransmitter dopamine have been proposed to account for abnormal sensory experiences, for instance, hallucinations in schizophrenia. In normal subjects, increased sensory experience in Yoga Nidra meditation is linked to striata...... performance in a forced-choice word recognition task. These results demonstrate neurotransmitter regulation of subjective conscious experience of perception and provide evidence for a crucial role of dopamine....... confidence of perception has never been recorded experimentally before. In a controlled study of 24 normal, healthy female university students with the dopamine agonist pergolide given orally, we show that dopaminergic activation increases confidence in seeing rapidly presented words. It also improves...

  6. The Effect of Dopaminergic Medication on Beat-Based Auditory Timing in Parkinson's Disease

    Directory of Open Access Journals (Sweden)

    Daniel J Cameron

    2016-02-01

    Full Text Available Parkinson’s disease (PD adversely affects timing abilities. Beat-based timing is a mechanism that times events relative to a regular interval, such as the ‘beat’ in musical rhythm, and is impaired in PD. It is unknown if dopaminergic medication influences beat-based timing in PD. Here we tested beat-based timing over two sessions in participants with PD (OFF then ON dopaminergic medication, and unmedicated control participants. People with PD and control participants completed two tasks. The first was a discrimination task in which participants compared two rhythms and determined whether they were the same or different. Rhythms either had a beat structure (metric simple rhythms, or did not (metric complex rhythms, as in previous studies. Discrimination accuracy was analyzed to test for the effects of beat structure, as well as differences between participants with PD and controls, and effects of medication (PD group only. The second task was the Beat Alignment Test (BAT, in which participants listened to music with regular tones superimposed, and responded as to whether the tones were ‘on’ or ‘off’ the beat of the music. Accuracy was analyzed to test for differences between participants with PD and controls, and for an effect of medication in patients.Both patients and controls discriminated metric simple rhythms better than metric complex rhythms. Controls also improved at the discrimination task in the second vs. first session, whereas people with PD did not. For participants with PD, the difference in performance between metric simple and metric complex rhythms was greater (sensitivity to changes in simple rhythms increased and sensitivity to changes in complex rhythms decreased when ON vs. OFF medication. Performance also worsened with disease severity. For the Beat Alignment Test, no group differences or effects of medication were found. Overall, these findings suggest that timing is impaired in PD, and that dopaminergic

  7. Relationship between nigrostriatal dopaminergic degeneration, urinary symptoms, and bladder control in Parkinson's disease

    DEFF Research Database (Denmark)

    Winge, K; Friberg, L; Werdelin, L

    2005-01-01

    Patients with Parkinson's disease (PD) often have lower urinary tract symptoms (LUTS). Studies have indicated a correlation between dopaminergic degeneration and LUTS and presence of overactive bladder. We evaluated 18 patients with Parkinson's disease using single-photon emission computerized....... The effects of medication on bladder control, as evaluated by urodynamics are believed to involve structures outside the basal ganglia....... tomography (SPECT) imaging of the dopamine transporter with [(123)I]-FP-CIT, and bladder symptoms were assessed using questionnaires and full urodynamic evaluation both in medicated state and after cessation. Bladder symptoms correlated with age, stage and severity of disease but not with uptake...

  8. Dopaminergic stimulation enhances confidence and accuracy in seeing rapidly presented words

    DEFF Research Database (Denmark)

    Lou, Hans Olav Christensen; Skewes, Joshua; Thomsen, Kristine Rømer

    2011-01-01

    dopamine release. We therefore hypothesize that the neurotransmitter dopamine may function as a regulator of subjective confidence of visual perception in the normal brain. Although much is known about the effect of stimulation by neurotransmitters on cognitive functions, their effect on subjective...... confidence of perception has never been recorded experimentally before. In a controlled study of 24 normal, healthy female university students with the dopamine agonist pergolide given orally, we show that dopaminergic activation increases confidence in seeing rapidly presented words. It also improves...

  9. Severe Dopaminergic Neurotoxicity in Primates After a Common Recreational Dose Regimen of MDMA (``Ecstasy'')

    Science.gov (United States)

    Ricaurte, George A.; Yuan, Jie; Hatzidimitriou, George; Cord, Branden J.; McCann, Una D.

    2002-09-01

    The prevailing view is that the popular recreational drug (+/-)3,4-methylenedioxymethamphetamine (MDMA, or ``ecstasy'') is a selective serotonin neurotoxin in animals and possibly in humans. Nonhuman primates exposed to several sequential doses of MDMA, a regimen modeled after one used by humans, developed severe brain dopaminergic neurotoxicity, in addition to less pronounced serotonergic neurotoxicity. MDMA neurotoxicity was associated with increased vulnerability to motor dysfunction secondary to dopamine depletion. These results have implications for mechanisms of MDMA neurotoxicity and suggest that recreational MDMA users may unwittingly be putting themselves at risk, either as young adults or later in life, for developing neuropsychiatric disorders related to brain dopamine and/or serotonin deficiency.

  10. Graphene derivative scaffolds facilitate in vitro cell survival and maturation of dopaminergic SN4741 cells

    OpenAIRE

    Rodriguez-Losada, Noela; Wendelbo, Rune; Garcia-Fernandez, Maria; Pavia, Jose; Martinez-Montañez, Elisa; Lara-Muñoz, José Pablo; Arenas, Ernest; Aguirre-Gomez, Jose Angel

    2014-01-01

    The emerging carbon nanomaterial Graphene (G), in the form of scaffold structure, has an efficient bioconjugation with common biomolecules and activates cell differentiation of neuronal stem cells, providing a promising approach for neural regeneration. We propose the use of G as a scaffold to re-address the dopaminergic (DA) neurons and the residual axons from dead or apoptotic DA neurons in Parkinson´s disease (PD). G could act as a physical support to promote the axonal sprout as a “decele...

  11. The role of alpha-synuclein in melanin synthesis in melanoma and dopaminergic neuronal cells.

    Directory of Open Access Journals (Sweden)

    Tianhong Pan

    Full Text Available The relatively high co-occurrence of Parkinson's disease (PD and melanoma has been established by a large number of epidemiological studies. However, a clear biological explanation for this finding is still lacking. Ultra-violet radiation (UVR-induced skin melanin synthesis is a defense mechanism against UVR-induced damage relevant to the initiation of melanoma, whereas, increased neuromelanin (NM, the melanin synthesized in dopaminergic neurons, may enhance the susceptibility to oxidative stress-induced neuronal injury relevant to PD. SNCA is a PD-causing gene coding for alpha-Synuclein (α-Syn that expresses not only in brain, but also in skin as well as in tumors, such as melanoma. The findings that α-Syn can interact with tyrosinase (TYR and inhibit tyrosine hydroxylase (TH, both of which are enzymes involved in the biosynthesis of melanin and dopamine (DA, led us to propose that α-Syn may participate in the regulation of melanin synthesis. In this study, by applying ultraviolet B (UVB light, a physiologically relevant stimulus of melanogenesis, we detected melanin synthesis in A375 and SK-MEL-28 melanoma cells and in SH-SY5Y and PC12 dopaminergic neuronal cells and determined effects of α-Syn on melanin synthesis. Our results showed that UVB light exposure increased melanin synthesis in all 4 cell lines. However, we found that α-Syn expression reduced UVB light-induced increase of melanin synthesis and that melanin content was lower when melanoma cells were expressed with α-Syn, indicating that α-Syn may have inhibitory effects on melanin synthesis in melanoma cells. Different from melanoma cells, the melanin content was higher in α-Syn-over-expressed dopaminergic neuronal SH-SY5Y and PC12 cells, cellular models of PD, than that in non-α-Syn-expressed control cells. We concluded that α-Syn could be one of the points responsible for the positive association between PD and melanoma via its differential roles in melanin synthesis in

  12. Linkage of cDNA expression profiles of mesencephalic dopaminergic neurons to a genome-wide in situ hybridization database

    Directory of Open Access Journals (Sweden)

    Simon Horst H

    2009-01-01

    Full Text Available Abstract Midbrain dopaminergic neurons are involved in control of emotion, motivation and motor behavior. The loss of one of the subpopulations, substantia nigra pars compacta, is the pathological hallmark of one of the most prominent neurological disorders, Parkinson's disease. Several groups have looked at the molecular identity of midbrain dopaminergic neurons and have suggested the gene expression profile of these neurons. Here, after determining the efficiency of each screen, we provide a linked database of the genes, expressed in this neuronal population, by combining and comparing the results of six previous studies and verification of expression of each gene in dopaminergic neurons, using the collection of in situ hybridization in the Allen Brain Atlas.

  13. Vanadium induces dopaminergic neurotoxicity via protein kinase Cdelta dependent oxidative signaling mechanisms: Relevance to etiopathogenesis of Parkinson's disease

    International Nuclear Information System (INIS)

    Afeseh Ngwa, Hilary; Kanthasamy, Arthi; Anantharam, Vellareddy; Song, Chunjuan; Witte, Travis; Houk, Robert; Kanthasamy, Anumantha G.

    2009-01-01

    Environmental exposure to neurotoxic metals through various sources including exposure to welding fumes has been linked to an increased incidence of Parkinson's disease (PD). Welding fumes contain many different metals including vanadium typically present as particulates containing vanadium pentoxide (V 2 O 5 ). However, possible neurotoxic effects of this metal oxide on dopaminergic neuronal cells are not well studied. In the present study, we characterized vanadium-induced oxidative stress-dependent cellular events in cell culture models of PD. V 2 O 5 was neurotoxic to dopaminergic neuronal cells including primary nigral dopaminergic neurons and the EC 50 was determined to be 37 μM in N27 dopaminergic neuronal cell model. The neurotoxic effect was accompanied by a time-dependent uptake of vanadium and upregulation of metal transporter proteins Tf and DMT1 in N27 cells. Additionally, vanadium resulted in a threefold increase in reactive oxygen species generation, followed by release of mitochondrial cytochrome c into cytoplasm and subsequent activation of caspase-9 (> fourfold) and caspase-3 (> ninefold). Interestingly, vanadium exposure induced proteolytic cleavage of native protein kinase Cdelta (PKCδ, 72-74 kDa) to yield a 41 kDa catalytically active fragment resulting in a persistent increase in PKCδ kinase activity. Co-treatment with pan-caspase inhibitor Z-VAD-FMK significantly blocked vanadium-induced PKCδ proteolytic activation, indicating that caspases mediate PKCδ cleavage. Also, co-treatment with Z-VAD-FMK almost completely inhibited V 2 O 5 -induced DNA fragmentation. Furthermore, PKCδ knockdown using siRNA protected N27 cells from V 2 O 5 -induced apoptotic cell death. Collectively, these results demonstrate that vanadium can exert neurotoxic effects in dopaminergic neuronal cells via caspase-3-dependent PKCδ cleavage, suggesting that metal exposure may promote nigral dopaminergic degeneration.

  14. Impulse control disorders with the use of dopaminergic agents in restless legs syndrome: a case-control study.

    Science.gov (United States)

    Cornelius, Jason R; Tippmann-Peikert, Maja; Slocumb, Nancy L; Frerichs, Courtney F; Silber, Michael H

    2010-01-01

    To determine the frequency of impulse control disorders (ICDs) with the use of dopaminergic agents in restless legs syndrome (RLS). Prospective case-control study using a screening questionnaire for ICDs, followed by phone interview to confirm diagnoses for those meeting preset scoring thresholds on the questionnaire. Academic, comprehensive sleep medicine center. (1) One hundred patients with RLS treated with dopaminergic agents, (2) 275 patients with obstructive sleep apnea (OSA) without RLS or exposure to dopaminergic agents; and (3) 52 patients with RLS who were never treated with dopaminergic agents. Subjects with parkinsonism were excluded. Not applicable. Based on the questionnaire, frequencies of ICDs for the RLS treatment group were 10% compulsive shopping, 7% pathologic gambling, 23% compulsive eating, 8% hypersexuality, and 10% punding. These values were statistically significant when compared with control subjects with OSA for compulsive shopping and pathologic gambling. With additional information from the phone interview, adjusted frequencies for the RLS treatment group were 9% compulsive shopping, 5% pathologic gambling, 11% compulsive eating, 3% hypersexuality, 7% punding, and 17% any ICD. These values were statistically significant when compared with those of control subjects with OSA for compulsive shopping, pathologic gambling, punding, and any ICD, as well as for compulsive shopping when compared with control subjects with RLS who were not treated with dopaminergic agents. In the RLS treatment group, a statistically significant dose effect was found for pramipexole in those subjects confirmed to have ICDs by both the questionnaire and phone interview. Mean duration of treatment at ICD onset was 9.5 months. ICDs are common with the use of dopaminergic agents for treatment of RLS. Given the potentially devastating psychosocial consequences of these behaviors, it is critical to actively screen for ICDs in this population.

  15. Direct lineage reprogramming of mouse fibroblasts to functional midbrain dopaminergic neuronal progenitors

    Directory of Open Access Journals (Sweden)

    Han-Seop Kim

    2014-01-01

    Full Text Available The direct lineage reprogramming of somatic cells to other lineages by defined factors has led to innovative cell-fate-change approaches for providing patient-specific cells. Recent reports have demonstrated that four pluripotency factors (Oct4, Sox2, Klf4, and c-Myc are sufficient to directly reprogram fibroblasts to other specific cells, including induced neural stem cells (iNSCs. Here, we show that mouse fibroblasts can be directly reprogrammed into midbrain dopaminergic neuronal progenitors (DPs by temporal expression of the pluripotency factors and environment containing sonic hedgehog and fibroblast growth factor 8. Within thirteen days, self-renewing and functional induced DPs (iDPs were generated. Interestingly, the inhibition of both Jak and Gsk3β notably enhanced the iDP reprogramming efficiency. We confirmed the functionality of the iDPs by showing that the dopaminergic neurons generated from iDPs express midbrain markers, release dopamine, and show typical electrophysiological profiles. Our results demonstrate that the pluripotency factors-mediated direct reprogramming is an invaluable strategy for supplying functional and proliferating iDPs and may be useful for other neural progenitors required for disease modeling and cell therapies for neurodegenerative disorders.

  16. Rasagiline protects against alpha-synuclein induced sensitivity to oxidative stress in dopaminergic cells.

    Science.gov (United States)

    Chau, K Y; Cooper, J M; Schapira, A H V

    2010-11-01

    Rasagiline is a propargylamine and irreversible monoamine oxidase (MAO) B inhibitor used for the treatment of Parkinson's disease (PD). It has demonstrated neuroprotective properties in laboratory studies. Current concepts of PD aetiopathogenesis include the role of alpha-synuclein, protein aggregation, free radical metabolism and mitochondrial dysfunction in contributing to cell death. We have used a combination of alpha-synuclein and free radical mediated toxicity in a dopaminergic cell line to provide a model of nigral toxicity in order to investigate the potential molecular mechanisms that mediate rasagiline protection. We demonstrate that rasagiline protects against cell death induced by the combination of free radicals generated by paraquat and either wild-type or A53T mutant alpha-synuclein over-expression. This protection was associated with a reduction in caspase 3 activation, a reduction in superoxide generation and a trend to ameliorate the fall in mitochondrial membrane potential. Rasagiline induced an increase in cellular glutathione levels. The results support a role for rasagiline in protecting dopaminergic cells against free radical mediated damage and apoptosis in the presence of alpha-synuclein over-expression. The data are of relevance to the interpretation of the potential mechanisms of action of rasagiline in explaining the results of disease modification trials in PD. Copyright 2010 Elsevier Ltd. All rights reserved.

  17. Dopaminergic Neurons Controlling Anterior Pituitary Functions: Anatomy and Ontogenesis in Zebrafish.

    Science.gov (United States)

    Fontaine, Romain; Affaticati, Pierre; Bureau, Charlotte; Colin, Ingrid; Demarque, Michaël; Dufour, Sylvie; Vernier, Philippe; Yamamoto, Kei; Pasqualini, Catherine

    2015-08-01

    Dopaminergic (DA) neurons located in the preoptico-hypothalamic region of the brain exert a major neuroendocrine control on reproduction, growth, and homeostasis by regulating the secretion of anterior pituitary (or adenohypophysis) hormones. Here, using a retrograde tract tracing experiment, we identified the neurons playing this role in the zebrafish. The DA cells projecting directly to the anterior pituitary are localized in the most anteroventral part of the preoptic area, and we named them preoptico-hypophyseal DA (POHDA) neurons. During development, these neurons do not appear before 72 hours postfertilization (hpf) and are the last dopaminergic cell group to differentiate. We found that the number of neurons in this cell population continues to increase throughout life proportionally to the growth of the fish. 5-Bromo-2'-deoxyuridine incorporation analysis suggested that this increase is due to continuous neurogenesis and not due to a phenotypic change in already-existing neurons. Finally, expression profiles of several genes (foxg1a, dlx2a, and nr4a2a/b) were different in the POHDA compared with the adjacent suprachiasmatic DA neurons, suggesting that POHDA neurons develop as a distinct DA cell population in the preoptic area. This study offers some insights into the regional identity of the preoptic area and provides the first bases for future functional genetic studies on the development of DA neurons controlling anterior pituitary functions.

  18. Protection against MDMA-induced dopaminergic neurotoxicity in mice by methyllycaconitine: involvement of nicotinic receptors.

    Science.gov (United States)

    Chipana, C; Camarasa, J; Pubill, D; Escubedo, E

    2006-09-01

    Methylenedioxymethamphetamine (MDMA) is a relatively selective dopaminergic neurotoxin in mice. Previous studies demonstrated the participation of alpha-7 nicotinic receptors (nAChR) in the neurotoxic effect of methamphetamine. The aim of this paper was to study the role of this receptor type in the acute effects and neurotoxicity of MDMA in mice. In vivo, methyllycaconitine (MLA), a specific alpha-7 nAChR antagonist, significantly prevented MDMA-induced neurotoxicity at dopaminergic but not at serotonergic level, without affecting MDMA-induced hyperthermia. Glial activation was also fully prevented by MLA. In vitro, MDMA induced intrasynaptosomal reactive oxygen species (ROS) generation, which was calcium-, nitric-oxide synthase-, and protein kinase C-dependent. Also, the increase in ROS was prevented by MLA and alpha-bungarotoxin. Experiments with reserpine point to endogenous dopamine (DA) as the main source of MDMA-induced ROS. MLA also brought the MDMA-induced inhibition of [3H]DA uptake down, from 73% to 11%. We demonstrate that a coordinated activation of alpha-7 nAChR, blockade of DA transporter function and displacement of DA from intracellular stores induced by MDMA produces a neurotoxic effect that can be prevented by MLA, suggesting that alpha-7 nAChR have a key role in the MDMA neurotoxicity in mice; however, the involvement of nicotinic receptors containing the beta2 subunit cannot be conclusively ruled out.

  19. In vivo dopaminergic and serotonergic dysfunction in DCTN1 gene mutation carriers.

    Science.gov (United States)

    Felicio, Andre C; Dinelle, Katherine; Agarwal, Pankaj A; McKenzie, Jessamyn; Heffernan, Nicole; Road, Jeremy D; Appel-Cresswell, Silke; Wszolek, Zbigniew K; Farrer, Matthew J; Schulzer, Michael; Sossi, Vesna; Stoessl, A Jon

    2014-08-01

    We used positron emission tomography (PET) to assess dopaminergic and serotonergic terminal density in three subjects carrying a mutation in the DCT1 gene, two clinically affected with Perry syndrome. All subjects had brain imaging using 18F-6-fluoro-l-dopa (FDOPA, dopamine synthesis and storage), (+)-11C-dihydrotetrabenazine (DTBZ, vesicular monoamine transporter type 2), and 11C-raclopride (RAC, dopamine D2/D3 receptors). One subject also underwent PET with 11C-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB, serotonin transporter). FDOPA-PET and DTBZ-PET in the affected individuals showed a reduction of striatal tracer uptake. Also, RAC-PET showed higher uptake in these area. DASB-PET showed significant uptake changes in left orbitofrontal cortex, bilateral anterior insula, left dorsolateral prefrontal cortex, left orbitofrontal cortex, left posterior cingulate cortex, left caudate, and left ventral striatum. Our data showed evidence of both striatal dopaminergic and widespread cortical/subcortical serotonergic dysfunctions in individuals carrying a mutation in the DCTN1 gene. © 2014 International Parkinson and Movement Disorder Society.

  20. Noradrenergic-Dopaminergic Interactions Due to DSP-4-MPTP Neurotoxin Treatments: Iron Connection.

    Science.gov (United States)

    Archer, Trevor

    The investigations of noradrenergic lesions and dopaminergic lesions have established particular profiles of functional deficits and accompanying alterations of biomarkers in brain regions and circuits. In the present account, the focus of these lesions is directed toward the effects upon dopaminergic neurotransmission and expression that are associated with the movement disorders and psychosis-like behavior. In this context, it was established that noradrenergic denervation, through administration of the selective noradrenaline (NA) neurotoxin, DSP-4, should be performed prior to the depletion of dopamine (DA) with the selective neurotoxin, MPTP. Employing this regime, it was shown that (i) following DSP-4 (50 mg/kg) pretreatment of C57/Bl6 mice, both the functional and neurochemical (DA loss) effects of MPTP (2 × 20 and 2 × 40 mg/kg) were markedly exacerbated, and (ii) following postnatal iron (Fe(2+), 7.5 mg/kg, on postnatal days 19-12), pretreatment with DSP-4 followed by the lower 2 × 20 mg/kg MPTP dose induced even greater losses of motor behavior and striatal DA. As yet, the combination of NA-DA depletions, and even more so Fe(2+)-NA-DA depletion, has been considered to present a movement disorder aspect although studies exploring cognitive domains are lacking. With intrusion of iron overload into this formula, the likelihood of neuropsychiatric disorder, as well, unfolds.

  1. TDP-43 Potentiates Alpha-synuclein Toxicity to Dopaminergic Neurons in Transgenic Mice

    Science.gov (United States)

    Tian, Tian; Huang, Cao; Tong, Jianbin; Yang, Ming; Zhou, Hongxia; Xia, Xu-Gang

    2011-01-01

    TDP-43 and α-synuclein are two disease proteins involved in a wide range of neurodegenerative diseases. While TDP-43 proteinopathy is considered a pathologic hallmark of sporadic amyotrophic lateral sclerosis and frontotemporal lobe degeneration, α-synuclein is a major component of Lewy body characteristic of Parkinson's disease. Intriguingly, TDP-43 proteinopathy also coexists with Lewy body and with synucleinopathy in certain disease conditions. Here we reported the effects of TDP-43 on α-synuclein neurotoxicity in transgenic mice. Overexpression of mutant TDP-43 (M337V substitution) in mice caused early death in transgenic founders, but overexpression of normal TDP-43 only induced a moderate loss of cortical neurons in the transgenic mice at advanced ages. Interestingly, concomitant overexpression of normal TDP-43 and mutant α-synuclein caused a more severe loss of dopaminergic neurons in the double transgenic mice as compared to single-gene transgenic mice. TDP-43 potentiated α-synuclein toxicity to dopaminergic neurons in living animals. Our finding provides in vivo evidence suggesting that disease proteins such as TDP-43 and α-synuclein may play a synergistic role in disease induction in neurodegenerative diseases. PMID:21448284

  2. Paraquat Induces Epigenetic Changes by Promoting Histone Acetylation in Cell Culture Models of Dopaminergic Degeneration

    Science.gov (United States)

    Song, C.; Kanthasamy, A.; Jin, H.; Anantharam, V.; Kanthasamy, A. G.

    2012-01-01

    Environmental neurotoxic exposure to agrochemicals has been implicated in the etiopathogenesis of Parkinson’s disease (PD). The widely used herbicide paraquat is among the few environmental chemicals potentially linked with PD. Since epigenetic changes are beginning to emerge as key mechanisms in neurodegenerative diseases, herein we examined the effects of paraquat on histone acetylation, a major epigenetic change in chromatin that can regulate gene expression, chromatin remodeling, cell survival and cell death. Exposure of N27 dopaminergic cells to paraquat induced histone H3 acetylation in a time-dependent manner. However, paraquat did not alter acetylation of another core histone H4. Paraquat-induced histone acetylation was associated with decreased total histone deacetylase (HDAC) activity and HDAC4 and 7 protein expression levels. To determine if histone acetylation plays a role in paraquat-induced apoptosis, the novel HAT inhibitor anacardic acid was used. Anacardic acid treatment significantly attenuated paraquat-induced caspase-3 enzyme activity, suppressed proteolytic activation and kinase activity of protein kinase C delta (PKCδ) and also blocked paraquat-induced cytotoxicity. Together, these results demonstrate that the neurotoxic agent paraquat induced acetylation of core histones in cell culture models of PD and that inhibition of HAT activity by anacardic acid protects against apoptotic cell death, indicating that histone acetylation may represent key epigenetic changes in dopaminergic neuronal cells during neurotoxic insults. PMID:21777615

  3. The Descending Diencephalic Dopamine System Is Tuned to Sensory Stimuli.

    Science.gov (United States)

    Reinig, Sebastian; Driever, Wolfgang; Arrenberg, Aristides B

    2017-02-06

    The vertebrate diencephalic A11 system provides the sole dopaminergic innervation of hindbrain and spinal cord and has been implicated in modulation of locomotion and sensory processes. However, the exact contributions of sensory stimuli and motor behavior to A11 dopaminergic activity remain unclear. We recorded cellular calcium activity in four anatomically distinct posterior tubercular A11-type dopaminergic subgroups and two adjacent hypothalamic dopaminergic groups in GCaMP7a-transgenic, semi-restrained zebrafish larvae. Our analyses reveal the contributions of different sensory modalities and motor states to dopaminergic activity. Each posterior tubercular and hypothalamic subgroup showed distinct activity patterns, while activity was synchronous within individual subgroups. Caudal and dorsomedial hypothalamic dopaminergic neurons are activated following vigorous tail movements and stay active for about 10 s, revealing predominantly post-motor activity. In contrast, posterior tubercular dopaminergic neurons are predominantly sensory driven, with subgroups differentially responding to different tactile or visual sensory modalities. In the anterior subgroups, neuronal response magnitudes are tuned to tactile stimulus intensities, revealing features similar to sensory systems. We identify the lateral line system as source for this tactile tuning. In contrast, the posterior subgroup is responsive to distinct moving visual stimuli. Specifically, translational forward stimuli, which may indicate insufficient rheotaxis and drift, induce dopaminergic activity, but backward or rotational stimuli not. The activation of posterior tubercular dopaminergic neurons by sensory stimuli, and their projections onto peripheral mechanosensory systems, suggests a participation of A11-type neurons in the feedback regulation of sensory systems. Together with the adjacent hypothalamic neurons, they may serve to set basic behavioral states. Copyright © 2017 Elsevier Ltd. All rights

  4. NMDA receptors on non-dopaminergic neurons in the VTA support cocaine sensitization.

    Directory of Open Access Journals (Sweden)

    Yu Luo

    2010-08-01

    Full Text Available The initiation of behavioral sensitization to cocaine and other psychomotor stimulants is thought to reflect N-methyl-D-aspartate receptor (NMDAR-mediated synaptic plasticity in the mesolimbic dopamine (DA circuitry. The importance of drug induced NMDAR mediated adaptations in ventral tegmental area (VTA DA neurons, and its association with drug seeking behaviors, has recently been evaluated in Cre-loxp mice lacking functional NMDARs in DA neurons expressing Cre recombinase under the control of the endogenous dopamine transporter gene (NR1(DATCre mice.Using an additional NR1(DATCre mouse transgenic model, we demonstrate that while the selective inactivation of NMDARs in DA neurons eliminates the induction of molecular changes leading to synaptic strengthening, behavioral measures such as cocaine induced locomotor sensitization and conditioned place preference remain intact in NR1(DATCre mice. Since VTA DA neurons projecting to the prefrontal cortex and amygdala express little or no detectable levels of the dopamine transporter, it has been speculated that NMDA receptors in DA neurons projecting to these brain areas may have been spared in NR1(DATCre mice. Here we demonstrate that the NMDA receptor gene is ablated in the majority of VTA DA neurons, including those exhibiting undetectable DAT expression levels in our NR1(DATCre transgenic model, and that application of an NMDAR antagonist within the VTA of NR1(DATCre animals still blocks sensitization to cocaine.These results eliminate the possibility of NMDAR mediated neuroplasticity in the different DA neuronal subpopulations in our NR1(DATCre mouse model and therefore suggest that NMDARs on non-DA neurons within the VTA must play a major role in cocaine-related addictive behavior.

  5. In vivo imaging of synaptic function in the central nervous system: II. Mental and affective disorders.

    Science.gov (United States)

    Nikolaus, Susanne; Antke, Christina; Müller, Hans-Wilhelm

    2009-12-01

    stages of the disease. Results, tentatively, may be interpreted in terms of an increased dopaminergic neurotransmission in the mesolimbic system. There is limited evidence of decreased dopamine synthesis in both children and adults with attention-deficit/hyperactivity disorder (4 out of a total of 10 reports). These findings as well as the reduction of striatal dopamine release observed in adults (merely 1 report) are in line with the notion of mesocortical dopaminergic hypofunction in attention-deficit/hyperactivity disorder. Thereby, however, in children, results on dopamine synthesis indicate a deficiency in the ventral tegmentum rather than in the prefrontal cortex, whereas, with increasing age, the prefrontal cortex rather than the sites of origin of DAergic innervation become predominantly affected (merely 1 report, each). In anxiety disorders, varying results have been obtained for both pre- and/or postsynaptic dopaminergic, serotonergic and GABAergic binding sites. Thereby, results on posttraumatic stress disorder are homogenous reporting a decrease of GABA A receptor binding in all investigated brain regions including striatum, thalamus, neocortex and limbic system (2 out of 2 reports, each). Moreover, patients with obsessive-compulsive disorder displayed increases of dopamine transporter binding (2 out of 4 reports) and decreases of both D1 (merely 1 report) and D2 receptor binding (4 out of 5 reports), respectively. These findings, tentatively, may be interpreted in terms of an increased availability of synaptic dopamine in the neostriatum, which is compensated for both pre- and postsynaptically by increasing dopamine reuptake into the presynaptic terminal, and decreasing (inhibitory) signal transduction of efferent fibers. The observed reduction of GABA A receptor binding in frontocortical neurons (in 11 out of a total of 21 reports on anxiety disorders) is in line with this assumption. The inconsistency (and, partially, also incompleteness) of in vivo

  6. Neuromodulation of Prefrontal Cortex in Non-Human Primates by Dopaminergic Receptors during Rule-Guided Flexible Behavior and Cognitive Control

    Science.gov (United States)

    Vijayraghavan, Susheel; Major, Alex J.; Everling, Stefan

    2017-01-01

    The prefrontal cortex (PFC) is indispensable for several higher-order cognitive and executive capacities of primates, including representation of salient stimuli in working memory (WM), maintenance of cognitive task set, inhibition of inappropriate responses and rule-guided flexible behavior. PFC networks are subject to robust neuromodulation from ascending catecholaminergic systems. Disruption of these systems in PFC has been implicated in cognitive deficits associated with several neuropsychiatric disorders. Over the past four decades, a considerable body of work has examined the influence of dopamine on macaque PFC activity representing spatial WM. There has also been burgeoning interest in neuromodulation of PFC circuits involved in other cognitive functions of PFC, including representation of rules to guide flexible behavior. Here, we review recent neuropharmacological investigations conducted in our laboratory and others of the role of PFC dopamine receptors in regulating rule-guided behavior in non-human primates. Employing iontophoresis, we examined the effects of local manipulation of dopaminergic subtypes on neuronal activity during performance of rule-guided pro- and antisaccades, an experimental paradigm sensitive to PFC integrity, wherein deficits in performance are reliably observed in many neuropsychiatric disorders. We found dissociable effects of dopamine receptors on neuronal activity for rule representation and oculomotor responses and discuss these findings in the context of prior studies that have examined the role of dopamine in spatial delayed response tasks, attention, target selection, abstract rules, visuomotor learning and reward. The findings we describe here highlight the common features, as well as heterogeneity and context dependence of dopaminergic neuromodulation in regulating the efficacy of cognitive functions of PFC in health and disease. PMID:29259545

  7. Moderate intensity treadmill exercise alters food preference via dopaminergic plasticity of ventral tegmental area-nucleus accumbens in obese mice.

    Science.gov (United States)

    Chen, Wei; Wang, Hai Jun; Shang, Ning Ning; Liu, Jun; Li, Juan; Tang, Dong Hui; Li, Qiong

    2017-02-22

    Obesity has been associated with the excessive intake of palatable food as well as physical inactivity. To investigate the neurobiological mechanism underlying the exercised-induced prevention and treatment of obesity, the present study examined the effect of treadmill exercise on the preference for palatable food in mice. Levels of tyrosine hydroxylase (TH) in the ventral tegmental area-nucleus accumbens system were also analysed, as well as levels of dopamine, dopamine transporter, and D2 receptors in the nucleus accumbens. Forty C57BL/6J mice were randomly divided into a control group (CG, n=10) and a high-fat diet group (HG, N=30). Mice of the HG group were fed a high-fat diet for 12 weeks in order to induce a model of obesity, following which the obese mice were randomly divided into an obese control group (OG, n=11) and an obese+exercise group (OEG, n=12). OEG mice received 8 weeks of treadmill exercise intervention. Our results indicate that, relative to animals in the OG group, OEG mice exhibited significant decreases in the preference for high-fat diets and insulin resistance, along with increases in the preference for sucrose and milk, TH and D2 receptor expression, and levels of dopamine in the ventral tegmental area-nucleus accumbens system. These results suggest that moderate-intensity treadmill exercise can alter food preference in obese mice, which may be mediated by dopaminergic plasticity of the ventral tegmental area-nucleus accumbens and enhanced insulin sensitivity. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Differences in efficacy on substance abuse between risperidone and clozapine supports the importance of differential modulation of dopaminergic neurotransmission

    NARCIS (Netherlands)

    Machielsen, Marise W. J.; de Haan, Lieuwe

    2009-01-01

    In patients with a psychotic disorder, substance abuse is a major problem. Substance abuse is associated with changes in dopaminergic neurotransmission of dopamine D1 and D2 receptors. Differences in efficacy between antipsychotics on substance abuse could be explained by differences in D2 receptor

  9. Serotonergic, noradrenergic and dopaminergic markers are related to cognitive function in adults with 22q11 deletion syndrome

    NARCIS (Netherlands)

    Evers, Laurens J. M.; Curfs, Leopold M. G.; Bakker, Jaap A.; Boot, Erik; da Silva Alves, Fabiana; Abeling, Nico; Bierau, Jörgen; Drukker, Marjan; van Amelsvoort, Therese A. M. J.

    2014-01-01

    Patients with 22q11 deletion syndrome (22q11DS) have a high prevalence of psychiatric disorders and intellectual disability. At present the neurobiology underlying psychopathology in 22q11DS is still not understood. In the present study, we analyzed urinary serotonergic, dopaminergic and

  10. Determination of dopaminergic prodrugs by high-performance liquid chromatography followed by post-column ion-pair extraction

    NARCIS (Netherlands)

    Haas, M; Moolenaar, Frits; Kluppel, A.C A; Dijkstra, D.; Meijer, D.K F; de Zeeuw, D

    1997-01-01

    One possibility to optimize the therapeutic application of dopaminergic compounds with a catechol function is the reversible protection of this moiety using a prodrug approach. Important features in this respect are a proper chemical stability in the gastrointestinal tract, an adequate release rate

  11. Gender-related changes in increase of dopaminergic neurons in the olfactory bulb of Parkinson's disease patients

    NARCIS (Netherlands)

    Huisman, E.; Uylings, H.B.M.; Hoogland, P.V.J.M.

    2008-01-01

    Gender differences in dopaminergic related neurodegenerative diseases have hardly been studied until now. It is generally accepted that more men than women suffer from Parkinson's disease. One of the most prevalent symptoms in Parkinson's patients, hyposmia, does not show gender differences, while

  12. Enhanced proliferation and dopaminergic differentiation of ventral mesencephalic precursor cells by synergistic effect of FGF2 and reduced oxygen tension

    Energy Technology Data Exchange (ETDEWEB)

    Jensen, Pia [Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Winslowparken 21, DK-5000 Odense C (Denmark); Department of Neurosurgery, University of Bern, CH-3010 Bern (Switzerland); Gramsbergen, Jan-Bert; Zimmer, Jens [Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Winslowparken 21, DK-5000 Odense C (Denmark); Widmer, Hans R. [Department of Neurosurgery, University of Bern, CH-3010 Bern (Switzerland); Meyer, Morten, E-mail: MMeyer@health.sdu.dk [Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Winslowparken 21, DK-5000 Odense C (Denmark)

    2011-07-15

    Effective numerical expansion of dopaminergic precursors might overcome the limited availability of transplantable cells in replacement strategies for Parkinson's disease. Here we investigated the effect of fibroblast growth factor-2 (FGF2) and FGF8 on expansion and dopaminergic differentiation of rat embryonic ventral mesencephalic neuroblasts cultured at high (20%) and low (3%) oxygen tension. More cells incorporated bromodeoxyuridine in cultures expanded at low as compared to high oxygen tension, and after 6 days of differentiation there were significantly more neuronal cells in low than in high oxygen cultures. Low oxygen during FGF2-mediated expansion resulted also in a significant increase in tyrosine hydroxylase-immunoreactive (TH-ir) dopaminergic neurons as compared to high oxygen tension, but no corresponding effect was observed for dopamine release into the culture medium. However, switching FGF2-expanded cultures from low to high oxygen tension during the last two days of differentiation significantly enhanced dopamine release and intracellular dopamine levels as compared to all other treatment groups. In addition, the short-term exposure to high oxygen enhanced in situ assessed TH enzyme activity, which may explain the elevated dopamine levels. Our findings demonstrate that modulation of oxygen tension is a recognizable factor for in vitro expansion and dopaminergic differentiation of rat embryonic midbrain precursor cells.

  13. [(123)I]beta-CIT SPECT is a useful method for monitoring dopaminergic degeneration in early stage Parkinson's disease

    NARCIS (Netherlands)

    Winogrodzka, A.; Bergmans, P.; Booij, J.; van Royen, E. A.; Stoof, J. C.; Wolters, E. C.

    2003-01-01

    OBJECTIVES: To examine the validity of [(123)I]beta-CIT SPECT for monitoring the progression of dopaminergic degeneration in Parkinson's disease; to investigate the influence of short term treatment with D(2)receptor agonists on striatal [(123)I]beta-CIT binding; and to determine the sample size and

  14. Association of Polymorphisms in BDNF, MTHFR, and Genes Involved in the Dopaminergic Pathway with Memory in a Healthy Chinese Population

    Science.gov (United States)

    Yeh, Ting-Kuang; Hu, Chung-Yi; Yeh, Ting-Chi; Lin, Pei-Jung; Wu, Chung-Hsin; Lee, Po-Lei; Chang, Chun-Yen

    2012-01-01

    The contribution of genetic factors to the memory is widely acknowledged. Research suggests that these factors include genes involved in the dopaminergic pathway, as well as the genes for brain-derived neurotrophic factor (BDNF) and methylenetetrahydrofolate reductase (MTHFR). The activity of the products of these genes is affected by single…

  15. Genetic Moderation of Intervention Efficacy : Dopaminergic Genes, The Incredible Years, and Externalizing Behavior in Children

    NARCIS (Netherlands)

    Chhangur, Rabia R.; Weeland, Joyce; Overbeek, Geertjan; Matthys, Walter; Orobio De Castro, Bram; Van Der Giessen, Danielle; Belsky, Jay

    This study investigated whether children scoring higher on a polygenic plasticity index based on five dopaminergic genes (DRD4, DRD2, DAT1, MAOA, and COMT) benefited the most from the Incredible Years (IY) parent program. Data were used from a randomized controlled trial including 341 Dutch families

  16. Impulse Control Disorders with the use of Dopaminergic Agents in Restless Legs Syndrome: a Case-Control Study

    Science.gov (United States)

    Cornelius, Jason R.; Tippmann-Peikert, Maja; Slocumb, Nancy L.; Frerichs, Courtney F.; Silber, Michael H.

    2010-01-01

    Study Objectives: To determine the frequency of impulse control disorders (ICDs) with the use of dopaminergic agents in restless legs syndrome (RLS). Design: Prospective case-control study using a screening questionnaire for ICDs, followed by phone interview to confirm diagnoses for those meeting preset scoring thresholds on the questionnaire. Setting: Academic, comprehensive sleep medicine center. Patients or Participants: (1) One hundred patients with RLS treated with dopaminergic agents, (2) 275 patients with obstructive sleep apnea (OSA) without RLS or exposure to dopaminergic agents; and (3) 52 patients with RLS who were never treated with dopaminergic agents. Subjects with parkinsonism were excluded. Interventions: Not applicable. Measurements and Results: Based on the questionnaire, frequencies of ICDs for the RLS treatment group were 10% compulsive shopping, 7% pathologic gambling, 23% compulsive eating, 8% hypersexuality, and 10% punding. These values were statistically significant when compared with control subjects with OSA for compulsive shopping and pathologic gambling. With additional information from the phone interview, adjusted frequencies for the RLS treatment group were 9% compulsive shopping, 5% pathologic gambling, 11% compulsive eating, 3% hypersexuality, 7% punding, and 17% any ICD. These values were statistically significant when compared with those of control subjects with OSA for compulsive shopping, pathologic gambling, punding, and any ICD, as well as for compulsive shopping when compared with control subjects with RLS who were not treated with dopaminergic agents. In the RLS treatment group, a statistically significant dose effect was found for pramipexole in those subjects confirmed to have ICDs by both the questionnaire and phone interview. Mean duration of treatment at ICD onset was 9.5 months. Conclusions: ICDs are common with the use of dopaminergic agents for treatment of RLS. Given the potentially devastating psychosocial

  17. Lmx1a encodes a rostral set of mesodiencephalic dopaminergic neurons marked by the Wnt/B-catenin signaling activator R-spondin 2.

    Directory of Open Access Journals (Sweden)

    Elisa J Hoekstra

    Full Text Available Recent developments in molecular programming of mesodiencephalic dopaminergic (mdDA neurons have led to the identification of many transcription factors playing a role in mdDA specification. LIM homeodomain transcription factor Lmx1a is essential for chick mdDA development, and for the efficient differentiation of ES-cells towards a dopaminergic phenotype. In this study, we aimed towards a more detailed understanding of the subtle phenotype in Lmx1a-deficient (dreher mice, by means of gene expression profiling. Transcriptome analysis was performed, to elucidate the exact molecular programming underlying the neuronal deficits after loss of Lmx1a. Subsequent expression analysis on brain sections, confirmed that Nurr1 is regulated by Lmx1a, and additional downstream targets were identified, like Pou4f1, Pbx1, Pitx2, C130021l20Rik, Calb2 and Rspo2. In line with a specific, rostral-lateral (prosomer 2/3 loss of expression of most of these genes during development, Nurr1 and C130021l20Rik were affected in the SNc of the mature mdDA system. Interestingly, this deficit was marked by the complete loss of the Wnt/b-catenin signaling activator Rspo2 in this domain. Subsequent analysis of Rspo2-/- embryos revealed affected mdDA neurons, partially phenocopying the Lmx1a mutant. To conclude, our study revealed that Lmx1a is essential for a rostral-lateral subset of the mdDA neuronal field, where it might serve a critical function in modulating proliferation and differentiation of mdDA progenitors through the regulation of the Wnt activator Rspo2.

  18. Apoptosis-mediated testicular alteration in Japanese quail (Coturnix coturnix japonica) in response to temporal phase relation of serotonergic and dopaminergic oscillations.

    Science.gov (United States)

    Banerjee, Somanshu; Tsutsui, Kazuyoshi; Chaturvedi, Chandra Mohini

    2016-05-15

    Reproductive performance of many avian species, including Japanese quail, is reported to be modulated by specific temporal phase relation of serotonergic and dopaminergic oscillations. Accordingly, it has been shown that the serotonin precursor 5-HTP and the dopamine precursor l-DOPA given 8 h apart induce gonadal suppression and given 12 h apart lead to gonadal stimulation, while other temporal relationships were found to be ineffective. In the present study, we investigated the effects of 8- and 12-h phase relation of neural oscillations on testicular responses including expression of GnRH-I, GnIH, pro-apoptotic proteins (p53 and Bax), inactive and active executioner caspase-3, and the uncleaved DNA repair enzyme PARP-1. Testicular volume and mass decreased significantly in 8-h quail and increased in 12-h quail compared with controls. Expression of ir-GnIH, p53, Bax and active-caspase-3 increased and that of GnRH-I, pro-caspase-3 and uncleaved PARP-1 decreased in 8-h quail compared with controls. A TUNEL assay also confirmed testicular regression in these quail. Testes of 12-h quail exhibited significantly increased expression of GnRH-I, pro-caspase-3 and uncleaved PARP-1 compared with the control group. Our findings suggest that differential response of avian testes to 8- and 12-h phase relation of serotonergic and dopaminergic neural oscillations may be attributed to autocrine/paracrine action of GnIH expression, which is upregulated in regressed testes, leading to apoptotic changes, and downregulated in developed testes, causing apoptotic inhibition. It is concluded that specific phase relation of neural oscillations may modulate the local testicular GnRH-GnIH system and alter the apoptotic mechanism in quail testes. Moreover, these findings highlight the physiological effects of time-dependent drug delivery, including the specific time intervals between two drugs. © 2016. Published by The Company of Biologists Ltd.

  19. Synergistic Effects of Aerobic Exercise after Bone Marrow Stem Cell Transplantation on Recovery of Dopaminergic Neurons and Angiogenesis Markers of Parkinsonian Rats

    Directory of Open Access Journals (Sweden)

    Seyed Abdollah Hashemvarzi

    2016-03-01

    Full Text Available Abstract: Parkinson is a progressive neurodegenerative disease in central nervous system. Non-pharmacologic treatment methods such as stem cell transplantation and exercise have been considered as a treatment. The purpose of this study was to evaluate the synergistic effects of aerobic exercise after bone marrow stem cells transplantation on recovery of dopaminergic neurons and promotion of angiogenesis markers in the striatum of parkinsonian rats. 42 rats were divided into six groups: Normal (N, Sham (S, Parkinson’s (P, Stem cells transplanted Parkinson’s (SP, Exercised Parkinson’s (EP and Stem cells transplanted+Exercised Parkinson’s (SEP. To create a model of Parkinson's, the striatum was destroyed by injection of 6-hydroxy-dopamine into the striatum through stereotaxic apparatus. Stem cells were derived from the bone marrow of femur and tibia of male rats aged 6-8 weeks. After cultivation, approximately 5×105 cells were injected into the striatum of rats through the channel. Aerobic exercise was included 8 weeks of running on treadmill with a speed of 15 meters per minute. At the end of the study, all subjects were decapitated and striatum tissues were separately isolated for measurement of vascular endothelial growth factor (VEGF, dopamine (DA and tyrosine hydroxylase (TH levels. VEGF, DA and TH levels in the striatum of parkinsonian rats significantly increased in treatment groups (SP, EP and SEP, especially in SEP group compared to P group after treatment (P<0.05. The BMSCs transplantation in combination with exercise would have synergistic effects leading to functional recovery, dopaminergic neurons recovery and promotion of angiogenesis marker in the striatum of parkinsonian rats. Keywords: Stem cells, Aerobic exercise, Neurotrophic factors, Parkinson

  20. Enhanced sensitivity of muscarinic cholinergic receptor associated with dopaminergic receptor subsensitivity after chronic antidepressant treatment

    International Nuclear Information System (INIS)

    Koide, T.; Matsushita, H.

    1981-01-01

    The chronic effects of antidepressant treatment on striatal dopaminergic (DA) and muscarinic cholinergic (mACh) receptors of the rat brain have been examined comparatively in this study using 3 H-spiroperidol ( 3 H-SPD) and 3 H-quinuclidinyl benzilate ( 3 H-QNB) as the respective radioactive ligands. Imipramine and desipramine were used as prototype antidepressants. Although a single administration of imipramine or desipramine did not affect each receptor sensitivity, chronic treatment with each drug caused a supersensitivity of mACh receptor subsequent to DA receptor subsensitivity. Furthermore, it has been suggested that anti-mACh properties of imipramine or desipramine may not necessarily be related to the manifestation of mACh receptor supersensitivity and that sustained DA receptor subsensitivity may play some role in the alterations of mACh receptor sensitivity

  1. Delta-like 1 participates in the specification of ventral midbrain progenitor derived dopaminergic neurons

    DEFF Research Database (Denmark)

    Bauer, Matthias; Szulc, Jolanta; Meyer, Morten

    2008-01-01

    Delta-like 1 (Dlk1), a member of the Delta/Notch protein family, is expressed in the mouse ventral midbrain (VM) as early as embryonic day 11.5 (E11.5) followed by exclusive expression in tyrosine 3-monooxygenase (TH) positive neurons from E12.5 onwards. To further elucidate the yet unknown...... function of Dlk1 in VM neuron development, we investigated the effect of soluble Dlk1 protein as well as the intrinsic Dlk1 function in the course of VM progenitor expansion and dopaminergic (DA) neuron differentiation in vitro. Dlk1 treatment during expansion increased DA progenitor proliferation...... neuron markers, which was not accompanied with alteration of overall or local proliferation. Due to the latter finding in combination with the absence of Dlk1 negative DA neurons in differentiated cultures, we suggest that Dlk1 expression might have a permissive effect on DA neuron differentiation...

  2. Dopaminergic inputs in the dentate gyrus direct the choice of memory encoding

    International Nuclear Information System (INIS)

    Du, Huiyun; Deng, Wei; Aimone, James B.; Ge, Minyan; Parylak, Sarah

    2016-01-01

    Rewarding experiences are often well remembered, and such memory formation is known to be dependent on dopamine modulation of the neural substrates engaged in learning and memory; however, it is unknown how and where in the brain dopamine signals bias episodic memory toward preceding rather than subsequent events. Here we found that photostimulation of channelrhodopsin-2–expressing dopaminergic fibers in the dentate gyrus induced a long-term depression of cortical inputs, diminished theta oscillations, and impaired subsequent contextual learning. Computational modeling based on this dopamine modulation indicated an asymmetric association of events occurring before and after reward in memory tasks. In subsequent behavioral experiments, preexposure to a natural reward suppressed hippocampus-dependent memory formation, with an effective time window consistent with the duration of dopamine-induced changes of dentate activity. Altogether, our results suggest a mechanism by which dopamine enables the hippocampus to encode memory with reduced interference from subsequent experience.

  3. Reduced noradrenergic innervation of ventral midbrain dopaminergic cell groups and the subthalamic nucleus in MPTP-treated parkinsonian monkeys.

    Science.gov (United States)

    Masilamoni, Gunasingh Jeyaraj; Groover, Olivia; Smith, Yoland

    2017-04-01

    There is anatomical and functional evidence that ventral midbrain dopaminergic (DA) cell groups and the subthalamic nucleus (STN) receive noradrenergic innervation in rodents, but much less is known about these interactions in primates. Degeneration of NE neurons in the locus coeruleus (LC) and related brainstem NE cell groups is a well-established pathological feature of Parkinson's disease (PD), but the development of such pathology in animal models of PD has been inconsistent across species and laboratories. We recently demonstrated 30-40% neuronal loss in the LC, A5 and A6 NE cell groups of rhesus monkeys rendered parkinsonian by chronic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this study, we used dopamine-beta-hydroxylase (DβH) immunocytochemistry to assess the impact of this neuronal loss on the number of NE terminal-like varicosities in the substantia nigra pars compacta (SNC), ventral tegmental area (VTA), retrorubral field (RRF) and STN of MPTP-treated parkinsonian monkeys. Our findings reveal that the NE innervation of the ventral midbrain and STN of normal monkeys is heterogeneously distributed being far more extensive in the VTA, RRF and dorsal tier of the SNC than in the ventral SNC and STN. In parkinsonian monkeys, all regions underwent a significant (~50-70%) decrease in NE innervation. At the electron microscopic level, some DβH-positive terminals formed asymmetric axo-dendritic synapses in VTA and STN. These findings demonstrate that the VTA, RRF and SNCd are the main ventral midbrain targets of ascending NE inputs, and that these connections undergo a major break-down in chronically MPTP-treated parkinsonian monkeys. This severe degeneration of the ascending NE system may contribute to the pathophysiology of ventral midbrain and STN neurons in PD. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Correlations between polymorphisms in genes coding elements of dopaminergic pathways and body mass index in overweight and obese women.

    Science.gov (United States)

    Sikora, Marcin; Gese, Anna; Czypicki, Ryszard; Gąsior, Marcin; Tretyn, Andrzej; Chojnowski, Jacek; Bieliński, Maciej; Jaracz, Marcin; Kamińska, Anna; Junik, Roman; Borkowska, Alina

    2013-01-01

    Dopamine is considered to be crucial for food craving and intake, drug abuse and electrical brain stimulation. Increased levels of dopamine occur after energy intake in the dorsal striatum. In the ventral tagmental area, dopamine is responsible for motivation. There is a natural synaptic dopamine level, and as a result its activity is controlled by density of receptors, amount of released neurotransmitter, and defectiveness of re-uptake by specific transporters. In our study, we wanted to investigate if there is a correlation between mean BMI values and VNTR polymorphisms in SLC6A3 (rs28363170) and DRD4 genes. Chosen gene fragments were amplified using polymerase chain reaction on the DNA template obtained from 506 women. The products of the reaction were electrophoresed and visualised in 3% agarose gel. The genotyping data was analysed with Kruskal-Wallis tests (p 〈 0.05). In the case of SLC6A3, statistically significant differences in mean BMI were found in the group of obese women (p 〈 0.05) but not for the whole population of women with normal weight or with overweight (p 〉 0.05). The mean BMI was higher for the SS genotype than for combined LL and LS genotypes. The difference in mean BMI values for variants of DRD4 was significant for the whole studied population and in the obese group (p 〉 0.05), and the higher value was correlated with the presence of a variant with seven or more repeats of 48 bp motif. When the two analysed polymorphisms were combined, the spread between the mean BMI values became greater than for single genes. This suggests that the effect on body mass of these two polymorphisms may combine and cause hypo-functionality of the dopaminergic reward system.

  5. Neurophysiological evidence of impaired self-monitoring in schizotypal personality disorder and its reversal by dopaminergic antagonism.

    Science.gov (United States)

    Rabella, Mireia; Grasa, Eva; Corripio, Iluminada; Romero, Sergio; Mañanas, Miquel Àngel; Antonijoan, Rosa M; Münte, Thomas F; Pérez, Víctor; Riba, Jordi

    2016-01-01

    Schizotypal personality disorder (SPD) is a schizophrenia-spectrum disorder characterized by odd or bizarre behavior, strange speech, magical thinking, unusual perceptual experiences, and social anhedonia. Schizophrenia proper has been associated with anomalies in dopaminergic neurotransmission and deficits in neurophysiological markers of self-monitoring, such as low amplitude in cognitive event-related brain potentials (ERPs) like the error-related negativity (ERN), and the error positivity (Pe). These components occur after performance errors, rely on adequate fronto-striatal function, and are sensitive to dopaminergic modulation. Here we postulated that analogous to observations in schizophrenia, SPD individuals would show deficits in self-monitoring, as measured by the ERN and the Pe. We also assessed the capacity of dopaminergic antagonists to reverse these postulated deficits. We recorded the electroencephalogram (EEG) from 9 SPD individuals and 12 healthy controls in two separate experimental sessions while they performed the Eriksen Flanker Task, a classical task recruiting behavioral monitoring. Participants received a placebo or 1 mg risperidone according to a double-blind randomized design. After placebo, SPD individuals showed slower reaction times to hits, longer correction times following errors and reduced ERN and Pe amplitudes. While risperidone impaired performance and decreased ERN and Pe in the control group, it led to behavioral improvements and ERN amplitude increases in the SPD individuals. These results indicate that SPD individuals show deficits in self-monitoring analogous to those in schizophrenia. These deficits can be evidenced by neurophysiological measures, suggest a dopaminergic imbalance, and can be reverted by dopaminergic antagonists.

  6. Generational association studies of dopaminergic genes in reward deficiency syndrome (RDS) subjects: selecting appropriate phenotypes for reward dependence behaviors.

    Science.gov (United States)

    Blum, Kenneth; Chen, Amanda L C; Oscar-Berman, Marlene; Chen, Thomas J H; Lubar, Joel; White, Nancy; Lubar, Judith; Bowirrat, Abdalla; Braverman, Eric; Schoolfield, John; Waite, Roger L; Downs, Bernard W; Madigan, Margaret; Comings, David E; Davis, Caroline; Kerner, Mallory M; Knopf, Jennifer; Palomo, Tomas; Giordano, John J; Morse, Siobhan A; Fornari, Frank; Barh, Debmalya; Femino, John; Bailey, John A

    2011-12-01

    Abnormal behaviors involving dopaminergic gene polymorphisms often reflect an insufficiency of usual feelings of satisfaction, or Reward Deficiency Syndrome (RDS). RDS results from a dysfunction in the "brain reward cascade," a complex interaction among neurotransmitters (primarily dopaminergic and opioidergic). Individuals with a family history of alcoholism or other addictions may be born with a deficiency in the ability to produce or use these neurotransmitters. Exposure to prolonged periods of stress and alcohol or other substances also can lead to a corruption of the brain reward cascade function. We evaluated the potential association of four variants of dopaminergic candidate genes in RDS (dopamine D1 receptor gene [DRD1]; dopamine D2 receptor gene [DRD2]; dopamine transporter gene [DAT1]; dopamine beta-hydroxylase gene [DBH]). We genotyped an experimental group of 55 subjects derived from up to five generations of two independent multiple-affected families compared to rigorously screened control subjects (e.g., N = 30 super controls for DRD2 gene polymorphisms). Data related to RDS behaviors were collected on these subjects plus 13 deceased family members. Among the genotyped family members, the DRD2 Taq1 and the DAT1 10/10 alleles were significantly (at least p < 0.015) more often found in the RDS families vs. controls. The TaqA1 allele occurred in 100% of Family A individuals (N = 32) and 47.8% of Family B subjects (11 of 23). No significant differences were found between the experimental and control positive rates for the other variants. Although our sample size was limited, and linkage analysis is necessary, the results support the putative role of dopaminergic polymorphisms in RDS behaviors. This study shows the importance of a nonspecific RDS phenotype and informs an understanding of how evaluating single subset behaviors of RDS may lead to spurious results. Utilization of a nonspecific "reward" phenotype may be a paradigm shift in future association

  7. Autologous transplants of Adipose-Derived Adult Stromal (ADAS) cells afford dopaminergic neuroprotection in a model of Parkinson's disease.

    Science.gov (United States)

    McCoy, Melissa K; Martinez, Terina N; Ruhn, Kelly A; Wrage, Philip C; Keefer, Edward W; Botterman, Barry R; Tansey, Keith E; Tansey, Malú G

    2008-03-01

    Adult adipose contains stromal progenitor cells with neurogenic potential. However, the stability of neuronal phenotypes adopted by Adipose-Derived Adult Stromal (ADAS) cells and whether terminal neuronal differentiation is required for their consideration as alternatives in cell replacement strategies to treat neurological disorders is largely unknown. We investigated whether in vitro neural induction of ADAS cells determined their ability to neuroprotect or restore function in a lesioned dopaminergic pathway. In vitro-expanded naïve or differentiated ADAS cells were autologously transplanted into substantia nigra 1 week after an intrastriatal 6-hydroxydopamine injection. Neurochemical and behavioral measures demonstrated neuroprotective effects of both ADAS grafts against 6-hydroxydopamine-induced dopaminergic neuron death, suggesting that pre-transplantation differentiation of the cells does not determine their ability to survive or neuroprotect in vivo. Therefore, we investigated whether equivalent protection by naïve and neurally-induced ADAS grafts resulted from robust in situ differentiation of both graft types into dopaminergic fates. Immunohistological analyses revealed that ADAS cells did not adopt dopaminergic cell fates in situ, consistent with the limited ability of these cells to undergo terminal differentiation into electrically active neurons in vitro. Moreover, re-exposure of neurally-differentiated ADAS cells to serum-containing medium in vitro confirmed ADAS cell phenotypic instability (plasticity). Lastly, given that gene expression analyses of in vitro-expanded ADAS cells revealed that both naïve and differentiated ADAS cells express potent dopaminergic survival factors, ADAS transplants may have exerted neuroprotective effects by production of trophic factors at the lesion site. ADAS cells may be ideal for ex vivo gene transfer therapies in Parkinson's disease treatment.

  8. Glutamate receptor properties of human mesencephalic neural progenitor cells: NMDA enhances dopaminergic neurogenesis in vitro.

    Science.gov (United States)

    Wegner, Florian; Kraft, Robert; Busse, Kathy; Schaarschmidt, Grit; Härtig, Wolfgang; Schwarz, Sigrid C; Schwarz, Johannes

    2009-10-01

    Human midbrain-derived neural progenitor cells (NPCs) may serve as a continuous source of dopaminergic neurons for the development of novel regenerative therapies in Parkinson's disease. However, the molecular and functional characteristics of glutamate receptors in human NPCs are largely unknown. Here, we show that differentiated human mesencepahlic NPCs display a distinct pattern of glutamate receptors. In whole-cell patch-clamp recordings, l-glutamate and NMDA elicited currents in 93% of NPCs after 3 weeks of differentiation in vitro. The concentration-response plots of differentiated NPCs yielded an EC(50) of 2.2 microM for glutamate and an EC(50) of 36 microM for NMDA. Glutamate-induced currents were markedly inhibited by memantine in contrast to 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) suggesting a higher density of functional NMDA than alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainate receptors. NMDA-evoked currents and calcium signals were blocked by the NR2B-subunit specific antagonist ifenprodil indicating functional expression of NMDA receptors containing subunits NR1 and NR2B. In calcium imaging experiments, the blockade of voltage-gated calcium channels by verapamil abolished AMPA-induced calcium responses but only partially reduced NMDA-evoked transients suggesting the expression of calcium-impermeable, GluR2-containing AMPA receptors. Quantitative real-time PCR showed a predominant expression of subunits NR2A and NR2B (NMDA), GluR2 (AMPA), GluR7 (kainate), and mGluR3 (metabotropic glutamate receptor). Treatment of NPCs with 100 microM NMDA in vitro during proliferation (2 weeks) and differentiation (1 week) increased the amount of tyrosine hydroxylase-immunopositive cells significantly, which was reversed by addition of memantine. These data suggest that NMDA receptors in differentiating human mesencephalic NPCs are important regulators of dopaminergic neurogenesis in vitro.

  9. Mulberry fruit protects dopaminergic neurons in toxin-induced Parkinson's disease models.

    Science.gov (United States)

    Kim, Hyo Geun; Ju, Mi Sun; Shim, Jin Sup; Kim, Min Cheol; Lee, Sang-Hun; Huh, Youngbuhm; Kim, Sun Yeou; Oh, Myung Sook

    2010-07-01

    Parkinson's disease (PD), one of the most common neurodegenerative disorders, is characterised by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) to the striatum (ST), and involves oxidative stress. Mulberry fruit from Morus alba L. (Moraceae) is commonly eaten, and has long been used in traditional oriental medicine. It contains well-known antioxidant agents such as anthocyanins. The present study examined the protective effects of 70 % ethanol extract of mulberry fruit (ME) against neurotoxicity in in vitro and in vivo PD models. In SH-SY5Y cells stressed with 6-hydroxydopamine (6-OHDA), ME significantly protected the cells from neurotoxicity in a dose-dependent manner. Other assays demonstrated that the protective effect of ME was mediated by its antioxidant and anti-apoptotic effects, regulating reactive oxygen species and NO generation, Bcl-2 and Bax proteins, mitochondrial membrane depolarisation and caspase-3 activation. In mesencephalic primary cells stressed with 6-OHDA or 1-methyl-4-phenylpyridinium (MPP+), pre-treatment with ME also protected dopamine neurons, showing a wide range of effective concentrations in MPP+-induced toxicity. In the sub-acute mouse PD model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), ME showed a preventative effect against PD-like symptoms (bradykinesia) in the behavioural test and prevented MPTP-induced dopaminergic neuronal damage in an immunocytochemical analysis of the SNpc and ST. These results indicate that ME has neuroprotective effects in in vitro and in vivo PD models, and that it may be useful in preventing or treating PD.

  10. PINK1 is necessary for long term survival and mitochondrial function in human dopaminergic neurons.

    Directory of Open Access Journals (Sweden)

    Alison Wood-Kaczmar

    2008-06-01

    Full Text Available Parkinson's disease (PD is a common age-related neurodegenerative disease and it is critical to develop models which recapitulate the pathogenic process including the effect of the ageing process. Although the pathogenesis of sporadic PD is unknown, the identification of the mendelian genetic factor PINK1 has provided new mechanistic insights. In order to investigate the role of PINK1 in Parkinson's disease, we studied PINK1 loss of function in human and primary mouse neurons. Using RNAi, we created stable PINK1 knockdown in human dopaminergic neurons differentiated from foetal ventral mesencephalon stem cells, as well as in an immortalised human neuroblastoma cell line. We sought to validate our findings in primary neurons derived from a transgenic PINK1 knockout mouse. For the first time we demonstrate an age dependent neurodegenerative phenotype in human and mouse neurons. PINK1 deficiency leads to reduced long-term viability in human neurons, which die via the mitochondrial apoptosis pathway. Human neurons lacking PINK1 demonstrate features of marked oxidative stress with widespread mitochondrial dysfunction and abnormal mitochondrial morphology. We report that PINK1 plays a neuroprotective role in the mitochondria of mammalian neurons, especially against stress such as staurosporine. In addition we provide evidence that cellular compensatory mechanisms such as mitochondrial biogenesis and upregulation of lysosomal degradation pathways occur in PINK1 deficiency. The phenotypic effects of PINK1 loss-of-function described here in mammalian neurons provides mechanistic insight into the age-related degeneration of nigral dopaminergic neurons seen in PD.

  11. Enhancing dopaminergic signaling and histone acetylation promotes long-term rescue of deficient fear extinction

    Science.gov (United States)

    Whittle, N; Maurer, V; Murphy, C; Rainer, J; Bindreither, D; Hauschild, M; Scharinger, A; Oberhauser, M; Keil, T; Brehm, C; Valovka, T; Striessnig, J; Singewald, N

    2016-01-01

    Extinction-based exposure therapy is used to treat anxiety- and trauma-related disorders; however, there is the need to improve its limited efficacy in individuals with impaired fear extinction learning and to promote greater protection against return-of-fear phenomena. Here, using 129S1/SvImJ mice, which display impaired fear extinction acquisition and extinction consolidation, we revealed that persistent and context-independent rescue of deficient fear extinction in these mice was associated with enhanced expression of dopamine-related genes, such as dopamine D1 (Drd1a) and -D2 (Drd2) receptor genes in the medial prefrontal cortex (mPFC) and amygdala, but not hippocampus. Moreover, enhanced histone acetylation was observed in the promoter of the extinction-regulated Drd2 gene in the mPFC, revealing a potential gene-regulatory mechanism. Although enhancing histone acetylation, via administering the histone deacetylase (HDAC) inhibitor MS-275, does not induce fear reduction during extinction training, it promoted enduring and context-independent rescue of deficient fear extinction consolidation/retrieval once extinction learning was initiated as shown following a mild conditioning protocol. This was associated with enhanced histone acetylation in neurons of the mPFC and amygdala. Finally, as a proof-of-principle, mimicking enhanced dopaminergic signaling by L-dopa treatment rescued deficient fear extinction and co-administration of MS-275 rendered this effect enduring and context-independent. In summary, current data reveal that combining dopaminergic and epigenetic mechanisms is a promising strategy to improve exposure-based behavior therapy in extinction-impaired individuals by initiating the formation of an enduring and context-independent fear-inhibitory memory. PMID:27922638

  12. Methamphetamine-induced dopaminergic toxicity prevented owing to the neuroprotective effects of salicylic acid.

    Science.gov (United States)

    Thrash-Williams, Bessy; Karuppagounder, Senthilkumar S; Bhattacharya, Dwipayan; Ahuja, Manuj; Suppiramaniam, Vishnu; Dhanasekaran, Muralikrishnan

    2016-06-01

    Methamphetamine (Schedule-II drug, U.S. Drug Enforcement Administration) is one of the most abused illicit drug following cocaine, marijuana, and heroin in the USA. There are numerous health impairments and substantial economic burden caused by methamphetamine abuse. Salicylic acid, potent anti-inflammatory drug and a known neuroprotectant has shown to protect against toxicity-induced by other dopaminergic neurotoxins. Hence, in this study we investigated the neuroprotective effects of salicylic acid against methamphetamine-induced toxicity in mice. The current study investigated the effects of sodium salicylate and/or methamphetamine on oxidative stress, monoamine oxidase, mitochondrial complex I & IV activities using spectrophotometric and fluorimetric methods. Behavioral analysis evaluated the effect on movement disorders-induced by methamphetamine. Monoaminergic neurotransmitter levels were evaluated using high pressure liquid chromatography-electrochemical detection. Methamphetamine caused significant generation of reactive oxygen species and decreased complex-I activity leading to dopamine depletion. Striatal dopamine depletion led to significant behavioral changes associated with movement disorders. Sodium salicylate (50 & 100mg/kg) significantly scavenged reactive oxygen species, blocked mitochondrial dysfunction and exhibited neuroprotection against methamphetamine-induced neurotoxicity. In addition, sodium salicylate significantly blocked methamphetamine-induced behavioral changes related to movement abnormalities. One of the leading causative theories in nigral degeneration associated with movement disorders such as Parkinson's disease is exposure to stimulants, drugs of abuse, insecticide and pesticides. These neurotoxic substances can induce dopaminergic neuronal insult by oxidative stress, apoptosis, mitochondrial dysfunction and inflammation. Salicylic acid due to its antioxidant and anti-inflammatory effects could provide neuroprotection against the

  13. A neural population model incorporating dopaminergic neurotransmission during complex voluntary behaviors.

    Directory of Open Access Journals (Sweden)

    Stefan Fürtinger

    2014-11-01

    Full Text Available Assessing brain activity during complex voluntary motor behaviors that require the recruitment of multiple neural sites is a field of active research. Our current knowledge is primarily based on human brain imaging studies that have clear limitations in terms of temporal and spatial resolution. We developed a physiologically informed non-linear multi-compartment stochastic neural model to simulate functional brain activity coupled with neurotransmitter release during complex voluntary behavior, such as speech production. Due to its state-dependent modulation of neural firing, dopaminergic neurotransmission plays a key role in the organization of functional brain circuits controlling speech and language and thus has been incorporated in our neural population model. A rigorous mathematical proof establishing existence and uniqueness of solutions to the proposed model as well as a computationally efficient strategy to numerically approximate these solutions are presented. Simulated brain activity during the resting state and sentence production was analyzed using functional network connectivity, and graph theoretical techniques were employed to highlight differences between the two conditions. We demonstrate that our model successfully reproduces characteristic changes seen in empirical data between the resting state and speech production, and dopaminergic neurotransmission evokes pronounced changes in modeled functional connectivity by acting on the underlying biological stochastic neural model. Specifically, model and data networks in both speech and rest conditions share task-specific network features: both the simulated and empirical functional connectivity networks show an increase in nodal influence and segregation in speech over the resting state. These commonalities confirm that dopamine is a key neuromodulator of the functional connectome of speech control. Based on reproducible characteristic aspects of empirical data, we suggest a number

  14. Distribution of GABAergic interneurons and dopaminergic cells in the functional territories of the human striatum.

    Science.gov (United States)

    Bernácer, Javier; Prensa, Lucía; Giménez-Amaya, José Manuel

    2012-01-01

    The afferent projections of the striatum (caudate nucleus and putamen) are segregated in three territories: associative, sensorimotor and limbic. Striatal interneurons are in part responsible for the integration of these different types of information. Among them, GABAergic interneurons are the most abundant, and can be sorted in three populations according to their content in the calcium binding proteins calretinin (CR), parvalbumin (PV) and calbindin (CB). Conversely, striatal dopaminergic cells (whose role as interneurons is still unclear) are scarce. This study aims to analyze the interneuron distribution in the striatal functional territories, as well as their organization regarding to the striosomal compartment. We used immunohistochemical methods to visualize CR, PV, CB and tyrosine hydroxylase (TH) positive striatal neurons. The interneuronal distribution was assessed by stereological methods applied to every striatal functional territory. Considering the four cell groups altogether, their density was higher in the associative (2120±91 cells/mm(3)) than in the sensorimotor (959±47 cells/mm(3)) or limbic (633±119 cells/mm(3)) territories. CB- and TH-immunoreactive(-ir) cells were distributed rather homogeneously in the three striatal territories. However, the density of CR and PV interneurons were more abundant in the associative and sensorimotor striatum, respectively. Regarding to their compartmental organization, CR-ir interneurons were frequently found in the border between compartments in the associative and sensorimotor territories, and CB-ir interneurons abounded at the striosome/matrix border in the sensorimotor domain. The present study demonstrates that the architecture of the human striatum in terms of its interneuron composition varies in its three functional territories. Furthermore, our data highlight the importance of CR-ir striatal interneurons in the integration of associative information, and the selective role of PV-ir interneurons in

  15. Dopaminergic Neurodegeneration in the Mouse Is Associated with Decrease of Viscoelasticity of Substantia Nigra Tissue.

    Directory of Open Access Journals (Sweden)

    Elisabeth G Hain

    Full Text Available The biomechanical properties of brain tissue are altered by histopathological changes due to neurodegenerative diseases like Parkinson's disease (PD. Such alterations can be measured by magnetic resonance elastography (MRE as a non-invasive technique to determine viscoelastic parameters of the brain. Until now, the correlation between histopathological mechanisms and observed alterations in tissue viscoelasticity in neurodegenerative diseases is still not completely understood. Thus, the objective of this study was to evaluate (1 the validity of MRE to detect viscoelastic changes in small and specific brain regions: the substantia nigra (SN, midbrain and hippocampus in a mouse model of PD, and (2 if the induced dopaminergic neurodegeneration and inflammation in the SN is reflected by local changes in viscoelasticity. Therefore, MRE measurements of the SN, midbrain and hippocampus were performed in adult female mice before and at five time points after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin hydrochloride (MPTP treatment specifically lesioning dopaminergic neurons in the SN. At each time point, additional mice were utilized for histological analysis of the SN. After treatment cessation, we observed opposed viscoelastic changes in the midbrain, hippocampus and SN with the midbrain showing a gradual rise and the hippocampus a distinct transient increase of viscous and elastic parameters, while viscosity and-to a lesser extent-elasticity in the SN decreased over time. The decrease in viscosity and elasticity in the SN was paralleled by a reduced number of neurons due to the MPTP-induced neurodegeneration. In conclusion, MRE is highly sensitive to detect local viscoelastic changes in specific and even small brain regions. Moreover, we confirmed that neuronal cells likely constitute the backbone of the adult brain mainly accounting for its viscoelasticity. Therefore, MRE could be established as a new potential instrument for clinical evaluation

  16. Dopaminergic Neurodegeneration in the Mouse Is Associated with Decrease of Viscoelasticity of Substantia Nigra Tissue.

    Science.gov (United States)

    Hain, Elisabeth G; Klein, Charlotte; Munder, Tonia; Braun, Juergen; Riek, Kerstin; Mueller, Susanne; Sack, Ingolf; Steiner, Barbara

    2016-01-01

    The biomechanical properties of brain tissue are altered by histopathological changes due to neurodegenerative diseases like Parkinson's disease (PD). Such alterations can be measured by magnetic resonance elastography (MRE) as a non-invasive technique to determine viscoelastic parameters of the brain. Until now, the correlation between histopathological mechanisms and observed alterations in tissue viscoelasticity in neurodegenerative diseases is still not completely understood. Thus, the objective of this study was to evaluate (1) the validity of MRE to detect viscoelastic changes in small and specific brain regions: the substantia nigra (SN), midbrain and hippocampus in a mouse model of PD, and (2) if the induced dopaminergic neurodegeneration and inflammation in the SN is reflected by local changes in viscoelasticity. Therefore, MRE measurements of the SN, midbrain and hippocampus were performed in adult female mice before and at five time points after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin hydrochloride (MPTP) treatment specifically lesioning dopaminergic neurons in the SN. At each time point, additional mice were utilized for histological analysis of the SN. After treatment cessation, we observed opposed viscoelastic changes in the midbrain, hippocampus and SN with the midbrain showing a gradual rise and the hippocampus a distinct transient increase of viscous and elastic parameters, while viscosity and-to a lesser extent-elasticity in the SN decreased over time. The decrease in viscosity and elasticity in the SN was paralleled by a reduced number of neurons due to the MPTP-induced neurodegeneration. In conclusion, MRE is highly sensitive to detect local viscoelastic changes in specific and even small brain regions. Moreover, we confirmed that neuronal cells likely constitute the backbone of the adult brain mainly accounting for its viscoelasticity. Therefore, MRE could be established as a new potential instrument for clinical evaluation and diagnostics

  17. Adolescent externalizing behaviour, psychological control, and peer rejection: Transactional links and dopaminergic moderation.

    Science.gov (United States)

    Janssens, Annelies; Van Den Noortgate, Wim; Goossens, Luc; Verschueren, Karine; Colpin, Hilde; Claes, Stephan; Van Heel, Martijn; Van Leeuwen, Karla

    2017-09-01

    This study investigated (1) reciprocal links among parental psychological control, peer rejection, and adolescent externalizing (aggressive and rule-breaking behaviour), and (2) the moderating effect of an adolescent genetic factor (biologically informed polygenic score for dopamine signalling). Three-year longitudinal data from 1,116 adolescents (51% boys; M age = 13.79) and their parents included psychological measures (adolescent-reported psychological control, peer-reported rejection, and parent-reported aggressive and rule-breaking behaviour). Cross-lagged analyses showed bidirectional effects between psychological control and both aggressive and rule-breaking behaviour and a unidirectional effect of peer rejection on both forms of problem behaviour over time. Multigroup structural equation modelling revealed genetic moderation only for rule-breaking behaviour: for adolescents with intermediate levels of dopamine signalling significant environmental effects were present, whereas adolescent effects of rule-breaking behaviour on psychological control were significant for adolescents with both intermediate and high profiles and effects on peer rejection only for adolescents with high dopamine profiles. Statement of contribution What is already known on this subject? Parental psychological control is related to adolescent externalizing problems. Experiencing peer rejection reinforces aggressive and rule-breaking behaviour. Single-gene studies show that dopaminergic genes influence externalizing problems directly or in interaction with the environment. What does this study add? Parental psychological control and adolescent aggressive and rule-breaking behaviour exacerbate one another longitudinally. Longitudinal associations between peer rejection and both subtypes of externalizing behaviour are unidirectional. With a polygenic approach, dopaminergic moderation is present for rule-breaking behaviour only. © 2017 The British Psychological Society.

  18. Neurobiology of KB220Z-Glutaminergic-Dopaminergic Optimization Complex [GDOC] as a Liquid Nano: Clinical Activation of Brain in a Highly Functional Clinician Improving Focus, Motivation and Overall Sensory Input Following Chronic Intake.

    Science.gov (United States)

    Duquette, Lucien L; Mattiace, Frank; Blum, Kenneth; Waite, Roger L; Boland, Teresa; McLaughlin, Thomas; Dushaj, Kristina; Febo, Marcelo; Badgaiyan, Rajendra D

    2016-01-01

    With neurogenetic and epigenetic tools utilized in research and neuroimaging, we are unraveling the mysteries of brain function, especially as it relates to Reward Deficiency (RDS). We encourage the development of pharmaceuticals or nutraceuticals that promote a reduction in dopamine resistance and balance brain neurochemistry, leading to dopamine homeostasis. We disclose self-assessment of a highly functional professional under work-related stress following KB220Z use, a liquid (aqua) nano glutaminergic-dopaminergic optimization complex (GDOC). Subject took GDOC for one month. Subject self-administered GDOC using one-half-ounce twice a day. During first three days, unique brain activation occurred; resembling white noise after 30 minutes and sensation was strong for 45 minutes and then dissipated. He described effect as if his eyesight improved slightly and pointed out that his sense of smell and sleep greatly improved. Subject experienced a calming effect similar to meditation that could be linked to dopamine release. He also reported control of going over the edge after a hard day's work, which was coupled with a slight increase in energy, increased motivation to work, increased focus and multi-tasking, with clearer purpose of task at hand. Subject felt less inhibited in a social setting and suggested Syndrome that GDOC increased his Behavior Activating System (reward), while having a decrease in the Behavior Inhibition System (caution). These results and other related studies reveal an improved mood, work-related focus, and sleep. These effects as a subjective feeling of brain activation maybe due to direct or indirect dopaminergic interaction. While this case is encouraging, we must await more research in a larger randomized placebo-controlled study to map the role of GDOC, especially in a nano-sized product, to determine the possible effects on circuit inhibitory control and memory banks and the induction of dopamine homeostasis independent of either hypo- or

  19. Expansion and characterization of ventral mesencephalic precursor cells: effect of mitogens and investigation of FA1 as a potential dopaminergic marker

    DEFF Research Database (Denmark)

    Jensen, Pia; Bauer, Matthias; Jensen, Charlotte H

    2007-01-01

    Methods for identification and in vitro expansion of ventral mesencephalic dopaminergic precursor cells are of interest in the search for transplantable neurons for cell therapy in Parkinson's disease (PD). We investigated the potential use of fibroblast growth factor 2 (FGF2) and fibroblast growth...... factor 8 (FGF8) for expansion of such dopaminergic precursor cells, and fetal antigen-1 (FA1), a secreted neuronal protein of unknown function, as a non-invasive dopaminergic marker. Tissue from embryonic day (ED) 12 rat ventral mesencephalon was dissociated mechanically and cultured for 4 days...

  20. Transient inactivation of the ventral hippocampus in neonatal rats impairs the mesolimbic regulation of prefrontal glutamate release in adulthood

    DEFF Research Database (Denmark)

    Bortz, D M; Jørgensen, Christinna Vangsgaard; Mikkelsen, J D

    2014-01-01

    Cognitive deficits in schizophrenia (SZ) reflect maturational disruptions within a neural system that includes the ventral hippocampus (VH), nucleus accumbens (NAc), basal forebrain, and prefrontal cortex (PFC). A better understanding of these changes may reveal drug targets for more efficacious...... male Wistar rats that had received saline (Sal) or tetrodotoxin (TTX) as neonates (PD7) or as adolescents (PD32). The nucleus accumbens shell (NAcSh) was activated by NMDA infusions (0.05-0.30 μg/0.5 μL). Basal and evoked glutamate levels were measured amperometrically using a glutamate...

  1. Correlating behaviour and gene expression endpoints in the dopaminergic system after modafinil administration in mouse.

    Science.gov (United States)

    De Ron, P; Dremier, S; Winlow, P; Jenkins, A; Hanon, E; Nogueira da Costa, A

    2016-04-01

    The mechanisms of action of modafinil continue to be poorly characterised and its potential for abuse in preclinical models remains controverted. The aim of this study was to further elucidate the mechanism of action of modafinil, through a potential behavioural and molecular association in the mouse. A conditioned place preference (CPP) paradigm was implemented to investigate the rewarding properties of modafinil. Whole genome expression and qRT-PCR analysis were performed on the ventral tegmental area (VTA), nucleus accumbens (NAC) and prefrontal cortex (PFC) of modafinil-treated and control animals. Modafinil administration (65 mg/kg) induced an increase in locomotor activity, an increase in the change of preference for the drug paired side after a conditioning period as well as changes to gene expression profiles in the VTA (120 genes), NAC (23 genes) and PFC (19 genes). A molecular signature consisting of twelve up-regulated genes was identified as common to the three brain regions. Multiple linear correlation analysis showed a strong correlation (R(2)>0.70) between the behavioural and molecular endpoints in the three brain regions. We show that modafinil had a concomitant effect on CPP, locomotor activity, and up-regulation of interferon-γ (IFN-γ) regulated genes (Gbp2, Gbp3, Gbp10, Cd274, Igtp), while correlating the latter set of genes with behaviour changes evaluated through the CPP. A potential association can be proposed based on the dysregulation of p47 family genes and Gbp family of IFN-γ induced GTPases. In conclusion, these findings suggest a link between the behavioural and molecular events in the context of modafinil administration. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

  2. Gnaz couples the circadian and dopaminergic system to G protein-mediated signaling in mouse photoreceptors.

    Directory of Open Access Journals (Sweden)

    Patrick Vancura

    Full Text Available The mammalian retina harbors a circadian clockwork that regulates vision and promotes healthiness of retinal neurons, mainly through directing the rhythmic release of the neurohormones dopamine-acting on dopamine D4 receptors-and melatonin-acting on MT1 and MT2 receptors. The gene Gnaz-a unique Gi/o subfamily member-was seen in the present study to be expressed in photoreceptors where its protein product Gαz shows a daily rhythm in its subcellular localization. Apart from subcellular localization, Gnaz displays a daily rhythm in expression-with peak values at night-in preparations of the whole retina, microdissected photoreceptors and photoreceptor-related pinealocytes. In retina, Gnaz rhythmicity was observed to persist under constant darkness and to be abolished in retina deficient for Clock or dopamine D4 receptors. Furthermore, circadian regulation of Gnaz was disturbed in the db/db mouse, a model of diabetic retinopathy. The data of the present study suggest that Gnaz links the circadian clockwork-via dopamine acting on D4 receptors-to G protein-mediated signaling in intact but not diabetic retina.

  3. Brain SPECT with Perfusion Radiopharmaceuticals and Dopaminergic System Radiocompounds in Dementia Disorders.

    Science.gov (United States)

    Nuvoli, Susanna; Spanu, Angela; Madeddu, Giuseppe

    2017-01-01

    As well known, the increase in life expectancy and the better physical condition of people in western countries will lead in the next 20 years to a dramatic development of neurodegenerative diseases, especially of dementia that could be considered one of the most important problems in clinical, social and economic fields for the future. Therefore, the differential diagnosis of the various types of dementia is a critical step for patients, clinicians and researchers since an accurate "in vivo" diagnosis can lead to a better patients management. Neuroimaging techniques and in particular the most diffuse and affordable single photon emission computed tomography (SPECT) have provided useful information about dementia disorders and these methods, on the basis of the recent advances, will have an increasingly important role in research and clinical practice. The purpose of this article is to analyze the different SPECT techniques now available which proved clinically useful in correctly formulating the differential diagnosis of dementia.

  4. Drugs Targeting the Dopaminergic Nervous System Alter Locomotion in Larval Zebrafish

    Science.gov (United States)

    As part of an effort at the US Environmental Protection Agency to develop a rapid in vivo screen for prioritization of toxic chemicals, we have begun to characterize the locomotor activity of zebrafish (Danio rerio) larvae. This includes assessing the acute effects of drugs that ...

  5. Glucose Metabolism and AMPK Signaling Regulate Dopaminergic Cell Death Induced by Gene (α-Synuclein)-Environment (Paraquat) Interactions.

    Science.gov (United States)

    Anandhan, Annadurai; Lei, Shulei; Levytskyy, Roman; Pappa, Aglaia; Panayiotidis, Mihalis I; Cerny, Ronald L; Khalimonchuk, Oleh; Powers, Robert; Franco, Rodrigo

    2017-07-01

    While environmental exposures are not the single cause of Parkinson's disease (PD), their interaction with genetic alterations is thought to contribute to neuronal dopaminergic degeneration. However, the mechanisms involved in dopaminergic cell death induced by gene-environment interactions remain unclear. In this work, we have revealed for the first time the role of central carbon metabolism and metabolic dysfunction in dopaminergic cell death induced by the paraquat (PQ)-α-synuclein interaction. The toxicity of PQ in dopaminergic N27 cells was significantly reduced by glucose deprivation, inhibition of hexokinase with 2-deoxy-D-glucose (2-DG), or equimolar substitution of glucose with galactose, which evidenced the contribution of glucose metabolism to PQ-induced cell death. PQ also stimulated an increase in glucose uptake, and in the levels of glucose transporter type 4 (GLUT4) and Na + -glucose transporters isoform 1 (SGLT1) proteins, but only inhibition of GLUT-like transport with STF-31 or ascorbic acid reduced PQ-induced cell death. Importantly, while autophagy protein 5 (ATG5)/unc-51 like autophagy activating kinase 1 (ULK1)-dependent autophagy protected against PQ toxicity, the inhibitory effect of glucose deprivation on cell death progression was largely independent of autophagy or mammalian target of rapamycin (mTOR) signaling. PQ selectively induced metabolomic alterations and adenosine monophosphate-activated protein kinase (AMPK) activation in the midbrain and striatum of mice chronically treated with PQ. Inhibition of AMPK signaling led to metabolic dysfunction and an enhanced sensitivity of dopaminergic cells to PQ. In addition, activation of AMPK by PQ was prevented by inhibition of the inducible nitric oxide syntase (iNOS) with 1400W, but PQ had no effect on iNOS levels. Overexpression of wild type or A53T mutant α-synuclein stimulated glucose accumulation and PQ toxicity, and this toxic synergism was reduced by inhibition of glucose metabolism

  6. The role of age in association analyses of ADHD and related neurocognitive functioning: A proof of concept for dopaminergic and serotonergic genes.

    NARCIS (Netherlands)

    Thissen, A.J.A.M.; Bralten, J.; Rommelse, N.N.J.; Arias Vazquez, A.; Greven, C.U.; Heslenfeld, D.J.; Luman, M.; Oosterlaan, J.; Hoekstra, P.J.; Hartman, C.A.; Franke, B.; Buitelaar, J.K.

    2015-01-01

    Elucidating genetic mechanisms involved in Attention-Deficit/Hyperactivity Disorder (ADHD) has been challenging. Relatively unexplored is the fact that genetic mechanisms can differ with age. The current study explored the association between dopaminergic and serotonergic genes, ADHD symptoms, and

  7. The role of age in association analyses of ADHD and related neurocognitive functioning : A proof of concept for dopaminergic and serotonergic genes

    NARCIS (Netherlands)

    Thissen, Andrieke J. A. M.; Bralten, Janita; Rommelse, Nanda N. J.; Arias-Vasquez, Alejandro; Greven, Corina U.; Heslenfeld, Dirk; Luman, Marjolein; Oosterlaan, Jaap; Hoekstra, Pieter J.; Hartman, Catharina; Franke, Barbara; Buitelaar, Jan K.

    Elucidating genetic mechanisms involved in Attention-Deficit/Hyperactivity Disorder (ADHD) has been challenging. Relatively unexplored is the fact that genetic mechanisms can differ with age. The current study explored the association between dopaminergic and serotonergic genes, ADHD symptoms, and

  8. Autopsy validation of 123I-FP-CIT dopaminergic neuroimaging for the diagnosis of DLB.

    Science.gov (United States)

    Thomas, Alan J; Attems, Johannes; Colloby, Sean J; O'Brien, John T; McKeith, Ian; Walker, Rodney; Lee, Lean; Burn, David; Lett, Debra J; Walker, Zuzana

    2017-01-17

    To conduct a validation study of 123 I-N-fluoropropyl-2b-carbomethoxy-3b-(4-iodophenyl) nortropane ( 123 I-FP-CIT) SPECT dopaminergic imaging in the clinical diagnosis of dementia with Lewy bodies (DLB) with autopsy as the gold standard. Patients >60 years of age with dementia who had undergone 123 I-FP-CIT imaging in research studies and who had donated their brain tissue to the Newcastle Brain Tissue Resource were included. All had structured clinical research assessments, and clinical diagnoses were applied by consensus panels using international diagnostic criteria. All underwent 123 I-FP-CIT imaging at baseline, and scans were rated as normal or abnormal by blinded raters. Patients were reviewed in prospective studies and after death underwent detailed autopsy assessment, and neuropathologic diagnoses were applied with the use of standard international criteria. Fifty-five patients (33 with DLB and 22 with Alzheimer disease) were included. Against autopsy diagnosis, 123 I-FP-CIT had a balanced diagnostic accuracy of 86% (sensitivity 80%, specificity 92%) compared with clinical diagnosis, which had an accuracy of 79% (sensitivity 87%, specificity 72%). Among patients with DLB, 10% (3 patients) met pathologic criteria for Lewy body disease but had normal 123 I-FP-CIT imaging. This large autopsy analysis of 123 I-FP-CIT imaging in dementia demonstrates that it is a valid and accurate biomarker for DLB, and the high specificity compared with clinical diagnosis (20% higher) is clinically important. The results need to be replicated with patients recruited from a wider range of settings, including movement disorder clinics and general practice. While an abnormal 123 I-FP-CIT scan strongly supports Lewy body disease, a normal scan does not exclude DLB with minimal brainstem involvement. This study provides Class I evidence that 123 I-FP-CIT dopaminergic neuroimaging accurately identifies patients with DLB. Copyright © 2016 The Author(s). Published by Wolters Kluwer

  9. Enhanced proliferation and dopaminergic differentiation of ventral mesencephalic precursor cells by synergistic effect of FGF2 and reduced oxygen tension

    DEFF Research Database (Denmark)

    Jensen, Pia; Gramsbergen, Jan-Bert; Zimmer, Jens

    2011-01-01

    Effective numerical expansion of dopaminergic precursors might overcome the limited availability of transplantable cells in replacement strategies for Parkinson's disease. Here we investigated the effect of fibroblast growth factor-2 (FGF2) and FGF8 on expansion and dopaminergic differentiation...... of rat embryonic ventral mesencephalic neuroblasts cultured at high (20%) and low (3%) oxygen tension. More cells incorporated bromodeoxyuridine in cultures expanded at low as compared to high oxygen tension, and after 6 days of differentiation there were significantly more neuronal cells in low than......, switching FGF2-expanded cultures from low to high oxygen tension during the last two days of differentiation significantly enhanced dopamine release and intracellular dopamine levels as compared to all other treatment groups. In addition, the short-term exposure to high oxygen enhanced in situ assessed TH...

  10. Midbrain expression of Delta-like 1 homologue is regulated by GDNF and is associated with dopaminergic differentiation

    DEFF Research Database (Denmark)

    Christophersen, Nicolai S.; Gronborg, Mette; Petersen, Thomas Nordahl

    2007-01-01

    upregulation with increased positive staining of cell bodies in the SNc and fibers in the striatum. Analysis of the developmental regulation of Dlk1 in the murine ventral midbrain showed that the upregulation of Dlk1 mRNA correlated with the generation of tyrosine hydroxylase (TH)-positive neurons. Furthermore......Affymetrix GeneChip technology and quantitative real-time PCR (Q-PCR) were used to examine changes in gene expression in the adult murine substantia nigra pars compacta (SNc) following lentiviral glial cell line-derived neurotrophic factor (GDNF) delivery in adult striatum. We identified several......, Dlk1 expression was analyzed in MesC2.10 cells, which are derived from embryonic human mesencephalon and capable of undergoing differentiation into dopaminergic neurons. We detected upregulation of Dlk1 mRNA and protein under conditions where MesC2.10 cells differentiate into a dopaminergic phenotype...

  11. Genetic Moderation of Intervention Efficacy: Dopaminergic Genes, The Incredible Years, and Externalizing Behavior in Children.

    Science.gov (United States)

    Chhangur, Rabia R; Weeland, Joyce; Overbeek, Geertjan; Matthys, Walter; Orobio de Castro, Bram; van der Giessen, Danielle; Belsky, Jay

    2017-05-01

    This study investigated whether children scoring higher on a polygenic plasticity index based on five dopaminergic genes (DRD4, DRD2, DAT1, MAOA, and COMT) benefited the most from the Incredible Years (IY) parent program. Data were used from a randomized controlled trial including 341 Dutch families with 4- to 8-year-old children (55.7% boys) showing moderate to high levels of problem behavior. IY proved to be most effective in decreasing parent-reported (but not observed) externalizing behavior in boys (but not girls) carrying more rather than fewer dopaminergic plasticity alleles; this Gene × Intervention effect was most pronounced in the case of boys whose parents' manifested the most positive change in parenting in response to the intervention. These results proved robust across a variety of sampling specifications (e.g., intention to treat, ethnicity). © 2016 The Authors. Child Development © 2016 Society for Research in Child Development, Inc.

  12. Evidence for a modulatory effect of sulbutiamine on glutamatergic and dopaminergic cortical transmissions in the rat brain.

    Science.gov (United States)

    Trovero, F; Gobbi, M; Weil-Fuggaza, J; Besson, M J; Brochet, D; Pirot, S

    2000-09-29

    Chronic treatment of rats by sulbutiamine induced no change in density of N-methyl-D-aspartate (NMDA) and (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors in the cingular cortex, but a significant decrease of the kainate binding sites, as measured by quantitative autoradiography. In the same treated animals, an increase of D1 dopaminergic (DA) binding sites was measured both in the prefrontal and the cingular cortex, while no modification of the D2 binding sites was detected. Furthermore, an acute sulbutiamine administration induced a decrease of kainate binding sites but no change of the density of D1 and D2 DA receptors. Acute sulbutiamine injection led to a decrease of the DA levels in the prefrontal cortex and 3,4-dihydroxyphenylacetic acid levels in both the cingular and the prefrontal cortex. These observations are discussed in terms of a modulatory effect of sulbutiamine on both dopaminergic and glutamatergic cortical transmissions.

  13. Generation of reactive oxygen species in 1-methyl-4-phenylpyridinium (MPP+) treated dopaminergic neurons occurs as an NADPH oxidase-dependent two-wave cascade

    OpenAIRE

    Das Mita; Rachubinski Angela L; Cantu David; Marriott Beth; Thornton Jennifer; Banninger Gregg P; Zawada W Michael; Griffin W Sue T; Jones Susan M

    2011-01-01

    Abstract Background Reactive oxygen species (ROS), superoxide and hydrogen peroxide (H2O2), are necessary for appropriate responses to immune challenges. In the brain, excess superoxide production predicts neuronal cell loss, suggesting that Parkinson's disease (PD) with its wholesale death of dopaminergic neurons in substantia nigra pars compacta (nigra) may be a case in point. Although microglial NADPH oxidase-produced superoxide contributes to dopaminergic neuron death in an MPTP mouse mod...

  14. Ganoderma Lucidum polysaccharides protect against MPP(+) and rotenone-induced apoptosis in primary dopaminergic cell cultures through inhibiting oxidative stress.

    Science.gov (United States)

    Guo, Shan-Shan; Cui, Xiao-Lan; Rausch, Wolf-Dieter

    2016-01-01

    Oxidative stress plays a pivotal role in the progressive neurodegeneration in Parkinson's disease (PD) which is responsible for disabling motor abnormalities in more than 6.5 million people worldwide. Polysaccharides are the main active constituents from Ganoderma lucidum which is characterized with anti-oxidant, antitumor and immunostimulant properties. In the present study, primary dopaminergic cell cultures prepared from embryonic mouse mesencephala were used to investigate the neuroprotective effects and the potential mechanisms of Ganoderma lucidum polysaccharides (GLP) on the degeneration of dopaminergic neurons induced by the neurotoxins methyl-4-phenylpyridine (MPP(+)) and rotenone. Results revealed that GLP can protect dopamine neurons against MPP(+) and rotenone at the concentrations of 100, 50 and 25 μg/ml in primary mesencephalic cultures in a dose-dependent manner. Interestingly, either with or without neurotoxin treatment, GLP treatment elevated the survival of THir neurons, and increased the length of neurites of dopaminergic neurons. The Trolox equivalent anti-oxidant capacity (TEAC) of GLP was determined to be 199.53 μmol Trolox/g extract, and the decrease of mitochondrial complex I activity induced by MPP(+) and rotenone was elevated by GLP treatment (100, 50, 25 and 12.5 μg/ml) in a dose dependent manner. Furthermore, GLP dramatically decreased the relative number of apoptotic cells and increased the declining mitochondrial membrane potential (ΔΨm) induced by MPP(+) and rotenone in a dose-dependent manner. In addition, GLP treatment reduced the ROS formation induced by MPP(+) and rotenone at the concentrations of 100, 50 and 25 μg/ml in a dose-dependent manner. Our study indicates that GLP possesses neuroprotective properties against MPP(+) and rotenone neurotoxicity through suppressing oxidative stress in primary mesencephalic dopaminergic cell culture owning to its antioxidant activities.

  15. Docosahexaenoic acid prevents paraquat-induced reactive oxygen species production in dopaminergic neurons via enhancement of glutathione homeostasis

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Hyoung Jun; Han, Jeongsu; Jang, Yunseon; Kim, Soo Jeong; Park, Ji Hoon; Seo, Kang Sik [Department of Biochemistry, College of Medicine, Chungnam National University, Daejeon (Korea, Republic of); Jeong, Soyeon; Shin, Soyeon; Lim, Kyu [Department of Biochemistry, College of Medicine, Chungnam National University, Daejeon (Korea, Republic of); Infection Signaling Network Research Center, Chungnam National University, Daejeon (Korea, Republic of); Heo, Jun Young, E-mail: junyoung3@gmail.com [Brainscience Institute, Chungnam National University, Daejeon (Korea, Republic of); Kweon, Gi Ryang, E-mail: mitochondria@cnu.ac.kr [Department of Biochemistry, College of Medicine, Chungnam National University, Daejeon (Korea, Republic of); Infection Signaling Network Research Center, Chungnam National University, Daejeon (Korea, Republic of)

    2015-01-30

    Highlights: • DHA prevents PQ-induced dopaminergic neuronal loss via decreasing of excessive ROS. • DHA increases GR and GCLm derivate GSH pool by enhancement of Nrf2 expression. • Protective mechanism is removal of PQ-induced ROS via DHA-dependent GSH pool. • DHA may be a good preventive strategy for Parkinson’s disease (PD) therapy. - Abstract: Omega-3 polyunsaturated fatty acid levels are reduced in the substantia nigra area in Parkinson’s disease patients and animal models, implicating docosahexaenoic acid (DHA) as a potential treatment for preventing Parkinson’s disease and suggesting the need for investigations into how DHA might protect against neurotoxin-induced dopaminergic neuron loss. The herbicide paraquat (PQ) induces dopaminergic neuron loss through the excessive production of reactive oxygen species (ROS). We found that treatment of dopaminergic SN4741 cells with PQ reduced cell viability in a dose-dependent manner, but pretreatment with DHA ameliorated the toxic effect of PQ. To determine the toxic mechanism of PQ, we measured intracellular ROS content in different organelles with specific dyes. As expected, all types of ROS were increased by PQ treatment, but DHA pretreatment selectively decreased cytosolic hydrogen peroxide content. Furthermore, DHA treatment-induced increases in glutathione reductase and glutamate cysteine ligase modifier subunit (GCLm) mRNA expression were positively correlated with glutathione (GSH) content. Consistent with this increase in GCLm mRNA levels, Western blot analysis revealed that DHA pretreatment increased nuclear factor-erythroid 2 related factor 2 (Nrf2) protein levels. These findings indicate that DHA prevents PQ-induced neuronal cell loss by enhancing Nrf2-regulated GSH homeostasis.

  16. Docosahexaenoic acid prevents paraquat-induced reactive oxygen species production in dopaminergic neurons via enhancement of glutathione homeostasis

    International Nuclear Information System (INIS)

    Lee, Hyoung Jun; Han, Jeongsu; Jang, Yunseon; Kim, Soo Jeong; Park, Ji Hoon; Seo, Kang Sik; Jeong, Soyeon; Shin, Soyeon; Lim, Kyu; Heo, Jun Young; Kweon, Gi Ryang

    2015-01-01

    Highlights: • DHA prevents PQ-induced dopaminergic neuronal loss via decreasing of excessive ROS. • DHA increases GR and GCLm derivate GSH pool by enhancement of Nrf2 expression. • Protective mechanism is removal of PQ-induced ROS via DHA-dependent GSH pool. • DHA may be a good preventive strategy for Parkinson’s disease (PD) therapy. - Abstract: Omega-3 polyunsaturated fatty acid levels are reduced in the substantia nigra area in Parkinson’s disease patients and animal models, implicating docosahexaenoic acid (DHA) as a potential treatment for preventing Parkinson’s disease and suggesting the need for investigations into how DHA might protect against neurotoxin-induced dopaminergic neuron loss. The herbicide paraquat (PQ) induces dopaminergic neuron loss through the excessive production of reactive oxygen species (ROS). We found that treatment of dopaminergic SN4741 cells with PQ reduced cell viability in a dose-dependent manner, but pretreatment with DHA ameliorated the toxic effect of PQ. To determine the toxic mechanism of PQ, we measured intracellular ROS content in different organelles with specific dyes. As expected, all types of ROS were increased by PQ treatment, but DHA pretreatment selectively decreased cytosolic hydrogen peroxide content. Furthermore, DHA treatment-induced increases in glutathione reductase and glutamate cysteine ligase modifier subunit (GCLm) mRNA expression were positively correlated with glutathione (GSH) content. Consistent with this increase in GCLm mRNA levels, Western blot analysis revealed that DHA pretreatment increased nuclear factor-erythroid 2 related factor 2 (Nrf2) protein levels. These findings indicate that DHA prevents PQ-induced neuronal cell loss by enhancing Nrf2-regulated GSH homeostasis

  17. Neurophysiological evidence of impaired self-monitoring in schizotypal personality disorder and its reversal by dopaminergic antagonism

    OpenAIRE

    Mireia Rabella; Eva Grasa; Iluminada Corripio; Sergio Romero; Miquel Àngel Mañanas; Rosa Mª. Antonijoan; Thomas F. Münte; Víctor Pérez; Jordi Riba

    2016-01-01

    BACKGROUND: Schizotypal personality disorder (SPD) is a schizophrenia-spectrum disorder characterized by odd or bizarre behavior, strange speech, magical thinking, unusual perceptual experiences, and social anhedonia. Schizophrenia proper has been associated with anomalies in dopaminergic neurotransmission and deficits in neurophysiological markers of self-monitoring, such as low amplitude in cognitive event-related brain potentials (ERPs) like the error-related negativity (ERN), and the erro...

  18. Depressive-like phenotype induced by AAV-mediated overexpression of human α-synuclein in midbrain dopaminergic neurons.

    Science.gov (United States)

    Caudal, D; Alvarsson, A; Björklund, A; Svenningsson, P

    2015-11-01

    Parkinson's disease (PD) is a neurodegenerative disorder characterized by a progressive loss of nigral dopaminergic neurons and by the presence of aggregates containing α-synuclein called Lewy bodies. Viral vector-induced overexpression of α-synuclein in dopaminergic neurons represents a model of PD which recapitulates disease progression better than commonly used neurotoxin models. Previous studies using this model have reported motor and cognitive impairments, whereas depression, mood and anxiety phenotypes are less described. To investigate these psychiatric phenotypes, Sprague-Dawley rats received bilateral injections of a recombinant adeno-associated virus (AAV) vector expressing human α-synuclein or GFP into the substantia nigra pars compacta. Behavior was assessed at two timepoints: 3 and 8 weeks post-injection. We report that nigral α-synuclein overexpression led to a pronounced nigral dopaminergic cell loss accompanied by a smaller cell loss in the ventral tegmental area, and to a decreased striatal density of dopaminergic fibers. The AAV-α-synuclein group exhibited modest, but significant motor impairments 8 weeks after vector administration. The AAV-α-synuclein group displayed depressive-like behavior in the forced swim test after 3 weeks, and reduced sucrose preference at week 8. At both timepoints, overexpression of α-synuclein was linked to a hyperactive hypothalamic-pituitary-adrenal (HPA) axis regulation of corticosterone. The depressive-like phenotype was also correlated with decreased nigral brain-derived neurotrophic factor and spinophilin levels, and with decreased striatal levels of the activity-regulated cytoskeleton-associated protein. This study demonstrates that AAV-mediated α-synuclein overexpression in dopamine neurons is not only useful to model motor impairments of PD, but also depression. This study also provides evidence that depression in experimental Parkinsonism is correlated to dysregulation of the HPA axis and to

  19. Sociosexual Investigation in Sexually Experienced, Hormonally Manipulated Male Leopard Geckos: Relation With Phosphorylated DARPP-32 in Dopaminergic Pathways

    OpenAIRE

    HUANG, VICTORIA; HEMMINGS, HUGH C.; CREWS, DAVID

    2014-01-01

    Dopaminergic activity is both associated with sociosexual exposure and modulated by sexual experience and hormonal state across vertebrate taxa. Mature leopard geckos, a reptile with temperature-dependent sex determination, have dopaminoceptive nuclei that are influenced by their embryonic environment and sensitive to adult hormonal manipulation. In this study, we exposed hormonally manipulated male leopard geckos from different incubation temperatures to conspecifics and measured their socio...

  20. Abnormal differentiation of dopaminergic neurons in zebrafish trpm7 mutant larvae i