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Sample records for mesocorticolimbic dopamine system

  1. Autoradiographic localization of mu and delta opioid receptors in the mesocorticolimbic dopamine system

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    Dilts, R.P. Jr.

    1989-01-01

    In vitro autoradiographic techniques were coupled with selective chemical lesions of the A10 dopamine cells and intrinsic perikarya of the region to delineate the anatomical localization of mu and delta opioid receptors, as well as, neurotensin receptors. Mu opioid receptors were labeled with {sup 125}I-DAGO. Delta receptors were labeled with {sup 125}I-DPDPE. Neurotensin receptors were labeled with {sup 125}I-NT3. Unilateral lesions of the dopamine perikarya were produced by injections of 6-OHDA administered in the ventral mesencephalon. Unilateral lesions of intrinsic perikarya were induced by injections of quinolinic acid in to the A10 dopamine cell region. Unilateral lesions produced with 6-OHDA resulted in the loss of neurotensin receptors in the A10 region and within the terminal fields. Mu opioid receptors were unaffected by this treatment, but delta opioid receptors increased in the contralateral striatum and nucleus accumbens following 6-OHDA administration. Quinolinic acid produced a reduction of mu opioid receptors within the A10 region with a concomitant reduction in neurotensin receptors in both the cell body region and terminal fields. These results are consistent with a variety of biochemical and behavioral data which suggest the indirect modulation of dopamine transmission by the opioids. In contrast these results strongly indicate a direct modulation of the mesolimbic dopamine system by neurotensin.

  2. Autoradiographic localization of delta opioid receptors within the mesocorticolimbic dopamine system using radioiodinated (2-D-penicillamine, 5-D-penicillamine)enkephalin ( sup 125 I-DPDPE)

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    Dilts, R.P.; Kalivas, P.W. (Washington State Univ., Pullman (USA))

    1990-01-01

    The enkephalin analog (2-D-penicillamine, 5-D-penicillamine)enkephalin was radioiodinated (125I-DPDPE) and shown to retain a pharmacological selectivity characteristic of the delta opioid receptor in in vitro binding studies. The distributions of 125I-DPDPE binding, using in vitro autoradiographic techniques, were similar to those previously reported for the delta opioid receptor. The nucleus accumbens, striatum, and medial prefrontal cortex contain dense gradients of 125I-DPDPE binding in regions known to receive dopaminergic afferents emanating from the mesencephalic tegmentum. Selective chemical lesions of the ventral tegmental area and substantia nigra were employed to deduce the location of the 125I-DPDPE binding within particular regions of the mesocorticolimbic dopamine system. Unilateral lesions of dopamine perikarya (A9 and A10) within the ventral tegmental area and substantia nigra produced by mesencephalic injection of 6-hydroxydopamine resulted in significant (20-30%) increases in 125I-DPDPE binding contralateral to the lesion within the striatum and nucleus accumbens. Lesions of the perikarya (dopaminergic and nondopaminergic) of the ventral tegmental area, induced by quinolinic acid injections, caused increases of less magnitude within these same nuclei. No significant alterations in 125I-DPDPE binding were observed within the mesencephalon as a result of either treatment. The specificity of the lesions was confirmed by immunocytochemistry for tyrosine hydroxylase. These results suggest that the enkephalins and opioid agonists acting through delta opioid receptors do not directly modulate dopaminergic afferents but do regulate postsynaptic targets of the mesocorticolimbic dopamine system.

  3. Glutamatergic synaptic plasticity in the mesocorticolimbic system in addiction.

    NARCIS (Netherlands)

    van Huijstee, A.N.; Mansvelder, H.D.

    2015-01-01

    Addictive drugs remodel the brain’s reward circuitry, the mesocorticolimbic dopamine (DA) system, by inducing widespread adaptations of glutamatergic synapses. This drug-induced synaptic plasticity is thought to contribute to both the development and the persistence of addiction. This review

  4. Glutamatergic synaptic plasticity in the mesocorticolimbic system in addiction

    Science.gov (United States)

    van Huijstee, Aile N.; Mansvelder, Huibert D.

    2015-01-01

    Addictive drugs remodel the brain’s reward circuitry, the mesocorticolimbic dopamine (DA) system, by inducing widespread adaptations of glutamatergic synapses. This drug-induced synaptic plasticity is thought to contribute to both the development and the persistence of addiction. This review highlights the synaptic modifications that are induced by in vivo exposure to addictive drugs and describes how these drug-induced synaptic changes may contribute to the different components of addictive behavior, such as compulsive drug use despite negative consequences and relapse. Initially, exposure to an addictive drug induces synaptic changes in the ventral tegmental area (VTA). This drug-induced synaptic potentiation in the VTA subsequently triggers synaptic changes in downstream areas of the mesocorticolimbic system, such as the nucleus accumbens (NAc) and the prefrontal cortex (PFC), with further drug exposure. These glutamatergic synaptic alterations are then thought to mediate many of the behavioral symptoms that characterize addiction. The later stages of glutamatergic synaptic plasticity in the NAc and in particular in the PFC play a role in maintaining addiction and drive relapse to drug-taking induced by drug-associated cues. Remodeling of PFC glutamatergic circuits can persist into adulthood, causing a lasting vulnerability to relapse. We will discuss how these neurobiological changes produced by drugs of abuse may provide novel targets for potential treatment strategies for addiction. PMID:25653591

  5. Effects of Methylphenidate on Resting-State Functional Connectivity of the Mesocorticolimbic Dopamine Pathways in Cocaine Addiction

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    Konova, Anna B.; Moeller, Scott J.; Tomasi, Dardo; Volkow, Nora D.; Goldstein, Rita Z.

    2013-08-01

    Cocaine addiction is associated with altered resting-state functional connectivity among regions of the mesocorticolimbic dopamine pathways. Methylphenidate hydrochloride, an indirect dopamine agonist, normalizes task-related regional brain activity and associated behavior in cocaine users; however, the neural systems–level effects of methylphenidate in this population have not yet been described. To use resting-state functional magnetic resonance imaging to examine changes in mesocorticolimbic connectivity with methylphenidate and how connectivity of affected pathways relates to severity of cocaine addiction.

  6. Site-specific activation of dopamine and serotonin transmission by aniracetam in the mesocorticolimbic pathway of rats.

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    Nakamura, K; Shirane, M; Koshikawa, N

    2001-04-06

    The effects of aniracetam on extracellular levels of dopamine (DA), serotonin (5-HT) and their metabolites were examined in five brain regions in freely moving stroke-prone spontaneously hypertensive rats (SHRSP) using in vivo microdialysis. Basal DA release in SHRSP was uniformly lower in all regions tested than that in age-matched control Wistar Kyoto rats. 3,4-Dihydroxyphenylacetic acid and homovanillic acid levels were altered in the basolateral amygdala, dorsal hippocampus and prefrontal cortex of SHRSP. While basal 5-HT release decreased in the striatum and increased in the basolateral amygdala, there was no associated change in 5-hydroxyindoleacetic acid levels. Systemic administration of aniracetam to SHRSP enhanced both DA and 5-HT release with partly associated change in their metabolite levels in the prefrontal cortex, basolateral amygdala and dorsal hippocampus, but not in the striatum and nucleus accumbens shell, in a dose-dependent manner (30 and/or 100 mg/kg p.o.). Microinjection (1 and 10 ng) of aniracetam or its metabolites (N-anisoyl-GABA and 2-pyrrolidinone) into the nucleus accumbens shell produced no turning behavior. These findings indicate that SHRSP have a dopaminergic hypofunction throughout the brain and that aniracetam elicits a site-specific activation in mesocorticolimbic dopaminergic and serotonergic pathways in SHRSP, possibly via nicotinic acetylcholine receptors in the ventral tegmental area and raphe nuclei. The physiological roles in the aniracetam-sensitive brain regions may closely link with their clinical efficacy towards emotional disturbances appearing after cerebral infarction.

  7. Cocaine activates Homer1 immediate early gene transcription in the mesocorticolimbic circuit: differential regulation by dopamine and glutamate signaling.

    Science.gov (United States)

    Ghasemzadeh, M Behnam; Windham, Lindsay K; Lake, Russell W; Acker, Christopher J; Kalivas, Peter W

    2009-01-01

    Homer proteins are intracellular scaffolding proteins that, among glutamate receptors, selectively bind to group1 metabotropic glutamate receptors and regulate their trafficking and intracellular signaling. Homer proteins have been implicated in synaptic and behavioral plasticity, including drug-seeking behavior after cocaine treatment. Homer1 gene activation leads to transcription of a variant mRNA (Homer1a), which functions as an immediate early gene. Homer1a competes with the constitutive Homer proteins (Homer1b/c/d, Homer2a/b, Homer3) for binding to group1 metabotropic glutamate and IP3 receptors. Binding of Homer1a to these proteins disrupts their association with the intracellular signaling scaffold and modulates receptor function. In this study, using RT-PCR, activation of Homer1a mRNA transcription in response to acute and repeated administration of cocaine was characterized in prefrontal cortex, nucleus accumbens, and ventral tegmental area, three mesocorticolimbic nuclei of the rat brain. Moreover, the dopaminergic and glutamatergic regulation of Homer1 gene activation by cocaine was investigated. Acute cocaine rapidly and transiently activated transcription of Homer1a mRNA in all three nuclei. However, repeated administration of cocaine was not effective in inducing the Homer1a mRNA transcription after various withdrawal times ranging from 2 h to 3 weeks. The acute cocaine-mediated activation of Homer1 gene was regulated by D1 but not D2 dopamine receptors. The blockade of AMPA or NMDA glutamate receptors did not prevent cocaine-mediated activation of Homer1 gene in the three mesocorticolimbic nuclei. These data indicate that acute administration of cocaine transiently activates Homer1 gene producing the immediate early gene Homer1a mRNA in the three mesocorticolimbic nuclei of the rat brain. Activation of Homer1 gene may contribute to the cocaine-mediated synaptic and behavioral plasticity.

  8. Chronic nicotine-induced changes in gene expression of delta and kappa-opioid receptors and their endogenous ligands in the mesocorticolimbic system of the rat.

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    Ugur, Muzeyyen; Kaya, Egemen; Gozen, Oguz; Koylu, Ersin O; Kanit, Lutfiye; Keser, Aysegul; Balkan, Burcu

    2017-09-01

    Delta and kappa opioid receptors (DOR and KOR, respectively) and their endogenous ligands, proenkephalin (PENK) and prodynorphin (PDYN)-derived opioid peptides are proposed as important mediators of nicotine reward. This study investigated the regulatory effect of chronic nicotine treatment on the gene expression of DOR, KOR, PENK and PDYN in the mesocorticolimbic system. Three groups of rats were injected subcutaneously with nicotine at doses of 0.2, 0.4, or 0.6 mg/kg/day for 6 days. Rats were decapitated 1 hr after the last dose on day six, as this timing coincides with increased dopamine release in the mesocorticolimbic system. mRNA levels in the ventral tegmental area (VTA), lateral hypothalamic area (LHA), amygdala (AMG), dorsal striatum (DST), nucleus accumbens, and medial prefrontal cortex were measured by quantitative real-time PCR. Our results showed that nicotine upregulated DOR mRNA in the VTA at all of the doses employed, in the AMG at the 0.4 and 0.6 mg/kg doses, and in the DST at the 0.4 mg/kg dose. Conversely, PDYN mRNA was reduced in the LHA with 0.6 mg/kg nicotine and in the AMG with 0.4 mg/kg nicotine. KOR mRNA was also decreased in the DST with 0.6 mg/kg nicotine. Nicotine did not regulate PENK mRNA in any brain region studied. © 2017 Wiley Periodicals, Inc.

  9. 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

  10. Gene expression of pro-opiomelanocortin and melanocortin receptors is regulated in the hypothalamus and mesocorticolimbic system following nicotine administration.

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    Tapinc, Damla E; Ilgin, Rabia; Kaya, Egemen; Gozen, Oguz; Ugur, Muzeyyen; Koylu, Ersin O; Kanit, Lutfiye; Keser, Aysegul; Balkan, Burcu

    2017-01-10

    Pro-opiomelanocortin (POMC)-derived peptides and their receptors have been shown to play important roles in natural and drug-induced reward and reinforcement. Reward process may involve the regulation of POMC gene expression and the gene expression of POMC-derived peptide receptors. The present study investigated the alterations observed in the transcript levels of POMC, melanocortin 3 (MC3R), melanocortin 4 (MC4R) and mu-opioid receptors (MOR) in the hypothalamus and mesocorticolimbic system during nicotine exposure. Rats were injected subcutaneously for 5days with one of the three doses (0.2, 0.4 or 0.6mg/kg/day, free base) of nicotine and were decapitated one hour after a challenge dose on the sixth day. mRNA levels of POMC in the hypothalamus, MC3R in the ventral tegmental area (VTA), MC4R and MOR in the medial prefrontal cortex (mPFC), nucleus accumbens, dorsal striatum, amygdala, lateral hypothalamic area and VTA were measured by quantitative real-time PCR. Our results showed that treatment with 0.6mg/kg/day nicotine upregulated POMC mRNA in the hypothalamus and MC4R mRNA in the mPFC. Additionally, all three nicotine doses increased MC3R mRNA expression in the VTA. On the other hand, none of the nicotine doses altered MOR mRNA levels in the mesocorticolimbic system and associated limbic structures. These results suggest that nicotine may enhance melanocortin signaling in the mesocorticolimbic system and this alteration may be an important mechanism mediating nicotine reward. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  11. Dopamine

    International Nuclear Information System (INIS)

    Walters, L.

    1983-01-01

    Dopamine is an important neurotransmittor in the central nervous system. The physiological function of the peripheral dopamine receptors is unknown, but they are of therapeutic importance as dopamine is used to improve renal blood flow in shocked patients. There are 4 dopamine receptors. The classification of these dopamine receptors has been made possible by research with radiopharmaceuticals. Dopamine sensitive adenylate cyclase is an inherent part of the dopamine-1-receptor. Dopamine-1-receptors are stimulated by micromolar (physiological) concentrations of dopamine and inhibited by micromolar (supratherapeutic) concentrations of the antipsychotic drugs. The vascular effect of dopamine is mediated through the dopamine-1-receptors. Dopamine-2-receptors are responsible for the effect of dopamine at the mesolimbic, nigrostriatal and chemoreceptortrigger areas. It is activated by micromolar concentrations of dopamine and blocked by nanomolar (therapeutic) concentrations of the anti-psychotic drugs. Dopamine-3-receptors are activated by nanomolar concentrations of dopamine and inhibited by micromolar concentrations of the antipsychotic drugs. They occur on presynaptic nerve terminals and have a negative feedback effect on the liberation of dopamine, noradrenaline and serotonin. The dopamine-4-receptors are activated by nanomolar concentrations of dopamine. These are the only dopamine receptors that could be responsible for effects in the hypophysis as only nanomolar concentrations of dopamine occur there. These receptors are blocked by nanomolar concentrations of the antipsychotic drugs

  12. Mesocorticolimbic monoamine correlates of methamphetamine sensitization and motivation

    Directory of Open Access Journals (Sweden)

    Kevin D Lominac

    2014-05-01

    Full Text Available Methamphetamine (MA is a highly addictive psychomotor stimulant, with life-time prevalence rates of abuse ranging from 5-10% world-wide. Yet, a paucity of research exists regarding MA addiction vulnerability/resiliency and neurobiological mediators of the transition to addiction that might occur upon repeated low-dose MA exposure, more characteristic of early drug use. As stimulant-elicited neuroplasticity within dopamine neurons innervating the nucleus accumbens (NAC and prefrontal cortex (PFC is theorized as central for addiction-related behavioral anomalies, we used a multi-disciplinary research approach in mice to examine the interactions between sub-toxic MA dosing, motivation for MA and mesocorticolimbic monoamines. Biochemical studies of C57BL/6J (B6 mice revealed short- (1 day, as well as longer-term (21 days, changes in extracellular dopamine, DAT and/or D2 receptors during withdrawal from 10, once daily, 2 mg/kg MA injections. Follow-up biochemical studies conducted in mice selectively bred for high versus low MA drinking (respectively, MAHDR vs. MALDR mice, provided novel support for anomalies in mesocorticolimbic dopamine as a correlate of genetic vulnerability to high MA intake. Finally, neuropharmacological targeting of NAC dopamine in MA-treated B6 mice demonstrated a bi-directional regulation of MA-induced place-conditioning. These results extend extant literature for MA neurotoxicity by demonstrating that even subchronic exposure to relatively low MA doses are sufficient to elicit relatively long-lasting changes in mesocorticolimbic dopamine and that drug-induced or idiopathic anomalies in mesocorticolimbic dopamine may underpin vulnerability/resiliency to MA addiction.

  13. Association analysis between polymorphisms in the conserved dopamine neurotrophic factor (CDNF) gene and cocaine dependence

    OpenAIRE

    Lohoff, Falk W.; Bloch, Paul J.; Ferraro, Thomas N.; Berrettini, Wade H.; Pettinati, Helen M.; Dackis, Charles A.; O’Brien, Charles P.; Kampman, Kyle M.; Oslin, David W.

    2009-01-01

    Cocaine induced neuroplasticity changes in the mesocorticolimbic dopamine systems are thought to be involved in the pathophysiology of cocaine dependence. Since neurotrophic factors have been observed to prevent/reverse and mimic cocaine-induced neurobiological changes in the brain, related genes are plausible candidates for susceptibility to cocaine dependence. The novel conserved dopamine neurotrophic factor protein (CDNF) promotes the survival, growth, and function of dopamine-specific neu...

  14. A novel approach to map induced activation of neuronal networks using chemogenetics and functional neuroimaging in rats: A proof-of-concept study on the mesocorticolimbic system.

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    Roelofs, Theresia J M; Verharen, Jeroen P H; van Tilborg, Geralda A F; Boekhoudt, Linde; van der Toorn, Annette; de Jong, Johannes W; Luijendijk, Mieneke C M; Otte, Willem M; Adan, Roger A H; Dijkhuizen, Rick M

    2017-08-01

    Linking neural circuit activation at whole-brain level to neuronal activity at cellular level remains one of the major challenges in neuroscience research. We set up a novel functional neuroimaging approach to map global effects of locally induced activation of specific midbrain projection neurons using chemogenetics (Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-technology) combined with pharmacological magnetic resonance imaging (phMRI) in the rat mesocorticolimbic system. Chemogenetic activation of DREADD-targeted mesolimbic or mesocortical pathways, i.e. projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAcc) or medial prefrontal cortex (mPFC), respectively, induced significant blood oxygenation level-dependent (BOLD) responses in areas with DREADD expression, but also in remote defined neural circuitry without DREADD expression. The time-course of brain activation corresponded with the behavioral output measure, i.e. locomotor (hyper)activity, in the mesolimbic pathway-targeted group. Chemogenetic activation specifically increased neuronal activity, whereas functional connectivity assessed with resting state functional MRI (rs-fMRI) remained stable. Positive and negative BOLD responses distinctively reflected simultaneous ventral pallidum activation and substantia nigra pars reticulata deactivation, respectively, demonstrating the concept of mesocorticolimbic network activity with concurrent activation of the direct and indirect pathways following stimulation of specific midbrain projection neurons. The presented methodology provides straightforward and widely applicable opportunities to elucidate relationships between local neuronal activity and global network activity in a controllable manner, which will increase our understanding of the functioning and dysfunctioning of large-scale neuronal networks in health and disease. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Computational systems analysis of dopamine metabolism.

    Directory of Open Access Journals (Sweden)

    Zhen Qi

    2008-06-01

    Full Text Available A prominent feature of Parkinson's disease (PD is the loss of dopamine in the striatum, and many therapeutic interventions for the disease are aimed at restoring dopamine signaling. Dopamine signaling includes the synthesis, storage, release, and recycling of dopamine in the presynaptic terminal and activation of pre- and post-synaptic receptors and various downstream signaling cascades. As an aid that might facilitate our understanding of dopamine dynamics in the pathogenesis and treatment in PD, we have begun to merge currently available information and expert knowledge regarding presynaptic dopamine homeostasis into a computational model, following the guidelines of biochemical systems theory. After subjecting our model to mathematical diagnosis and analysis, we made direct comparisons between model predictions and experimental observations and found that the model exhibited a high degree of predictive capacity with respect to genetic and pharmacological changes in gene expression or function. Our results suggest potential approaches to restoring the dopamine imbalance and the associated generation of oxidative stress. While the proposed model of dopamine metabolism is preliminary, future extensions and refinements may eventually serve as an in silico platform for prescreening potential therapeutics, identifying immediate side effects, screening for biomarkers, and assessing the impact of risk factors of the disease.

  16. Altered mesocorticolimbic functional connectivity in psychotic disorder: an analysis of proxy genetic and environmental effects

    NARCIS (Netherlands)

    Peeters, S. C. T.; Gronenschild, E. H. B. M.; van de Ven, V.; Habets, P.; Goebel, R.; van Os, J.; Marcelis, M.; Kahn, Rene; Linszen, Don; van Os, Jim; Wiersma, Durk; Bruggeman, Richard; Cahn, Wiepke; de Haan, Lieuwe; Krabbendam, Lydia; Myin-Germeys, Inez

    2015-01-01

    Altered dopaminergic neurotransmission in the mesocorticolimbic (MCL) system may mediate psychotic symptoms. In addition, pharmacological dopaminergic manipulation may coincide with altered functional connectivity (fc) 'in rest'. We set out to test whether MCL-fc is conditional on (familial risk

  17. PET evaluation of the dopamine system of the human brain.

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    Volkow, N D; Fowler, J S; Gatley, S J; Logan, J; Wang, G J; Ding, Y S; Dewey, S

    1996-07-01

    Dopamine plays a pivotal role in the regulation and control of movement, motivation and cognition. It also is closely linked to reward, reinforcement and addiction. Abnormalities in brain dopamine are associated with many neurological and psychiatric disorders including Parkinson's disease, schizophrenia and substance abuse. This close association between dopamine and neurological and psychiatric diseases and with substance abuse make it an important topic in research in the neurosciences and an important molecular target in drug development. PET enables the direct measurement of components of the dopamine system in the living human brain. It relies on radiotracers which label dopamine receptors, dopamine transporters, precursors of dopamine or compounds which have specificity for the enzymes which degrade dopamine. Additionally, by using tracers that provide information on regional brain metabolism or blood flow as well as neurochemically specific pharmacological interventions, PET can be used to assess the functional consequences of changes in brain dopamine activity. PET dopamine measurements have been used to investigate the normal human brain and its involvement in psychiatric and neurological diseases. It has also been used in psychopharmacological research to investigate dopamine drugs used in the treatment of Parkinson's disease and of schizophrenia as well as to investigate the effects of drugs of abuse on the dopamine system. Since various functional and neurological parameters can be studied in the same subject, PET enables investigation of the functional integrity of the dopamine system in the human brain and investigation of the interactions of dopamine with other neurotransmitters. Through the parallel development of new radiotracers, kinetic models and better instruments, PET technology is enabling investigation of increasingly more complex aspects of the human brain dopamine system. This paper summarizes the different tracers and experimental

  18. A Brain on a Roller Coaster: Can the Dopamine Reward System Act as a Protagonist to Subdue the Ups and Downs of Bipolar Disorder?

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    Arjmand, Shokouh; Behzadi, Mina; Stephens, Gary J; Ezzatabadipour, Sara; Seifaddini, Rostam; Arjmand, Shahrad; Shabani, Mohammad

    2017-06-01

    One of the most interesting but tenebrous parts of the bipolar disorder (BD) story is the switch between (hypo)mania and depression, which can give bipolar patients a thrilling, but somewhat perilous, 'ride'. Numerous studies have pointed out that there are some recognizable differences (either state-dependent or state-independent) in several brain regions of people with BD, including components of the brain's reward system. Understanding the underpinning mechanisms of high and low mood statuses in BD has potential, not only for the development of highly specific and selective pharmaceutical agents, but also for better treatment approaches and psychological interventions to manage BD and, thus, give patients a safer ride. Herein, we review evidence that supports involvement of the reward system in the pathophysiology of mood swings, with the main focus on the mesocorticolimbic dopaminergic neural circuitry. Principally using findings from neuroimaging studies, we aim to signpost readers as to how mood alterations may affect different areas of the reward system and how antipsychotic drugs can influence the activity of these brain areas. Finally, we critically evaluate the hypothesis that the mesocorticolimbic dopamine reward system may act as a functional rheostat for different mood states.

  19. Social and neural determinants of aggressive behavior: pharmacotherapeutic targets at serotonin, dopamine and gamma-aminobutyric acid systems.

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    Miczek, Klaus A; Fish, Eric W; De Bold, Joseph F; De Almeida, Rosa M M

    2002-10-01

    Aggressive outbursts that result in harm and injury present a major problem for the public health and criminal justice systems, but there are no adequate treatment options. Obstacles at the level of social policy, institutional regulation, and scientific strategy in developing animal models continue to impede the development of specific anti-aggressive agents for emergency and long-term treatments. To be more relevant to the clinical situation, preclinical aggression research has begun to focus on the neurobiological determinants of escalated aggressive behavior that exceeds species-typical patterns. It is the goal of this review to examine novel pharmacological and molecular tools that target the neural mechanisms for different kinds of aggressive behavior more selectively than previously possible and to outline potential pharmacotherapeutic options. (1) The preclinical focus on the behavioral characteristics and determinants of intense aggression promises to be most relevant to the clinical distinction between the proposed impulsive-reactive-hostile-affective subtypes of human aggression and the controlled-proactive-instrumental-predatory subtypes of aggression. The neural circuits for many types of human and animal aggression critically involve serotonin, dopamine and gamma-aminobutyric acid (GABA) and specific receptor subtypes. (2) The dynamic changes in frontal cortical serotonin that are triggered by engaging in aggressive behavior imply that serotonergic drug effects are largely determined by the functional state of the receptors at the time of drug treatment. Of the numerous 5-HT receptors currently identified, the 5-HT(1B) receptors offer a promising target for reducing impulsive aggressive behavior, particularly if the action can be limited to sites in the central nervous system. (3) Aggressive confrontations are salient stressors, both for the aggressor as well as the victim of aggression, that are accompanied by activation of the mesocorticolimbic but

  20. The effects of Δ9-tetrahydrocannabinol on the dopamine system.

    Science.gov (United States)

    Bloomfield, Michael A P; Ashok, Abhishekh H; Volkow, Nora D; Howes, Oliver D

    2016-11-17

    The effects of Δ 9 -tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, are a pressing concern for global mental health. Patterns of cannabis use are changing drastically owing to legalization, the availability of synthetic analogues (commonly termed spice), cannavaping and an emphasis on the purported therapeutic effects of cannabis. Many of the reinforcing effects of THC are mediated by the dopamine system. Owing to the complexity of the cannabinoid-dopamine interactions that take place, there is conflicting evidence from human and animal studies concerning the effects of THC on the dopamine system. Acute THC administration causes increased dopamine release and neuron activity, whereas long-term use is associated with blunting of the dopamine system. Future research must examine the long-term and developmental dopaminergic effects of THC.

  1. Modeling the dopamine system in vivo

    International Nuclear Information System (INIS)

    Gjedde, A.

    1991-01-01

    Positron Emission Tomography (PET) can be used to measure several steps in the synthesis, binding, and metabolism of dopamine in the normal or abnormal living human brain. Fluorodopa is a PET tracer of DOPA metabolism. Recent evidence suggests that only a fraction of striatal fluorodopamine accumulates in the large, static pool of dopamine. Hence, the accumulation of FDOPA-derived radioactivity in striatum reflects the dopamine turnover of this pool. Labeled L-deprenyl is a PET tracer of monoamine oxidase B. The accumulation in striatum and other regions of the human brain reflects the number of reactive sites on the enzyme. The densities of dopamine-binding neuroreceptors may be calculated from the accumulation of reversibly binding tracers by equilibrium kinetics or from the accumulation of irreversibly binding tracers by transient analysis. The reversible tracers include labeled SCH 23390 and raclopride. An irreversibly binding tracer is N- methylspiperone

  2. The evolution of dopamine systems in chordates

    Directory of Open Access Journals (Sweden)

    Kei eYamamoto

    2011-03-01

    Full Text Available Dopamine (DA neurotransmission in the central nervous system (CNS is found throughout chordates, and its emergence predates the divergence of chordates. Many of the molecular components of DA systems, such as biosynthetic enzymes, transporters and receptors, are shared with those of other monoamine systems, suggesting the common origin of these systems. In the mammalian CNS, the DA neurotransmitter systems are diversified and serve for visual and olfactory perception, sensory-motor programming, motivation, memory, emotion, and endocrine regulations. Some of the functions are conserved among different vertebrate groups, while others are not, and this is reflected in the anatomical aspects of DA systems in the forebrain and midbrain. Recent findings concerning a second tyrosine hydroxylase gene (TH2 revealed new populations of DA synthesizing cells, as evidenced in the periventricular hypothalamic zones of teleost fish. It is likely that the ancestor of vertebrates possessed TH2 DA-synthesizing cells, and the TH2 gene has been lost secondarily in placental mammals. All the vertebrates possess DA cells in the olfactory bulb, retina and in the diencephalon. Midbrain DA cells are abundant in amniotes while absent in some groups, e.g. teleosts. Studies of protochordate DA cells suggest that the diencephalic DA cells were present before the divergence of the chordate lineage. In contrast, the midbrain cell populations have probably emerged in the vertebrate lineage following the development of the midbrain-hindbrain boundary. The functional flexibility of the DA systems, and the evolvability provided by duplication of the corresponding genes permitted a large diversification of these systems. These features were instrumental in the adaptation of brain functions to the very variable way of life of vertebrates.

  3. The effects of Δ9-tetrahydrocannabinol on the dopamine system

    Science.gov (United States)

    Bloomfield, Michael A P; Ashok, Abhishekh H; Volkow, Nora D; Howes, Oliver D

    2016-01-01

    Preface Δ9-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, is a pressing concern to global mental health. Patterns of use are changing drastically due to legalisation, availability of synthetic analogues (‘spice’), cannavaping and aggrandizements in the purported therapeutic effects of cannabis. Many of THC’s reinforcing effects are mediated by the dopamine system. Due to complex cannabinoid-dopamine interactions there is conflicting evidence from human and animal research fields. Acute THC causes increased dopamine release and neuron activity, whilst long-term use is associated with blunting of the dopamine system. Future research must examine the long-term and developmental dopaminergic effects of the drug. PMID:27853201

  4. The effects of Δ9-tetrahydrocannabinol on the dopamine system

    OpenAIRE

    Bloomfield, Michael A. P.; Ashok, Abhishekh H.; Volkow, Nora D.; Howes, Oliver D.

    2016-01-01

    The effects of Δ9-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, are a pressing concern for global mental health. Patterns of cannabis use are changing drastically owing to legalization, the availability of synthetic analogues (commonly termed spice), cannavaping and an emphasis on the purported therapeutic effects of cannabis. Many of the reinforcing effects of THC are mediated by the dopamine system. Owing to the complexity of the cannabinoid–dopamine interactions...

  5. Dopamine system: Manager of neural pathways

    Directory of Open Access Journals (Sweden)

    Simon eHong

    2013-12-01

    Full Text Available There are a growing number of roles that midbrain dopamine (DA neurons assume, such as, reward, aversion, alerting and vigor. Here I propose a theory that may be able to explain why the suggested functions of DA came about. It has been suggested that largely parallel cortico-basal ganglia-thalamo-cortico loops exist to control different aspects of behavior. I propose that (1 the midbrain DA system is organized in a similar manner, with different groups of DA neurons corresponding to these parallel neural pathways (NPs. The DA system can be viewed as the manager of these parallel NPs in that it recruits and activates only the task-relevant NPs when they are needed. It is likely that the functions of those NPs that have been consistently activated by the corresponding DA groups are facilitated. I also propose that (2 there are two levels of DA roles: the How and What roles. The How role is encoded in tonic and phasic DA neuron firing patterns and gives a directive to its target NP: how vigorously its function needs to be carried out. The tonic DA firing is to maintain a certain level of DA in the target NPs to support their expected behavioral and mental functions; it is only when a sudden unexpected boost or suppression of activity is required by the relevant target NP that DA neurons in the corresponding NP act in a phasic manner. The What role is the implementational aspect of the role of DA in the target NP, such as binding to D1 receptors to boost working memory. This What aspect of DA explains why DA seems to assume different functions depending on the region of the brain in which it is involved. In terms of the role of the lateral habenula (LHb, the LHb is expected to suppress maladaptive behaviors and mental processes by controlling the DA system. The demand-based smart management by the DA system may have given animals an edge in evolution with adaptive behaviors and a better survival rate in resource-scarce situations.

  6. The dopamine motive system: implications for drug and food addiction.

    Science.gov (United States)

    Volkow, Nora D; Wise, Roy A; Baler, Ruben

    2017-11-16

    Behaviours such as eating, copulating, defending oneself or taking addictive drugs begin with a motivation to initiate the behaviour. Both this motivational drive and the behaviours that follow are influenced by past and present experience with the reinforcing stimuli (such as drugs or energy-rich foods) that increase the likelihood and/or strength of the behavioural response (such as drug taking or overeating). At a cellular and circuit level, motivational drive is dependent on the concentration of extrasynaptic dopamine present in specific brain areas such as the striatum. Cues that predict a reinforcing stimulus also modulate extrasynaptic dopamine concentrations, energizing motivation. Repeated administration of the reinforcer (drugs, energy-rich foods) generates conditioned associations between the reinforcer and the predicting cues, which is accompanied by downregulated dopaminergic response to other incentives and downregulated capacity for top-down self-regulation, facilitating the emergence of impulsive and compulsive responses to food or drug cues. Thus, dopamine contributes to addiction and obesity through its differentiated roles in reinforcement, motivation and self-regulation, referred to here as the 'dopamine motive system', which, if compromised, can result in increased, habitual and inflexible responding. Thus, interventions to rebalance the dopamine motive system might have therapeutic potential for obesity and addiction.

  7. Genetic Variation in the Dopamine System Influences Intervention Outcome in Children with Cerebral Palsy

    Directory of Open Access Journals (Sweden)

    Rochellys Diaz Heijtz

    2018-02-01

    Interpretation: Naturally occurring genetic variation in the dopamine system can influence treatment outcomes in children with cerebral palsy. A polygenic dopamine score might be valid for treatment outcome prediction and for designing individually tailored interventions for children with cerebral palsy.

  8. Study and development of retinal dopamine nervous system in experimental myopia

    International Nuclear Information System (INIS)

    Zhao Juan; Liu Xingdang

    2007-01-01

    Myopia is the most familiar ametropia. Animal experimental models include form deprivation myopia and defocus myopia. Experimental animals we often use are chicken and mammals. The retinal dopamine system and vision experience have close relations with the regulation of eyeball's growth after birth, while the change of dopamine transporter may reflect the change of dopamine in the synaptic cleft more directly. (authors)

  9. Glucocorticoid receptor gene inactivation in dopamine-innervated areas selectively decreases behavioral responses to amphetamine

    Directory of Open Access Journals (Sweden)

    Sebastien eParnaudeau

    2014-02-01

    Full Text Available The meso-cortico-limbic system, via dopamine release, encodes the rewarding and reinforcing properties of natural rewards. It is also activated in response to abused substances and is believed to support drug-related behaviors. Dysfunctions of this system lead to several psychiatric conditions including feeding disorders and drug addiction. These disorders are also largely influenced by environmental factors and in particular stress exposure. Stressors activate the corticotrope axis ultimately leading to glucocorticoid hormone (GCs release. GCs bind the glucocorticoid receptor (GR a transcription factor ubiquitously expressed including within the meso-cortico-limbic tract. While the GR within dopamine-innervated areas drives cocaine’s behavioral responses, its implication in responses to other psychostimulants such as amphetamine has never been clearly established. Moreover, while extensive work has been made to uncover the role of this receptor in addicted behaviors, its contribution to the rewarding and reinforcing properties of food has yet to be investigated. Using mouse models carrying GR gene inactivation in either dopamine neurons or in dopamine-innervated areas, we found that GR in dopamine responsive neurones is essential to properly build amphetamine-induced conditioned place preference and locomotor sensitization. c-Fos quantification in the nucleus accumbens further confirmed defective neuronal activation following amphetamine injection. These diminished neuronal and behavioral responses to amphetamine may involve alterations in glutamate transmission as suggested by the decreased MK801-elicited hyperlocomotion and by the hyporeactivity to glutamate of a subpopulation of medium spiny neurons. In contrast, GR inactivation did not affect rewarding and reinforcing properties of food suggesting that responding for natural reward under basal conditions is preserved in these mice.

  10. Dopamine, nitric oxide and their interactions in models for the study of schizophrenia / Dopamina, óxido nítrico e suas interações em modelos para o estudo da esquizofrenia

    Directory of Open Access Journals (Sweden)

    Cristiane Salum

    2008-01-01

    Full Text Available Experimental models based on the increase of dopaminergic neurotransmission mimic behavioral and neurochemical schizophrenia-like aspects. Psychostimulants, as amphetamine, are used with this purpose because they increase extracellular dopamine levels in mesocorticolimbic and mesostriatal pathways. The limitations of direct manipulation uniquely based on the dopamine system in animal models have encouraged the use of new approaches. Nitric oxide (NO, an atypical neurotransmitter which inhibits dopamine reuptake and stimulates its release, seems to modulate dopamine-controlled behaviors. The prepulse inhibition test reveals deficits on the sensorimotor filter found in schizophrenics or after psichotomimetic treatments. This review presents evidences for the interaction between NO and DA systems on schizophrenia models as a new tool for the investigation of this pathology.

  11. Dopamine systems adaptation during acquisition and consolidation of a skill

    Directory of Open Access Journals (Sweden)

    Wolfgang H Sommer

    2014-11-01

    Full Text Available The striatum plays a key role in motor learning. Striatal function depends strongly on dopaminergic neurotransmission, but little is known about neuroadaptions of the dopamine system during striatal learning. Using an established task that allows differentiation between acquisition and consolidation of motor learning, we here investigate D1 and D2-like receptor binding and transcriptional levels after initial and long-term training of mice. We found profound reduction in D1 binding within the dorsomedial striatum (DMS after the first training session on the accelerated rotarod and a progressive reduction in D2-like binding within the dorsolateral striatum (DLS after extended training. Given that similar phase- and region-specific striatal neuroadaptations have been found also during learning of complex procedural tasks including habit formation and automatic responding, the here observed neurochemical alterations are important for our understanding of neuropsychiatric disorders that show a dysbalance in the function of striatal circuits, such as in addictive behaviours.

  12. Response contingency directs long-term cocaine-induced neuroplasticity in prefrontal and striatal dopamine terminals.

    Science.gov (United States)

    Wiskerke, Joost; Schoffelmeer, Anton N M; De Vries, Taco J

    2016-10-01

    Exposure to addictive substances such as cocaine is well-known to alter brain organisation. Cocaine-induced neuroadaptations depend on several factors, including drug administration paradigm. To date, studies addressing the consequences of cocaine exposure on dopamine transmission have either not been designed to investigate the role of response contingency or focused only on short-term neuroplasticity. We demonstrate a key role of response contingency in directing long-term cocaine-induced neuroplasticity throughout projection areas of the mesocorticolimbic dopamine system. We found enhanced electrically-evoked [(3)H]dopamine release from superfused brain slices of nucleus accumbens shell and core, dorsal striatum and medial prefrontal cortex three weeks after cessation of cocaine self-administration. In yoked cocaine rats receiving the same amount of cocaine passively, sensitised dopamine terminal reactivity was only observed in the nucleus accumbens core. Control sucrose self-administration experiments demonstrated that the observed neuroadaptations were not the result of instrumental learning per se. Thus, long-term withdrawal from cocaine self-administration is associated with widespread sensitisation of dopamine terminals throughout frontostriatal circuitries. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

  13. Cocaine serves as a peripheral interoceptive conditioned stimulus for central glutamate and dopamine release.

    Directory of Open Access Journals (Sweden)

    Roy A Wise

    Full Text Available Intravenous injections of cocaine HCl are habit-forming because, among their many actions, they elevate extracellular dopamine levels in the terminal fields of the mesocorticolimbic dopamine system. This action, thought to be very important for cocaine's strong addiction liability, is believed to have very short latency and is assumed to reflect rapid brain entry and pharmacokinetics of the drug. However, while intravenous cocaine HCl has almost immediate effects on behavior and extracellular dopamine levels, recent evidence suggests that its central pharmacological effects are not evident until 10 or more seconds after IV injection. Thus the immediate effects of a given intravenous cocaine injection on extracellular dopamine concentration and behavior appear to occur before there is sufficient time for cocaine to act centrally as a dopamine uptake inhibitor. To explore the contribution of peripheral effects of cocaine to the early activation of the dopamine system, we used brain microdialysis to measure the effects of cocaine methiodide (MI--a cocaine analogue that does not cross the blood brain barrier--on glutamate (excitatory input to the dopamine cells. IP injections of cocaine MI were ineffective in cocaine-naïve animals but stimulated ventral tegmental glutamate release in rats previously trained to lever-press for cocaine HCl. This peripherally triggered glutamate input was sufficient to reinstate cocaine-seeking in previously trained animals that had undergone extinction of the habit. These findings offer an explanation for short-latency behavioral responses and immediate dopamine elevations seen following cocaine injections in cocaine-experienced but not cocaine-naïve animals.

  14. Distinct Roles of Opioid and Dopamine Systems in Lateral Hypothalamic Intracranial Self-Stimulation.

    Science.gov (United States)

    Ide, Soichiro; Takahashi, Takehiro; Takamatsu, Yukio; Uhl, George R; Niki, Hiroaki; Sora, Ichiro; Ikeda, Kazutaka

    2017-05-01

    Opioid and dopamine systems play crucial roles in reward. Similarities and differences in the neural mechanisms of reward that are mediated by these 2 systems have remained largely unknown. Thus, in the present study, we investigated the differences in reward function in both µ-opioid receptor knockout mice and dopamine transporter knockout mice, important molecules in the opioid and dopamine systems. Mice were implanted with electrodes into the right lateral hypothalamus (l hour). Mice were then trained to put their muzzle into the hole in the head-dipping chamber for intracranial electrical stimulation, and the influences of gene knockout were assessed. Significant differences are observed between opioid and dopamine systems in reward function. µ-Opioid receptor knockout mice exhibited enhanced intracranial electrical stimulation, which induced dopamine release. They also exhibited greater motility under conditions of "despair" in both the tail suspension test and water wheel test. In contrast, dopamine transporter knockout mice maintained intracranial electrical stimulation responding even when more active efforts were required to obtain the reward. The absence of µ-opioid receptor or dopamine transporter did not lead to the absence of intracranial electrical stimulation responsiveness but rather differentially altered it. The present results in µ-opioid receptor knockout mice are consistent with the suppressive involvement of µ-opioid receptors in both positive incentive motivation associated with intracranial electrical stimulation and negative incentive motivation associated with depressive states. In contrast, the results in dopamine transporter knockout mice are consistent with the involvement of dopamine transporters in positive incentive motivation, especially its persistence. Differences in intracranial electrical stimulation in µ-opioid receptor and dopamine transporter knockout mice underscore the multidimensional nature of reward. © The Author

  15. The melanin-concentrating hormone (MCH system modulates behaviors associated with psychiatric disorders.

    Directory of Open Access Journals (Sweden)

    Shinjae Chung

    Full Text Available Deficits in sensorimotor gating measured by prepulse inhibition (PPI of the startle have been known as characteristics of patients with schizophrenia and related neuropsychiatric disorders. PPI disruption is thought to rely on the activity of the mesocorticolimbic dopaminergic system and is inhibited by most antipsychotic drugs. These drugs however act also at the nigrostriatal dopaminergic pathway and exert adverse locomotor responses. Finding a way to inhibit the mesocorticolimbic- without affecting the nigrostriatal-dopaminergic pathway may thus be beneficial to antipsychotic therapies. The melanin-concentrating hormone (MCH system has been shown to modulate dopamine-related responses. Its receptor (MCH1R is expressed at high levels in the mesocorticolimbic and not in the nigrostriatal dopaminergic pathways. Interestingly a genomic linkage study revealed significant associations between schizophrenia and markers located in the MCH1R gene locus. We hypothesize that the MCH system can selectively modulate the behavior associated with the mesocorticolimbic dopamine pathway. Using mice, we found that central administration of MCH potentiates apomorphine-induced PPI deficits. Using congenic rat lines that differ in their responses to PPI, we found that the rats that are susceptible to apomorphine (APO-SUS rats and exhibit PPI deficits display higher MCH mRNA expression in the lateral hypothalamic region and that blocking the MCH system reverses their PPI deficits. On the other hand, in mice and rats, activation or inactivation of the MCH system does not affect stereotyped behaviors, dopamine-related responses that depend on the activity of the nigrostriatal pathway. Furthermore MCH does not affect dizocilpine-induced PPI deficit, a glutamate related response. Thus, our data present the MCH system as a regulator of sensorimotor gating, and provide a new rationale to understand the etiologies of schizophrenia and related psychiatric disorders.

  16. In vivo binding of (/sup 18/F)GBR 13119 to the brain dopamine uptake system

    Energy Technology Data Exchange (ETDEWEB)

    Kilbourn, M.R.

    1988-01-01

    Regional rat brain uptake of (/sup 18/F)GBR 13119, a high specific activity, positron-emitter labeled derivative of the potent dopamine uptake antagonist GBR 12935, is reported. Striatum to cerebellum ratios of 3 are obtained at 90 minutes post injection. Specific binding in striatum can be blocked by pretreatment with dopamine uptake system antagonists (mazindol, nomifensine) but not with receptor antagonists (spiperone, flupenthixol). (/sup 18/F)GBR 13119 is proposed as a new positron-emitting radioligand for in vivo PET studies of the pre-synaptic dopamine uptake system.

  17. In vivo binding of [18F]GBR 13119 to the brain dopamine uptake system

    International Nuclear Information System (INIS)

    Kilbourn, M.R.

    1988-01-01

    Regional rat brain uptake of [ 18 F]GBR 13119, a high specific activity, positron-emitter labeled derivative of the potent dopamine uptake antagonist GBR 12935, is reported. Striatum to cerebellum ratios of 3 are obtained at 90 minutes post injection. Specific binding in striatum can be blocked by pretreatment with dopamine uptake system antagonists (mazindol, nomifensine) but not with receptor antagonists (spiperone, flupenthixol). [ 18 F]GBR 13119 is proposed as a new positron-emitting radioligand for in vivo PET studies of the pre-synaptic dopamine uptake system

  18. Antidepressant activity of curcumin: involvement of serotonin and dopamine system.

    Science.gov (United States)

    Kulkarni, Shrinivas K; Bhutani, Mohit Kumar; Bishnoi, Mahendra

    2008-12-01

    Curcumin is a major active principle of Curcuma longa, one of the widely used preparations in the Indian system of medicine. It is known for its diverse biological actions. The present study was designed to investigate the involvement of monoaminergic system(s) in the antidepressant activity of curcumin and the effect of piperine, a bioavailability enhancer, on the bioavailability and biological effects of curcumin. Behavioral (forced swim test), biochemical (monoamine oxidase (MAO) enzyme inhibitory activity), and neurochemical (neurotransmitter levels estimation) tests were carried out. Curcumin (10-80 mg/kg, i.p.) dose dependently inhibited the immobility period, increased serotonin (5-hydroxytryptamine, 5-HT) as well as dopamine levels (at higher doses), and inhibited the monoamine oxidase enzymes (both MAO-A and MAO-B, higher doses) in mice. Curcumin (20 mg/kg, i.p.) enhanced the anti-immobility effect of subthreshold doses of various antidepressant drugs like fluoxetine, venlafaxine, or bupropion. However, no significant change in the anti-immobility effect of imipramine and desipramine was observed. Furthermore, combination of subthreshold dose of curcumin and various antidepressant drugs resulted in synergistic increase in serotonin (5-HT) levels as compared to their effect per se. There was no change in the norepinephrine levels. The coadministration of piperine (2.5 mg/kg, i.p.), a bioavailability enhancing agent, with curcumin (20 and 40 mg/kg, i.p.) resulted in potentiation of pharmacological, biochemical, and neurochemical activities. The study provides evidences for mechanism-based antidepressant actions of curcumin. The coadministration of curcumin along with piperine may prove to be a useful and potent natural antidepressant approach in the management of depression.

  19. The risky business of dopamine agonists in Parkinson disease and impulse control disorders

    NARCIS (Netherlands)

    Claassen, D.O.; van den Wildenberg, W.P.M.; Ridderinkhof, K.R.; Jessup, C.K.; Harrison, M.B.; Wooten, G.F.; Wylie, S.A.

    2011-01-01

    Risk-taking behavior is characterized by pursuit of reward in spite of potential negative consequences. Dopamine neurotransmission along the mesocorticolimbic pathway is a potential modulator of risk behavior. In patients with Parkinson's disease (PD), impulse control disorder (ICD) can result from

  20. Reward vs. Retaliation?the Role of the Mesocorticolimbic Salience Network in Human Reactive Aggression

    OpenAIRE

    Gan, Gabriela; Preston-Campbell, Rebecca N.; Moeller, Scott J.; Steinberg, Joel L.; Lane, Scott D.; Maloney, Thomas; Parvaz, Muhammad A.; Goldstein, Rita Z.; Alia-Klein, Nelly

    2016-01-01

    The propensity for reactive aggression (RA) which occurs in response to provocation has been linked to hyperresponsivity of the mesocorticolimbic reward network in healthy adults. Here, we aim to elucidate the role of the mesocorticolimbic network in clinically significant RA for two competing motivated behaviors, reward-seeking vs. retaliation. 18 male participants performed a variant of the Point-Subtraction Aggression Paradigm (PSAP) during functional magnetic resonance imaging (fMRI). We ...

  1. Alterations in dopamine system function across the estrous cycle of the MAM rodent model of schizophrenia.

    Science.gov (United States)

    Perez, Stephanie M; Chen, Li; Lodge, Daniel J

    2014-09-01

    Clinical studies have reported differences in the incidence and severity of schizophrenia symptoms between male and female schizophrenia patients. Unfortunately, the cause of these differences is not currently known due, in part, to the fact that preclinical studies largely focus on male subjects. Dopamine neuron activity has been previously demonstrated to change across the estrous cycle, and may therefore be of relevance, as aberrant dopamine signaling is thought to underlie the positive symptoms of schizophrenia. Here we examine dopamine neuron activity across the estrous cycle in the MAM rodent model of schizophrenia. We demonstrate that the elevation in dopamine neuron activity, consistently observed in male MAM-treated rats, is most prominent during estrus and attenuated in met-estrus. Furthermore, this appears to be mediated, in part, by progesterone in the ventral hippocampus, as increases in dopamine neuron population activity (observed in estrus) were normalized by the intra-hippocampal administration of the progesterone receptor antagonist, mifepristone (but not the estrogen receptor antagonists, fulvestrant). Taken together, these data suggest that changes in dopamine system function occur across the estrous cycle in MAM-treated rats and may contribute to the differences in symptomatology between male and female schizophrenia patients. Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. 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.

  3. Polymorphisms in Dopamine System Genes Are Associated with Individual Differences in Attention in Infancy

    Science.gov (United States)

    Holmboe, Karla; Nemoda, Zsofia; Fearon, R. M. Pasco; Csibra, Gergely; Sasvari-Szekely, Maria; Johnson, Mark H.

    2010-01-01

    Knowledge about the functional status of the frontal cortex in infancy is limited. This study investigated the effects of polymorphisms in four dopamine system genes on performance in a task developed to assess such functioning, the Freeze-Frame task, at 9 months of age. Polymorphisms in the catechol-O-methyltransferase ("COMT") and the…

  4. [Age-related features of neurohumoral effects of dopamine activity on the cardiovascular system in elderly people].

    Science.gov (United States)

    Lyzohub, V H; Dolynna, O V; Zaval's'ka, T V

    2012-12-01

    Determined the decrease in dopamine activity with age, that contributes to the pathogenesis of hypertension, abdominal obesity, the development of left ventricular hypertrophy. The article presents information describing the age-sensitive regulation of the cardiovascular system in elderly people, confirming the influence of the activity of dopamine receptors in the development of age pathology.

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

    Science.gov (United States)

    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

  6. Human Dopamine Receptors Interaction Network (DRIN): a systems biology perspective on topology, stability and functionality of the network.

    Science.gov (United States)

    Podder, Avijit; Jatana, Nidhi; Latha, N

    2014-09-21

    Dopamine receptors (DR) are one of the major neurotransmitter receptors present in human brain. Malfunctioning of these receptors is well established to trigger many neurological and psychiatric disorders. Taking into consideration that proteins function collectively in a network for most of the biological processes, the present study is aimed to depict the interactions between all dopamine receptors following a systems biology approach. To capture comprehensive interactions of candidate proteins associated with human dopamine receptors, we performed a protein-protein interaction network (PPIN) analysis of all five receptors and their protein partners by mapping them into human interactome and constructed a human Dopamine Receptors Interaction Network (DRIN). We explored the topology of dopamine receptors as molecular network, revealing their characteristics and the role of central network elements. More to the point, a sub-network analysis was done to determine major functional clusters in human DRIN that govern key neurological pathways. Besides, interacting proteins in a pathway were characterized and prioritized based on their affinity for utmost drug molecules. The vulnerability of different networks to the dysfunction of diverse combination of components was estimated under random and direct attack scenarios. To the best of our knowledge, the current study is unique to put all five dopamine receptors together in a common interaction network and to understand the functionality of interacting proteins collectively. Our study pinpointed distinctive topological and functional properties of human dopamine receptors that have helped in identifying potential therapeutic drug targets in the dopamine interaction network. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. Synthesis of dopamine in E. coli using plasmid-based expression system and its marked effect on host growth profiles.

    Science.gov (United States)

    Das, Arunangshu; Verma, Anita; Mukherjee, Krishna J

    2017-09-14

    L-Dopa and dopamine are important pathway intermediates toward the synthesis of catecholamine such as epinephrine and norepinephrine from amino acid L-tyrosine. Dopamine, secreted from dopaminergic nerve cells, serves as an important neurotransmitter. We report the synthesis of dopamine by extending the aromatic amino acid pathway of Escherichia coli DH5α by the expression of 4-hydroxyphenylacetate-3-hydrolase (HpaBC) from E. coli and an engineered dopa decarboxylase (DDC) from pig kidney cell. The activity of HpaBC and DDC require 200 µM iron supplementation and 50 µM vitamin B6, respectively as additives to the growth media. The maximum concentration of L-dopa and dopamine obtained from the broth was around 26 and 27 mg/L after 24 hr of separate shake flask studies. We observed that in the presence of dopamine synthesized in vivo host growth was remarkably enhanced. These observations lead us to an interesting finding about the role of these catecholamines on bacterial growth. It is clear that synthesis of dopamine in vivo actually promotes growth much efficiently as compared to when dopamine is added to the system from outside. From HPLC and GC-MS data it was further observed that L-dopa was stable within the observable time of experiments whereas dopamine actually was subjected to degradation via oxidation and host consumption.

  8. 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

  9. Molecular players in the development and maintenance of mesencephalic dopamine systems.

    Science.gov (United States)

    Burbach, J P; Cazorla, P; Smidt, M P

    1999-06-01

    Several psychiatric diseases are considered to be neuro-developmental disorders. Amongst these are schizophrenia and autism, in which genetic and environmental components have been indicated. In these disorders intrinsic molecular mechanisms of brain development may be deranged due to genetic predispositions, or modified by external influences. Brain development is a delicate process of well-tuned cellular proliferation and differentiation of multipotent neural progenitor cells driven by spatiotemporal cues. One of the fundamental mechanisms is the interaction between external signals, e.g. growth factors, and internal regulators, e.g. transcription factors. An important transmitter system involved in behavioural and affective functions relevant for psychiatric disorders is the mesencephalic dopamine (DA) system. The mesencephalic DA system is organized in two anatomically and functionally different systems. DA neurons in the ventral tegmental area project to the mesolimbic system and are mostly related to control of behaviour. It has been implicated in drug addiction and affective disorders like dipolar disorder and schizophrenia. The dopamine system of the substantia nigra (nigro-striatal pathway) is implicated in movement control. Degeneration of this system, as in Parkinson's disease, or altered function in tardive dyskinesia have highlighted its importance in human disease. Recent findings in molecular neurobiology have provided the first clues to molecular mechanisms involved in developing and mature DA neurons. These may have clinical implications in novel therapeutic strategies.

  10. Organization of Monosynaptic Inputs to the Serotonin and Dopamine Neuromodulatory Systems

    Directory of Open Access Journals (Sweden)

    Sachie K. Ogawa

    2014-08-01

    Full Text Available Serotonin and dopamine are major neuromodulators. Here, we used a modified rabies virus to identify monosynaptic inputs to serotonin neurons in the dorsal and median raphe (DR and MR. We found that inputs to DR and MR serotonin neurons are spatially shifted in the forebrain, and MR serotonin neurons receive inputs from more medial structures. Then, we compared these data with inputs to dopamine neurons in the ventral tegmental area (VTA and substantia nigra pars compacta (SNc. We found that DR serotonin neurons receive inputs from a remarkably similar set of areas as VTA dopamine neurons apart from the striatum, which preferentially targets dopamine neurons. Our results suggest three major input streams: a medial stream regulates MR serotonin neurons, an intermediate stream regulates DR serotonin and VTA dopamine neurons, and a lateral stream regulates SNc dopamine neurons. These results provide fundamental organizational principles of afferent control for serotonin and dopamine.

  11. Systemic effects of low-dose dopamine during administration of cytarabine.

    Science.gov (United States)

    Connelly, James; Benani, Dina J; Newman, Matthew; Burton, Bradley; Crow, Jessica; Levis, Mark

    2017-09-01

    Purpose Low-dose dopamine has been utilized to improve renal blood flow, urine output, and reduce drug-induced nephrotoxicity. The purpose of this study was to assess changes in renal function, cardiovascular adverse events, and neurologic toxicity in patients receiving cytarabine with or without low-dose dopamine. Methods A retrospective, single-center, cohort study of patients receiving cytarabine at 667 mg/m 2 /dose or greater, with or without dopamine at ≤5 mcg/kg/min. Cohorts were based upon initiation or absence of low-dose dopamine; cytarabine only, cytarabine + pre- and day of low-dose dopamine, and cytarabine + post-low-dose dopamine. Renal outcomes (urine output, serum creatinine, and creatinine clearance) were compared with baseline and between cohorts. Safety endpoints (arrhythmias, tachycardia, and neurotoxicity) were compared between cohorts based on low-dose dopamine exposure. Results There was no difference in urine output from baseline in all cohorts. Comparing cytarabine only and pre- and day of low-dose dopamine cohorts, there was no difference in urine output. In those receiving low-dose dopamine, there was no difference in serum creatinine and creatinine clearance from baseline. No arrhythmias were documented during the study period, and there was no difference in the incidence of tachycardia between groups (P = 0.66). Neurotoxicity was reported in three patients who were on low-dose dopamine. Conclusion Though variation existed in individual patients administered low-dose dopamine, the use of low-dose dopamine did not significantly impact renal function in this small sample at a single institution. In addition, low-dose dopamine did not negatively impact cardiovascular function.

  12. Activity-Based Anorexia Alters the Expression of BDNF Transcripts in the Mesocorticolimbic Reward Circuit.

    Science.gov (United States)

    Ho, Emily V; Klenotich, Stephanie J; McMurray, Matthew S; Dulawa, Stephanie C

    2016-01-01

    Anorexia nervosa (AN) is a complex eating disorder with severe dysregulation of appetitive behavior. The activity-based anorexia (ABA) paradigm is an animal model in which rodents exposed to both running wheels and scheduled feeding develop aspects of AN including paradoxical hypophagia, dramatic weight loss, and hyperactivity, while animals exposed to only one condition maintain normal body weight. Brain-derived neurotrophic factor (BDNF), an activity-dependent modulator of neuronal plasticity, is reduced in the serum of AN patients, and is a known regulator of feeding and weight maintenance. We assessed the effects of scheduled feeding, running wheel access, or both on the expression of BDNF transcripts within the mesocorticolimbic pathway. We also assessed the expression of neuronal cell adhesion molecule 1 (NCAM1) to explore the specificity of effects on BDNF within the mesocorticolimbic pathway. Scheduled feeding increased the levels of both transcripts in the hippocampus (HPC), increased NCAM1 mRNA expression in the ventral tegmental area (VTA), and decreased BDNF mRNA levels in the medial prefrontal cortex (mPFC). In addition, wheel running increased BDNF mRNA expression in the VTA. No changes in either transcript were observed in the nucleus accumbens (NAc). Furthermore, no changes in either transcript were induced by the combined scheduled feeding and wheel access condition. These data indicate that scheduled feeding or wheel running alter BDNF and NCAM1 expression levels in specific regions of the mesocorticolimbic pathway. These findings contribute to our current knowledge of the molecular alterations induced by ABA and may help elucidate possible mechanisms of AN pathology.

  13. The Nigrostriatal Dopamine System and Methamphetamine: Roles for Excitoxicity and Environmental, Metabolic and Oxidative Stress

    National Research Council Canada - National Science Library

    Yamamoto, Bryan

    2002-01-01

    .... Similarly, the psychostimulant drug, methamphetamine also produces relatively selective damage to nigrostriatal dopamine neurons and is a widespread problem and drug of abuse throughout the U.S...

  14. The Nigrostriatal Dopamine System and Methamphetamine: Roles for Excitotoxicity and Environmental, Metabolic and Oxidative Stress

    National Research Council Canada - National Science Library

    Yamamoto, Bryan

    2005-01-01

    .... Similarly, the psychostimulant drug, methamphetamine also produces relatively selective damage to nigrostriatal dopamine neurons and is a widespread problem and drug of abuse throughout the U.S...

  15. LOCALIZATION OF DOPAMINE AND ITS RELATION TO THE GROWTH-HORMONE PRODUCING CELLS IN THE CENTRAL-NERVOUS-SYSTEM OF THE SNAIL LYMNAEA-STAGNALIS

    NARCIS (Netherlands)

    WERKMAN, TR; VANMINNEN, J; STEINBUSCH, HWM; WESTERINK, BHC; DEVLIEGER, TA; STOOF, JC

    1991-01-01

    The distribution of dopamine in the central nervous system of the pond snail Lymnaea stagnalis was investigated by using immunocytochemistry and HPLC measurements. With both methods it was demonstrated that dopamine is predominantly present in the cerebral and pedal ganglia. The

  16. Unusual compulsive behaviors primarily related to dopamine agonist therapy in Parkinson's disease and multiple system atrophy.

    Science.gov (United States)

    McKeon, Andrew; Josephs, Keith A; Klos, Kevin J; Hecksel, Kathleen; Bower, James H; Michael Bostwick, J; Eric Ahlskog, J

    2007-12-01

    Unusual compulsive behaviors (weighing, card and video game playing, fishing, gardening, intense interest in established hobbies, locking and unlocking doors, repetitive dressing and undressing) occurred in relation to dopamine agonist therapy (six patients) and levodopa therapy (one patient) in seven patients with parkinsonism (seven Parkinson's disease, one multiple system atrophy). These behaviors occurred in tandem with pathological gambling, hypersexuality, compulsive eating, compulsive shopping or punding in six of the seven cases. Obsessive thoughts were present in one patient, with no prior history of obsessive-compulsive disorder. The simultaneous occurrence of these phenomenologically distinct behaviors in this group of patients suggests that a broad spectrum of psychopathology may occur in this context and should be monitored for in routine neurological practice.

  17. Increased dopamine D1 receptor binding in the human mesocortical system following central cholinergic activation

    International Nuclear Information System (INIS)

    Fedi, M.; Berkovic, S.F.; Tochon-Danguy, H.J.; Reutens, D.C.

    2002-01-01

    Full text: The interaction between the cholinergic and dopaminergic system has been implicated in many pathological processes including, Alzheimer's disease, schizophrenia and drug addiction. Little is known about the control of dopamine (DA) release following central cholinergic activation in humans, but experimental studies suggest that endogenously released Acetylcholine (ACh) achieved by the administration of cholinesterase inhibitors, can increase dopamine efflux in different regions of the brain. This leads to the activation of different types of post-synaptic dopaminergic receptors which belong to the family of G-protein coupled receptors (GPCRs). A common paradigm of the GPCRs desensitization is that agonist-induced receptor signaling is rapidly attenuated by receptor internalisation. Several experiments have shown that the activation of Dl receptors in acute conditions leads, within minutes, to translocation of the receptor from the surface of the neurons to the endosomal compartment in the cytoplasm and increased receptor turnover. To assess changes in Dl receptor density following an intravenous infusion of the selective cholinesterase inhibitor physostigmine salicylate (PHY), we studied eleven normal subjects (10 male and 1 female, mean age 36.1 and 61617; 9.9) using [11C]-SCH23390 and PET The binding potential (BP) for SCH23390 was significantly (p 0.05). There was no statistically significant difference between baseline and physostigmine Kl ratio (p>0.05) suggesting that BP changes observed were not secondary to regional blood flow changes or to an order effect of the scans. Copyright (2002) The Australian and New Zealand Society of Nuclear Medicine Inc

  18. Pleasure systems in the brain

    Science.gov (United States)

    Berridge, Kent C.; Kringelbach, Morten L.

    2015-01-01

    Pleasure is mediated by well-developed mesocorticolimbic circuitry, and serves adaptive functions. In affective disorders anhedonia (lack of pleasure) or dysphoria (negative affect) can result from breakdowns of that hedonic system. Human neuroimaging studies indicate that surprisingly similar circuitry is activated by quite diverse pleasures, suggesting a common neural currency shared by all. Wanting for rewards is generated by a large and distributed brain system. Liking, or pleasure itself, is generated by a smaller set of hedonic hotspots within limbic circuitry. Those hotspots also can be embedded in broader anatomical patterns of valence organization, such as in a keyboard pattern of nucleus accumbens generators for desire versus dread. In contrast, some of the best known textbook candidates for pleasure generators, including classic pleasure electrodes and the mesolimbic dopamine system, may not generate pleasure after all. These emerging insights into brain pleasure mechanisms may eventually facilitate better treatments for affective disorders. PMID:25950633

  19. Suboptimal maternal diets alter mu opioid receptor and dopamine type 1 receptor binding but exert no effect on dopamine transporters in the offspring brain.

    Science.gov (United States)

    Thanos, Panayotis K; Zhuo, Jianmin; Robison, Lisa; Kim, Ronald; Ananth, Mala; Choai, Ilon; Grunseich, Adam; Grissom, Nicola M; George, Robert; Delis, Foteini; Reyes, Teresa M

    2018-02-01

    Birthweight is a marker for suboptimal fetal growth and development in utero. Offspring can be born large for gestational age (LGA), which is linked to maternal obesity or excessive gestational weight gain, as well as small for gestational age (SGA), arising from nutrient or calorie deficiency, placental dysfunction, or other maternal conditions (hypertension, infection). In humans, LGA and SGA babies are at an increased risk for certain neurodevelopmental disorders, including Attention Deficit/Hyperactivity Disorder, schizophrenia, and social and mood disorders. Using mouse models of LGA (maternal high fat (HF) diet) and SGA (maternal low protein (LP) diet) offspring, our lab has previously shown that these offspring display alterations in the expression of mesocorticolimbic genes that regulate dopamine and opioid function, thus indicating that these brain regions and neurotransmitter systems are vulnerable to gestational insults. Interestingly, these two maternal diets affected dopamine and opioid systems in somewhat opposing directions (e.g., LP offspring are generally hyperdopaminergic with reduced opioid expression, and the reverse is found for the HF offspring). These data largely involved evaluation at the transcriptional level, so the present experiment was designed to extend these analyses through an assessment of receptor binding. In this study, control, SGA and LGA offspring were generated from dams fed control, low protein or high fat diet, respectively, throughout pregnancy and lactation. At weaning, mice were placed on the control diet and sacrificed at 12 weeks of age. In vitro autoradiography was used to measure mu-opioid receptor (MOR), dopamine type 1 receptor (D1R), and dopamine transporter (DAT) binding level in mesolimbic brain regions. Results showed that the LP offspring (males and females) had significantly higher MOR and D1R binding than the control animals in the regions associated with reward. In HF offspring there were no differences in

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

    Science.gov (United States)

    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.

  1. Pro-psychotic effects of synthetic cannabinoids: interactions with central dopamine, serotonin, and glutamate systems.

    Science.gov (United States)

    Fantegrossi, William E; Wilson, Catheryn D; Berquist, Michael D

    2018-02-01

    An association between marijuana use and schizophrenia has been noted for decades, and the recent emergence of high-efficacy synthetic cannabinoids (SCBs) as drugs of abuse has lead to a growing number of clinical reports of persistent psychotic effects in users of these substances. The mechanisms underlying SCB-elicited pro-psychotic effects is unknown, but given the ubiquitous neuromodulatory functions of the endocannabinoid system, it seems likely that agonist actions at cannabinoid type-1 receptors (CB1Rs) might modulate the functions of other neurotransmitter systems known to be involved in schizophrenia. The present review surveys what is currently known about the interactions of CB1Rs with dopamine, serotonin, and glutamate systems, because all three of those neurotransmitters are well-established in the pathophysiology of schizophrenia and psychosis. Identification of molecular mechanisms underlying the pro-psychotic effects of SCB drugs of abuse may establish certain classes of these substances as particularly dangerous, guiding regulations to control availability of these drugs. Likewise, an understanding of the pharmacological interactions which lead to schizophrenia and psychosis subsequent to SCB exposure might guide the development of novel therapies to treat afflicted users.

  2. The Nigrostriatal Dopamine System and Methamphetamine: Roles for Excitotoxicity and Environment, Metabolic and Oxidative Stress

    National Research Council Canada - National Science Library

    Yamamoto, Bryan

    2000-01-01

    .... Similarly, the psycho stimulant drug, methamphetamine also produces relatively selective damage to nigrostriatal dopamine neurons and is rapidly becoming a widespread problem and drug of abuse throughout the U.S...

  3. The Nigrostriatal Dopamine System and Methamphetamine: Roles for Excitotoxicity and Environment, Metabolic and Oxidative Stress

    National Research Council Canada - National Science Library

    Yamamoto, Bryan

    2001-01-01

    .... Similarly, the psychostimulant drug, methamphetamine also produces relatively selective damage to nigrostriatal dopamine neurons and is rapidly becoming a widespread problem and drug of abuse throughout the U.S...

  4. Relationship between dopamine deficit and the expression of depressive behavior resulted from alteration of serotonin system.

    Science.gov (United States)

    Lee, Minkyung; Ryu, Young Hoon; Cho, Won Gil; Kang, Yeo Wool; Lee, Soo Jin; Jeon, Tae Joo; Lyoo, Chul Hyoung; Kim, Chul Hoon; Kim, Dong Goo; Lee, Kyochul; Choi, Tae Hyun; Choi, Jae Yong

    2015-09-01

    Depression frequently accompanies in Parkinson's disease (PD). Previous research suggested that dopamine (DA) and serotonin systems are closely linked with depression in PD. However, comprehensive studies about the relationship between these two neurotransmitter systems are limited. Therefore, the purpose of this study is to evaluate the effect of dopaminergic destruction on the serotonin system. The interconnection between motor and depression was also examined. Two PET scans were performed in the 6-hydroxydopamine (6-OHDA) lesioned and sham operated rats: [(18) F]FP-CIT for DA transporters and [(18) F]Mefway for serotonin 1A (5-HT(1A)) receptors. Here, 6-OHDA is a neurotoxin for dopaminergic neurons. Behavioral tests were used to evaluate the severity of symptoms: rotational number for motor impairment and immobility time, acquired from the forced swim test for depression. Region-of-interests were drawn in the striatum and cerebellum for the DA system and hippocampus and cerebellum for the 5-HT system. The cerebellum was chosen as a reference region. Nondisplaceable binding potential in the striatum and hippocampus were compared between 6-OHDA and sham groups. As a result, the degree of DA depletion was negatively correlated with rotational behavior (R(2)  = 0.79, P = 0.003). In 6-OHDA lesioned rats, binding values for 5-HT(1A) receptors was 22% lower than the sham operated group. This decrement of 5-HT(1A) receptor binding was also correlated with the severity of depression (R(2)  = 0.81, P = 0.006). Taken together, this research demonstrated that the destruction of dopaminergic system causes the reduction of the serotonergic system resulting in the expression of depressive behavior. The degree of dopaminergic dysfunction was positively correlated with the impairment of the serotonin system. Severity of motor symptoms was also closely related to depressive behavior. © 2015 Wiley Periodicals, Inc.

  5. Aniracetam enhances cortical dopamine and serotonin release via cholinergic and glutamatergic mechanisms in SHRSP.

    Science.gov (United States)

    Shirane, M; Nakamura, K

    2001-10-19

    Aniracetam, a cognition enhancer, has been recently found to preferentially increase extracellular levels of dopamine (DA) and serotonin (5-HT) in the prefrontal cortex (PFC), basolateral amygdala and dorsal hippocampus of the mesocorticolimbic system in stroke-prone spontaneously hypertensive rats. In the present study, we aimed to identify actually active substances among aniracetam and its major metabolites and to clarify the mode of action in DA and 5-HT release in the PFC. Local perfusion of mecamylamine, a nicotinic acetylcholine (nACh) and N-methyl-D-aspartate (NMDA) receptor antagonist, into the ventral tegmental area (VTA) and dorsal raphe nucleus (DRN) completely blocked DA and 5-HT release, respectively, in the PFC elicited by orally administered aniracetam. The effects of aniracetam were mimicked by local perfusion of N-anisoyl-gamma-aminobutyric acid [corrected] (N-anisoyl-GABA), one of the major metabolites of aniracetam, into the VTA and DRN. The cortical DA release induced by N-anisoyl-GABA applied to the VTA was also completely abolished by co-perfusion of mecamylamine. Additionally, when p-anisic acid, another metabolite of aniracetam, and N-anisoyl-GABA were locally perfused into the PFC, they induced DA and 5-HT release in the same region, respectively. These results indicate that aniracetam enhances DA and 5-HT release by mainly mediating the action of N-anisoyl-GABA that targets not only somatodendritic nACh and NMDA receptors but also presynaptic nACh receptors.

  6. Neuronal Subset-Specific Migration and Axonal Wiring Mechanisms in the Developing Midbrain Dopamine System

    Directory of Open Access Journals (Sweden)

    Sara Brignani

    2017-07-01

    Full Text Available The midbrain dopamine (mDA system is involved in the control of cognitive and motor behaviors, and is associated with several psychiatric and neurodegenerative diseases. mDA neurons receive diverse afferent inputs and establish efferent connections with many brain areas. Recent studies have unveiled a high level of molecular and cellular heterogeneity within the mDA system with specific subsets of mDA neurons displaying select molecular profiles and connectivity patterns. During mDA neuron development, molecular differences between mDA neuron subsets allow the establishment of subset-specific afferent and efferent connections and functional roles. In this review, we summarize and discuss recent work defining novel mDA neuron subsets based on specific molecular signatures. Then, molecular cues are highlighted that control mDA neuron migration during embryonic development and that facilitate the formation of selective patterns of efferent connections. The review focuses largely on studies that show differences in these mechanisms between different subsets of mDA neurons and for which in vivo data is available, and is concluded by a section that discusses open questions and provides directions for further research.

  7. Toward a molecular understanding of psychostimulant actions using genetically engineered dopamine receptor knockout mice as model systems.

    Science.gov (United States)

    Zhang, J; Xu, M

    2001-01-01

    A major focus in studying the progression and prevention of addictive diseases has been to understand the molecular and cellular mechanisms underlying drug addiction. The brain dopaminergic system plays a central role in reward and motivation and is thought to be the main neural substrate for the actions of abusive drugs. We have used the gene targeting technology to generate dopamine D1 and D3 receptor knockout mice and used these mice as model systems to gain a molecular understanding of acute effects of psychostimulants cocaine and amphetamine. The use of a combined approach involving behavioral, electrophysiological as well as molecular studies has allowed us to define initially the roles of dopamine D1 and D3 receptors in the acute effects of psychostimulants and will enable us to understand mechanisms underlying their chronic actions in the future.

  8. Radioiodinated ligands for dopamine receptors

    International Nuclear Information System (INIS)

    Kung, H.F.

    1994-01-01

    The dopamine receptor system is important for normal brain function; it is also the apparent action site for various neuroleptic drugs for the treatment of schizophrenia and other metal disorders. In the past few years radioiodinated ligands for single photon emission tomography (SPECT) have been successfully developed and tested in humans: [ 123 I]TISCH for D1 dopamine receptors; [ 123 I]IBZM, epidepride, IBF and FIDA2, four iodobenzamide derivatives, for D2/D3 dopamine receptors. In addition, [ 123 I]β-CIT (RTI-55) and IPT, cocaine derivatives, for the dopamine reuptake site are potentially useful for diagnosis of loss of dopamine neurons. The first iodinated ligand, (R)trans-7-OH-PIPAT, for D3 dopamine receptors, was synthesized and characterized with cloned cell lines (Spodoptera frugiperda, Sf9) expressing the D2 and D3 dopamine receptors and with rat basal forebrain membrane preparations. Most of the known iodobenzamides displayed similar potency in binding to both D2 and D3 dopamine receptors expressed in the cell lines. Initial studies appear to suggest that by fine tuning the structures it may be possible to develop agents specific for D2 and D3 dopamine receptors. It is important to investigate D2/D3 selectivity for this series of potent ligands

  9. Systemic blockade of dopamine D2-like receptors increases high-voltage spindles in the globus pallidus and motor cortex of freely moving rats.

    Directory of Open Access Journals (Sweden)

    Chen Yang

    Full Text Available High-voltage spindles (HVSs have been reported to appear spontaneously and widely in the cortical-basal ganglia networks of rats. Our previous study showed that dopamine depletion can significantly increase the power and coherence of HVSs in the globus pallidus (GP and motor cortex of freely moving rats. However, it is unclear whether dopamine regulates HVS activity by acting on dopamine D₁-like receptors or D₂-like receptors. We employed local-field potential and electrocorticogram methods to simultaneously record the oscillatory activities in the GP and primary motor cortex (M1 in freely moving rats following systemic administration of dopamine receptor antagonists or saline. The results showed that the dopamine D₂-like receptor antagonists, raclopride and haloperidol, significantly increased the number and duration of HVSs, and the relative power associated with HVS activity in the GP and M1 cortex. Coherence values for HVS activity between the GP and M1 cortex area were also significantly increased by dopamine D₂-like receptor antagonists. On the contrary, the selective dopamine D₁-like receptor antagonist, SCH23390, had no significant effect on the number, duration, or relative power of HVSs, or HVS-related coherence between M1 and GP. In conclusion, dopamine D₂-like receptors, but not D₁-like receptors, were involved in HVS regulation. This supports the important role of dopamine D₂-like receptors in the regulation of HVSs. An siRNA knock-down experiment on the striatum confirmed our conclusion.

  10. Potentiation of Morphine-Induced Antinociception by Propranolol: The Involvement of Dopamine and GABA Systems

    Directory of Open Access Journals (Sweden)

    Elham A. Afify

    2017-11-01

    Full Text Available Tolerance to the analgesic effect of morphine is a major clinical problem which can be managed by co-administration of another drug. This study investigated the ability of propranolol to potentiate the antinociceptive action of morphine and the possible mechanisms underlying this effect. Antinociception was assessed in three nociceptive tests (thermal, hot plate, (visceral, acetic acid, and (inflammatory, formalin test in mice and quantified by measuring the percent maximum possible effect, the percent inhibition of acetic acid-evoked writhing response, and the area under the curve values of number of flinches for treated mice, respectively. The study revealed that propranolol (0.25–20 mg/Kg, IP administration did not produce analgesia in mice. However, 10 mg/Kg propranolol, enhanced the antinociceptive effect of sub-analgesic doses of morphine (0.2, 1, and 2 mg/Kg, IP in the three nociceptive tests. It also shifted the dose response curve of morphine to the left. The combined effect of propranolol and morphine was attenuated by haloperidol (D2 receptor antagonist, 1.5 mg/Kg, IP, and bicuculline (GABAA receptor antagonist, 2 mg/Kg, IP. Repeated daily administration of propranolol (10 mg/Kg, IP did not alter the nociceptive responses in the three pain tests, but it significantly potentiated morphine-induced antinociception in the hot plate, acetic acid-evoked writhing, and in the second phase of formalin tests. Together, the data suggest that a cross-talk exists between the opioidergic and adrenergic systems and implicate dopamine and GABA systems in this synergistic effect of morphine-propranolol combination. Propranolol may serve as an adjuvant therapy to potentiate the effect of opioid analgesics.

  11. Distinct effects of ketamine and acetyl l-carnitine on the dopamine system in zebrafish

    Science.gov (United States)

    Robinson, Bonnie L.; Dumas, Melanie; Cuevas, Elvis; Gu, Qiang; Paule, Merle G.; Ali, Syed F.; Kanungo, Jyotshna

    2016-01-01

    Ketamine, a noncompetitive N-methyl-d-aspartic acid (NMDA) receptor antagonist is commonly used as a pediatric anesthetic. We have previously shown that acetyl L-carnitine (ALCAR) prevents ketamine toxicity in zebrafish embryos. In mammals, ketamine is known to modulate the dopaminergic system. NMDA receptor antagonists are considered as promising anti-depressants, but the exact mechanism of their function is unclear. Here, we measured the levels of dopamine (DA) and its metabolites, 3, 4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the zebrafish embryos exposed to ketamine in the presence and absence of 0.5 mM ALCAR. Ketamine, at lower doses (0.1–0.3 mM), did not produce significant changes in DA, DOPAC or HVA levels in 52 h post-fertilization embryos treated for 24 h. In these embryos, tyrosine hydroxylase (TH) mRNA expression remained unchanged. However, 2 mM ketamine (internal embryo exposure levels equivalent to human anesthetic plasma concentration) significantly reduced DA level and TH mRNA indicating that DA synthesis was adversely affected. In the presence or absence of 2 mM ketamine, ALCAR showed similar effects on DA level and TH mRNA, but increased DOPAC level compared to control. ALCAR reversed 2 mM ketamine-induced reduction in HVA levels. With ALCAR alone, the expression of genes encoding the DA metabolizing enzymes, MAO (monoamine oxidase) and catechol-O-methyltransferase (COMT), was not affected. However, ketamine altered MAO mRNA expression, except at the 0.1 mM dose. COMT transcripts were reduced in the 2 mM ketamine-treated group. These distinct effects of ketamine and ALCAR on the DA system may shed some light on the mechanism on how ketamine can work as an anti-depressant, especially at sub-anesthetic doses that do not affect DA metabolism and suppress MAO gene expression. PMID:26898327

  12. Multilevel impact of the dopamine system on the emotion-potentiated startle reflex.

    Science.gov (United States)

    Domschke, Katharina; Winter, Bernward; Gajewska, Agnieszka; Unterecker, Stefan; Warrings, Bodo; Dlugos, Andrea; Notzon, Swantje; Nienhaus, Kathrin; Markulin, Falko; Gieselmann, Astrid; Jacob, Christian; Herrmann, Martin J; Arolt, Volker; Mühlberger, Andreas; Reif, Andreas; Pauli, Paul; Deckert, Jürgen; Zwanzger, Peter

    2015-06-01

    The pathogenetic mechanism of emotion-related disorders such as anxiety disorders is considered to be complex with an interaction of genetic, biochemical, and environmental factors. Particular evidence has accumulated for alterations in the dopaminergic system-partly conferred by catechol-O-methyltransferase (COMT) gene variation-and for distorted emotional processing to constitute risk factors for anxiety and anxiety-related disorders. Applying a multilevel approach, we analyzed the main and interactive effects of the functional COMT val158met polymorphism and L-dopa (single-dose 50 mg levodopa and 12.5 mg carbidopa; double-blind, placebo-controlled design) on the emotion-potentiated (unpleasant, neutral, and pleasant IAPS pictures) startle response as an intermediate phenotype of anxiety in a sample of 100 healthy probands (f = 52, m = 48). The COMT 158val allele was associated with an increased startle potentiation by unpleasant stimuli as compared with neutral stimuli irrespective of L-dopa or placebo intervention. COMT 158met/met genotype carriers, while displaying no difference in startle magnitude in response to unpleasant or neutral pictures in the placebo condition, showed startle potentiation by unpleasant pictures under L-dopa administration only. The present proof-of-concept study provides preliminary support for a complex, multilevel impact of the dopaminergic system on the emotion-potentiated startle reflex suggesting increased phasic dopamine transmission driven by the more active COMT 158val allele and/or a single dose of L-dopa to predispose to maladaptive emotional processing and thereby potentially also to anxiety-related psychopathological states.

  13. Amygdala-prefrontal pathways and the dopamine system affect nociceptive responses in the prefrontal cortex

    Directory of Open Access Journals (Sweden)

    Onozawa Kitaro

    2011-11-01

    Full Text Available Abstract Background We previously demonstrated nociceptive discharges to be evoked by mechanical noxious stimulation in the prefrontal cortex (PFC. The nociceptive responses recorded in the PFC are conceivably involved in the affective rather than the sensory-discriminative dimension of pain. The PFC receives dense projection from the limbic system. Monosynaptic projections from the basolateral nucleus of the amygdala (BLA to the PFC are known to produce long-lasting synaptic plasticity. We examined effects of high frequency stimulation (HFS delivered to the BLA on nociceptive responses in the rat PFC. Results HFS induced long lasting suppression (LLS of the specific high threshold responses of nociceptive neurons in the PFC. Microinjection of N-methyl-D-aspartic acid (NMDA receptor antagonists (2-amino-5-phosphonovaleric acid (APV, dizocilpine (MK-801 and also metabotropic glutamate receptor (mGluR group antagonists (α-methyl-4-carboxyphenylglycine (MCPG, and 2-[(1S,2S-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl-D-alanine (LY341495, prevented the induction of LLS of nociceptive responses. We also examined modulatory effects of dopamine (DA on the LLS of nociceptive responses. With depletion of DA in response to 6-hydroxydopamine (6-OHDA injection into the ipsilateral forebrain bundle, LLS of nociceptive responses was decreased, while nociceptive responses were normally evoked. Antagonists of DA receptor subtypes D2 (sulpiride and D4 (3-{[4-(4-chlorophenyl piperazin-1-yl] methyl}-1H-pyrrolo [2, 3-b] pyridine (L-745,870, microinjected into the PFC, inhibited LLS of nociceptive responses. Conclusions Our results indicate that BLA-PFC pathways inhibited PFC nociceptive cell activities and that the DA system modifies the BLA-PFC regulatory function.

  14. Dopamina, óxido nítrico e suas interações em modelos para o estudo da esquizofrenia Dopamine, nitric oxide and their interactions in models for the study of schizophrenia

    Directory of Open Access Journals (Sweden)

    Cristiane Salum

    2008-01-01

    Full Text Available Modelos experimentais baseados no aumento da neurotransmissão dopaminérgica mimetizam aspectos comportamentais e neuroquímicos característicos da esquizofrenia. Psicoestimulantes, como a anfetamina, são utilizados com esta finalidade, pois aumentam os níveis de dopamina extracelular nas vias mesocorticolímbica e mesoestriatal. As limitações da manipulação direta do sistema dopaminérgico nos modelos animais incentivam abordagens complementares. O óxido nítrico (NO, um neurotransmissor atípico que inibe a recaptação de dopamina e estimula sua liberação, parece modular comportamentos controlados pelo sistema dopaminérgico. O teste de inibição pré-pulso revela uma deficiência no filtro sensório-motor, verificada em esquizofrênicos ou após tratamentos com psicotomiméticos, podendo ser prevenida pela inibição do NO. Esta revisão apresenta evidências da interação do NO com o sistema dopaminérgico em modelos para o estudo da esquizofrenia como uma nova ferramenta de investigação desta patologia.Experimental models based on the increase of dopaminergic neurotransmission mimic behavioral and neurochemical schizophrenia-like aspects. Psychostimulants, as amphetamine, are used with this purpose because they increase extracellular dopamine levels in mesocorticolimbic and mesostriatal pathways. The limitations of direct manipulation uniquely based on the dopamine system in animal models have encouraged the use of new approaches. Nitric oxide (NO, an atypical neurotransmitter which inhibits dopamine reuptake and stimulates its release, seems to modulate dopamine-controlled behaviors. The prepulse inhibition test reveals deficits on the sensorimotor filter found in schizophrenics or after psichotomimetic treatments. This review presents evidences for the interaction between NO and DA systems on schizophrenia models as a new tool for the investigation of this pathology.

  15. Pre-Existing Differences and Diet-Induced Alterations in Striatal Dopamine Systems of Obesity-Prone Rats

    Science.gov (United States)

    Vollbrecht, Peter J.; Mabrouk, Omar S.; Nelson, Andrew D.; Kennedy, Robert T.; Ferrario, Carrie R.

    2016-01-01

    Objective Interactions between pre-existing differences in mesolimbic function and neuroadaptations induced by consumption of fatty, sugary foods are thought to contribute to human obesity. This study examined basal and cocaine-induced changes in striatal neurotransmitter levels without diet manipulation and D2/D3 dopamine receptor-mediated transmission prior to and after consumption of “junk-foods” in obesity-prone and obesity-resistant rats. Methods Microdialysis and liquid chromatography-mass spectrometry were used to determine basal and cocaine-induced changes in neurotransmitter levels in real time with cocaine-induced locomotor activity. Sensitivity to the D2/D3 dopamine receptor agonist quinpirole was examined before and after restricted junk-food exposure. Selectively bred obesity-prone and obesity-resistant rats were used. Results Cocaine-induced locomotion was greater in obesity-prone rats versus obesity-resistant rats prior to diet manipulation. Basal and cocaine-induced increases in dopamine and serotonin levels did not differ. Obesity-prone rats were more sensitive to the D2 receptor-mediated effects of quinpirole, and junk-food produced modest alterations in quinpirole sensitivity in obesity-resistant rats. Conclusions These data show that mesolimbic systems differ prior to diet manipulation in susceptible versus resistant rats, and that consumption of fatty, sugary foods produce different neuroadaptations in these populations. These differences may contribute to enhanced food craving and an inability to limit food intake in susceptible individuals. PMID:26847484

  16. Dopamine and Stress System Modulation of Sex Differences in Decision Making.

    Science.gov (United States)

    Georgiou, Polymnia; Zanos, Panos; Bhat, Shambhu; Tracy, J Kathleen; Merchenthaler, Istvan J; McCarthy, Margaret M; Gould, Todd D

    2018-01-01

    Maladaptive decision making is associated with several neuropsychiatric disorders, including problem gambling and suicidal behavior. The prevalence of these disorders is higher in men vs women, suggesting gender-dependent regulation of their pathophysiology underpinnings. We assessed sex differences in decision making using the rat version of the Iowa gambling task. Female rats identified the most optimal choice from session 1, whereas male rats from session 5. Male, but not female rats, progressively improved their advantageous option responding and surpassed females. Estrus cycle phase did not affect decision making. To test whether pharmacological manipulations targeting the dopaminergic and stress systems affect decision making in a sex-dependent manner, male and female rats received injections of a dopamine D 2 receptor (D 2 R) antagonist (eticlopride), D 2 R agonist (quinpirole), corticotropin-releasing factor 1 (CRF 1 ) antagonist (antalarmin), and α 2 -adrenergic receptor antagonist (yohimbine; used as a pharmacological stressor). Alterations in mRNA levels of D 2 R and CRF 1 were also assessed. Eticlopride decreased advantageous responding in male, but not female rats, whereas quinpirole decreased advantageous responding specifically in females. Yohimbine dose-dependently decreased advantageous responding in female rats, whereas decreased advantageous responding was only observed at higher doses in males. Antalarmin increased optimal choice responding only in female rats. Higher Drd2 and Crhr1 expression in the amygdala were observed in female vs male rats. Higher amygdalar Crhr1 expression was negatively correlated with advantageous responding specifically in females. This study demonstrates the relevance of dopaminergic- and stress-dependent sex differences to maladaptive decision making.

  17. Exercise-Induced Neuroprotection of the Nigrostriatal Dopamine System in Parkinson's Disease

    Directory of Open Access Journals (Sweden)

    Lijuan Hou

    2017-11-01

    Full Text Available Epidemiological studies indicate that physical activity and exercise may reduce the risk of developing Parkinson's disease (PD, and clinical observations suggest that physical exercise can reduce the motor symptoms in PD patients. In experimental animals, a profound observation is that exercise of appropriate timing, duration, and intensity can reduce toxin-induced lesion of the nigrostriatal dopamine (DA system in animal PD models, although negative results have also been reported, potentially due to inappropriate timing and intensity of the exercise regimen. Exercise may also minimize DA denervation-induced medium spiny neuron (MSN dendritic atrophy and other abnormalities such as enlarged corticostriatal synapse and abnormal MSN excitability and spiking activity. Taken together, epidemiological studies, clinical observations, and animal research indicate that appropriately dosed physical activity and exercise may not only reduce the risk of developing PD in vulnerable populations but also benefit PD patients by potentially protecting the residual DA neurons or directly restoring the dysfunctional cortico-basal ganglia motor control circuit, and these benefits may be mediated by exercise-triggered production of endogenous neuroprotective molecules such as neurotrophic factors. Thus, exercise is a universally available, side effect-free medicine that should be prescribed to vulnerable populations as a preventive measure and to PD patients as a component of treatment. Future research needs to establish standardized exercise protocols that can reliably induce DA neuron protection, enabling the delineation of the underlying cellular and molecular mechanisms that in turn can maximize exercise-induced neuroprotection and neurorestoration in animal PD models and eventually in PD patients.

  18. Systemic Blockade of D2-Like Dopamine Receptors Facilitates Extinction of Conditioned Fear in Mice

    Science.gov (United States)

    Ponnusamy, Ravikumar; Nissim, Helen A.; Barad, Mark

    2005-01-01

    Extinction of conditioned fear in animals is the explicit model of behavior therapy for human anxiety disorders, including panic disorder, obsessive-compulsive disorder, and post-traumatic stress disorder. Based on previous data indicating that fear extinction in rats is blocked by quinpirole, an agonist of dopamine D2 receptors, we hypothesized…

  19. Voluntary Exercise Improves Performance of a Discrimination Task through Effects on the Striatal Dopamine System

    Science.gov (United States)

    Eddy, Meghan C.; Stansfield, Katherine J.; Green, John T.

    2014-01-01

    We have previously demonstrated that voluntary exercise facilitates discrimination learning in a modified T-maze. There is evidence implicating the dorsolateral striatum (DLS) as the substrate for this task. The present experiments examined whether changes in DLS dopamine receptors might underlie the exercise-associated facilitation. Infusing a…

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

    Directory of Open Access Journals (Sweden)

    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

  1. Effects of systemic carbidopa on dopamine synthesis in rat hypothalamus and striatum

    Science.gov (United States)

    Kaakkola, S.; Tuomainen, P.; Wurtman, R. J.; Mannisto, P. T.

    1992-01-01

    Significant concentrations of carbidopa (CD) were found in rat hypothalamus, striatum, and in striatal microdialysis efflux after intraperitoneal administration of the drug. Efflux levels peaked one hour after administration of 100 mg/kg at 0.37 micrograms/ml, or about 2% of serum levels. Concurrent CD levels in hypothalamus and striatum were about 2.5% and 1.5%, respectively, of corresponding serum levels. Levels of dopamine and its principal metabolites in striatal efflux were unaffected. The removal of the brain blood by saline perfusion decreased the striatal and hypothalamic CD concentrations only by 33% and 16%, respectively. In other rats receiving both CD and levodopa (LD), brain L-dopa, dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels after one hour tended to be proportionate to LD dose. When the LD dose remained constant, increasing the CD dose dose-dependently enhanced L-dopa levels in the hypothalamus and striatum. However dopamine levels did not increase but, in contrast, decreased dose-dependently (although significantly only in the hypothalamus). CD also caused dose-dependent decrease in striatal 3-O-methyldopa (3-OMD) and in striatal and hypothalamic homovanillic acid (HVA), when the LD dose was 50 mg/kg. We conclude that, at doses exceeding 50 mg/kg, sufficient quantities of CD enter the brain to inhibit dopamine formation, especially in the hypothalamus. Moreover, high doses of LD/CD, both of which are themselves catechols, can inhibit the O-methylation of brain catecholamines formed from the LD.

  2. Systemic blockade of D2-like dopamine receptors facilitates extinction of conditioned fear in mice

    OpenAIRE

    Ponnusamy, Ravikumar; Nissim, Helen A.; Barad, Mark

    2005-01-01

    Extinction of conditioned fear in animals is the explicit model of behavior therapy for human anxiety disorders, including panic disorder, obsessive-compulsive disorder, and post-traumatic stress disorder. Based on previous data indicating that fear extinction in rats is blocked by quinpirole, an agonist of dopamine D2 receptors, we hypothesized that blockade of D2 receptors might facilitate extinction in mice, while agonists should block extinction, as they do in rats. One day after fear con...

  3. ETUDE FONCTIONNELLE DES SYSTEMES DE CAPTURE SYNAPTOSOMALE ET VESICULAIRE DE DOPAMINE

    Directory of Open Access Journals (Sweden)

    M SLIMANI

    2001-06-01

    Full Text Available L‘injection stéréotaxique unilatérale dans la substance noire de la 6 hydroxy-dopamine ( 6OH-DA se traduit par une chute  parallèle  de  la   capture de dopamine tritiée au  niveau  synaptosomale de  l'ordre  de -70 % et dans les préparations vésiculaires de l'ordre de -69 %, comparées aux préparations issues de Rats non lésés. Ces résultats montrent que ces deux préparations synaptosomales et vésiculaires sont bien d'origine dopaminergique. D'autre part, une étude comparative de l'effet de quelques agents pharmacologiques (β carbolines, imipraminiques, amphétamine et les inhibiteurs purs de la capture synaptosomale sur la capture synaptosomale et vésiculaire de la dopamine tritiée in-vitro, montre qu'ils agissent comme de puissants inhibiteurs. Nous montrons également que le transporteur vésiculaire diffère du transporteur synaptosomal par sa stéréospécificité et sa sensibilité aux agents pharmacologiques.

  4. Different loss of dopamine transporter according to subtype of multiple system atrophy

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Hae Won [Keimyung University Dongsan Medical Center, Department of Nuclear Medicine, Daegu (Korea, Republic of); Keimyung University, Department of Nuclear Medicine, School of Medicine, Jung-gu, Daegu (Korea, Republic of); Kim, Jae Seung; Oh, Minyoung; Oh, Jungsu S.; Lee, Sang Joo; Oh, Seung Jun [University of Ulsan College of Medicine, Department of Nuclear Medicine, Asan Medical Center, Songpa-gu, Seoul (Korea, Republic of); Chung, Sun Ju; Lee, Chong Sik [University of Ulsan College of Medicine, Department of Neurology, Asan Medical Center, Seoul (Korea, Republic of)

    2016-03-15

    The aim of this study was to evaluate whether striatal dopamine transporter (DAT) loss as measured by {sup 18}F-fluorinated-N-3-fluoropropyl-2-b-carboxymethoxy-3-b-(4-iodophenyl) nortropane ([{sup 18}F]FP-CIT) PET differs according to the metabolic subtype of multiple system atrophy (MSA) as assessed by [{sup 18}F]FDG PET. This retrospective study included 50 patients with clinically diagnosed MSA who underwent [{sup 18}F]FP-CIT and [{sup 18}F]FDG brain PET scans. The PET images were analysed using 12 striatal subregional volume-of-interest templates (bilateral ventral striatum, anterior caudate, posterior caudate, anterior putamen, posterior putamen, and ventral putamen). The patients were classified into three metabolic subtypes according to the [{sup 18}F]FDG PET findings: MSA-P{sub m} (striatal hypometabolism only), MSA-mixed{sub m} (both striatal and cerebellar hypometabolism), and MSA-C{sub m} (cerebellar hypometabolism only). The subregional glucose metabolic ratio (MR{sub gluc}), subregional DAT binding ratio (BR{sub DAT}), and intersubregional ratio (ISR{sub DAT}; defined as the BR{sub DAT} ratio of one striatal subregion to that of another striatal subregion) were compared according to metabolic subtype. Of the 50 patients, 13 presented with MSA-P{sub m}, 16 presented with MSA-mixed{sub m}, and 21 presented with MSA-C{sub m}. The BR{sub DAT} of all striatal subregions in the MSA-P{sub m} and MSA-mixed{sub m} groups were significantly lower than those in the MSA-C{sub m} group. The posterior putamen/anterior putamen ISR{sub DAT} and anterior putamen/ventral striatum ISR{sub DAT} in the MSA-P{sub m} and MSA-mixed{sub m} groups were significantly lower than those in the MSA-C{sub m} group. Patients with MSA-P{sub m} and MSA-mixed{sub m} showed more severe DAT loss in the striatum than patients with MSA-C{sub m}. Patients with MSA-C{sub m} had more diffuse DAT loss than patients with MSA-P{sub m} and MSA-mixed{sub m}. (orig.)

  5. Regulation of the mesolimbic dopamine circuit by feeding peptides.

    Science.gov (United States)

    Liu, S; Borgland, S L

    2015-03-19

    Polypeptides produced in the gastrointestinal tract, stomach, adipocytes, pancreas and brain that influence food intake are referred to as 'feeding-related' peptides. Most peptides that influence feeding exert an inhibitory effect (anorexigenic peptides). In contrast, only a few exert a stimulating effect (orexigenic peptides), such as ghrelin. Homeostatic feeding refers to when food consumed matches energy deficits. However, in western society where access to palatable energy-dense food is nearly unlimited, food is mostly consumed for non-homeostatic reasons. Emerging evidence implicates the mesocorticolimbic circuitry, including dopamine neurons of the ventral tegmental area (VTA), as a key substrate for non-homeostatic feeding. VTA dopamine neurons encode cues that predict rewards and phasic release of dopamine in the ventral striatum motivates animals to forage for food. To elucidate how feeding-related peptides regulate reward pathways is of importance to reveal the mechanisms underlying non-homeostatic or hedonic feeding. Here, we review the current knowledge of how anorexigenic peptides and orexigenic peptides act within the VTA. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  6. Design of a multi-dopamine-modified polymer ligand optimally suited for interfacing magnetic nanoparticles with biological systems.

    Science.gov (United States)

    Wang, Wentao; Ji, Xin; Na, Hyon Bin; Safi, Malak; Smith, Alexandra; Palui, Goutam; Perez, J Manuel; Mattoussi, Hedi

    2014-06-03

    We have designed a set of multifunctional and multicoordinating polymer ligands that are optimally suited for surface functionalizing iron oxide and potentially other magnetic nanoparticles (NPs) and promoting their integration into biological systems. The amphiphilic polymers are prepared by coupling (via nucleophilic addition) several amine-terminated dopamine anchoring groups, poly(ethylene glycol) moieties, and reactive groups onto a poly(isobutylene-alt-maleic anhydride) (PIMA) chain. This design greatly benefits from the highly efficient and reagent-free one-step reaction of maleic anhydride groups with amine-containing molecules. The availability of several dopamine groups in the same ligand greatly enhances the ligand affinity, via multiple coordination, to the magnetic NPs, while the hydrophilic and reactive groups promote colloidal stability in buffer media and allow subsequent conjugation with target biomolecules. Iron oxide nanoparticles ligand exchanged with these polymer ligands have a compact hydrodynamic size and exhibit enhanced long-term colloidal stability over the pH range of 4-12 and in the presence of excess electrolytes. Nanoparticles ligated with terminally reactive polymers have been easily coupled to target dyes and tested in live cell imaging with no measurable cytotoxicity. Finally, the resulting hydrophilic nanoparticles exhibit large and size-dependent r2 relaxivity values.

  7. Levodopa acts centrally to induce an antinociceptive action against colonic distension through activation of D2 dopamine receptors and the orexinergic system in the brain in conscious rats

    Directory of Open Access Journals (Sweden)

    Toshikatsu Okumura

    2016-02-01

    Subcutaneously (80 mg/rat or intracisternally (2.5 μg/rat administered levodopa significantly increased the threshold of colonic distension-induced AWR in conscious rats. The dose difference to induce the antinociceptive action suggests levodopa acts centrally to exert its antinociceptive action against colonic distension. While neither sulpiride, a D2 dopamine receptor antagonist, nor SCH23390, a D1 dopamine receptor antagonist by itself changed the threshold of colonic distension-induced AWR, the intracisternally injected levodopa-induced antinociceptive action was significantly blocked by pretreatment with subcutaneously administered sulpiride but not SCH23390. Treatment with intracisternal SB334867, an orexin 1 receptor antagonist, significantly blocked the subcutaneously administered levodopa-induced antinociceptive action. These results suggest that levodopa acts centrally to induce an antinociceptive action against colonic distension through activation of D2 dopamine receptors and the orexinergic system in the brain.

  8. Differential mesocorticolimbic responses to palatable food in binge eating prone and binge eating resistant female rats.

    Science.gov (United States)

    Sinclair, Elaine B; Culbert, Kristen M; Gradl, Dana R; Richardson, Kimberlei A; Klump, Kelly L; Sisk, Cheryl L

    2015-12-01

    Binge eating is a key symptom of many eating disorders (e.g. binge eating disorder, bulimia nervosa, anorexia nervosa binge/purge type), yet the neurobiological underpinnings of binge eating are poorly understood. The mesocorticolimbic reward circuit, including the nucleus accumbens and the medial prefrontal cortex, is likely involved because this circuit mediates the hedonic value and incentive salience of palatable foods (PF). Here we tested the hypothesis that higher propensity for binge eating is associated with a heightened response (i.e., Fos induction) of the nucleus accumbens and medial prefrontal cortex to PF, using an animal model that identifies binge eating prone (BEP) and binge eating resistant (BER) rats. Forty adult female Sprague-Dawley rats were given intermittent access to PF (high fat pellets) 3×/week for 3 weeks. Based on a pattern of either consistently high or consistently low PF consumption across these feeding tests, 8 rats met criteria for categorization as BEP, and 11 rats met criteria for categorization as BER. One week after the final feeding test, BEP and BER rats were either exposed to PF in their home cages or were given no PF in their home cages for 1h prior to perfusion, leading to three experimental groups for the Fos analysis: BEPs given PF, BERs given PF, and a No PF control group. The total number of Fos-immunoreactive (Fos-ir) cells in the nucleus accumbens core and shell, and the cingulate, prelimbic, and infralimbic regions of the medial prefrontal cortex was estimated by stereological analysis. PF induced higher Fos expression in the nucleus accumbens shell and core and in the prelimbic and infralimbic cortex of BEP rats compared to No PF controls. Throughout the nucleus accumbens and medial prefrontal cortex, PF induced higher Fos expression in BEP than in BER rats, even after adjusting for differences in PF intake. Differences in the neural activation pattern between BEP and BER rats were more robust in prefrontal cortex

  9. PRESYNAPTIC DOPAMINE MODULATION BY STIMULANT SELF ADMINISTRATION

    Science.gov (United States)

    España, Rodrigo A.; Jones, Sara R.

    2013-01-01

    The mesolimbic dopamine system is an essential participant in the initiation and modulation of various forms of goal-directed behavior, including drug reinforcement and addiction processes. Dopamine neurotransmission is increased by acute administration of all drugs of abuse, including the stimulants cocaine and amphetamine. Chronic exposure to these drugs via voluntary self-administration provides a model of stimulant abuse that is useful in evaluating potential behavioral and neurochemical adaptations that occur during addiction. This review describes commonly used methodologies to measure dopamine and baseline parameters of presynaptic dopamine regulation, including exocytotic release and reuptake through the dopamine transporter in the nucleus accumbens core, as well as dramatic adaptations in dopamine neurotransmission and drug sensitivity that occur with acute non-contingent and chronic, contingent self-administration of cocaine and amphetamine. PMID:23277050

  10. The influence of leptin on the dopamine system and implications for ingestive behavior.

    Science.gov (United States)

    DiLeone, R J

    2009-06-01

    Food intake is regulated by many factors, including sensory information, metabolic hormones and the state of hunger. In modern humans, the drive to eat has proven to be incompatible with the excess food supply present in industrialized societies. A result of this imbalance is the dramatically increased rates of obesity during the last 20 years. The rise in obesity rates poses one of the most significant public health issues facing the United States and yet we do not understand the neural basis of ingestive behavior, and specifically, our motivation to eat. Understanding how the brain controls eating will lay the foundation for systematic dissection, understanding and treatment of obesity and related disorders. The lack of control over food intake bears resemblance to drug addiction, where loss of control over behavior leads to compulsive drug use. Work in laboratory animals has long suggested that there exist common neural substrates underlying both food and drug intake behaviors. Recent studies have shown direct leptin effects on dopamine neuron function and behavior. This provides a new mechanism by which peripheral hormones influence behavior and contribute to a more comprehensive model of neural control over food intake.

  11. Nature of rate-limiting steps in a compartmentalized enzyme system. Quantitation of dopamine transport and hydroxylation rates in resealed chromaffin granule ghosts

    International Nuclear Information System (INIS)

    Ahn, N.G.; Klinman, J.P.

    1989-01-01

    Using isolated chromaffin granule ghosts from bovine adrenal medullae, we have studied the kinetics of dopamine beta-monooxygenase (D beta M) activity as it is linked to dopamine transport. Measurements of the initial rates of transport and of transport-linked norepinephrine formation suggested that enzyme activity may be partially rate-limiting in the coupled carrier/enzyme system. This was confirmed by (i) measurements of initial rates of norepinephrine formation using deuterated substrate, which gave isotope effects greater than 2.0, and (ii) kinetic measurements using ghosts pulsed with varying concentrations of labeled dopamine, which indicated substantial substrate accumulation in the vesicle interior as a function of time. Initial rates of product formation, when combined with approximations of internal substrate concentrations, allowed estimates of Kcat and Km for intravesicular D beta M. Activation by external reductant was apparent in both initial rate parameters and the measurements of transients. Under conditions of optimal D beta M activity, the enzyme rate parameters (kcat = 0.31 nmol/s.mg and Km = 2 mM) indicated partial rate limitation compared to dopamine transport (kcat = 0.38 nmol/s.mg and Km = 32 microM). Compartmental analysis of the time curves, performed using numerical nonlinear least squares methods, gave least squares estimates of rate constants for a simple carrier mechanism and kcat values for D beta M which were consistent with estimates from initial rates

  12. β(3)-Adrenoceptor Antagonist SR59230A Attenuates the Imbalance of Systemic and Myocardial Oxygen Transport Induced by Dopamine in Newborn Lambs.

    Science.gov (United States)

    Gill, Richdeep S; Cheung, Po-Yin; Yu, Xiaoyang; Aklabi, Mohammed Al; Nagendran, Jeevan; Quinonez, Luis G; Li, Ying Qian; Miller, John; Ross, David B; Rebeyka, Ivan M; Li, Jia

    2012-01-01

    In neonates, the increase in O(2)-delivery (DO(2)) by dopamine is offset by a greater increase in O(2)-consumption (VO(2)). This has been attributed to β(3)-adrenergic receptors in neonatal brown fat tissue. β(3) receptors in the heart have negative inotropic properties. We evaluated the effects of SR59230A, a β(3)-antagonist, on the balance of systemic and myocardial O(2)-transport in newborn lambs treated with dopamine. Lambs (2-5 days old, n = 12) were anesthetized and mechanically ventilated. Heart rate (HR) and rectal temperature were monitored. VO(2) was measured by respiratory mass spectrometry and cardiac output (CO) by a pulmonary artery transonic flowmeter. Arterial, jugular bulb venous and coronary sinus blood gases and lactate were measured to calculate DO(2), O(2) extraction ratio (ERO(2)), myocardial O(2) and lactate extraction ratios (mERO(2), mERlac). After baseline measurements, lambs were randomized to receive SR59230A at 5 mg/kg iv (SRG) or placebo. Both groups received incremental doses of a dopamine infusion (0-5-10-15-20 mcg/kg/min) every 15 min. Measurements were repeated at the end of each dose. After SR59230A infusion, CO and HR trended to decrease (P = 0.06), but no significant changes occurred in other parameters. Over the incremental doses of dopamine, temperature increased in both groups (P 0.1). DO(2) trended to a small increase (P = 0.08). VO(2) increased in both groups (P transport induced by dopamine at higher doses. Studies are warranted to examine the effect of SR59230A in cases of cardiac dysfunction and increased VO(2), observed after cardiac surgery.

  13. NEUROTRANSMITTERS AND IMMUNITY: 1. DOPAMINE

    Directory of Open Access Journals (Sweden)

    Lucian Hritcu

    2007-08-01

    Full Text Available Dopamine is one of the principal neurotransmitters in the central nervous system (CNC, and its neuronal pathways are involved in several key functions such as behavior (Hefco et al., 2003a,b, control of movement, endocrine regulation, immune response (Fiserova et al., 2002; Levite et al., 2001, Hritcu et al., 2006a,b,c, and cardiovascular function. Dopamine has at least five G-protein, coupled receptor subtypes, D1-D5, each arising from a different gene (Sibley et al., 1993. Traditionally, these receptors have been classified into D1-like (the D1 and D5 and D2-like (D2, D3 and D4 receptors subtypes, primarily according to their ability to stimulate or inhibit adenylate cyclase, respectively, and to their pharmacological characteristics (Seeman et al., 1993. Receptors for dopamine (particularly of D2 subclass are the primary therapeutic target in a number of neuropathological disorders including schizophrenia, Parkinson’s disease and Huntington’s chorea (Seeman et al., 1987. Neither dopamine by itself, nor dopaminergic agonists by themselves, has been shown to activate T cell function. Nevertheless, lymphocytes are most probably exposed to dopamine since the primary and secondary lymphoid organs of various mammals are markedly innervated, and contain nerve fibers which stain for tyrosine hydroxylase (Weihe et al., 1991, the enzyme responsible for dopamine synthesis. Moreover, cathecolamines and their metabolites are present in single lymphocytes and in extracts of T and B cell clones, and pharmacological inhibition of tyrosine hydroxylase reduces catecholamine levels, suggesting catecholamine synthesis by lymphocytes (Bergquist et al., 1994. The existence of putative dopamine receptors of D2, D3, D4 and D5 subtypes on immune cells has been proposed of several authors, primarily on the basis of dopaminergic ligand binding assays and specific mRNA expression as monitored by reverse transcription-PCR. Several experiments evoked the idea of a

  14. Contribution of vesicular and cytosolic dopamine to the increased striatal dopamine efflux elicited by intrastriatal injection of dexamphetamine.

    NARCIS (Netherlands)

    Watanabe, S.; Aono, Y.; Fusa, K.; Takada, K.; Saigusa, T.; Koshikawa, N.; Cools, A.R.

    2005-01-01

    Systemic administration of high doses of dexamphetamine induces a dopamine efflux that has its intracellular origin in both the vesicular, reserpine-sensitive dopamine pool and the cytosolic, alpha-methyl-para-tyrosine-sensitive, newly synthesized dopamine pool. It remains unknown whether locally

  15. Dopamine agonists and Othello's syndrome

    Science.gov (United States)

    Graff-Radford, Jonathan; Ahlskog, J Eric.; Bower, James H.; Josephs, Keith A.

    2014-01-01

    Background Othello's syndrome (OS) is a delusion of infidelity. We describe seven cases of OS in Parkinson's disease (iPD) patients using dopamine agonists. Methods We searched the Mayo Clinic Medical Records System to identify all patients with OS. Clinical data abstracted include sex, age of onset of iPD, age of onset of OS, medications, effect of discontinuing the dopamine agonist, neuroimaging, and comorbidities. Results Seven non-demented iPD patients with dopamine agonist implementation time locked to the development and resolution of OS are reported. The average age of iPD onset was 46.6 years (Standard deviation: 5.0 years), and OS onset was 53.7 years (7.1 years). All seven patients had significant marital conflict as a result of the delusions. Conclusions OS can be associated with dopamine agonist use and can lead to serious consequences. Dopamine agonist cessation eliminates the delusion of infidelity and should be the first treatment option. PMID:20829092

  16. Peripubertal diazepam administration prevents the emergence of dopamine system hyperresponsivity in the MAM developmental disruption model of schizophrenia.

    Science.gov (United States)

    Du, Yijuan; Grace, Anthony A

    2013-09-01

    Schizophrenia is believed to arise from an interaction of genetic predisposition and adverse environmental factors, with stress being a primary variable. We propose that alleviating anxiety produced in response to stress during a sensitive developmental period may circumvent the dopamine (DA) system alterations that may correspond to psychosis in adults. This was tested in a developmental rat model of schizophrenia based on prenatal administration of the mitotoxin methyl azoxymethanol acetate (MAM). MAM administration leads to a hyperdopaminergic state consisting of an increase in the number of DA neurons firing spontaneously, which correlates with an increased behavioral response to amphetamine. MAM-treated rats exhibited a heightened level of anxiety during adolescence. Peripubertal administration of the antianxiety agent diazepam was found to prevent the increase in DA neuron activity and blunt the behavioral hyperresponsivity to amphetamine in these rats. These data suggest that the pathophysiological factors leading to the onset of psychosis in early adulthood may be circumvented by controlling the response to stress during the peripubertal period.

  17. Peripubertal Diazepam Administration Prevents the Emergence of Dopamine System Hyperresponsivity in the MAM Developmental Disruption Model of Schizophrenia

    Science.gov (United States)

    Du, Yijuan; Grace, Anthony A

    2013-01-01

    Schizophrenia is believed to arise from an interaction of genetic predisposition and adverse environmental factors, with stress being a primary variable. We propose that alleviating anxiety produced in response to stress during a sensitive developmental period may circumvent the dopamine (DA) system alterations that may correspond to psychosis in adults. This was tested in a developmental rat model of schizophrenia based on prenatal administration of the mitotoxin methyl azoxymethanol acetate (MAM). MAM administration leads to a hyperdopaminergic state consisting of an increase in the number of DA neurons firing spontaneously, which correlates with an increased behavioral response to amphetamine. MAM-treated rats exhibited a heightened level of anxiety during adolescence. Peripubertal administration of the antianxiety agent diazepam was found to prevent the increase in DA neuron activity and blunt the behavioral hyperresponsivity to amphetamine in these rats. These data suggest that the pathophysiological factors leading to the onset of psychosis in early adulthood may be circumvented by controlling the response to stress during the peripubertal period. PMID:23612434

  18. Distribution of serotonin and dopamine in the central nervous system of the female mud crab, Scylla olivacea (Herbst).

    Science.gov (United States)

    Khornchatri, Kanjana; Kornthong, Napamanee; Saetan, Jirawat; Tinikul, Yotsawan; Chotwiwatthanakun, Charoonroj; Cummins, Scott F; Hanna, Peter J; Sobhon, Prasert

    2015-03-01

    In crustaceans serotonin (5-HT) and dopamine (DA) are neurotransmitters that play roles in the modulation of numerous physiological functions, including reproduction. However, in the mud crab, Scylla olivacea, the distributions of 5-HT and DA in the CNS have not yet been investigated. The aim of our study was to map the distributions of these two neurotransmitters in the central nervous system (CNS) of the female of this crab during the late stage of ovarian development. We found 5-HT immunoreactivity (-ir) and DA-ir in many parts of the CNS, including the eyestalk, brain, and thoracic ganglia. In the eyestalk, 5-HT-ir was localized in the medulla terminalis (MT), hemi-ellipsoid body (HB), and protocerebral tract (PT), whereas DA-ir was present in neuronal cluster 1, the LG neuropils, and PT. In the brain, 5-HT-ir and DA-ir were detected in cells and fibers of neuronal clusters 6, 7, 8, 9, 10, 11, 14, and 15. In the ventral nerve cord, 5-HT-ir was present in neurons of the abdominal ganglia, whereas DA was only present in fibers. These spatial distributions of 5-HT and DA suggest that they may be involved in the neuromodulation of important physiological functions, including ovarian maturation, as shown in other non-crab decapods. Copyright © 2014 Elsevier GmbH. All rights reserved.

  19. Prenatal exposure to methylphenidate affects the dopamine system and the reactivity to natural reward in adulthood in rats.

    Science.gov (United States)

    Lepelletier, François-Xavier; Tauber, Clovis; Nicolas, Céline; Solinas, Marcello; Castelnau, Pierre; Belzung, Catherine; Emond, Patrick; Cortese, Samuele; Faraone, Stephen V; Chalon, Sylvie; Galineau, Laurent

    2014-10-31

    Methylphenidate (MPH) is a commonly-used medication for the treatment of children with Attention-Deficit/Hyperactivity Disorders (ADHD). However, its prescription to adults with ADHD and narcolepsy raises the question of how the brain is impacted by MPH exposure during pregnancy. The goal of this study was to elucidate the long-term neurobiological consequences of prenatal exposure to MPH using a rat model. We focused on the effects of such treatment on the adult dopamine (DA) system and on the reactivity of animals to natural rewards. This study shows that adult male rats prenatally exposed to MPH display elevated expression of presynaptic DA markers in the DA cell bodies and the striatum. Our results also suggest that MPH-treated animals could exhibit increased tonic DA activity in the mesolimbic pathway, altered signal-to-noise ratio after a pharmacological stimulation, and decreased reactivity to the locomotor effects of cocaine. Finally, we demonstrated that MPH rats display a decreased preference and motivation for sucrose. This is the first preclinical study reporting long-lasting neurobiological alterations of DA networks as well as alterations in motivational behaviors for natural rewards after a prenatal exposure to MPH. These results raise concerns about the possible neurobiological consequences of MPH treatment during pregnancy. © The Author 2015. Published by Oxford University Press on behalf of CINP.

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

    Science.gov (United States)

    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.

  1. Dopamine attenuates the chemoattractant effect of interleukin-8: a novel role in the systemic inflammatory response syndrome.

    LENUS (Irish Health Repository)

    Sookhai, S

    2012-02-03

    Activated neutrophil (PMN) adherence to vascular endothelium comprises a key step for both transendothelial migration and initiation of potentially deleterious release of PMN products. The biogenic amine, dopamine (DA), has been used for several decades in patients to maintain hemodynamic stability. The effect of dopamine on PMN transendothelial migration and adhesion receptor expression and on the endothelial molecules, E-selectin and ICAM-1, was evaluated. PMN were isolated from healthy controls, stimulated with lipopolysaccharide (LPS), and tumor necrosis factor-alpha (TNF-alpha) and treated with dopamine. CD 11b and CD 18 PMN adhesion receptor expression were assessed flow cytometrically. In a separate experiment, the chemoattractant peptide, IL-8, was placed in the lower chamber of transwells, and PMN migration was assessed. Human umbilical vein endothelial cells (HUVEC) were stimulated with LPS\\/TNF-alpha and incubated with dopamine. ICAM-1 and E-selectin endothelial molecule expression were assessed flow cytometrically. There was a significant increase in transendothelial migration in stimulated PMN compared with normal PMN (40 vs. 14%, P < 0.001). In addition, PMN CD11b\\/CD18 was significantly upregulated in stimulated PMN compared with normal PMN (252.4\\/352.4 vs. 76.7\\/139.4, P < 0.001) as were endothelial E-selectin\\/ICAM-1 expression compared with normal EC (8.1\\/9 vs. 3.9\\/3.8, P < 0.05). After treatment with dopamine, PMN transmigration was significantly decreased compared with stimulated PMN (8% vs. 40%, P < 0.001). Furthermore, dopamine also attenuated PMN CD11b\\/CD18 and the endothelial molecules E-selectin and ICAM-1 compared with stimulated PMN\\/EC that were not treated dopamine (174\\/240 vs. 252\\/352, P < 0.05 and 4\\/4.4 vs. 8.1\\/9, P < 0.05. respectively). The chemoattractant effect of IL-8 was also attenuated. These results identify for the first time that dopamine attenuates the initial interaction between PMN and the endothelium

  2. The crystal structure of human dopamine  β-hydroxylase at 2.9 Å resolution

    DEFF Research Database (Denmark)

    Vendelboe, Trine Vammen; Harris, Pernille; Zhao, Y.

    2016-01-01

    , Alzheimer’s disease, attention deficit hyperactivity disorder, and cocaine dependence. We report the crystal structure of human dopamine β-hydroxylase, which is the enzyme converting dopamine to norepinephrine. The structure of the DOMON (dopamine β-monooxygenase N-terminal) domain, also found in >1600...... into the numerous devastating disorders of both physiological and neurological origins associated with the dopamine system....

  3. Effects of co-administration of ketamine and ethanol on the dopamine system via the cortex-striatum circuitry.

    Science.gov (United States)

    Liu, Qing; Xu, Tian-Yong; Zhang, Zhi-Bi; Leung, Chi-Kwan; You, Ding-Yun; Wang, Shang-Wen; Yi, Shuai; Jing, Qiang; Xie, Run-Fang; Li, Huifang-Jie; Zeng, Xiao-Feng

    2017-06-15

    Ketamine and ethanol are increasingly being used together as recreational drugs in rave parties. Their effects on the dopamine (DA) system remain largely unknown. This study aimed to investigate the effects of consuming two different concentrations of ketamine with and without alcohol on the DA system. We employed the conditioned place preference (CPP) paradigm to evaluate the rewarding effects of the combined administration of two different doses of ketamine (30mg/kg and 60mg/kg) with ethanol (0.3156g/kg). We evaluated the effects of the combined drug treatment on the transcriptional output of tyrosine hydroxylase (TH), dopa decarboxylase (DDC), synaptosomal-associated protein 25 (SNAP25), and vesicular monoamine transporter 2 (VMAT2) as well as protein expression level of brain-derived neurotrophic factor (BDNF) in rat prefrontal cortex (PFC) and striatum. We found that rats exhibited a dose-dependent, drug-paired, place preference to ketamine and ethanol associated with an elevated DA level in the striatum but not in the PFC. Moreover, treatment involving low- or high-dose ketamine with or without ethanol caused a differential regulatory response in the mRNA levels of the four DA metabolism genes and the cellular protein abundance of BDNF via the cortex-striatum circuitry. This study investigated the molecular mechanisms that occur following the combined administration of ketamine and ethanol in the DA system, which could potentially lead to alterations in the mental status and behavior of ketamine/ethanol users. Our findings may aid the development of therapeutic strategies for substance abuse patients. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Fighting food temptations: the modulating effects of short-term cognitive reappraisal, suppression and up-regulation on mesocorticolimbic activity related to appetitive motivation.

    Science.gov (United States)

    Siep, Nicolette; Roefs, Anne; Roebroeck, Alard; Havermans, Remco; Bonte, Milene; Jansen, Anita

    2012-03-01

    The premise of cognitive therapy is that one can overcome the irresistible temptation of highly palatable foods by actively restructuring the way one thinks about food. Testing this idea, participants in the present study were instructed to passively view foods, up-regulate food palatability thoughts, apply cognitive reappraisal (e.g., thinking about health consequences), or suppress food palatability thoughts and cravings. We examined whether these strategies affect self-reported food craving and mesocorticolimbic activity as assessed by functional magnetic resonance imaging. It was hypothesized that cognitive reappraisal would most effectively inhibit the mesocorticolimbic activity and associated food craving as compared to suppression. In addition, it was hypothesized that suppression would lead to more prefrontal cortex activity, reflecting the use of more control resources, as compared to cognitive reappraisal. Self-report results indicated that up-regulation increased food craving compared to the other two conditions, but that there was no difference in craving between the suppression and cognitive reappraisal strategy. Corroborating self-report results, the neuroimaging results showed that up-regulation increased activity in important regions of the mesocorticolimbic circuitry, including the ventral tegmental area, ventral striatum, operculum, posterior insular gyrus, medial orbitofrontal cortex and ventromedial prefrontal cortex. Contrary to our hypothesis, suppression more effectively decreased activity in the core of the mesocorticolimbic circuitry (i.e., ventral tegmental area and ventral striatum) compared to cognitive reappraisal. Overall, the results support the contention that appetitive motivation can be modulated by the application of short-term cognitive control strategies. Copyright © 2012 Elsevier Inc. All rights reserved.

  5. Effect of U and 137Cs chronic contamination on dopamine and serotonin metabolism in the central nervous system of the rat

    International Nuclear Information System (INIS)

    Houpert, P.; Lestaevel, P.; Amourette, C.; Dhieux, B.; Bussy, C.; Paquet, F.

    2004-01-01

    Following the Chernobyl accident, the most significant problem for the population of the former Soviet Union for the next 50-70 years will be chronic internal contamination by radionuclides. One of the few experiments carried out in this field reported that neurotransmitter metabolism in the central nervous system of the rat was disturbed after feeding with oats contaminated by 137 Cs for 1 month. The present study assessed the effect of chronic contamination by depleted U or 137 Cs on the metabolism of two neurotransmitters in cerebral areas of rats. Dopamine and serotonin were chosen because their metabolism has been shown to be disturbed after external irradiation, even at moderate doses. Dopamine, serotonin, and some of their catabolites were measured by high-pressure liquid chromatography coupled with an electrochemical detector in five cerebral structures of rats contaminated over a 1-month period by drinking water (40 mg U·L -1 or 6500 Bq 137 Cs·L -1 ). In the striatum, hippocampus, cerebral cortex, thalamus, and cerebellum, the dopamine, serotonin, and catabolite levels were not significantly different between the control rats and rats contaminated by U or 137 Cs. These results are not in accordance with those previously described. (author)

  6. Effect of U and {sup 137}Cs chronic contamination on dopamine and serotonin metabolism in the central nervous system of the rat

    Energy Technology Data Exchange (ETDEWEB)

    Houpert, P.; Lestaevel, P. [Inst. de Radioprotection et de Surete Nucleaire (IRSN), Inst. de Radioprotection et de Surete Nucleaire, Dept. de la RadioProtection de l' Homme, Service de RadioBiologie et d' Epidemiologie, Lab. RadioToxicologie experimentale, Pierrelatte (France)]. E-mail: philippe.lestaevel@irsn.fr; Amourette, C. [Centre de Recherches du Service de Sante des Armees Emile Parde, Dept. de Radiobiologie et Radiopathologie, La Tronche (France); Dhieux, B.; Bussy, C.; Paquet, F. [Inst. de Radioprotection et de Surete Nucleaire (IRSN), Inst. de Radioprotection et de Surete Nucleaire, Dept. de la RadioProtection de l' Homme, Service de RadioBiologie et d' Epidemiologie, Lab. RadioToxicologie experimentale, Pierrelatte (France)

    2004-02-01

    Following the Chernobyl accident, the most significant problem for the population of the former Soviet Union for the next 50-70 years will be chronic internal contamination by radionuclides. One of the few experiments carried out in this field reported that neurotransmitter metabolism in the central nervous system of the rat was disturbed after feeding with oats contaminated by {sup 137}Cs for 1 month. The present study assessed the effect of chronic contamination by depleted U or {sup 137}Cs on the metabolism of two neurotransmitters in cerebral areas of rats. Dopamine and serotonin were chosen because their metabolism has been shown to be disturbed after external irradiation, even at moderate doses. Dopamine, serotonin, and some of their catabolites were measured by high-pressure liquid chromatography coupled with an electrochemical detector in five cerebral structures of rats contaminated over a 1-month period by drinking water (40 mg U{center_dot}L{sup -1} or 6500 Bq {sup 137}Cs{center_dot}L{sup -1}). In the striatum, hippocampus, cerebral cortex, thalamus, and cerebellum, the dopamine, serotonin, and catabolite levels were not significantly different between the control rats and rats contaminated by U or {sup 137}Cs. These results are not in accordance with those previously described. (author)

  7. Dopamine uptake inhibitors but not dopamine releasers induce greater increases in motor behavior and extracellular dopamine in adolescent rats than in adult male rats.

    Science.gov (United States)

    Walker, Q David; Morris, Sarah E; Arrant, Andrew E; Nagel, Jacqueline M; Parylak, Sarah; Zhou, Guiying; Caster, Joseph M; Kuhn, Cynthia M

    2010-10-01

    Most life-long drug addiction begins during adolescence. Important structural and functional changes in brain occur during adolescence and developmental differences in forebrain dopamine systems could mediate a biologic vulnerability to drug addiction during adolescence. Studies investigating age differences in psychostimulant responses have yielded mixed results, possibly because of different mechanisms for increasing extracellular dopamine. Recent research from our laboratory suggests that adolescent dopamine systems may be most affected by selective dopamine uptake inhibitors. We investigated age-related behavioral responses to acute administration of several dopamine uptake inhibitors [methylphenidate, 1-{2-[bis-(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine (GBR12909), and nomifensine] and releasing agents [amphetamine and methylenedioxymethamphetamine (MDMA)] in adolescent and adult male rats. Methylphenidate and amphetamine effects on stimulated dopamine efflux were determined using fast-scan cyclic voltammetry in vivo. Dopamine uptake inhibitors but not dopamine releasing agents induced more locomotion and/or stereotypy in adolescent relative to adult rats. MDMA effects were greater in adults at early time points after dosing. Methylphenidate but not amphetamine induced much greater dopamine efflux in periadolescent relative to adult rats. Periadolescent male rats are particularly sensitive to psychostimulants that are DAT inhibitors but are not internalized and do not release dopamine. Immaturity of DAT and/or DAT associated signaling systems in adolescence specifically enhances behavioral and dopaminergic responses in adolescence.

  8. VTA GABA neurons modulate specific learning behaviours through the control of dopamine and cholinergic systems

    Directory of Open Access Journals (Sweden)

    Meaghan C Creed

    2014-01-01

    Full Text Available The mesolimbic reward system is primarily comprised of the ventral tegmental area (VTA and the nucleus accumbens (NAc as well as their afferent and efferent connections. This circuitry is essential for learning about stimuli associated with motivationally-relevant outcomes. Moreover, addictive drugs affect and remodel this system, which may underlie their addictive properties. In addition to DA neurons, the VTA also contains approximately 30% ɣ-aminobutyric acid (GABA neurons. The task of signalling both rewarding and aversive events from the VTA to the NAc has mostly been ascribed to DA neurons and the role of GABA neurons has been largely neglected until recently. GABA neurons provide local inhibition of DA neurons and also long-range inhibition of projection regions, including the NAc. Here we review studies using a combination of in vivo and ex vivo electrophysiology, pharmacogenetic and optogenetic manipulations that have characterized the functional neuroanatomy of inhibitory circuits in the mesolimbic system, and describe how GABA neurons of the VTA regulate reward and aversion-related learning. We also discuss pharmacogenetic manipulation of this system with benzodiazepines (BDZs, a class of addictive drugs, which act directly on GABAA receptors located on GABA neurons of the VTA. The results gathered with each of these approaches suggest that VTA GABA neurons bi-directionally modulate activity of local DA neurons, underlying reward or aversion at the behavioural level. Conversely, long-range GABA projections from the VTA to the NAc selectively target cholinergic interneurons (CINs to pause their firing and temporarily reduce cholinergic tone in the NAc, which modulates associative learning. Further characterization of inhibitory circuit function within and beyond the VTA is needed in order to fully understand the function of the mesolimbic system under normal and pathological conditions.

  9. Contributions of dopamine-related genes and environmental factors to highly sensitive personality: a multi-step neuronal system-level approach.

    Directory of Open Access Journals (Sweden)

    Chunhui Chen

    Full Text Available Traditional behavioral genetic studies (e.g., twin, adoption studies have shown that human personality has moderate to high heritability, but recent molecular behavioral genetic studies have failed to identify quantitative trait loci (QTL with consistent effects. The current study adopted a multi-step approach (ANOVA followed by multiple regression and permutation to assess the cumulative effects of multiple QTLs. Using a system-level (dopamine system genetic approach, we investigated a personality trait deeply rooted in the nervous system (the Highly Sensitive Personality, HSP. 480 healthy Chinese college students were given the HSP scale and genotyped for 98 representative polymorphisms in all major dopamine neurotransmitter genes. In addition, two environment factors (stressful life events and parental warmth that have been implicated for their contributions to personality development were included to investigate their relative contributions as compared to genetic factors. In Step 1, using ANOVA, we identified 10 polymorphisms that made statistically significant contributions to HSP. In Step 2, these polymorphism's main effects and interactions were assessed using multiple regression. This model accounted for 15% of the variance of HSP (p<0.001. Recent stressful life events accounted for an additional 2% of the variance. Finally, permutation analyses ascertained the probability of obtaining these findings by chance to be very low, p ranging from 0.001 to 0.006. Dividing these loci by the subsystems of dopamine synthesis, degradation/transport, receptor and modulation, we found that the modulation and receptor subsystems made the most significant contribution to HSP. The results of this study demonstrate the utility of a multi-step neuronal system-level approach in assessing genetic contributions to individual differences in human behavior. It can potentially bridge the gap between the high heritability estimates based on traditional

  10. Contributions of dopamine-related genes and environmental factors to highly sensitive personality: a multi-step neuronal system-level approach.

    Science.gov (United States)

    Chen, Chunhui; Chen, Chuansheng; Moyzis, Robert; Stern, Hal; He, Qinghua; Li, He; Li, Jin; Zhu, Bi; Dong, Qi

    2011-01-01

    Traditional behavioral genetic studies (e.g., twin, adoption studies) have shown that human personality has moderate to high heritability, but recent molecular behavioral genetic studies have failed to identify quantitative trait loci (QTL) with consistent effects. The current study adopted a multi-step approach (ANOVA followed by multiple regression and permutation) to assess the cumulative effects of multiple QTLs. Using a system-level (dopamine system) genetic approach, we investigated a personality trait deeply rooted in the nervous system (the Highly Sensitive Personality, HSP). 480 healthy Chinese college students were given the HSP scale and genotyped for 98 representative polymorphisms in all major dopamine neurotransmitter genes. In addition, two environment factors (stressful life events and parental warmth) that have been implicated for their contributions to personality development were included to investigate their relative contributions as compared to genetic factors. In Step 1, using ANOVA, we identified 10 polymorphisms that made statistically significant contributions to HSP. In Step 2, these polymorphism's main effects and interactions were assessed using multiple regression. This model accounted for 15% of the variance of HSP (p<0.001). Recent stressful life events accounted for an additional 2% of the variance. Finally, permutation analyses ascertained the probability of obtaining these findings by chance to be very low, p ranging from 0.001 to 0.006. Dividing these loci by the subsystems of dopamine synthesis, degradation/transport, receptor and modulation, we found that the modulation and receptor subsystems made the most significant contribution to HSP. The results of this study demonstrate the utility of a multi-step neuronal system-level approach in assessing genetic contributions to individual differences in human behavior. It can potentially bridge the gap between the high heritability estimates based on traditional behavioral genetics

  11. Effects of prenatal ethanol exposure on central dopamine and Met-enkephalin system ontogeny

    Energy Technology Data Exchange (ETDEWEB)

    Hand, D.E.

    1987-01-01

    The effect of utero ethanol exposure on the development of central neurotransmitter systems was examined in rat offspring of dams that consumed liquid diets containing 35% ethanol derived calories either before and during pregnancy (E-P and P), or exclusively during gestation (E-Preg). Autoradiography of tritiated ligand receptor binding was used to rapidly screen neurotransmitter receptors in cholinergic, dopaminergic, serotonergic, noradrenergic, GABAergic, and opiatergic systems. The results led to a more comprehensive study of (1) the dopaminergic D-2 receptor binding using (/sup 3/H)spiroperidol, and (2) the opiatergic mu and delta receptor binding defined by (/sup 3/H)Met-enkephalin. Significant reductions in (/sup 3/H)spiroperidol binding were found in the 15 day old E-Preg caudate-putamen, which may be related to reductions in neurotransmission and increased locomotor activity. This provides a link between the hyperactivity reported in animal models and children with fetal alcohol syndrome (FAS) and its attenuation by drugs that facilitate dopaminergic transmission. Significant reductions were also seen in D-2 receptor binding in the inferior colliculus, which may be related to the functional deficits in the auditory processing of information by hyperactive children and the changes in the auditory evoked potentials of FAS children found at the level of that structure. The hyperactivity and auditory dysfunction improve with age, consistent with the trend in binding of (/sup 3/H)spiroperidol to D-2 receptors. The D-2 receptor binding in the E-P and P group was normal in nearly all brain regions which suggests that ethanol exposure begun during pregnancy may be more harmful than when initiated before pregnancy.

  12. Impulsive and compulsive behaviors during dopamine replacement treatment in Parkinson's Disease and other disorders.

    Science.gov (United States)

    Raja, Michele; Bentivoglio, Anna Rita

    2012-02-01

    Impulsive and compulsive behaviors, including pathologic gambling, hypersexuality, compulsive shopping, compulsive eating, excessive engagement in hobbies, punding, and Dopamine Dysregulation Syndrome (DDS), are increasingly reported serious side-effects of dopaminergic medication, used in the treatment of Parkinson's Disease (PD) and other disorders. Dopamine Agonists (DA) are strongly related with Impulse Control Disorders (ICDs), while L-dopa is associated with DDS. The present paper focuses on ICDs. The estimated prevalence of ICDs in PD patients treated with DA is as high as 14%. ICDs pathophysiology is complex, due to multiple contributing factors. Dopamine neurotransmission along the meso-cortico-limbic pathway is a modulator of risk behavior and can be altered in PD and in the course of dopaminergic treatment. Psychiatric complications, associated with treatment of PD are still underdiagnosed, although their consequences can be serious, even catastrophic. Physicians treating PD with DA should warn the patients and their relatives of the risk of inducing ICDs. Psychiatrists should be trained to recognize these side effects, that can mimic primary psychiatric conditions. The management of ICDs includes discontinuation of DA or switching from DA to other drugs for the treatment of PD. Cognitive behavior therapy, serotonin selective reuptake inhibitors, nalmefene, zonisamide, low dose of anti-dopaminergic drugs, as quetiapine or clozapine, can be effective. Psychological, spiritual, and ethical support (familial or individual) can help.

  13. Apathy and striatal dopamine defects in non-demented patients with Parkinson's disease.

    Science.gov (United States)

    Chung, Su Jin; Lee, Jae Jung; Ham, Jee Hyun; Lee, Phil Hyu; Sohn, Young H

    2016-02-01

    Apathy is a common, disabling symptom in Parkinson's disease (PD). The mechanisms underlying apathy in PD are still unclear, although they may be related to dysfunction in the meso-cortico-limbic circuit, including the ventral striatum. Thus, we performed this study to investigate whether dopamine depletion in the ventral striatum contributes to apathy in PD. We conducted a survey of the degree of apathy (using the Korean version of the Apathy Evaluation Scale, AES-S) in 108 non-demented patients with PD who underwent dopamine transporter (DAT) positron emission tomography scans as an initial diagnostic work-up. Patients with AES-S scores of 37 or higher were defined as having apathetic PD. The Beck Depression Inventory (BDI) was administered to assess the severity of depression. Patients with BDI scores of 15 or higher were regarded as having depression. Apathetic patients (n = 34) tended to exhibit higher BDI scores than non-apathetic patients (n = 74); however, other clinical variables were comparable between the two groups. DAT activity in the striatal sub-regions was also similar between the two groups. Selecting only non-depressed patients, including 20 apathetic and 47 non-apathetic patients, did not alter the results. This study demonstrated that the pattern of striatal dopamine depletion does not contribute to the degree of apathy in early PD. Apathy in PD may be associated with extra-striatal lesions that accompany PD rather than striatal dopaminergic deficits. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. The possible interaction of dopamine system in nucleus accumbens shell and glutamate system of prelimbic region on locomotor activity in rat

    Directory of Open Access Journals (Sweden)

    Hatam Ahmadi

    2013-06-01

    Full Text Available Background: Nucleus accumbens (NAc and prefrontal cortex (PFC dopaminergic and glutamatergic systems are involved in regulating of locomotor activity behaviors. This study has investigated the interaction of NAc shell dopaminergic system and prelimbic glutamatergic systems in regulating locomotor activity and related parameters. Methods: The aim of this study was the effect the drugs injection interaction in the brain of male Wistar rats on locomotor activity and related parameters, in the order of this purpose, open field apparatus that automatically recorded locomotor activity was employed. Unilateral intra-cerebral injection of drugs was done. Results: Unilateral intra-prelimbic injection of D-AP7 (N-methyl-D-aspartic acid= NMDA receptor antagonist; 0.25, 0.5 and 1μg/μl did not alter locomotor activity behaviors. However, infusion of NMDA (0.9μg/μl in this region increased locomotor activity (P<0.01, whereas decreased rearing (P<0.01 and grooming (P<0.01 which was blocked by D-AP7 (0.25μg/μl (P<0.01. Moreover, unilateral infusion of SCH23390 (dopamine D1 receptor antagonist; 0.25, 0.5 and 1μg/μl into the left NAc shell did not alter locomotor activity. However, injection of SKF38393 (dopamine D1 receptor agonist; 4μg/μl into the left NAc shell increased locomotor activity (P<0.05 which was blocked by SCH23390 (0.25μg/μl (P<0.01. Furthermore, the subthreshold dose infusion of SCH23390 (0.25μg/μl into the left NAc shell reduced the effect of intra- prelimbic NMDA on locomotor activity (P<0.01. In addition, intra-NAc shell administration of the subthreshold dose of SKF38393 (1μg/μl potentiated the middle dose (P<0.05, whereas decreased the higher dose of intra-left prelimbic NMDA response (P<0.05 on locomotor activity. Conclusion: The results suggested a modulatory effect of the NAc shell dopaminergic system on increased locomotor activity by activating glutamate system in prelimbic.

  15. Dopamins renale virkninger

    DEFF Research Database (Denmark)

    Olsen, Niels Vidiendal

    1990-01-01

    is frequently employed in cases of acute oliguric renal failure but the results available concerning the therapeutic effect are frequently retrospective and uncontrolled. The results suggest that early treatment with 1-3 micrograms/kg/min dopamine combined with furosemide can postpone or possibly render...... are possible not exclusively secondary to alterations in the renal haemodynamics but may also be due to specific tubular effects. Recent investigations have revealed that dopamine does not increase RBF and GFR in patients with chronic renal failure if GFR is less than 60 ml/minute. Dopamine in low doses......Dopamine is an endogenic catecholamine which, in addition to being the direct precursor of noradrenaline, has also an effect on peripheral dopaminergic receptors. These are localized mainly in the heart, splanchnic nerves and the kidneys. Dopamine is produced in the kidneys and the renal metabolism...

  16. Adverse effects of bisphenol A (BPA) on the dopamine system in two distinct cell models and corpus striatum of the Sprague-Dawley rat.

    Science.gov (United States)

    Nowicki, Brittney A; Hamada, Matt A; Robinson, Gina Y; Jones, Douglas C

    2016-01-01

    The aim of this study was to examine the effects of bisphenol A (BPA) on the brain dopamine (DA) system utilizing both in vitro models (GH3 cells, a rat pituitary cell line, and SH-SY5Y cells, a human neuroblastoma cell line) and an animal model such as Sprague-Dawley (SD) rats. First, cellular DA uptake was measured 2 or 8 h following BPA exposure (0.1-400 μM) in SH-SY5Y cells, where a significant increase in DA uptake was noted. BPA exerted no marked effect on dopamine active transporter levels in GH3 cells exposed for 8 or 24 h. However, SH-SY5Y cells displayed an increase in dopamine transporter (DAT) levels following 24 h of exposure to BPA. In contrast to DAT levels, BPA exposure produced no marked effect on DA D1 receptor levels in SH-SY5Y cells, yet a significant decrease in GH3 cells following both 8- and 24-h exposure periods was noted, suggesting that BPA exerts differential effects dependent upon cell type. BPA produced no significant effects on prolactin levels at 2 h, but a marked fall occurred at 24 h of exposure in GH3 cells. Finally, to examine the influence of dietary developmental exposure to BPA on brain DA levels in F1 offspring, SD rats were exposed to BPA (0.5-20 mg/kg) through maternal transfer and/or diet and striatal DA levels were measured on postnatal day (PND) 60 using high-performance liquid chromatography (HPLC). Data demonstrated that chronic exposure to BPA did not significantly alter striatal DA levels in the SD rat.

  17. Dopamine Receptor Activation Increases HIV Entry into Primary Human Macrophages

    Science.gov (United States)

    Gaskill, Peter J.; Yano, Hideaki H.; Kalpana, Ganjam V.; Javitch, Jonathan A.; Berman, Joan W.

    2014-01-01

    Macrophages are the primary cell type infected with HIV in the central nervous system, and infection of these cells is a major component in the development of neuropathogenesis and HIV-associated neurocognitive disorders. Within the brains of drug abusers, macrophages are exposed to increased levels of dopamine, a neurotransmitter that mediates the addictive and reinforcing effects of drugs of abuse such as cocaine and methamphetamine. In this study we examined the effects of dopamine on HIV entry into primary human macrophages. Exposure to dopamine during infection increased the entry of R5 tropic HIV into macrophages, irrespective of the concentration of the viral inoculum. The entry pathway affected was CCR5 dependent, as antagonizing CCR5 with the small molecule inhibitor TAK779 completely blocked entry. The effect was dose-dependent and had a steep threshold, only occurring above 108 M dopamine. The dopamine-mediated increase in entry required dopamine receptor activation, as it was abrogated by the pan-dopamine receptor antagonist flupenthixol, and could be mediated through both subtypes of dopamine receptors. These findings indicate that the effects of dopamine on macrophages may have a significant impact on HIV pathogenesis. They also suggest that drug-induced increases in CNS dopamine may be a common mechanism by which drugs of abuse with distinct modes of action exacerbate neuroinflammation and contribute to HIV-associated neurocognitive disorders in infected drug abusers. PMID:25268786

  18. Dopamine receptor activation increases HIV entry into primary human macrophages.

    Directory of Open Access Journals (Sweden)

    Peter J Gaskill

    Full Text Available Macrophages are the primary cell type infected with HIV in the central nervous system, and infection of these cells is a major component in the development of neuropathogenesis and HIV-associated neurocognitive disorders. Within the brains of drug abusers, macrophages are exposed to increased levels of dopamine, a neurotransmitter that mediates the addictive and reinforcing effects of drugs of abuse such as cocaine and methamphetamine. In this study we examined the effects of dopamine on HIV entry into primary human macrophages. Exposure to dopamine during infection increased the entry of R5 tropic HIV into macrophages, irrespective of the concentration of the viral inoculum. The entry pathway affected was CCR5 dependent, as antagonizing CCR5 with the small molecule inhibitor TAK779 completely blocked entry. The effect was dose-dependent and had a steep threshold, only occurring above 108 M dopamine. The dopamine-mediated increase in entry required dopamine receptor activation, as it was abrogated by the pan-dopamine receptor antagonist flupenthixol, and could be mediated through both subtypes of dopamine receptors. These findings indicate that the effects of dopamine on macrophages may have a significant impact on HIV pathogenesis. They also suggest that drug-induced increases in CNS dopamine may be a common mechanism by which drugs of abuse with distinct modes of action exacerbate neuroinflammation and contribute to HIV-associated neurocognitive disorders in infected drug abusers.

  19. Striatal dopamine release codes uncertainty in pathological gambling

    DEFF Research Database (Denmark)

    Linnet, Jakob; Mouridsen, Kim; Peterson, Ericka

    2012-01-01

    Two mechanisms of midbrain and striatal dopaminergic projections may be involved in pathological gambling: hypersensitivity to reward and sustained activation toward uncertainty. The midbrain—striatal dopamine system distinctly codes reward and uncertainty, where dopaminergic activation is a linear...... dopamine release, and we used performance on the Iowa Gambling Task (IGT) to determine overall reward and uncertainty. We hypothesized that we would find a linear function between dopamine release and IGT performance, if dopamine release coded reward in pathological gambling. If, on the other hand......, dopamine release coded uncertainty, we would find an inversely U-shaped function. The data supported an inverse U-shaped relation between striatal dopamine release and IGT performance if the pathological gambling group, but not in the healthy control group. These results are consistent with the hypothesis...

  20. Dopamine, psychosis and schizophrenia

    DEFF Research Database (Denmark)

    Kesby, J P; Eyles, D W; McGrath, J J

    2018-01-01

    The stagnation in drug development for schizophrenia highlights the need for better translation between basic and clinical research. Understanding the neurobiology of schizophrenia presents substantial challenges but a key feature continues to be the involvement of subcortical dopaminergic...... dysfunction in those with psychotic symptoms. Our contemporary knowledge regarding dopamine dysfunction has clarified where and when dopaminergic alterations may present in schizophrenia. For example, clinical studies have shown patients with schizophrenia show increased presynaptic dopamine function...... in the associative striatum, rather than the limbic striatum as previously presumed. Furthermore, subjects deemed at high risk of developing schizophrenia show similar presynaptic dopamine abnormalities in the associative striatum. Thus, our view of subcortical dopamine function in schizophrenia continues to evolve...

  1. Homeostatic mechanisms in dopamine synthesis and release: a mathematical model

    Directory of Open Access Journals (Sweden)

    Nijhout H Frederik

    2009-09-01

    Full Text Available Abstract Background Dopamine is a catecholamine that is used as a neurotransmitter both in the periphery and in the central nervous system. Dysfunction in various dopaminergic systems is known to be associated with various disorders, including schizophrenia, Parkinson's disease, and Tourette's syndrome. Furthermore, microdialysis studies have shown that addictive drugs increase extracellular dopamine and brain imaging has shown a correlation between euphoria and psycho-stimulant-induced increases in extracellular dopamine 1. These consequences of dopamine dysfunction indicate the importance of maintaining dopamine functionality through homeostatic mechanisms that have been attributed to the delicate balance between synthesis, storage, release, metabolism, and reuptake. Methods We construct a mathematical model of dopamine synthesis, release, and reuptake and use it to study homeostasis in single dopaminergic neuron terminals. We investigate the substrate inhibition of tyrosine hydroxylase by tyrosine, the consequences of the rapid uptake of extracellular dopamine by the dopamine transporters, and the effects of the autoreceoptors on dopaminergic function. The main focus is to understand the regulation and control of synthesis and release and to explicate and interpret experimental findings. Results We show that the substrate inhibition of tyrosine hydroxylase by tyrosine stabilizes cytosolic and vesicular dopamine against changes in tyrosine availability due to meals. We find that the autoreceptors dampen the fluctuations in extracellular dopamine caused by changes in tyrosine hydroxylase expression and changes in the rate of firing. We show that short bursts of action potentials create significant dopamine signals against the background of tonic firing. We explain the observed time courses of extracellular dopamine responses to stimulation in wild type mice and mice that have genetically altered dopamine transporter densities and the observed

  2. Cross-hemispheric dopamine projections have functional significance

    Science.gov (United States)

    Fox, Megan E.; Mikhailova, Maria A.; Bass, Caroline E.; Takmakov, Pavel; Gainetdinov, Raul R.; Budygin, Evgeny A.; Wightman, R. Mark

    2016-01-01

    Dopamine signaling occurs on a subsecond timescale, and its dysregulation is implicated in pathologies ranging from drug addiction to Parkinson’s disease. Anatomic evidence suggests that some dopamine neurons have cross-hemispheric projections, but the significance of these projections is unknown. Here we report unprecedented interhemispheric communication in the midbrain dopamine system of awake and anesthetized rats. In the anesthetized rats, optogenetic and electrical stimulation of dopamine cells elicited physiologically relevant dopamine release in the contralateral striatum. Contralateral release differed between the dorsal and ventral striatum owing to differential regulation by D2-like receptors. In the freely moving animals, simultaneous bilateral measurements revealed that dopamine release synchronizes between hemispheres and intact, contralateral projections can release dopamine in the midbrain of 6-hydroxydopamine–lesioned rats. These experiments are the first, to our knowledge, to show cross-hemispheric synchronicity in dopamine signaling and support a functional role for contralateral projections. In addition, our data reveal that psychostimulants, such as amphetamine, promote the coupling of dopamine transients between hemispheres. PMID:27298371

  3. Presence and function of dopamine transporter (DAT in stallion sperm: dopamine modulates sperm motility and acrosomal integrity.

    Directory of Open Access Journals (Sweden)

    Javier A Urra

    Full Text Available Dopamine is a catecholamine with multiple physiological functions, playing a key role in nervous system; however its participation in reproductive processes and sperm physiology is controversial. High dopamine concentrations have been reported in different portions of the feminine and masculine reproductive tract, although the role fulfilled by this catecholamine in reproductive physiology is as yet unknown. We have previously shown that dopamine type 2 receptor is functional in boar sperm, suggesting that dopamine acts as a physiological modulator of sperm viability, capacitation and motility. In the present study, using immunodetection methods, we revealed the presence of several proteins important for the dopamine uptake and signalling in mammalian sperm, specifically monoamine transporters as dopamine (DAT, serotonin (SERT and norepinephrine (NET transporters in equine sperm. We also demonstrated for the first time in equine sperm a functional dopamine transporter using 4-[4-(Dimethylaminostyryl]-N-methylpyridinium iodide (ASP(+, as substrate. In addition, we also showed that dopamine (1 mM treatment in vitro, does not affect sperm viability but decreases total and progressive sperm motility. This effect is reversed by blocking the dopamine transporter with the selective inhibitor vanoxerine (GBR12909 and non-selective inhibitors of dopamine reuptake such as nomifensine and bupropion. The effect of dopamine in sperm physiology was evaluated and we demonstrated that acrosome integrity and thyrosine phosphorylation in equine sperm is significantly reduced at high concentrations of this catecholamine. In summary, our results revealed the presence of monoamine transporter DAT, NET and SERT in equine sperm, and that the dopamine uptake by DAT can regulate sperm function, specifically acrosomal integrity and sperm motility.

  4. A novel α5GABA(A)R-positive allosteric modulator reverses hyperactivation of the dopamine system in the MAM model of schizophrenia.

    Science.gov (United States)

    Gill, Kathryn M; Lodge, Daniel J; Cook, James M; Aras, Shamim; Grace, Anthony A

    2011-08-01

    We have shown previously that aberrant hippocampal (HPC) output underlies the dopamine (DA) dysfunction observed in the methylazoxymethanol acetate (MAM) developmental model of schizophrenia in the rodent. This alteration of HPC activity was proposed to result from a reduction in parvalbumin (PV)-expressing GABAergic interneurons and consequent destabilization of the output of pyramidal neurons, as well as disrupted activation across a broad neural network. In vivo extracellular recordings were performed in the ventral tegmental area (VTA) and ventral HPC of saline- (SAL) and MAM-treated animals. A novel benzodiazepine-positive allosteric modulator (PAM), selective for the α5 subunit of the GABA(A) receptor, SH-053-2'F-R-CH3, was tested for its effects on the output of the HPC, leading to dopamine system hyperactivity in MAM-treated animals. In addition, the effect of SH-053-2'F-R-CH3 on the hyperactive locomotor response to amphetamine in MAM animals was examined. We demonstrate that treatment with the α5GABA(A)R PAM reduced the number of spontaneously active DA neurons in the VTA of MAM animals to levels observed in SAL rats, both when administered systemically and when directly infused into the ventral HPC. Moreover, HPC neurons in both SAL and MAM animals showed diminished cortical-evoked responses following α5GABA(A)R PAM treatment. In addition, the increased locomotor response to amphetamine observed in MAM rats was reduced following α5GABA(A)R treatment. This study supports a novel treatment of schizophrenia that targets abnormal HPC output, which in turn normalizes dopaminergic neuronal activity.

  5. The risky business of dopamine agonists in Parkinson disease and impulse control disorders.

    Science.gov (United States)

    Claassen, Daniel O; van den Wildenberg, Wery P M; Ridderinkhof, K Richard; Jessup, Charles K; Harrison, Madaline B; Wooten, G Frederick; Wylie, Scott A

    2011-08-01

    Risk-taking behavior is characterized by pursuit of reward in spite of potential negative consequences. Dopamine neurotransmission along the mesocorticolimbic pathway is a potential modulator of risk behavior. In patients with Parkinson's disease (PD), impulse control disorder (ICD) can result from dopaminergic medication use, particularly dopamine agonists (DAA). Behaviors associated with ICD include hypersexuality as well as compulsive gambling, shopping, and eating, and these behaviors are potentially linked to alterations to risk processing. Using the Balloon Analogue Risk Task, we assessed the role of agonist therapy on risk-taking behavior in PD patients with (n = 22) and without (n = 19) active ICD symptoms. Patients performed the task both "on" and "off" DAA. DAA increased risk-taking in PD patients with active ICD symptoms, but it did not affect risk behavior of PD controls. DAA dose was also important in explaining risk behavior. Both groups similarly reduced their risk-taking in high compared to low risk conditions and following the occurrence of a negative consequence, suggesting that ICD patients do not necessarily differ in their abilities to process and adjust to some aspects of negative consequences. Our findings suggest dopaminergic augmentation of risk-taking behavior as a potential contributing mechanism for the emergence of ICD in PD patients. (PsycINFO Database Record (c) 2011 APA, all rights reserved).

  6. Dopamine induces neutrophil apoptosis through a dopamine D-1 receptor-independent mechanism.

    LENUS (Irish Health Repository)

    Sookhai, S

    2012-02-03

    BACKGROUND: For the normal resolution of an acute inflammatory response, neutrophil (PMN) apoptosis is essential to maintain immune homeostasis and to limit inappropriate host tissue damage. A delay in PMN apoptosis has been implicated in the pathogenesis of the systemic inflammatory response syndrome (SIRS). Dopamine, a biogenic amine with known cardiovascular and neurotransmitter properties, is used in patients with SIRS to maintain hemodynamic stability. We sought to determine whether dopamine may also have immunoregulatory properties capable of influencing PMN apoptosis, function, and activation state in patients with SIRS. METHODS: PMNs were isolated from healthy volunteers and patients with SIRS and treated with varying doses of dopamine and a dopamine D-1 receptor agonist, fenoldopam. PMN apoptosis was assessed every 6 hours with use of propidium iodide DNA staining and PMN function was assessed with use of respiratory burst activity, phagocytosis ability, and CD11a, CD11b, and CD18 receptor expression as functional markers. RESULTS: There was a significant delay in PMN apotosis in patients with SIRS compared with controls. Treatment of isolated PMNs from both healthy controls and patients with SIRS with 10 and 100 mumol\\/L dopamine induced apoptosis. PMN ingestive and cytocidal capacity were both decreased in patients with SIRS compared with controls. Treatment with dopamine significantly increased phagocytic function. Fenoldopam did not induce PMN apoptosis. CONCLUSION: Our data demonstrate for the first time that dopamine induces PMN apoptosis and modulates PMN function both in healthy controls and in patients with SIRS. These results indicate that dopamine may be beneficial during SIRS through a nonhemodynamic PMN-dependent proapoptotic mechanism.

  7. Amphetamine Paradoxically Augments Exocytotic Dopamine Release and Phasic Dopamine Signals

    Science.gov (United States)

    Daberkow, DP; Brown, HD; Bunner, KD; Kraniotis, SA; Doellman, MA; Ragozzino, ME; Garris, PA; Roitman, MF

    2013-01-01

    Drugs of abuse hijack brain reward circuitry during the addiction process by augmenting action potential-dependent phasic dopamine release events associated with learning and goal-directed behavior. One prominent exception to this notion would appear to be amphetamine (AMPH) and related analogs, which are proposed instead to disrupt normal patterns of dopamine neurotransmission by depleting vesicular stores and promoting non-exocytotic dopamine efflux via reverse transport. This mechanism of AMPH action, though, is inconsistent with its therapeutic effects and addictive properties - which are thought to be reliant on phasic dopamine signaling. Here we used fast-scan cyclic voltammetry in freely moving rats to interrogate principal neurochemical responses to AMPH in the striatum and relate these changes to behavior. First, we showed that AMPH dose-dependently enhanced evoked dopamine responses to phasic-like current pulse trains for up to two hours. Modeling the data revealed that AMPH inhibited dopamine uptake but also unexpectedly potentiated vesicular dopamine release. Second, we found that AMPH increased the amplitude, duration and frequency of spontaneous dopamine transients, the naturally occurring, non-electrically evoked, phasic increases in extracellular dopamine. Finally, using an operant sucrose reward paradigm, we showed that low-dose AMPH augmented dopamine transients elicited by sucrose-predictive cues. However, operant behavior failed at high-dose AMPH, which was due to phasic dopamine hyperactivity and the decoupling of dopamine transients from the reward predictive cue. These findings identify up-regulation of exocytotic dopamine release as a key AMPH action in behaving animals and support a unified mechanism of abused drugs to activate phasic dopamine signaling. PMID:23303926

  8. Dopamine and anorexia nervosa.

    Science.gov (United States)

    Södersten, P; Bergh, C; Leon, M; Zandian, M

    2016-01-01

    We have suggested that reduced food intake increases the risk for anorexia nervosa by engaging mesolimbic dopamine neurons, thereby initially rewarding dieting. Recent fMRI studies have confirmed that dopamine neurons are activated in anorexia nervosa, but it is not clear whether this response is due to the disorder or to its resulting nutritional deficit. When the body senses the shortage of nutrients, it rapidly shifts behavior toward foraging for food as a normal physiological response and the mesolimbic dopamine neurons may be involved in that process. On the other hand, the altered dopamine status of anorexics has been suggested to result from a brain abnormality that underlies their complex emotional disorder. We suggest that the outcomes of the treatments that emerge from that perspective remain poor because they target the mental symptoms that are actually the consequences of the food deprivation that accompanies anorexia. On the other hand, a method that normalizes the disordered eating behavior of anorexics results in much better physiological, behavioral, and emotional outcomes. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Dopamins renale virkninger

    DEFF Research Database (Denmark)

    Olsen, Niels Vidiendal

    1990-01-01

    is frequently employed in cases of acute oliguric renal failure but the results available concerning the therapeutic effect are frequently retrospective and uncontrolled. The results suggest that early treatment with 1-3 micrograms/kg/min dopamine combined with furosemide can postpone or possibly render...

  10. ILLICIT DOPAMINE TRANSIENTS: RECONCILING ACTIONS OF ABUSED DRUGS

    Science.gov (United States)

    Covey, Dan P.; Roitman, Mitchell F.; Garris, Paul A.

    2014-01-01

    Phasic increases in brain dopamine are required for cue-directed reward seeking. While compelling within the framework of appetitive behavior, the view that illicit drugs hijack reward circuits by hyper-activating these dopamine transients is inconsistent with established psychostimulant pharmacology. However, recent work reclassifying amphetamine (AMPH), cocaine, and other addictive dopamine-transporter inhibitors (DAT-Is) supports transient hyper-activation as a unifying hypothesis of abused drugs. We argue here that reclassification also identifies generating burst firing by dopamine neurons as a keystone action. Unlike natural rewards, which are processed by sensory systems, drugs act directly on the brain. Consequently, to mimic natural reward and exploit reward circuits, dopamine transients must be elicited de novo. Of available drug targets, only burst firing achieves this essential outcome. PMID:24656971

  11. Dopamine, T cells and multiple sclerosis (MS).

    Science.gov (United States)

    Levite, Mia; Marino, Franca; Cosentino, Marco

    2017-05-01

    Dopamine is a key neurotransmitter that induces critical effects in the nervous system and in many peripheral organs, via 5 dopamine receptors (DRs): D1R-D5R. Dopamine also induces many direct and very potent effects on many DR-expressing immune cells, primarily T cells and dendritic cells. In this review, we focus only on dopamine receptors, effects and production in T cells. Dopamine by itself (at an optimal concentration of~0.1 nM) induces multiple function of resting normal human T cells, among them: T cell adhesion, chemotactic migration, homing, cytokine secretion and others. Interestingly, dopamine activates resting effector T cells (Teffs), but suppresses regulatory T cells (Tregs), and both effects lead eventually to Teff activation. Dopamine-induced effects on T cells are dynamic, context-sensitive and determined by the: T cell activation state, T cell type, DR type, and dopamine concentration. Dopamine itself, and also few dopaminergic molecules/ drugs that are in clinical use for cardiac, neurological and other non-immune indications, have direct effects on human T cells (summarized in this review). These dopaminergic drugs include: dopamine = intropin, L-DOPA, bromocriptine, pramipexole, pergolide, haloperidol, pimozide, and amantadine. Other dopaminergic drugs were not yet tested for their direct effects on T cells. Extensive evidence in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) show dopaminergic dysregulations in T cells in these diseases: D1-like DRs are decreased in Teffs of MS patients, and dopamine does not affect these cells. In contrast, D1-like DRs are increased in Tregs of MS patients, possibly causing functional Treg impairment in MS. Treatment of MS patients with interferon β (IFN-β) increases D1-like DRs and decreases D2-like DRs in Teffs, decreases D1-like DRs in Tregs, and most important: restores responsiveness of patient's Teffs to dopamine. DR agonists and antagonists confer some benefits in

  12. Temporal Profiles Dissociate Regional Extracellular Ethanol versus Dopamine Concentrations

    Science.gov (United States)

    2015-01-01

    In vivo monitoring of dopamine via microdialysis has demonstrated that acute, systemic ethanol increases extracellular dopamine in regions innervated by dopaminergic neurons originating in the ventral tegmental area and substantia nigra. Simultaneous measurement of dialysate dopamine and ethanol allows comparison of the time courses of their extracellular concentrations. Early studies demonstrated dissociations between the time courses of brain ethanol concentrations and dopaminergic responses in the nucleus accumbens (NAc) elicited by acute ethanol administration. Both brain ethanol and extracellular dopamine levels peak during the first 5 min following systemic ethanol administration, but the dopamine response returns to baseline while brain ethanol concentrations remain elevated. Post hoc analyses examined ratios of the dopamine response (represented as a percent above baseline) to tissue concentrations of ethanol at different time points within the first 25–30 min in the prefrontal cortex, NAc core and shell, and dorsomedial striatum following a single intravenous infusion of ethanol (1 g/kg). The temporal patterns of these “response ratios” differed across brain regions, possibly due to regional differences in the mechanisms underlying the decline of the dopamine signal associated with acute intravenous ethanol administration and/or to the differential effects of acute ethanol on the properties of subpopulations of midbrain dopamine neurons. This Review draws on neurochemical, physiological, and molecular studies to summarize the effects of acute ethanol administration on dopamine activity in the prefrontal cortex and striatal regions, to explore the potential reasons for the regional differences observed in the decline of ethanol-induced dopamine signals, and to suggest directions for future research. PMID:25537116

  13. Firing properties of dopamine neurons in freely moving dopamine-deficient mice: Effects of dopamine receptor activation and anesthesia

    OpenAIRE

    Robinson, Siobhan; Smith, David M.; Mizumori, Sheri J. Y.; Palmiter, Richard D.

    2004-01-01

    To examine the regulation of midbrain dopamine neurons, recordings were obtained from single neurons of freely moving, genetically engineered dopamine-deficient (DD) mice. DD mice were tested without dopamine signaling (basal state) and with endogenous dopamine signaling (after L-dopa administration). In the basal state, when dopamine concentration in DD mice is

  14. Serotonin and dopamine transporters in relation to neuropsychological functioning, personality traits and mood in young adult healthy subjects

    NARCIS (Netherlands)

    Burke, S. M.; van de Giessen, E.; de Win, M.; Schilt, T.; van Herk, M.; van den Brink, W.; Booij, J.

    2011-01-01

    BACKGROUND: Serotonin and dopamine neurotransmitter systems are implicated in the regulation of mood, cognition and personality traits and their dysfunction is thought to be implicated in diverse psychopathologies. However, in healthy subjects the relationship between the serotonin and dopamine

  15. The central adrenergic system. An immunofluorescence study of the location of cell bodies and their efferent connections in the rat utilizing dopamine-beta-hydroxylase as a marker.

    Science.gov (United States)

    Swanson, L W; Hartman, B K

    1975-10-15

    A sensitive immunofluorescence technique was used to describe systematically the distrubution of dopamine-beta-hydroxylase (DBH)-containing cell bodies, non-terminal fiber pathways, and terminal fields in the brain of the male albino rat. DBH is the enzyme that catalyzes the conversion of dopamine to noradrenaline, and as such is useful as an anatomical marker for noradrenaline and possibly adrenaline neurons. The enzyme is not present in dopamine- or indolamine-containing neurons. Ten micron frozen sections (1-in 20 series) were prepared in the frontal, sagittal, and horizontal planes from the olfactory bulb to the upper cervical segments of the spinal cord; adjacent sections in each plane were stained for DBH and for cells (toluidine blue=azure II). An atlas consisting of 40 projection drawings of selected frontal sections illustrates the results of the investigation. DBH perikarya are confined to three groups in the pons and medulla: the well defined locus coeruleus, a more diffuse but continuous subcoeruleus group that arches through the pons and ventral medulla, and a third dorsal medullary group centered in the dorsal motor nucleus of the vagus. A single principal adrenergic fiber system distributes a great many of the axons from these neuron groups to a majority of nuclear areas in the brain. In the pons and medulla two components of the fiber system may be distinguished. A medullary branch may be followed from the posterior aspect of the subcoeruleus group dorsally and then anteriorly through the lateral tegmental field and ventral aspect of the vestibular complex to a position subjacent to the locus coeruleus, where it is joined by a subcoeruleus branch consisting of a large number of fibers coursing among cells along the length of the subcoeruleus group, and by fibers arising from the locus coeruleus. Anterior to the locus coeruleus the principal adrenergic bundle courses as a single fiber tract immediately ventrolateral to the central gray in the

  16. Trivalent copper chelate-luminol chemiluminescence system for highly sensitive CE detection of dopamine in biological sample after clean-up using SPE.

    Science.gov (United States)

    Wang, Lin; Liu, Ying; Xie, Haoyue; Fu, Zhifeng

    2012-06-01

    A transition metal chelate unstable at a high oxidation state, diperiodatocuprate (III) (K₅[Cu(HIO₆)₂], DPC), was synthesized and applied in the luminol-based chemiluminescence (CL) system for highly sensitive CE end-column detection of dopamine (DA). This method was based on the fact that DA enhanced the CL emission resulting from the reaction between luminol and DPC in alkaline medium. The DPC-luminol-DA CL system showed very intensive emission and very fast kinetic characteristics, thus resulting in a high sensitivity in flow-through detection mode for CE. Under optimal conditions, the linear range was 1.0 × 10⁻⁸-5.0 × 10⁻⁵ g/mL (R² = 0.9984) with a limit of detection of 6.0 × 10⁻⁹ g/mL (S/N = 3). The RSDs of the peak height and the migration time were about 4.2 and 2.4% for a standard sample at 3.0 × 10⁻⁶ g/mL (n = 5), respectively. The presented method has been successfully used for the determination of DA in commercial preparation and human urine samples after clean-up using SPE. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. The Feasibility of Using CT-Guided ROI for Semiquantifying Striatal Dopamine Transporter Availability in a Hybrid SPECT/CT System

    Directory of Open Access Journals (Sweden)

    Chien-Chin Hsu

    2014-01-01

    Full Text Available A hybrid SPECT/CT system provides accurate coregistration of functional and morphological images. CT-guided region of interest (ROI for semiquantifying striatal dopamine transporter (DAT availability may be a feasible method. We therefore assessed the intra- and interobserver reproducibility of manual SPECT and CT-guided ROI methods and compared their semiquantitative data with data from MRI-guided ROIs. We enrolled twenty-eight patients who underwent Tc-99m TRODAT-1 brain SPECT/CT and brain MRI. ROIs of the striatal, caudate, putamen, and occipital cortex were manually delineated on the SPECT, CT, and MRI. ROIs from CT and MRI were transferred to the coregistered SPECT for semiquantification. The striatal, caudate, and putamen nondisplaceable binding potential (BPND were calculated. Using CT-guided ROIs had higher intra- and interobserver concordance correlation coefficients, closer Bland-Altman biases to zero, and narrower limits of agreement than using manual SPECT ROIs. The correlation coefficients of striatal, caudate, and putamen BPND were good between manual SPECT and MRI-guided ROI methods and even better between CT-guided and MRI-guided ROI methods. Conclusively, CT-guided ROI delineation for semiquantifying striatal DAT availability in a hybrid SPECT/CT system is highly reproducible, and the semiquantitative data correlate well with data from MRI-guided ROIs.

  18. NEW DOPAMINE AGONISTS IN CARDIOVASCULAR THERAPY

    NARCIS (Netherlands)

    GIRBES, ARJ; VANVELDHUISEN, DJ; SMIT, AJ

    1992-01-01

    Dopamine, a naturally occurring catecholamine, has been extensively used in intensive care for many years. Dopamine stimulates different types of adrenergic receptors: alpha-1 and -2, beta-1 and -2, and dopamine-1 and -2. The renal effects of dopamine are the result of dopamine-1 receptor (DA1)

  19. Dopamine Agonists and Pathologic Behaviors

    Directory of Open Access Journals (Sweden)

    Brendan J. Kelley

    2012-01-01

    Full Text Available The dopamine agonists ropinirole and pramipexole exhibit highly specific affinity for the cerebral dopamine D3 receptor. Use of these medications in Parkinson’s disease has been complicated by the emergence of pathologic behavioral patterns such as hypersexuality, pathologic gambling, excessive hobbying, and other circumscribed obsessive-compulsive disorders of impulse control in people having no history of such disorders. These behavioral changes typically remit following discontinuation of the medication, further demonstrating a causal relationship. Expression of the D3 receptor is particularly rich within the limbic system, where it plays an important role in modulating the physiologic and emotional experience of novelty, reward, and risk assessment. Converging neuroanatomical, physiological, and behavioral science data suggest the high D3 affinity of these medications as the basis for these behavioral changes. These observations suggest the D3 receptor as a therapeutic target for obsessive-compulsive disorder and substance abuse, and improved understanding of D3 receptor function may aid drug design of future atypical antipsychotics.

  20. Growth of dopamine crystals

    Energy Technology Data Exchange (ETDEWEB)

    Patil, Vidya, E-mail: vidya.patil@ruparel.edu; Patki, Mugdha, E-mail: mugdha.patki@ruparel.edu [D. G. Ruparel College, Senapati Bapat Marg, Mahim, Mumbai – 400 016 (India)

    2016-05-06

    Many nonlinear optical (NLO) crystals have been identified as potential candidates in optical and electro-optical devices. Use of NLO organic crystals is expected in photonic applications. Hence organic nonlinear optical materials have been intensely investigated due to their potentially high nonlinearities, and rapid response in electro-optic effect compared to inorganic NLO materials. There are many methods to grow organic crystals such as vapor growth method, melt growth method and solution growth method. Out of these methods, solution growth method is useful in providing constraint free crystal. Single crystals of Dopamine have been grown by evaporating the solvents from aqueous solution. Crystals obtained were of the size of orders of mm. The crystal structure of dopamine was determined using XRD technique. Images of crystals were obtained using FEG SEM Quanta Series under high vacuum and low KV.

  1. Acute fasting increases somatodendritic dopamine release in the ventral tegmental area.

    Science.gov (United States)

    Roseberry, Aaron G

    2015-08-01

    Fasting and food restriction alter the activity of the mesolimbic dopamine system to affect multiple reward-related behaviors. Food restriction decreases baseline dopamine levels in efferent target sites and enhances dopamine release in response to rewards such as food and drugs. In addition to releasing dopamine from axon terminals, dopamine neurons in the ventral tegmental area (VTA) also release dopamine from their soma and dendrites, and this somatodendritic dopamine release acts as an autoinhibitory signal to inhibit neighboring VTA dopamine neurons. It is unknown whether acute fasting also affects dopamine release, including the local inhibitory somatodendritic dopamine release in the VTA. In these studies, I have tested whether fasting affects the inhibitory somatodendritic dopamine release within the VTA by examining whether an acute 24-h fast affects the inhibitory postsynaptic current mediated by evoked somatodendritic dopamine release (D2R IPSC). Fasting increased the contribution of the first action potential to the overall D2R IPSC and increased the ratio of repeated D2R IPSCs evoked at short intervals. Fasting also reduced the effect of forskolin on the D2R IPSC and led to a significantly bigger decrease in the D2R IPSC in low extracellular calcium. Finally, fasting resulted in an increase in the D2R IPSCs when a more physiologically relevant train of D2R IPSCs was used. Taken together, these results indicate that fasting caused a change in the properties of somatodendritic dopamine release, possibly by increasing dopamine release, and that this increased release can be sustained under conditions where dopamine neurons are highly active. Copyright © 2015 the American Physiological Society.

  2. Differences in [99mTc]TRODAT-1 SPECT binding to dopamine transporters in patients with multiple system atrophy and Parkinson's disease

    International Nuclear Information System (INIS)

    Swanson, Randel L.; Newberg, Andrew B.; Acton, Paul D.; Siderowf, Andrew; Wintering, Nancy; Alavi, Abass; Mozley, P. David; Plossl, Karl; Udeshi, Michelle; Hurtig, Howard

    2005-01-01

    Multiple system atrophy (MSA), a disorder causing autonomic dysfunction, parkinsonism, and cerebellar dysfunction, is difficult to differentiate from other movement disorders, particularly early in the course of disease. This study evaluated whether [ 99m Tc]TRODAT-1 binding to the dopamine transporter differentiates MSA from other movement disorders. Single-photon emission computed tomographic brain scans were acquired in 25 MSA patients, 48 age-matched controls, and 130 PD patients, 3 h after the injection of 740 MBq (20 mCi) of [ 99m Tc]TRODAT-1. Regions of interest (ROIs) were placed manually on subregions of both basal ganglia and distribution volume ratios (DVRs) were calculated. Regional DVRs were compared between study groups in MSA patients. Student's ttests were used to compare MSA patients with other study groups. Spearman correlations were used to compare DVRs with NP measures. Based upon various motor scores, MSA and PD patients had comparable motor impairment, and were significantly impaired compared with controls. Mean DVRs in the basal ganglia of MSA patients were significantly less than those of controls, but generally higher (p 99m Tc]TRODAT-1 binding, particularly in the posterior putamen, compared with PD patients and significantly lower binding compared with controls. This may reflect different pathophysiological processes of the two neurodegenerative diseases. (orig.)

  3. Genetics Home Reference: dopamine transporter deficiency syndrome

    Science.gov (United States)

    ... Twitter Home Health Conditions Dopamine transporter deficiency syndrome Dopamine transporter deficiency syndrome Printable PDF Open All Close ... Javascript to view the expand/collapse boxes. Description Dopamine transporter deficiency syndrome is a rare movement disorder. ...

  4. Dopamine modulates metabolic rate and temperature sensitivity in Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Taro Ueno

    Full Text Available Homeothermal animals, such as mammals, maintain their body temperature by heat generation and heat dissipation, while poikilothermal animals, such as insects, accomplish it by relocating to an environment of their favored temperature. Catecholamines are known to regulate thermogenesis and metabolic rate in mammals, but their roles in other animals are poorly understood. The fruit fly, Drosophila melanogaster, has been used as a model system for the genetic studies of temperature preference behavior. Here, we demonstrate that metabolic rate and temperature sensitivity of some temperature sensitive behaviors are regulated by dopamine in Drosophila. Temperature-sensitive molecules like dTrpA1 and shi(ts induce temperature-dependent behavioral changes, and the temperature at which the changes are induced were lowered in the dopamine transporter-defective mutant, fumin. The mutant also displays a preference for lower temperatures. This thermophobic phenotype was rescued by the genetic recovery of the dopamine transporter in dopamine neurons. Flies fed with a dopamine biosynthesis inhibitor (3-iodo-L-tyrosine, which diminishes dopamine signaling, exhibited preference for a higher temperature. Furthermore, we found that the metabolic rate is up-regulated in the fumin mutant. Taken together, dopamine has functions in the temperature sensitivity of behavioral changes and metabolic rate regulation in Drosophila, as well as its previously reported functions in arousal/sleep regulation.

  5. Successful treatment of dopamine dysregulation syndrome with dopamine D2 partial agonist antipsychotic drug

    Directory of Open Access Journals (Sweden)

    Mizushima Jin

    2012-07-01

    Full Text Available Abstract Dopamine dysregulation syndrome (DDS consists of a series of complications such as compulsive use of dopaminergic medications, aggressive or hypomanic behaviors during excessive use, and withdrawal states characterized by dysphoria and anxiety, caused by long-term dopaminergic treatment in patients with Parkinson’s disease (PD. Although several ways to manage DDS have been suggested, there has been no established treatment that can manage DDS without deterioration of motor symptoms. In this article, we present a case of PD in whom the administration of the dopamine D2 partial agonistic antipsychotic drug aripiprazole improved DDS symptoms such as craving and compulsive behavior without worsening of motor symptoms. Considering the profile of this drug as a partial agonist at D2 receptors, it is possible that it exerts its therapeutic effect on DDS by modulating the dysfunctional dopamine system.

  6. Effects of irradiation on neuronal dopamine uptake

    International Nuclear Information System (INIS)

    Martin, C.; Pham, H.T.; Becker, C.; Fatome, M.

    1996-01-01

    The aim of this study was to better understand the mechanism of action of gamma and neutron radiation on the central nervous system, particularly the dopaminergic system. The influence of the two irradiation modalities on the 3 H-DA uptake by synaptosomes prepared from striatum was studied in mice. Four hours after increase of neuronal dopamine uptake is observed. (Authors). 6 refs., 2 figs

  7. Clinical usefulness of dopamine transporter imaging

    International Nuclear Information System (INIS)

    Kim, Jong Min; Kim, Yu Kyeong; Kim, Sang Eun; Jeon, Beom S.

    2007-01-01

    Imaging of the dopamine transporter (DAT) provides a marker for the integrity of presynaptic nigrostriatal dopaminergic system. DAT density is reduced in Parkinson disease, multiple system atrophy, and progressive supranuclear palsy. In patients with suspicious parkinsonism, normal DAT imaging suggests an alternative diagnosis such as essential tremor, vascular parkinsonism, or drug-induced parkinsonism. DAT imaging is a useful tool to aid clinician's differential diagnosis in parkinsonism

  8. Sleep Deprivation Decreases [11C]Raclopride’s Binding to Dopamine D2/D3 Receptors in the Human Brain

    OpenAIRE

    Volkow, Nora D.; Wang, Gene-Jack; Telang, Frank; Fowler, Joanna S.; Logan, Jean; Wong, Christopher; Ma, Jim; Pradhan, Kith; Tomasi, Dardo; Thanos, Peter K.; Ferré, Sergi; Jayne, Millard

    2008-01-01

    Sleep deprivation can markedly impair human performance contributing to accidents and poor productivity. The mechanisms underlying this impairment are not well understood but brain dopamine systems have been implicated. Here we test whether one night of sleep deprivation changes dopamine brain activity. We studied fifteen healthy subjects using positron emission tomography and [11C]raclopride (dopamine D2/3 receptor radioligand) and [11C]cocaine (dopamine transporter radioligand). Subjects we...

  9. Regulation of bat echolocation pulse acoustics by striatal dopamine.

    Science.gov (United States)

    Tressler, Jedediah; Schwartz, Christine; Wellman, Paul; Hughes, Samuel; Smotherman, Michael

    2011-10-01

    The ability to control the bandwidth, amplitude and duration of echolocation pulses is a crucial aspect of echolocation performance but few details are known about the neural mechanisms underlying the control of these voice parameters in any mammal. The basal ganglia (BG) are a suite of forebrain nuclei centrally involved in sensory-motor control and are characterized by their dependence on dopamine. We hypothesized that pharmacological manipulation of brain dopamine levels could reveal how BG circuits might influence the acoustic structure of bat echolocation pulses. A single intraperitoneal injection of a low dose (5 mg kg(-1)) of the neurotoxin 1-methyl-4-phenylpyridine (MPTP), which selectively targets dopamine-producing cells of the substantia nigra, produced a rapid degradation in pulse acoustic structure and eliminated the bat's ability to make compensatory changes in pulse amplitude in response to background noise, i.e. the Lombard response. However, high-performance liquid chromatography (HPLC) measurements of striatal dopamine concentrations revealed that the main effect of MPTP was a fourfold increase rather than the predicted decrease in striatal dopamine levels. After first using autoradiographic methods to confirm the presence and location of D(1)- and D(2)-type dopamine receptors in the bat striatum, systemic injections of receptor subtype-specific agonists showed that MPTP's effects on pulse acoustics were mimicked by a D(2)-type dopamine receptor agonist (Quinpirole) but not by a D(1)-type dopamine receptor agonist (SKF82958). The results suggest that BG circuits have the capacity to influence echolocation pulse acoustics, particularly via D(2)-type dopamine receptor-mediated pathways, and may therefore represent an important mechanism for vocal control in bats.

  10. The roles of serine protease, intracellular and extracellular phenoloxidase in activation of prophenoloxidase system, and characterization of phenoloxidase from shrimp haemocytes induced by lipopolysaccharide or dopamine

    Science.gov (United States)

    Xie, Peng; Pan, Luqing; Xu, Wujie; Yue, Feng

    2013-09-01

    We investigated the effects of lipopolysaccharide (LPS) and dopamine (DA) on the activation of the prophenoloxidase (proPO) system of Litopenaeus vannamei. LPS and DA were shown with a negative dose-dependent effect on hyalne cells (HC), semi-granular cells (SGC), large granular cells (LGC), and total haemocyte count (THC). When haemocytes were treated with LPS or DA, serine proteinase activity and intracellular phenoloxidase (PO) activity were significantly reduced, but extracellular PO activity increased significantly. These findings indicated that the reduction in haemocyte counts was mainly because of the degranulation and activation of the proPO system from semi-granule and large granule cells. The PKC inhibitor, chelerythrine, and the TPK inhibitor, genistein, had an inhibitory effect on extracellular PO activity, while serine proteinase and intracellular PO activity increased. This suggests that the LPS and DA induce the activation of proPO in haemocytes via PKC and TPK-related signaling pathways, but serine proteinase may be activated only by PKC, as the genistein effects were not statistically significant. Electrophoresis analysis revealed that POs induced by LPS or DA have the same molecular mass and high diphenolase activity. Two PO bands at 526 kDa and 272 kDa were observed in PAGE, while in the haemocyte lysate supernatant (HLS), only a 272-kDa band was observed. This band was resolved after SDS-PAGE under non-reducing and reducing conditions into two groups of POs, 166 kDa and 126 kDa, and 78.1 kDa and 73.6 kDa, respectively, suggesting that PO in L. vannamei is an oligomer, which may have different compositions intra- and extracellularly.

  11. Activation of mesocorticolimbic reward circuits for assessment of relief of ongoing pain: a potential biomarker of efficacy.

    Science.gov (United States)

    Xie, Jennifer Y; Qu, Chaoling; Patwardhan, Amol; Ossipov, Michael H; Navratilova, Edita; Becerra, Lino; Borsook, David; Porreca, Frank

    2014-08-01

    Preclinical assessment of pain has increasingly explored operant methods that may allow behavioral assessment of ongoing pain. In animals with incisional injury, peripheral nerve block produces conditioned place preference (CPP) and activates the mesolimbic dopaminergic reward pathway. We hypothesized that activation of this circuit could serve as a neurochemical output measure of relief of ongoing pain. Medications commonly used clinically, including gabapentin and nonsteroidal anti-inflammatory drugs (NSAIDs), were evaluated in models of post-surgical (1 day after incision) or neuropathic (14 days after spinal nerve ligation [SNL]) pain to determine whether the clinical efficacy profile of these drugs in these pain conditions was reflected by extracellular dopamine (DA) release in the nucleus accumbens (NAc) shell. Microdialysis was performed in awake rats. Basal DA levels were not significantly different between experimental groups, and no significant treatment effects were seen in sham-operated animals. Consistent with clinical observation, spinal clonidine produced CPP and produced a dose-related increase in net NAc DA release in SNL rats. Gabapentin, commonly used to treat neuropathic pain, produced increased NAc DA in rats with SNL but not in animals with incisional, injury. In contrast, ketorolac or naproxen produced increased NAc DA in animals with incisional but not neuropathic pain. Increased extracellular NAc DA release was consistent with CPP and was observed selectively with treatments commonly used clinically for post-surgical or neuropathic pain. Evaluation of NAc DA efflux in animal pain models may represent an objective neurochemical assay that may serve as a biomarker of efficacy for novel pain-relieving mechanisms. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  12. Developmental changes in human dopamine neurotransmission: cortical receptors and terminators

    Directory of Open Access Journals (Sweden)

    Rothmond Debora A

    2012-02-01

    Full Text Available Abstract Background Dopamine is integral to cognition, learning and memory, and dysfunctions of the frontal cortical dopamine system have been implicated in several developmental neuropsychiatric disorders. The dorsolateral prefrontal cortex (DLPFC is critical for working memory which does not fully mature until the third decade of life. Few studies have reported on the normal development of the dopamine system in human DLPFC during postnatal life. We assessed pre- and postsynaptic components of the dopamine system including tyrosine hydroxylase, the dopamine receptors (D1, D2 short and D2 long isoforms, D4, D5, catechol-O-methyltransferase, and monoamine oxidase (A and B in the developing human DLPFC (6 weeks -50 years. Results Gene expression was first analysed by microarray and then by quantitative real-time PCR. Protein expression was analysed by western blot. Protein levels for tyrosine hydroxylase peaked during the first year of life (p O-methyltransferase (p = 0.024 were significantly higher in neonates and infants as was catechol-O-methyltransferase protein (32 kDa, p = 0.027. In contrast, dopamine D1 receptor mRNA correlated positively with age (p = 0.002 and dopamine D1 receptor protein expression increased throughout development (p Conclusions We find distinct developmental changes in key components of the dopamine system in DLPFC over postnatal life. Those genes that are highly expressed during the first year of postnatal life may influence and orchestrate the early development of cortical neural circuitry while genes portraying a pattern of increasing expression with age may indicate a role in DLPFC maturation and attainment of adult levels of cognitive function.

  13. Syntaxin 1A interaction with the dopamine transporter promotes amphetamine-induced dopamine efflux

    DEFF Research Database (Denmark)

    Binda, Francesca; Dipace, Concetta; Bowton, Erica

    2008-01-01

    of the dopamine (DA) transporter (DAT) as the site of direct interaction with SYN1A. Amphetamine (AMPH) increases the association of SYN1A with human DAT (hDAT) in a heterologous expression system (hDAT cells) and with native DAT in murine striatal synaptosomes. Immunoprecipitation of DAT from the biotinylated...

  14. Possible involvement of dopamine and dopamine2 receptors in the inhibitions of gastric emptying by escin Ib in mice.

    Science.gov (United States)

    Matsuda, H; Li, Y; Yoshikawa, M

    2000-11-03

    It was previously reported that escin Ib isolated from horse chestnut inhibited gastric emptying (GE) in mice, in which the capsaicin-sensitive sensory nerves (CPSN), the central nervous system and endogenous prostaglandins (PGs) were involved. In the present study, the possible involvement of dopamine and dopamine receptors in the inhibition of GE by escin Ib were investigated in mice. GE inhibition by escin Ib (25 mg/kg, p.o.) was attenuated after pretreatment with a single bolus of DL-alpha-methyl-p-tyrosine methyl ester (400 mg/kg, s.c., an inhibitor of tyrosine hydroxylase), reserpine (5 mg/kg, p.o., a catecholamine depletor), 6-hydroxydopamine (80 mg/kg, i.p., a dopamine depletor). Furthermore, pretreatment with spiperone (0.5-5 mg/kg, s.c., a dopamine2 receptor antagonist), haloperidol (0.5-10 mg/kg, s.c.) and metoclopramide (1-10 mg/kg, s.c.) (centrally acting dopamine2 receptor antagonists) attenuated the effect of escin Ib. Domperidone (0.1-5 mg/kg, s.c., a peripheral-acting dopamine2 antagonist) showed a weak attenuation, but SCH 23390 (1-5 mg/kg, s.c., a dopamine, receptor antagonist) did not. It is postulated that escin Ib inhibits GE, at least in part, mediated by CPSN, to stimulate the synthesis and/or release of dopamine, to act through central dopamine2 receptor, which in turn causes the release of PGs.

  15. Genetics of dopamine and its contribution to cocaine addiction.

    Science.gov (United States)

    Haile, Colin N; Kosten, Thomas R; Kosten, Therese A

    2007-01-01

    Cocaine addiction is a major health and social problem for which there are presently no effective pharmacotherapies. Many of the most promising medications target dopamine based on the large literature that supports its role in addiction. Recent studies show that genetic factors are also important. Rodent models and gene knock-out technology have helped elucidate the involvement of specific genes in the function of the dopamine reward system and intracellular cascades that lead to neuronal changes in this system. Human epidemiological, linkage, and association studies have identified allelic variants (polymorphisms) that give rise to altered metabolism of dopamine and its functional consequences. Individuals with these polymorphisms respond differently to psychostimulants and possibly to pharmacotherapies. Here we review the literature on genetic variations that affect dopamine neurotransmission, responses to psychostimulants and potential treatments for cocaine addiction. Behavioral responses to psychostimulants in animals with different or modified genetics in dopamine signaling are discussed. We also review polymorphisms in humans that affect dopaminergic neurotransmission and alter the subjective effects of psychostimulants. Pharmacotherapies may have increased efficacy when targeted to individuals possessing specific genetic polymophisms in dopamine's metabolic and intracellular messenger systems.

  16. Could dopamine agonists aid in drug development for anorexia nervosa?

    Science.gov (United States)

    Frank, Guido K W

    2014-01-01

    Anorexia nervosa is a severe psychiatric disorder most commonly starting during the teenage-years and associated with food refusal and low body weight. Typically there is a loss of menses, intense fear of gaining weight, and an often delusional quality of altered body perception. Anorexia nervosa is also associated with a pattern of high cognitive rigidity, which may contribute to treatment resistance and relapse. The complex interplay of state and trait biological, psychological, and social factors has complicated identifying neurobiological mechanisms that contribute to the illness. The dopamine D1 and D2 neurotransmitter receptors are involved in motivational aspects of food approach, fear extinction, and cognitive flexibility. They could therefore be important targets to improve core and associated behaviors in anorexia nervosa. Treatment with dopamine antagonists has shown little benefit, and it is possible that antagonists over time increase an already hypersensitive dopamine pathway activity in anorexia nervosa. On the contrary, application of dopamine receptor agonists could reduce circuit responsiveness, facilitate fear extinction, and improve cognitive flexibility in anorexia nervosa, as they may be particularly effective during underweight and low gonadal hormone states. This article provides evidence that the dopamine receptor system could be a key factor in the pathophysiology of anorexia nervosa and dopamine agonists could be helpful in reducing core symptoms of the disorder. This review is a theoretical approach that primarily focuses on dopamine receptor function as this system has been mechanistically better described than other neurotransmitters that are altered in anorexia nervosa. However, those proposed dopamine mechanisms in anorexia nervosa also warrant further study with respect to their interaction with other neurotransmitter systems, such as serotonin pathways.

  17. Could Dopamine Agonists Aid in Drug Development for Anorexia Nervosa?

    Science.gov (United States)

    Frank, Guido K. W.

    2014-01-01

    Anorexia nervosa is a severe psychiatric disorder most commonly starting during the teenage-years and associated with food refusal and low body weight. Typically there is a loss of menses, intense fear of gaining weight, and an often delusional quality of altered body perception. Anorexia nervosa is also associated with a pattern of high cognitive rigidity, which may contribute to treatment resistance and relapse. The complex interplay of state and trait biological, psychological, and social factors has complicated identifying neurobiological mechanisms that contribute to the illness. The dopamine D1 and D2 neurotransmitter receptors are involved in motivational aspects of food approach, fear extinction, and cognitive flexibility. They could therefore be important targets to improve core and associated behaviors in anorexia nervosa. Treatment with dopamine antagonists has shown little benefit, and it is possible that antagonists over time increase an already hypersensitive dopamine pathway activity in anorexia nervosa. On the contrary, application of dopamine receptor agonists could reduce circuit responsiveness, facilitate fear extinction, and improve cognitive flexibility in anorexia nervosa, as they may be particularly effective during underweight and low gonadal hormone states. This article provides evidence that the dopamine receptor system could be a key factor in the pathophysiology of anorexia nervosa and dopamine agonists could be helpful in reducing core symptoms of the disorder. This review is a theoretical approach that primarily focuses on dopamine receptor function as this system has been mechanistically better described than other neurotransmitters that are altered in anorexia nervosa. However, those proposed dopamine mechanisms in anorexia nervosa also warrant further study with respect to their interaction with other neurotransmitter systems, such as serotonin pathways. PMID:25988121

  18. Could Dopamine Agonists Aid in Drug Development for Anorexia Nervosa?

    Directory of Open Access Journals (Sweden)

    Guido eFrank

    2014-11-01

    Full Text Available Anorexia nervosa is a severe psychiatric disorder most commonly starting during the teenage years and associated with food refusal and low body weight. Typically there is a loss of menses, intense fear of gaining weight and an often delusional quality of altered body perception. Anorexia nervosa is also associated with a pattern of high cognitive rigidity, which may contribute to treatment resistance and relapse. The complex interplay of state and trait biological, psychological and social factors has complicated identifying neurobiological mechanisms that contribute to the illness. The dopamine D1 and D2 neurotransmitter receptors are involved in motivational aspects of food approach, fear extinction and cognitive flexibility. They could therefore be important targets to improve core and associated behaviors in anorexia nervosa. Treatment with dopamine antagonists has shown little benefit, and it is possible that antagonists over time increase an already hypersensitive dopamine pathway activity in anorexia nervosa. On the contrary, application of dopamine receptor agonists could reduce circuit responsiveness, facilitate fear extinction and improve cognitive flexibility in anorexia nervosa, as they may be particularly effective during underweight and low gonadal hormone states. This article provides evidence that the dopamine receptor system could be a key factor in the pathophysiology of anorexia nervosa and dopamine agonists could be helpful in reducing core symptoms of the disorder. This review is a theoretical approach that primarily focuses on dopamine receptor function as this system has been mechanistically better described than other neurotransmitters that are altered in anorexia nervosa. However, those proposed dopamine mechanisms in anorexia nervosa also warrant further study with respect to their interaction with other neurotransmitter systems, such as serotonin pathways.

  19. Dopamine Oxidation and Autophagy

    Directory of Open Access Journals (Sweden)

    Patricia Muñoz

    2012-01-01

    Full Text Available The molecular mechanisms involved in the neurodegenerative process of Parkinson's disease remain unclear. Currently, there is a general agreement that mitochondrial dysfunction, α-synuclein aggregation, oxidative stress, neuroinflammation, and impaired protein degradation are involved in the neurodegeneration of dopaminergic neurons containing neuromelanin in Parkinson's disease. Aminochrome has been proposed to play an essential role in the degeneration of dopaminergic neurons containing neuromelanin by inducing mitochondrial dysfunction, oxidative stress, the formation of neurotoxic α-synuclein protofibrils, and impaired protein degradation. Here, we discuss the relationship between the oxidation of dopamine to aminochrome, the precursor of neuromelanin, autophagy dysfunction in dopaminergic neurons containing neuromelanin, and the role of dopamine oxidation to aminochrome in autophagy dysfunction in dopaminergic neurons. Aminochrome induces the following: (i the formation of α-synuclein protofibrils that inactivate chaperone-mediated autophagy; (ii the formation of adducts with α- and β-tubulin, which induce the aggregation of the microtubules required for the fusion of autophagy vacuoles and lysosomes.

  20. Striatal dopamine release codes uncertainty in pathological gambling

    DEFF Research Database (Denmark)

    Linnet, Jakob; Mouridsen, Kim; Peterson, Ericka

    2012-01-01

    Two mechanisms of midbrain and striatal dopaminergic projections may be involved in pathological gambling: hypersensitivity to reward and sustained activation toward uncertainty. The midbrain—striatal dopamine system distinctly codes reward and uncertainty, where dopaminergic activation is a linear...... function of expected reward and an inverse U-shaped function of uncertainty. In this study, we investigated the dopaminergic coding of reward and uncertainty in 18 pathological gambling sufferers and 16 healthy controls. We used positron emission tomography (PET) with the tracer [11C]raclopride to measure...... dopamine release, and we used performance on the Iowa Gambling Task (IGT) to determine overall reward and uncertainty. We hypothesized that we would find a linear function between dopamine release and IGT performance, if dopamine release coded reward in pathological gambling. If, on the other hand...

  1. Reinforcement signalling in Drosophila; dopamine does it all after all.

    Science.gov (United States)

    Waddell, Scott

    2013-06-01

    Reinforcement systems are believed to drive synaptic plasticity within neural circuits that store memories. Recent evidence from the fruit fly suggests that anatomically distinct dopaminergic neurons ultimately provide the key instructive signals for both appetitive and aversive learning. This dual role for dopamine overturns the previous model that octopamine signalled reward and dopamine punishment. More importantly, this anatomically segregated double role for dopamine in reward and aversion mirrors that emerging in mammals. Therefore, an antagonistic organization of distinct reinforcing dopaminegic neurons is a conserved feature of brains. It now seems crucial to understand how the dopaminergic neurons are controlled and what the released dopamine does to the underlying circuits to convey opposite valence. Copyright © 2013 Elsevier Ltd. All rights reserved.

  2. Effect of long-term actual spaceflight on the expression of key genes encoding serotonin and dopamine system

    Science.gov (United States)

    Popova, Nina; Shenkman, Boris; Naumenko, Vladimir; Kulikov, Alexander; Kondaurova, Elena; Tsybko, Anton; Kulikova, Elisabeth; Krasnov, I. B.; Bazhenova, Ekaterina; Sinyakova, Nadezhda

    The effect of long-term spaceflight on the central nervous system represents important but yet undeveloped problem. The aim of our work was to study the effect of 30-days spaceflight of mice on Russian biosatellite BION-M1 on the expression in the brain regions of key genes of a) serotonin (5-HT) system (main enzymes in 5-HT metabolism - tryptophan hydroxylase-2 (TPH-2), monoamine oxydase A (MAO A), 5-HT1A, 5-HT2A and 5-HT3 receptors); b) pivotal enzymes in DA metabolism (tyrosine hydroxylase, COMT, MAO A, MAO B) and D1, D2 receptors. Decreased expression of genes encoding the 5-HT catabolism (MAO A) and 5-HT2A receptor in some brain regions was shown. There were no differences between “spaceflight” and control mice in the expression of TPH-2 and 5-HT1A, 5-HT3 receptor genes. Significant changes were found in genetic control of DA system. Long-term spaceflight decreased the expression of genes encoding the enzyme in DA synthesis (tyrosine hydroxylase in s.nigra), DA metabolism (MAO B in the midbrain and COMT in the striatum), and D1 receptor in hypothalamus. These data suggested that 1) microgravity affected genetic control of 5-HT and especially the nigrostriatal DA system implicated in the central regulation of muscular tonus and movement, 2) the decrease in the expression of genes encoding key enzyme in DA synthesis, DA degradation and D1 receptor contributes to the movement impairment and dyskinesia produced by the spaceflight. The study was supported by Russian Foundation for Basic Research grant No. 14-04-00173.

  3. Cocaine produces conditioned place aversion in mice with a cocaine insensitive dopamine transporter

    OpenAIRE

    O’Neill, Brian; Tilley, Michael R.; Gu, Howard H.

    2012-01-01

    Cocaine is an inhibitor of the dopamine, norepinephrine, and serotonin reuptake transporters. Because its administration would therefore elevate signaling of all these three neurotransmitters, many studies have been aimed at attributing individual effects of cocaine to specific transmitter systems. Using mice with a cocaine insensitive dopamine transporter (DAT-CI mice), we previously showed that cocaine-induced dopamine elevations were necessary for its rewarding and stimulating effects. In ...

  4. Immunomodulatory Effects Mediated by Dopamine

    Directory of Open Access Journals (Sweden)

    Rodrigo Arreola

    2016-01-01

    Full Text Available Dopamine (DA, a neurotransmitter in the central nervous system (CNS, has modulatory functions at the systemic level. The peripheral and central nervous systems have independent dopaminergic system (DAS that share mechanisms and molecular machinery. In the past century, experimental evidence has accumulated on the proteins knowledge that is involved in the synthesis, reuptake, and transportation of DA in leukocytes and the differential expression of the D1-like (D1R and D5R and D2-like receptors (D2R, D3R, and D4R. The expression of these components depends on the state of cellular activation and the concentration and time of exposure to DA. Receptors that are expressed in leukocytes are linked to signaling pathways that are mediated by changes in cAMP concentration, which in turn triggers changes in phenotype and cellular function. According to the leukocyte lineage, the effects of DA are associated with such processes as respiratory burst, cytokine and antibody secretion, chemotaxis, apoptosis, and cytotoxicity. In clinical conditions such as schizophrenia, Parkinson disease, Tourette syndrome, and multiple sclerosis (MS, there are evident alterations during immune responses in leukocytes, in which changes in DA receptor density have been observed. Several groups have proposed that these findings are useful in establishing clinical status and clinical markers.

  5. Activation of the dopamine 1 and dopamine 5 receptors increase skeletal muscle mass and force production under non-atrophying and atrophying conditions

    Directory of Open Access Journals (Sweden)

    Dietrich Jeffrey A

    2011-01-01

    Full Text Available Abstract Background Control of skeletal muscle mass and force production is a complex physiological process involving numerous regulatory systems. Agents that increase skeletal muscle cAMP levels have been shown to modulate skeletal muscle mass and force production. The dopamine 1 receptor and its closely related homolog, the dopamine 5 receptor, are G-protein coupled receptors that are expressed in skeletal muscle and increase cAMP levels when activated. Thus we hypothesize that activation of the dopamine 1 and/or 5 receptor will increase skeletal muscle cAMP levels thereby modulating skeletal muscle mass and force production. Methods We treated isolated mouse tibialis anterior (TA and medial gastrocnemius (MG muscles in tissue bath with the selective dopamine 1 receptor and dopamine 5 receptor agonist SKF 81297 to determine if activation of skeletal muscle dopamine 1 and dopamine 5 receptors will increase cAMP. We dosed wild-type mice, dopamine 1 receptor knockout mice and dopamine 5 receptor knockout mice undergoing casting-induced disuse atrophy with SKF 81297 to determine if activation of the dopamine 1 and dopamine 5 receptors results in hypertrophy of non-atrophying skeletal muscle and preservation of atrophying skeletal muscle mass and force production. Results In tissue bath, isolated mouse TA and MG muscles responded to SKF 81297 treatment with increased cAMP levels. Treating wild-type mice with SKF 81297 reduced casting-induced TA and MG muscle mass loss in addition to increasing the mass of non-atrophying TA and MG muscles. In dopamine 1 receptor knockout mice, extensor digitorum longus (EDL and soleus muscle mass and force was not preserved during casting with SKF 81297 treatment, in contrast to significant preservation of casted wild-type mouse EDL and soleus mass and EDL force with SKF 81297 treatment. Dosing dopamine 5 receptor knockout mice with SKF 81297 did not significantly preserve EDL and soleus muscle mass and force

  6. Dopamine and glucose, obesity and Reward Deficiency Syndrome

    Directory of Open Access Journals (Sweden)

    Kenneth eBlum

    2014-09-01

    Full Text Available Obesity and many well described eating disorders are accurately considered a global epidemic. The consequences of Reward Deficiency Syndrome, a genetic and epigenetic phenomena that involves the interactions of powerful neurotransmitters, are impairments of brain reward circuitry, hypodopaminergic function and abnormal craving behavior. Numerous sound neurochemical and genetic studies provide strong evidence that food addiction is similar to psychoactive drug addiction. Important facts which could translate to potential therapeutic targets espoused in this review include: 1 brain dopamine (DA production and use is stimulated by consumption of alcohol in large quantities or carbohydrates bingeing; 2 in the mesolimbic system the enkephalinergic neurons are in close proximity, to glucose receptors; 3 highly concentrated glucose activates the calcium channel to stimulate dopamine release from P12 cells; 4 blood glucose and cerebrospinal fluid concentrations of homovanillic acid, the dopamine metabolite, are significantly correlated and 5 2-deoxyglucose the glucose analogue, in pharmacological doses associates with enhanced dopamine turnover and causes acute glucoprivation. Evidence from animal studies and human fMRI support the hypothesis that multiple, but similar brain circuits are disrupted in obesity and drug dependence and DA-modulated reward circuits are involved in pathologic eating behaviors. Treatment for addiction to glucose and drugs alike, based on a consensus of neuroscience research, should incorporate dopamine agonist therapy, in contrast to current theories and practices that use dopamine antagonists. Until now, powerful dopamine-D2 agonists have failed clinically, due to chronic down regulation of D2 receptors instead, consideration of novel less powerful D2 agonists that up-regulate D2 receptors seems prudent. We encourage new strategies targeted at improving DA function in the treatment and prevention of obesity a subtype of

  7. Stronger Dopamine D1 Receptor-Mediated Neurotransmission in Dyskinesia.

    Science.gov (United States)

    Farré, Daniel; Muñoz, Ana; Moreno, Estefanía; Reyes-Resina, Irene; Canet-Pons, Júlia; Dopeso-Reyes, Iria G; Rico, Alberto J; Lluís, Carme; Mallol, Josefa; Navarro, Gemma; Canela, Enric I; Cortés, Antonio; Labandeira-García, José L; Casadó, Vicent; Lanciego, José L; Franco, Rafael

    2015-12-01

    Radioligand binding assays to rat striatal dopamine D1 receptors showed that brain lateralization of the dopaminergic system were not due to changes in expression but in agonist affinity. D1 receptor-mediated striatal imbalance resulted from a significantly higher agonist affinity in the left striatum. D1 receptors heteromerize with dopamine D3 receptors, which are considered therapeutic targets for dyskinesia in parkinsonian patients. Expression of both D3 and D1-D3 receptor heteromers were increased in samples from 6-hydroxy-dopamine-hemilesioned rats rendered dyskinetic by treatment with 3, 4-dihydroxyphenyl-L-alanine (L-DOPA). Similar findings were obtained using striatal samples from primates. Radioligand binding studies in the presence of a D3 agonist led in dyskinetic, but not in lesioned or L-DOPA-treated rats, to a higher dopamine sensitivity. Upon D3-receptor activation, the affinity of agonists for binding to the right striatal D1 receptor increased. Excess dopamine coming from L-DOPA medication likely activates D3 receptors thus making right and left striatal D1 receptors equally responsive to dopamine. These results show that dyskinesia occurs concurrently with a right/left striatal balance in D1 receptor-mediated neurotransmission.

  8. Purity and Enrichment of Laser-Microdissected Midbrain Dopamine Neurons

    Directory of Open Access Journals (Sweden)

    Amanda L. Brown

    2013-01-01

    Full Text Available The ability to microdissect individual cells from the nervous system has enormous potential, as it can allow for the study of gene expression in phenotypically identified cells. However, if the resultant gene expression profiles are to be accurately ascribed, it is necessary to determine the extent of contamination by nontarget cells in the microdissected sample. Here, we show that midbrain dopamine neurons can be laser-microdissected to a high degree of enrichment and purity. The average enrichment for tyrosine hydroxylase (TH gene expression in the microdissected sample relative to midbrain sections was approximately 200-fold. For the dopamine transporter (DAT and the vesicular monoamine transporter type 2 (Vmat2, average enrichments were approximately 100- and 60-fold, respectively. Glutamic acid decarboxylase (Gad65 expression, a marker for GABAergic neurons, was several hundredfold lower than dopamine neuron-specific genes. Glial cell and glutamatergic neuron gene expression were not detected in microdissected samples. Additionally, SN and VTA dopamine neurons had significantly different expression levels of dopamine neuron-specific genes, which likely reflects functional differences between the two cell groups. This study demonstrates that it is possible to laser-microdissect dopamine neurons to a high degree of cell purity. Therefore gene expression profiles can be precisely attributed to the targeted microdissected cells.

  9. Selective Activation of Cholinergic Interneurons Enhances Accumbal Phasic Dopamine Release: Setting the Tone for Reward Processing

    Directory of Open Access Journals (Sweden)

    Roger Cachope

    2012-07-01

    Full Text Available Dopamine plays a critical role in motor control, addiction, and reward-seeking behaviors, and its release dynamics have traditionally been linked to changes in midbrain dopamine neuron activity. Here, we report that selective endogenous cholinergic activation achieved via in vitro optogenetic stimulation of nucleus accumbens, a terminal field of dopaminergic neurons, elicits real-time dopamine release. This mechanism occurs via direct actions on dopamine terminals, does not require changes in neuron firing within the midbrain, and is dependent on glutamatergic receptor activity. More importantly, we demonstrate that in vivo selective activation of cholinergic interneurons is sufficient to elicit dopamine release in the nucleus accumbens. Therefore, the control of accumbal extracellular dopamine levels by endogenous cholinergic activity results from a complex convergence of neurotransmitter/neuromodulator systems that may ultimately synergize to drive motivated behavior.

  10. Flow injection fluorescence determination of dopamine using a photo induced electron transfer (PET) boronic acid derivative

    International Nuclear Information System (INIS)

    Ebru Seckin, Z.; Volkan, Muervet

    2005-01-01

    An automated flow injection analysis system was developed for the fluorometric determination of dopamine in pharmaceutical injections. The method is based on the quenching effect of dopamine on m-dansylaminophenyl boronic acid (DAPB) fluorescence due to the reverse photo induced electron transfer (PET) mechanism. Effects of pH and interfering species on the determination of dopamine were examined. Calibration for dopamine, based on quenching data, was linear in the concentration range of 1.0 x 10 -5 to 1.0 x 10 -4 M. Detection limit (3 s) of the method was found to be 3.7 x 10 -6 M. Relative standard deviation of 1.2% (n = 10) was obtained with 1.0 x 10 -5 M dopamine standard solution. The proposed method was applied successfully for the determination of dopamine in pharmaceutical injection sample. The sampling rate was determined as 24 samples per hour

  11. Ventral tegmental area dopamine revisited: effects of acute and repeated stress

    Science.gov (United States)

    Holly, Elizabeth N.; Miczek, Klaus A.

    2015-01-01

    Aversive events rapidly and potently excite certain dopamine neurons in the ventral tegmental area (VTA), promoting phasic increases in the medial prefrontal cortex and nucleus accumbens. This is in apparent contradiction to a wealth of literature demonstrating that most VTA dopamine neurons are strongly activated by reward and reward-predictive cues while inhibited by aversive stimuli. How can these divergent processes both be mediated by VTA dopamine neurons? The answer may lie within the functional and anatomical heterogeneity of the VTA. We focus on VTA heterogeneity in anatomy, neurochemistry, electrophysiology, and afferent/efferent connectivity. Second, recent evidence for a critical role of VTA dopamine neurons in response to both acute and repeated stress will be discussed. Understanding which dopamine neurons are activated by stress, the neural mechanisms driving the activation, and where these neurons project will provide valuable insight into how stress can promote psychiatric disorders associated with the dopamine system, such as addiction and depression. PMID:26676983

  12. The Dopamine Receptor D4 Gene ("DRD4") Moderates Family Environmental Effects on ADHD

    Science.gov (United States)

    Martel, Michelle M.; Nikolas, Molly; Jernigan, Katherine; Friderici, Karen; Waldman, Irwin; Nigg, Joel T.

    2011-01-01

    Attention-Deficit/Hyperactivity Disorder (ADHD) is a prime candidate for exploration of gene-by-environment interaction (i.e., G x E), particularly in relation to dopamine system genes, due to strong evidence that dopamine systems are dysregulated in the disorder. Using a G x E design, we examined whether the "DRD4" promoter 120-bp tandem repeat…

  13. Dopamine signaling: target in glioblastoma

    Czech Academy of Sciences Publication Activity Database

    Bartek, Jiří; Hodný, Zdeněk

    2014-01-01

    Roč. 5, č. 5 (2014), 1116-1117 ISSN 1949-2553 Institutional support: RVO:68378050 Keywords : Dopamine signaling * glioblastoma * MAPK Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 6.359, year: 2014

  14. Neuroprotective Effects of Jitai Tablet, a Traditional Chinese Medicine, on the MPTP-Induced Acute Model of Parkinson’s Disease: Involvement of the Dopamine System

    Directory of Open Access Journals (Sweden)

    Jia Liu

    2014-01-01

    Full Text Available Jitai tablet (JTT is a traditional Chinese medicine used to treat neuropsychiatric disorders. We previously demonstrated that JTT treatment led to increased level of dopamine transporter (DAT in the striatum, thus indicating that JTT might have therapeutic potential for Parkinson’s disease (PD, which is characterized by dysregulated dopamine (DA transmission and decreased striatal DAT expression. The aim of this study was to investigate the neuroprotective effect of JTT on MPTP-induced PD mice. Using locomotor activity test and rotarod test, we evaluated the effects of JTT (0.50, 0.15, or 0.05 g/kg on MPTP-induced behavioral impairments. Tyrosine hydroxylase TH-positive neurons in the substantia nigra and DAT and dopamine D2 receptor (D2R levels in the striatum were detected by immunohistochemical staining and/or autoradiography. Levels of DA and its metabolites were determined by HPLC. In MPTP-treated mice, behavioral impairments were alleviated by JTT treatment. Moreover, JTT protected against impairment of TH-positive neurons and attenuated the MPTP-induced decreases in DAT and D2R. Finally, high dose of JTT (0.50 g/kg inhibited the MPTP-induced increase in DA metabolism rate. Taken together, results from our present study provide evidence that JTT offers neuroprotective effects against the neurotoxicity of MPTP and thus might be a potential treatment for PD.

  15. Dopamine, behavioral economics, and effort

    Directory of Open Access Journals (Sweden)

    John D Salamone

    2009-09-01

    Full Text Available Abstract. There are numerous problems with the hypothesis that brain dopamine (DA systems, particularly in the nucleus accumbens, directly mediate the rewarding or primary motivational characteristics of natural stimuli such as food. Research and theory related to the functions of mesolimbic DA are undergoing a substantial conceptual restructuring, with the traditional emphasis on hedonia and primary reward yielding to other concepts and lines of inquiry. The present review is focused upon the involvement of nucleus accumbens DA in behavioral activation and effort-related processes. Viewed from the framework of behavioral economics, the effects of accumbens DA depletions and antagonism on food-reinforced behavior are highly dependent upon the work requirements of the instrumental task, and DA depleted rats are more sensitive to increases in response costs (i.e., ratio requirements. Moreover, interference with accumbens DA transmission exerts a powerful influence over effort-related choice behavior. Rats with accumbens DA depletions or antagonism reallocate their instrumental behavior away from food-reinforced tasks that have high response requirements, and instead these rats select a less-effortful type of food-seeking behavior. Nucleus accumbens DA and adenosine interact in the regulation of effort-related functions, and other brain structures (anterior cingulate cortex, amygdala, ventral pallidum also are involved. Studies of the brain systems regulating effort-based processes may have implications for understanding drug abuse, as well as energy-related disorders such as psychomotor slowing, fatigue or anergia in depression and other neurological disorders.

  16. Dopamine and extinction: A convergence of theory with fear and reward circuitry

    Science.gov (United States)

    Abraham, Antony D.; Neve, Kim A.; Lattal, K. Matthew

    2014-01-01

    Research on dopamine lies at the intersection of sophisticated theoretical and neurobiological approaches to learning and memory. Dopamine has been shown to be critical for many processes that drive learning and memory, including motivation, prediction error, incentive salience, memory consolidation, and response output. Theories of dopamine’s function in these processes have, for the most part, been developed from behavioral approaches that examine learning mechanisms in reward-related tasks. A parallel and growing literature indicates that dopamine is involved in fear conditioning and extinction. These studies are consistent with long-standing ideas about appetitive-aversive interactions in learning theory and they speak to the general nature of cellular and molecular processes that underlie behavior. We review the behavioral and neurobiological literature showing a role for dopamine in fear conditioning and extinction. At a cellular level, we review dopamine signaling and receptor pharmacology, cellular and molecular events that follow dopamine receptor activation, and brain systems in which dopamine functions. At a behavioral level, we describe theories of learning and dopamine function that could describe the fundamental rules underlying how dopamine modulates different aspects of learning and memory processes. PMID:24269353

  17. Prefrontal Markers and Cognitive Performance Are Dissociated during Progressive Dopamine Lesion.

    Science.gov (United States)

    Wilson, Charles R E; Vezoli, Julien; Stoll, Frederic M; Faraut, Maïlys C M; Leviel, Vincent; Knoblauch, Kenneth; Procyk, Emmanuel

    2016-11-01

    Dopamine is thought to directly influence the neurophysiological mechanisms of both performance monitoring and cognitive control-two processes that are critically linked in the production of adapted behaviour. Changing dopamine levels are also thought to induce cognitive changes in several neurological and psychiatric conditions. But the working model of this system as a whole remains untested. Specifically, although many researchers assume that changing dopamine levels modify neurophysiological mechanisms and their markers in frontal cortex, and that this in turn leads to cognitive changes, this causal chain needs to be verified. Using longitudinal recordings of frontal neurophysiological markers over many months during progressive dopaminergic lesion in non-human primates, we provide data that fail to support a simple interaction between dopamine, frontal function, and cognition. Feedback potentials, which are performance-monitoring signals sometimes thought to drive successful control, ceased to differentiate feedback valence at the end of the lesion, just before clinical motor threshold. In contrast, cognitive control performance and beta oscillatory markers of cognitive control were unimpaired by the lesion. The differing dynamics of these measures throughout a dopamine lesion suggests they are not all driven by dopamine in the same way. These dynamics also demonstrate that a complex non-linear set of mechanisms is engaged in the brain in response to a progressive dopamine lesion. These results question the direct causal chain from dopamine to frontal physiology and on to cognition. They imply that biomarkers of cognitive functions are not directly predictive of dopamine loss.

  18. Prefrontal Markers and Cognitive Performance Are Dissociated during Progressive Dopamine Lesion.

    Directory of Open Access Journals (Sweden)

    Charles R E Wilson

    2016-11-01

    Full Text Available Dopamine is thought to directly influence the neurophysiological mechanisms of both performance monitoring and cognitive control-two processes that are critically linked in the production of adapted behaviour. Changing dopamine levels are also thought to induce cognitive changes in several neurological and psychiatric conditions. But the working model of this system as a whole remains untested. Specifically, although many researchers assume that changing dopamine levels modify neurophysiological mechanisms and their markers in frontal cortex, and that this in turn leads to cognitive changes, this causal chain needs to be verified. Using longitudinal recordings of frontal neurophysiological markers over many months during progressive dopaminergic lesion in non-human primates, we provide data that fail to support a simple interaction between dopamine, frontal function, and cognition. Feedback potentials, which are performance-monitoring signals sometimes thought to drive successful control, ceased to differentiate feedback valence at the end of the lesion, just before clinical motor threshold. In contrast, cognitive control performance and beta oscillatory markers of cognitive control were unimpaired by the lesion. The differing dynamics of these measures throughout a dopamine lesion suggests they are not all driven by dopamine in the same way. These dynamics also demonstrate that a complex non-linear set of mechanisms is engaged in the brain in response to a progressive dopamine lesion. These results question the direct causal chain from dopamine to frontal physiology and on to cognition. They imply that biomarkers of cognitive functions are not directly predictive of dopamine loss.

  19. Endocannabinoid modulation of dopamine neurotransmission.

    Science.gov (United States)

    Covey, Dan P; Mateo, Yolanda; Sulzer, David; Cheer, Joseph F; Lovinger, David M

    2017-09-15

    Dopamine (DA) is a major catecholamine neurotransmitter in the mammalian brain that controls neural circuits involved in the cognitive, emotional, and motor aspects of goal-directed behavior. Accordingly, perturbations in DA neurotransmission play a central role in several neuropsychiatric disorders. Somewhat surprisingly given its prominent role in numerous behaviors, DA is released by a relatively small number of densely packed neurons originating in the midbrain. The dopaminergic midbrain innervates numerous brain regions where extracellular DA release and receptor binding promote short- and long-term changes in postsynaptic neuron function. Striatal forebrain nuclei receive the greatest proportion of DA projections and are a predominant hub at which DA influences behavior. A number of excitatory, inhibitory, and modulatory inputs orchestrate DA neurotransmission by controlling DA cell body firing patterns, terminal release, and effects on postsynaptic sites in the striatum. The endocannabinoid (eCB) system serves as an important filter of afferent input that acts locally at midbrain and terminal regions to shape how incoming information is conveyed onto DA neurons and to output targets. In this review, we aim to highlight existing knowledge regarding how eCB signaling controls DA neuron function through modifications in synaptic strength at midbrain and striatal sites, and to raise outstanding questions on this topic. This article is part of the Special Issue entitled "A New Dawn in Cannabinoid Neurobiology". Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Imaging dopamine transmission in schizophrenia

    International Nuclear Information System (INIS)

    Laruelle, M.

    1998-01-01

    Over the last ten years, several positron emission tomography (PET) and single photon computerized tomography (SPECT) studies of the dopamine (DA) system in patients with schizophrenia were performed to test the hypothesis that DA hyperactivity is associated with this illness. In this paper are reviewed the results of fifteen brain imaging studies comparing indices of DA function in drug naive or drug free patients with schizophrenia and healthy controls: thirteen studies included measurements of Da D 2 receptor density, two studies compared amphetamine-induced DA release, and two studies measured DOPA decarboxylase activity, an enzyme involved in DA synthesis. It was conducted a meta-analysis of the studies measuring D 2 receptor density parameters, under the assumption that all tracers labeled the same population of D 2 receptors. This analysis revealed that, compared to healthy controls, patients with schizophrenia present a significant but mild elevation of D 2 receptor density parameters and a significant larger variability of these indices. It was found no statistical evidence that studies performed with radiolabeled butyrophenones detected a larger increase in D 2 receptor density parameters than studies performed with other radioligands, such as benzamides. Studies of presynaptic activity revealed an increase in DA transmission response to amphetamine challenge, and an increase in DOPA decarboxylase activity. Together, these data are compatible with both pre- and post-synaptic alterations of DA transmission in schizophrenia. Future studies should aim at a better characterization of these alterations, and at defining their role in the pathophysiology of the illness

  1. Addiction: Beyond dopamine reward circuitry

    Energy Technology Data Exchange (ETDEWEB)

    Volkow, N.D.; Wang, G.; Volkow, N.D.; Wang, G.-J.; Fowler, J.S.; Tomasi, D.; Telang, F.

    2011-09-13

    Dopamine (DA) is considered crucial for the rewarding effects of drugs of abuse, but its role in addiction is much less clear. This review focuses on studies that used PET to characterize the brain DA system in addicted subjects. These studies have corroborated in humans the relevance of drug-induced fast DA increases in striatum [including nucleus accumbens (NAc)] in their rewarding effects but have unexpectedly shown that in addicted subjects, drug-induced DA increases (as well as their subjective reinforcing effects) are markedly blunted compared with controls. In contrast, addicted subjects show significant DA increases in striatum in response to drug-conditioned cues that are associated with self-reports of drug craving and appear to be of a greater magnitude than the DA responses to the drug. We postulate that the discrepancy between the expectation for the drug effects (conditioned responses) and the blunted pharmacological effects maintains drug taking in an attempt to achieve the expected reward. Also, whether tested during early or protracted withdrawal, addicted subjects show lower levels of D2 receptors in striatum (including NAc), which are associated with decreases in baseline activity in frontal brain regions implicated in salience attribution (orbitofrontal cortex) and inhibitory control (anterior cingulate gyrus), whose disruption results in compulsivity and impulsivity. These results point to an imbalance between dopaminergic circuits that underlie reward and conditioning and those that underlie executive function (emotional control and decision making), which we postulate contributes to the compulsive drug use and loss of control in addiction.

  2. Addiction: Beyond dopamine reward circuitry

    International Nuclear Information System (INIS)

    Volkow, N.D.; Wang, G.-J.; Fowler, J.S.; Tomasi, D.; Telang, F.

    2011-01-01

    Dopamine (DA) is considered crucial for the rewarding effects of drugs of abuse, but its role in addiction is much less clear. This review focuses on studies that used PET to characterize the brain DA system in addicted subjects. These studies have corroborated in humans the relevance of drug-induced fast DA increases in striatum [including nucleus accumbens (NAc)] in their rewarding effects but have unexpectedly shown that in addicted subjects, drug-induced DA increases (as well as their subjective reinforcing effects) are markedly blunted compared with controls. In contrast, addicted subjects show significant DA increases in striatum in response to drug-conditioned cues that are associated with self-reports of drug craving and appear to be of a greater magnitude than the DA responses to the drug. We postulate that the discrepancy between the expectation for the drug effects (conditioned responses) and the blunted pharmacological effects maintains drug taking in an attempt to achieve the expected reward. Also, whether tested during early or protracted withdrawal, addicted subjects show lower levels of D2 receptors in striatum (including NAc), which are associated with decreases in baseline activity in frontal brain regions implicated in salience attribution (orbitofrontal cortex) and inhibitory control (anterior cingulate gyrus), whose disruption results in compulsivity and impulsivity. These results point to an imbalance between dopaminergic circuits that underlie reward and conditioning and those that underlie executive function (emotional control and decision making), which we postulate contributes to the compulsive drug use and loss of control in addiction.

  3. Blockade of Dopamine Activity in the Nucleus Accumbens Impairs Learning Extinction of Conditioned Fear

    Science.gov (United States)

    Holtzman-Assif, Orit; Laurent, Vincent; Westbrook, R. Frederick

    2010-01-01

    Three experiments used rats to investigate the role of dopamine activity in learning to inhibit conditioned fear responses (freezing) in extinction. In Experiment 1, rats systemically injected with the D2 dopamine antagonist, haloperidol, froze more across multiple extinction sessions and on a drug-free retention test than control rats. In…

  4. 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...

  5. A role for accumbal glycine receptors in modulation of dopamine release by the glycine transporter-1 inhibitor Org25935

    Directory of Open Access Journals (Sweden)

    Helga eHöifödt Lidö

    2011-03-01

    Full Text Available AbstractAccumbal glycine modulates basal and ethanol-induced dopamine levels in the nucleus accumbens (nAc as well as voluntary ethanol consumption. Also, systemic administration of the glycine transporter-1 inhibitor Org25935 elevates dopamine levels in nAc, prevents a further ethanol-induced dopamine elevation and robustly and dose-dependently decreases ethanol consumption in rats. Here we investigated whether Org25935 applied locally in nAc modulates dopamine release, and whether accumbal glycine receptors or NMDA receptors are involved in this tentative effect. We also addressed whether Org25935 and ethanol applied locally in nAc interact with dopamine levels, as seen after systemic administration. We used in vivo microdialysis coupled to HPLC-ED in freely moving male Wistar rats to monitor dopamine output in nAc after local perfusion of Org25935 alone, with ethanol, or Org25935-perfusion after pre-treatment with the glycine receptor antagonist strychnine or the NMDA receptor glycine site antagonist L-701.324. Local Org25935 increased extracellular dopamine levels in a subpopulation of rats. Local strychnine, but not systemic L-701.324, antagonized the dopamine-activating effect of Org25935. Ethanol failed to induce a dopamine overflow in the subpopulation responding to Org25935 with a dopamine elevation. The study supports a role for accumbal glycine receptors rather than NMDA receptor signaling in the dopamine-activating effect of Org25935. The results further indicate that the previously reported systemic Org25935-ethanol interaction with regard to accumbal dopamine is localized to the nAc. This adds to the growing evidence for the glycine receptor as an important player in the dopamine reward circuitry and in ethanol’s effects within this system.

  6. Dopamine alleviates nutrient deficiency-induced stress in Malus hupehensis.

    Science.gov (United States)

    Liang, Bowen; Li, Cuiying; Ma, Changqing; Wei, Zhiwei; Wang, Qian; Huang, Dong; Chen, Qi; Li, Chao; Ma, Fengwang

    2017-10-01

    Dopamine mediates many physiological processes in plants. We investigated its role in regulating growth, root system architecture, nutrient uptake, and responses to nutrient deficiencies in Malus hupehensis Rehd. Under a nutrient deficiency, plants showed significant reductions in growth, chlorophyll concentrations, and net photosynthesis, along with disruptions in nutrient uptake, transport, and distribution. However, pretreatment with 100 μM dopamine markedly alleviated such inhibitions. Supplementation with that compound enabled plants to maintain their photosynthetic capacity and development of the root system while promoting the uptake of N, P, K, Ca, Mg, Fe, Mn, Cu, Zn, and B, altering the way in which those nutrients were partitioned throughout the plant. The addition of dopamine up-regulated genes for antioxidant enzymes involved in the ascorbate-glutathione cycle (MdcAPX, MdcGR, MdMDHAR, MdDHAR-1, and MdDHAR-2) but down-regulated genes for senescence (SAG12, PAO, and MdHXK). These results indicate that exogenous dopamine has an important antioxidant and anti-senescence effect that might be helpful for improving nutrient uptake. Our findings demonstrate that dopamine offers new opportunities for its use in agriculture, especially when addressing the problem of nutrient deficiencies. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  7. Dopamine natriuresis in salt-repleted, water-loaded humans

    DEFF Research Database (Denmark)

    Olsen, Niels Vidiendal; Olsen, M H; Bonde, J

    1997-01-01

    The purpose of the present study was to define the dose-response relationship between exogenous dopamine and systemic haemodynamics, renal haemodynamics, and renal excretory function at infusion rates in the range 0 to 12.5 microg kg(-1) min(-1) in normal volunteers.......The purpose of the present study was to define the dose-response relationship between exogenous dopamine and systemic haemodynamics, renal haemodynamics, and renal excretory function at infusion rates in the range 0 to 12.5 microg kg(-1) min(-1) in normal volunteers....

  8. Behavioural effects of chemogenetic dopamine neuron activation

    NARCIS (Netherlands)

    Boekhoudt, L

    2016-01-01

    Various psychiatric disorders, including schizophrenia, attention-deficit/hyperactivity disorder (ADHD) and major depressive disorder, have been associated with altered dopamine signalling in the brain. However, it remains unclear which specific changes in dopamine activity are related to specific

  9. Molecular Mechanisms of Dopamine Receptor Mediated Neuroprotection

    National Research Council Canada - National Science Library

    Sealfon, Stuart

    2000-01-01

    ... of the cellular changes characteristic of this process. Evidence from our laboratory and others suggest that activation of dopamine receptors can oppose the induction of apoptosis in dopamine neurons...

  10. Dopamine, reward learning, and active inference

    Directory of Open Access Journals (Sweden)

    Thomas eFitzgerald

    2015-11-01

    Full Text Available Temporal difference learning models propose phasic dopamine signalling encodes reward prediction errors that drive learning. This is supported by studies where optogenetic stimulation of dopamine neurons can stand in lieu of actual reward. Nevertheless, a large body of data also shows that dopamine is not necessary for learning, and that dopamine depletion primarily affects task performance. We offer a resolution to this paradox based on an hypothesis that dopamine encodes the precision of beliefs about alternative actions, and thus controls the outcome-sensitivity of behaviour. We extend an active inference scheme for solving Markov decision processes to include learning, and show that simulated dopamine dynamics strongly resemble those actually observed during instrumental conditioning. Furthermore, simulated dopamine depletion impairs performance but spares learning, while simulated excitation of dopamine neurons drives reward learning, through aberrant inference about outcome states. Our formal approach provides a novel and parsimonious reconciliation of apparently divergent experimental findings.

  11. Neurotrophic actions of dopamine on the development of a serotonergic feeding circuit in Drosophila melanogaster.

    Science.gov (United States)

    Neckameyer, Wendi S; Bhatt, Parag

    2012-03-13

    In the fruit fly, Drosophila melanogaster, serotonin functions both as a neurotransmitter to regulate larval feeding, and in the development of the stomatogastric feeding circuit. There is an inverse relationship between neuronal serotonin levels during late embryogenesis and the complexity of the serotonergic fibers projecting from the larval brain to the foregut, which correlate with perturbations in feeding, the functional output of the circuit. Dopamine does not modulate larval feeding, and dopaminergic fibers do not innervate the larval foregut. Since dopamine can function in central nervous system development, separate from its role as a neurotransmitter, the role of neuronal dopamine was assessed on the development, and mature function, of the 5-HT larval feeding circuit. Both decreased and increased neuronal dopamine levels in late embryogenesis during development of this circuit result in depressed levels of larval feeding. Perturbations in neuronal dopamine during this developmental period also result in greater branch complexity of the serotonergic fibers innervating the gut, as well as increased size and number of the serotonin-containing vesicles along the neurite length. This neurotrophic action for dopamine is modulated by the D2 dopamine receptor expressed during late embryogenesis in central 5-HT neurons. Animals carrying transgenic RNAi constructs to knock down both dopamine and serotonin synthesis in the central nervous system display normal feeding and fiber architecture. However, disparate levels of neuronal dopamine and serotonin during development of the circuit result in abnormal gut fiber architecture and feeding behavior. These results suggest that dopamine can exert a direct trophic influence on the development of a specific neural circuit, and that dopamine and serotonin may interact with each other to generate the neural architecture necessary for normal function of the circuit.

  12. Neurotrophic actions of dopamine on the development of a serotonergic feeding circuit in Drosophila melanogaster

    Directory of Open Access Journals (Sweden)

    Neckameyer Wendi S

    2012-03-01

    Full Text Available Abstract Background In the fruit fly, Drosophila melanogaster, serotonin functions both as a neurotransmitter to regulate larval feeding, and in the development of the stomatogastric feeding circuit. There is an inverse relationship between neuronal serotonin levels during late embryogenesis and the complexity of the serotonergic fibers projecting from the larval brain to the foregut, which correlate with perturbations in feeding, the functional output of the circuit. Dopamine does not modulate larval feeding, and dopaminergic fibers do not innervate the larval foregut. Since dopamine can function in central nervous system development, separate from its role as a neurotransmitter, the role of neuronal dopamine was assessed on the development, and mature function, of the 5-HT larval feeding circuit. Results Both decreased and increased neuronal dopamine levels in late embryogenesis during development of this circuit result in depressed levels of larval feeding. Perturbations in neuronal dopamine during this developmental period also result in greater branch complexity of the serotonergic fibers innervating the gut, as well as increased size and number of the serotonin-containing vesicles along the neurite length. This neurotrophic action for dopamine is modulated by the D2 dopamine receptor expressed during late embryogenesis in central 5-HT neurons. Animals carrying transgenic RNAi constructs to knock down both dopamine and serotonin synthesis in the central nervous system display normal feeding and fiber architecture. However, disparate levels of neuronal dopamine and serotonin during development of the circuit result in abnormal gut fiber architecture and feeding behavior. Conclusions These results suggest that dopamine can exert a direct trophic influence on the development of a specific neural circuit, and that dopamine and serotonin may interact with each other to generate the neural architecture necessary for normal function of the circuit.

  13. Changes in cardiovascular effects of dopamine in response to graded hypothermia in vivo.

    Science.gov (United States)

    Filseth, Ole Magnus; How, Ole-Jakob; Kondratiev, Timofei; Gamst, Tor Magne; Sager, Georg; Tveita, Torkjel

    2012-01-01

    Inotropic drugs are frequently administered in hypothermic patients to support an assumed inadequate circulation, but their pharmacologic properties at reduced temperatures are largely unknown. Thus we estimated dopamine pharmacokinetics as well as left ventricular function and global hemodynamics after dopamine infusions at various core temperatures in a pig model of surface cooling and rewarming. Prospective, randomized, open, placebo-controlled experimental study. University-affiliated animal research laboratory. Sixteen healthy, anesthetized juvenile (2-3 months) castrated male pigs. After normothermic infusions of dopamine at different doses (4, 8, and 16 μg/kg/min), effects of dopamine (n = 8) or saline (n = 8) were tested at 25 °C and during rewarming (30-34 °C). Dopamine half-time was 5.4 ± 0.7 min at normothermia, increased to 11.6 ± 0.8 min at 25 °C, but returned to control during rewarming at 34-35 °C. Dopamine infusion at 25 °C elevated dopamine plasma concentration four-fold compared to the same infusion rate at normothermia, leading to increased systemic vascular resistance index not seen at normothermia. Also, in contrast to the dopamine-mediated increase in cardiac index observed at normothermia, high-dose dopamine at 25 °C left cardiac index unchanged despite a concomitant increase in heart rate, since stroke index decreased by 43%. During rewarming, cardiovascular effects of dopamine at moderate hypothermia (30-34 °C) were principally similar to responses during normothermia. Pharmacodynamic effects and pharmacokinetics of dopamine are maintained during the rewarming phase at moderate hypothermia. However, at 25 °C dopamine pharmacokinetics were seriously altered and dopamine failed to increase cardiac index since stroke index was reduced with incrementing dosages. Properties of the low-flow, high-viscosity circulatory state, combined with altered pharmacokinetics of dopamine, may explain lack of beneficial--and potentially harmful

  14. Preparation of (7,8-3H) dopamine

    International Nuclear Information System (INIS)

    Shen Qiyuan; Tang Guozhong; Guo Zili

    1986-01-01

    Dopamine is a neurotransmitter in the central nervous system. (7,8- 3 H) dopamine is an important tracer for the study of physiological functions and metabolic processes. It was prepared by catalytic reduction of 3-hydroxy-4-methoxy-8-nitro-styrene with tritium gas. At the end of reaction, hydrobromic acid was added and heated to remove the methoxyl group. The crude product was purified by paper chromatography. The purity of (7,8- 3 H) dopamine was identified by IR, UV, PC and 3 H-NMR spectra. The radiochemical purity was over 95% and the specific activity was 1.26 x 10 12 Bq/mmol (34 Ci/mmol). The distribution of labelled tritium in molecule was shown as follows: 55.4% at position 7 and 44.6% at position 8

  15. The involvement of dopaminergic system on LH secretion Nelore heifers Sistema dopaminérgico na secreção de LH de novilhas Nelore

    Directory of Open Access Journals (Sweden)

    Silvia Helena Venturoli Perri

    2009-12-01

    Full Text Available The aim of this study was to evaluate the response of sulpiride administration (dopamine D2 antagonist, 0.59 m/kg body weight, s.c. and blood collected every 15 min for 10 h thereafter on Luteinizing Hormone (LH secretion in B. indicus pre-pubertal heifers at 8, 12 and 16 month of age. LH was quantified by RIA, sensitivity (0.039 ng/ml and CV (15.51%. In heifers given sulpiride treatment didn’t differ (P≥0.05 in LH concentration, total secretion area, peak total area, number of peaks, area of highest secretion peak and time to highest peak occurrence and maximum LH secretion, from control group. The results suggest absence of dopamine D2 antagonist effect on LH secretion in pre-pubertal Nellore heifers, didn’t neurotransmitter participating on sexual maturation.O presente trabalho foi realizado com o objetivo de investigar a variação na secreção do Hormônio Luteinizante (LH em resposta ao tratamento com sulpiride, antagonista de receptor (D2 dopaminérgico, com administração de 0,59mg/kg, s.c. e colheita de amostras de sangue a cada 15min, por 10h. Foram utilizadas 10 novilhas da raça Nelore pré-púberes, aos 8, 12 e 16 meses de idade. A concentração de LH foi quantificada por radioimunoensaio, e o coeficiente de variação intra, o interensaio e a sensibilidade dos ensaios de LH foram respectivamente de: 11,86%; 15,51%; 0,039ng/mL. O tratamento com sulpiride não diferiu na concentração média de LH, área total de secreção de LH e picos, número de picos, área do maior pico, tempo necessário ao aparecimento do maior pico de secreção de LH e amplitude máxima de LH, em comparação ao grupo controle. Os resultados indicam ausência de efeito da dopamina, através de receptores D2, durante a fase pré-púbere, em novilhas da raça Nelore, o que sinaliza a não participação como neurotransmissora na secreção de LH durante o processo de maturação sexual.

  16. Dopamine agents for hepatic encephalopathy

    DEFF Research Database (Denmark)

    Junker, Anders Ellekær; Als-Nielsen, Bodil; Gluud, Christian

    2014-01-01

    BACKGROUND: Patients with hepatic encephalopathy may present with extrapyramidal symptoms and changes in basal ganglia. These changes are similar to those seen in patients with Parkinson's disease. Dopamine agents (such as bromocriptine and levodopa, used for patients with Parkinson's disease) have...

  17. Subsecond dopamine release promotes cocaine seeking.

    Science.gov (United States)

    Phillips, Paul E M; Stuber, Garret D; Heien, Michael L A V; Wightman, R Mark; Carelli, Regina M

    2003-04-10

    The dopamine-containing projection from the ventral tegmental area of the midbrain to the nucleus accumbens is critically involved in mediating the reinforcing properties of cocaine. Although neurons in this area respond to rewards on a subsecond timescale, neurochemical studies have only addressed the role of dopamine in drug addiction by examining changes in the tonic (minute-to-minute) levels of extracellular dopamine. To investigate the role of phasic (subsecond) dopamine signalling, we measured dopamine every 100 ms in the nucleus accumbens using electrochemical technology. Rapid changes in extracellular dopamine concentration were observed at key aspects of drug-taking behaviour in rats. Before lever presses for cocaine, there was an increase in dopamine that coincided with the initiation of drug-seeking behaviours. Notably, these behaviours could be reproduced by electrically evoking dopamine release on this timescale. After lever presses, there were further increases in dopamine concentration at the concurrent presentation of cocaine-related cues. These cues alone also elicited similar, rapid dopamine signalling, but only in animals where they had previously been paired to cocaine delivery. These findings reveal an unprecedented role for dopamine in the regulation of drug taking in real time.

  18. Study of the dopamine effect into cell solutions by impedance analysis

    Science.gov (United States)

    Paivana, G.; Apostolou, T.; Kaltsas, G.; Kintzios, S.

    2017-11-01

    Electrochemical Impedance Spectroscopy (EIS) has become a technique that is frequently used for biological assays. Impedance is defined as a complex - valued generalization of resistance and varies depending on its use per application field. In health sciences, bioimpedance is widely used as non-invasive and low cost alternative in many medical areas that provides valuable information about health status. This work focuses on assessing the effects of a bioactive substance applied to immobilized cells. Dopamine was used as a stimulant in order to implement impedance analysis with a specific type of cells. Dopamine constitutes one of the most important catecholamine neurotransmitters in both the mammalian central and peripheral nervous systems. The main purpose is to extract calibration curves at different frequencies with known dopamine concentrations in order to describe the behavior of cells applied to dopamine using an impedance measurement device. For comparison purposes, non-immobilized cells were tested for the same dopamine concentrations.

  19. Dopamine Dynamics during Continuous Intracranial Self-Stimulation: Effect of Waveform on Fast-Scan Cyclic Voltammetry Data

    Science.gov (United States)

    2016-01-01

    The neurotransmitter dopamine is heavily implicated in intracranial self-stimulation (ICSS). Many drugs of abuse that affect ICSS behavior target the dopaminergic system, and optogenetic activation of dopamine neurons is sufficient to support self-stimulation. However, the patterns of phasic dopamine release during ICSS remain unclear. Early ICSS studies using fast-scan cyclic voltammetry (FSCV) rarely observed phasic dopamine release, which led to the surprising conclusion that it is dissociated from ICSS. However, several advances in the sensitivity (i.e., the use of waveforms with extended anodic limits) and analysis (i.e., principal component regression) of FSCV measurements have made it possible to detect smaller, yet physiologically relevant, dopamine release events. Therefore, this study revisits phasic dopamine release during ICSS using these tools. It was found that the anodic limit of the voltammetric waveform has a substantial effect on the patterns of dopamine release observed during continuous ICSS. While data collected with low anodic limits (i.e., +1.0 V) support the disappearance of phasic dopamine release observed in previous investigation, the use of high anodic limits (+1.3 V, +1.4 V) allows for continual detection of dopamine release throughout ICSS. However, the +1.4 V waveform lacks the ability to resolve narrowly spaced events, with the best balance of temporal resolution and sensitivity provided by the +1.3 V waveform. Ultimately, it is revealed that the amplitude of phasic dopamine release decays but does not fully disappear during continuous ICSS. PMID:27548680

  20. Dopamine or biopterin deficiency potentiates phosphorylation at (40)Ser and ubiquitination of tyrosine hydroxylase to be degraded by the ubiquitin proteasome system.

    Science.gov (United States)

    Kawahata, Ichiro; Ohtaku, Shiori; Tomioka, Yoshihisa; Ichinose, Hiroshi; Yamakuni, Tohru

    2015-09-11

    The protein amount of tyrosine hydroxylase (TH), that is the rate-limiting enzyme for the biosynthesis of dopamine (DA), should be tightly regulated, whereas its degradation pathway is largely unknown. In this study, we analyzed how the TH protein is chemically modified and subsequently degraded under deficiencies of DA and tetrahydrobiopterin (BH4), a cofactor for TH, by using pharmacological agents in PC12D cells and cultured mesencephalic neurons. When inhibition of DA- or BH4-synthesizing enzymes greatly reduced the DA contents in PC12D cells, a marked and persistent increase in phosphorylated TH at (40)Ser (p40-TH) was concomitantly observed. This phosphorylation was mediated by D2 dopamine auto-receptor and cAMP-dependent protein kinase (PKA). Our immunoprecipitation experiments showed that the increase in the p40-TH level was accompanied with its poly-ubiquitination. Treatment of PC12D cells with cycloheximide showed that total-TH protein level was reduced by the DA- or BH4-depletion. Notably, this reduction in the total-TH protein level was sensitive not only to a 26S proteasomal inhibitor, MG-132, but also to a PKA inhibitor, H-89. These data demonstrated that DA deficiency should induce compensatory activation of TH via phosphorylation at (40)Ser through D2-autoreceptor and PKA-mediated pathways, which in turn give a rise to its degradation through an ubiquitin-proteasome pathway, resulting in a negative spiral of DA production when DA deficiency persists. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Psychostimulants affect dopamine transmission through both dopamine transporter-dependent and independent mechanisms

    Science.gov (United States)

    dela Peña, Ike; Gevorkiana, Ruzanna; Shi, Wei-Xing

    2015-01-01

    The precise mechanisms by which cocaine and amphetamine-like psychostimulants exert their reinforcing effects are not yet fully defined. It is widely believed, however, that these drugs produce their effects by enhancing dopamine neurotransmission in the brain, especially in limbic areas such as the nucleus accumbens, by inducing dopamine transporter-mediated reverse transport and/or blocking dopamine reuptake though the dopamine transporter. Here, we present the evidence that aside from dopamine transporter, non-dopamine transporter-mediated mechanisms also participate in psychostimulant-induced dopamine release and contribute to the behavioral effects of these drugs, such as locomotor activation and reward. Accordingly, psychostimulants could increase norepinephrine release in the prefrontal cortex, the latter then alters the firing pattern of dopamine neurons resulting in changes in action potential-dependent dopamine release. These alterations would further affect the temporal pattern of dopamine release in the nucleus accumbens, thereby modifying information processing in that area. Hence, a synaptic input to a nucleus accumbens neuron may be enhanced or inhibited by dopamine depending on its temporal relationship to dopamine release. Specific temporal patterns of dopamine release may also be required for certain forms of synaptic plasticity in the nucleus accumbens. Together, these effects induced by psychostimulants, mediated through a non-dopamine transporter-mediated mechanism involving norepinephrine and the prefrontal cortex, may also contribute importantly to the reinforcing properties of these drugs. PMID:26209364

  2. Sleep deprivation decreases binding of [11C]raclopride to dopamine D2/D3 receptors in the human brain.

    Science.gov (United States)

    Volkow, Nora D; Wang, Gene-Jack; Telang, Frank; Fowler, Joanna S; Logan, Jean; Wong, Christopher; Ma, Jim; Pradhan, Kith; Tomasi, Dardo; Thanos, Peter K; Ferré, Sergi; Jayne, Millard

    2008-08-20

    Sleep deprivation did not affect dopamine transporters (target for most wake-promoting medications) and thus dopamine increases are likely to reflect increases in dopamine cell firing and/or release rather than decreases in dopamine reuptake. Because dopamine-enhancing drugs increase wakefulness, we postulate that dopamine increases after sleep deprivation is a mechanism by which the brain maintains arousal as the drive to sleep increases but one that is insufficient to counteract behavioral and cognitive impairment. Sleep deprivation can markedly impair human performance contributing to accidents and poor productivity. The mechanisms underlying this impairment are not well understood, but brain dopamine systems have been implicated. Here, we test whether one night of sleep deprivation changes dopamine brain activity. We studied 15 healthy subjects using positron emission tomography and [11C]raclopride (dopamine D2/D3 receptor radioligand) and [11C]cocaine (dopamine transporter radioligand). Subjects were tested twice: after one night of rested sleep and after one night of sleep deprivation. The specific binding of [11C]raclopride in the striatum and thalamus were significantly reduced after sleep deprivation and the magnitude of this reduction correlated with increases in fatigue (tiredness and sleepiness) and with deterioration in cognitive performance (visual attention and working memory). In contrast, sleep deprivation did not affect the specific binding of [11C]cocaine in the striatum. Because [11C]raclopride competes with endogenous dopamine for binding to D2/D3 receptors, we interpret the decreases in binding to reflect dopamine increases with sleep deprivation. However, we cannot rule out the possibility that decreased [11C]raclopride binding reflects decreases in receptor levels or affinity. Sleep deprivation did not affect dopamine transporters (target for most wake-promoting medications) and thus dopamine increases are likely to reflect increases in

  3. Does activation of midbrain dopamine neurons promote or reduce feeding?

    NARCIS (Netherlands)

    Boekhoudt, L.; Roelofs, T. J.M.; de Jong, J. W.; de Leeuw, A. E.; Luijendijk, M. C.M.; Wolterink-Donselaar, I. G.; van der Plasse, G.; Adan, R. A.H.

    Background:Dopamine (DA) signalling in the brain is necessary for feeding behaviour, and alterations in the DA system have been linked to obesity. However, the precise role of DA in the control of food intake remains debated. On the one hand, food reward and motivation are associated with enhanced

  4. Does activation of midbrain dopamine neurons promote or reduce feeding?

    NARCIS (Netherlands)

    Boekhoudt, L.; Roelofs, T. J. M.; de Jong, J. W.; de Leeuw, A. E.; Luijendijk, M. C. M.; Wolterink-Donselaar, I. G.; van der Plasse, G.; Adan, R. A. H.

    2017-01-01

    BACKGROUND: Dopamine (DA) signalling in the brain is necessary for feeding behaviour, and alterations in the DA system have been linked to obesity. However, the precise role of DA in the control of food intake remains debated. On the one hand, food reward and motivation are associated with enhanced

  5. Dopamine signals for reward value and risk: basic and recent data

    Directory of Open Access Journals (Sweden)

    Schultz Wolfram

    2010-04-01

    Full Text Available Abstract Background Previous lesion, electrical self-stimulation and drug addiction studies suggest that the midbrain dopamine systems are parts of the reward system of the brain. This review provides an updated overview about the basic signals of dopamine neurons to environmental stimuli. Methods The described experiments used standard behavioral and neurophysiological methods to record the activity of single dopamine neurons in awake monkeys during specific behavioral tasks. Results Dopamine neurons show phasic activations to external stimuli. The signal reflects reward, physical salience, risk and punishment, in descending order of fractions of responding neurons. Expected reward value is a key decision variable for economic choices. The reward response codes reward value, probability and their summed product, expected value. The neurons code reward value as it differs from prediction, thus fulfilling the basic requirement for a bidirectional prediction error teaching signal postulated by learning theory. This response is scaled in units of standard deviation. By contrast, relatively few dopamine neurons show the phasic activation following punishers and conditioned aversive stimuli, suggesting a lack of relationship of the reward response to general attention and arousal. Large proportions of dopamine neurons are also activated by intense, physically salient stimuli. This response is enhanced when the stimuli are novel; it appears to be distinct from the reward value signal. Dopamine neurons show also unspecific activations to non-rewarding stimuli that are possibly due to generalization by similar stimuli and pseudoconditioning by primary rewards. These activations are shorter than reward responses and are often followed by depression of activity. A separate, slower dopamine signal informs about risk, another important decision variable. The prediction error response occurs only with reward; it is scaled by the risk of predicted reward

  6. Encoding of aversion by dopamine and the nucleus accumbens

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    James Edgar Mccutcheon

    2012-09-01

    Full Text Available Adaptive motivated behavior requires rapid discrimination between beneficial and harmful stimuli. Such discrimination leads to the generation of either an approach or rejection response, as appropriate, and enables organisms to maximize reward and minimize punishment. Classically, the nucleus accumbens (NAc and the dopamine projection to it are considered an integral part of the brain’s reward circuit, i.e., they direct approach and consumption behaviors and underlie positive reinforcement. This reward-centered framing ignores important evidence about the role of this system in encoding aversive events. One reason for bias towards reward is the difficulty in designing experiments in which animals repeatedly experience punishments; another is the challenge in dissociating the response to an aversive stimulus itself from the reward/relief experienced when an aversive stimulus is terminated. Here, we review studies that employ techniques with sufficient time resolution to measure responses in ventral tegmental area (VTA and NAc to aversive stimuli as they are delivered. We also present novel findings showing that the same stimulus – intraoral infusion of sucrose – has differing effects on NAc shell dopamine release depending on the prior experience. Here, for some rats, sucrose was rendered aversive by explicitly pairing it with malaise in a conditioned taste aversion paradigm. Thereafter, sucrose infusions led to a suppression of dopamine with a similar magnitude and time course to intra-oral infusions of a bitter quinine solution. The results are discussed in the context of regional differences in dopamine signaling and the implications of a pause in phasic dopamine release within the NAc shell. Together with our data, the emerging literature suggests an important role for differential phasic dopamine signaling in aversion versus reward.

  7. Mathematical model of dopamine autoreceptors and uptake inhibitors and their influence on tonic and phasic dopamine signaling

    DEFF Research Database (Denmark)

    Dreyer, Jakob Kristoffer Kisbye; Hounsgaard, Jørn Dybkjær

    2013-01-01

    Dopamine (DA) D2-like autoreceptors are an important component of the DA system, but their influence on postsynaptic DA signaling is not well understood. They are, directly or indirectly, involved in drug abuse and in treatment of schizophrenia and attention deficit hyperactive disorder: DA...

  8. Increased brain dopamine and dopamine receptors in schizophrenia

    International Nuclear Information System (INIS)

    Mackay, A.V.; Iversen, L.L.; Rossor, M.; Spokes, E.; Bird, E.; Arregui, A.; Creese, I.; Synder, S.H.

    1982-01-01

    In postmortem samples of caudate nucleus and nucleus accumbens from 48 schizophrenic patients, there were significant increases in both the maximum number of binding sites (Bmax) and the apparent dissociation constant (KD) for tritiated spiperone. The increase in apparent KD probably reflects the presence of residual neuroleptic drugs, but changes in Bmax for tritiated spiperone reflect genuine changes in receptor numbers. The increases in receptors were seen only in patients in whom neuroleptic medication had been maintained until the time of death, indicating that they may be entirely iatrogenic. Dopamine measurements for a larger series of schizophrenic and control cases (n greater than 60) show significantly increased concentrations in both the nucleus accumbens and caudate nucleus. The changes in dopamine were not obviously related to neuroleptic medication and, unlike the receptor changes, were most severe in younger patients

  9. A fluorescent sensor based on thioglycolic acid capped cadmium sulfide quantum dots for the determination of dopamine

    Science.gov (United States)

    Kulchat, Sirinan; Boonta, Wissuta; Todee, Apinya; Sianglam, Pradthana; Ngeontae, Wittaya

    2018-05-01

    A fluorescent sensor based on thioglycolic acid-capped cadmium sulfide quantum dots (TGA-CdS QDs) has been designed for the sensitive and selective detection of dopamine (DA). In the presence of dopamine (DA), the addition of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS) activates the reaction between the carboxylic group of the TGA and the amino group of dopamine to form an amide bond, quenching the fluorescence of the QDs. The fluorescence intensity of TGA-CdS QDs can be used to sense the presence of dopamine with a limit of detection of 0.68 μM and a working linear range of 1.0-17.5 μM. This sensor system shows great potential application for dopamine detection in dopamine drug samples and for future easy-to-make analytical devices.

  10. Peripheral Dopamine in Restless Legs Syndrome

    Directory of Open Access Journals (Sweden)

    Ulrike H. Mitchell

    2018-03-01

    Full Text Available Objective/BackgroundRestless Legs Syndrome (RLS is a dopamine-dependent disorder characterized by a strong urge to move. The objective of this study was to evalulate blood levels of dopamine and other catecholamines and blood D2-subtype dopamine receptors (D2Rs in RLS.Patients/MethodsDopamine levels in blood samples from age-matched unmedicated RLS subjects, medicated RLS subjects and Controls were evaluated with high performance liquid chromatography and dopamine D2R white blood cell (WBC expression levels were determined with fluorescence-activated cell sorting and immunocytochemistry.ResultsBlood plasma dopamine levels, but not norepinepherine or epinephrine levels, were significantly increased in medicated RLS subjects vs unmedicated RLS subjects and Controls. The percentage of lymphocytes and monocytes expressing D2Rs differed between Control, RLS medicated and RLS unmedicated subjects. Total D2R expression in lymphocytes, but not monocytes, differed between Control, RLS medicated and RLS unmedicated subjects. D2Rs in lymphocytes, but not monocytes, were sensitive to dopamine in Controls only.ConclusionDownregulation of WBCs D2Rs occurs in RLS. This downregulation is not reversed by medication, although commonly used RLS medications increase plasma dopamine levels. The insensitivity of monocytes to dopamine levels, but their downregulation in RLS, may reflect their utility as a biomarker for RLS and perhaps brain dopamine homeostasis.

  11. The Neuromodulator of Exploration: A Unifying Theory of the Role of Dopamine in Personality

    Directory of Open Access Journals (Sweden)

    Colin G DeYoung

    2013-11-01

    Full Text Available The neuromodulator dopamine is centrally involved in reward, approach behavior, exploration, and various aspects of cognition. Variations in dopaminergic function are assumed to be associated with variations in personality, but exactly which traits are influenced by dopamine remains an open question. This paper proposes a theory of the role of dopamine in personality that organizes and explains the diversity of findings, utilizing the division of the dopaminergic system into value coding and salience coding neurons (Bromberg-Martin, Matsumoto, and Hikosaka, 2010. The value coding system is proposed to be related primarily to Extraversion and the salience coding system to Openness/Intellect. Global levels of dopamine influence the higher order personality factor, Plasticity, which comprises the shared variance of Extraversion and Openness/Intellect. All other traits related to dopamine are linked to Plasticity or its subtraits. The general function of dopamine is to promote exploration, by facilitating engagement with cues of specific reward (value and cues of the reward value of information (salience. This theory constitutes an extension of the entropy model of uncertainty (EMU; Hirsh, Mar, & Peterson, 2012, enabling EMU to account for the fact that uncertainty is an innate incentive reward as well as an innate threat. The theory accounts for the association of dopamine with traits ranging from sensation and novelty seeking, to impulsivity and aggression, to achievement striving, creativity, and cognitive abilities, to the overinclusive thinking characteristic of schizotypy.

  12. Variability in Dopamine Genes Dissociates Model-Based and Model-Free Reinforcement Learning.

    Science.gov (United States)

    Doll, Bradley B; Bath, Kevin G; Daw, Nathaniel D; Frank, Michael J

    2016-01-27

    Considerable evidence suggests that multiple learning systems can drive behavior. Choice can proceed reflexively from previous actions and their associated outcomes, as captured by "model-free" learning algorithms, or flexibly from prospective consideration of outcomes that might occur, as captured by "model-based" learning algorithms. However, differential contributions of dopamine to these systems are poorly understood. Dopamine is widely thought to support model-free learning by modulating plasticity in striatum. Model-based learning may also be affected by these striatal effects, or by other dopaminergic effects elsewhere, notably on prefrontal working memory function. Indeed, prominent demonstrations linking striatal dopamine to putatively model-free learning did not rule out model-based effects, whereas other studies have reported dopaminergic modulation of verifiably model-based learning, but without distinguishing a prefrontal versus striatal locus. To clarify the relationships between dopamine, neural systems, and learning strategies, we combine a genetic association approach in humans with two well-studied reinforcement learning tasks: one isolating model-based from model-free behavior and the other sensitive to key aspects of striatal plasticity. Prefrontal function was indexed by a polymorphism in the COMT gene, differences of which reflect dopamine levels in the prefrontal cortex. This polymorphism has been associated with differences in prefrontal activity and working memory. Striatal function was indexed by a gene coding for DARPP-32, which is densely expressed in the striatum where it is necessary for synaptic plasticity. We found evidence for our hypothesis that variations in prefrontal dopamine relate to model-based learning, whereas variations in striatal dopamine function relate to model-free learning. Decisions can stem reflexively from their previously associated outcomes or flexibly from deliberative consideration of potential choice outcomes

  13. Differential vulnerability of primate caudate-putamen and striosome-matrix dopamine systems to the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

    Science.gov (United States)

    Moratalla, R; Quinn, B; DeLanney, L E; Irwin, I; Langston, J W; Graybiel, A M

    1992-01-01

    The meperidine analogue derivative 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces nigrostriatal fiber damage and severe parkinsonism in humans and animals. MPTP-induced parkinsonism has been proposed as a model of Parkinson disease, but doubts have been raised about whether the patterns of nigrostriatal fiber loss in the two conditions are similar. We report here observations on [3H]mazindol monoamine (principally dopamine) uptake-site binding in the striatum of monkeys (Saimiri sciureus) exposed to low doses of MPTP. We show that this treatment can produce a pattern of nigrostriatal degeneration characteristic of that seen in Parkinson disease, in which there is greater depletion of dopaminergic markers in the putamen than in the caudate nucleus, especially posteriorly. Moreover, within the regions of diminished uptake-site binding in the MPTP-treated monkeys, there is differential preservation of binding in striosomes relative to the surrounding matrix. We suggest that both regional and striosome/matrix patterns of nigrostriatal depletion are key features of MPTP-induced neurodegeneration and that both patterns may provide clues to the mechanisms underlying neurodegeneration in Parkinson disease as well. Images PMID:1570304

  14. Dopamine Signaling in reward-related behaviors

    Directory of Open Access Journals (Sweden)

    Ja-Hyun eBaik

    2013-10-01

    Full Text Available Dopamine (DA regulates emotional and motivational behavior through the mesolimbic dopaminergic pathway. Changes in DAmesolimbic neurotransmission have been found to modify behavioral responses to various environmental stimuli associated with reward behaviors. Psychostimulants, drugs of abuse, and natural rewards such as food can cause substantial synaptic modifications to the mesolimbic DA system. Recent studies using optogenetics and DREADDs, together with neuron-specific or circuit-specific genetic manipulations have improved our understanding of DA signaling in the reward circuit, and provided a means to identify the neural substrates of complex behaviors such as drug addiction and eating disorders. This review focuses on the role of the DA system in drug addiction and food motivation, with an overview of the role of D1 and D2 receptors in the control of reward-associated behaviors.

  15. Genetics Home Reference: dopamine beta-hydroxylase deficiency

    Science.gov (United States)

    ... Twitter Home Health Conditions Dopamine beta-hydroxylase deficiency Dopamine beta-hydroxylase deficiency Printable PDF Open All Close ... Javascript to view the expand/collapse boxes. Description Dopamine beta (β)-hydroxylase deficiency is a condition that ...

  16. Serotonin 2B Receptors in Mesoaccumbens Dopamine Pathway Regulate Cocaine Responses.

    Science.gov (United States)

    Doly, Stéphane; Quentin, Emily; Eddine, Raphaël; Tolu, Stefania; Fernandez, Sebastian P; Bertran-Gonzalez, Jesus; Valjent, Emmanuel; Belmer, Arnauld; Viñals, Xavier; Callebert, Jacques; Faure, Philippe; Meye, Frank J; Hervé, Denis; Robledo, Patricia; Mameli, Manuel; Launay, Jean-Marie; Maldonado, Rafael; Maroteaux, Luc

    2017-10-25

    Addiction is a maladaptive pattern of behavior following repeated use of reinforcing drugs in predisposed individuals, leading to lifelong changes. Common among these changes are alterations of neurons releasing dopamine in the ventral and dorsal territories of the striatum. The serotonin 5-HT 2B receptor has been involved in various behaviors, including impulsivity, response to antidepressants, and response to psychostimulants, pointing toward putative interactions with the dopamine system. Despite these findings, it remains unknown whether 5-HT 2B receptors directly modulate dopaminergic activity and the possible mechanisms involved. To answer these questions, we investigated the contribution of 5-HT 2B receptors to cocaine-dependent behavioral responses. Male mice permanently lacking 5-HT 2B receptors, even restricted to dopamine neurons, developed heightened cocaine-induced locomotor responses. Retrograde tracing combined with single-cell mRNA amplification indicated that 5-HT 2B receptors are expressed by mesolimbic dopamine neurons. In vivo and ex vivo electrophysiological recordings showed that 5-HT 2B -receptor inactivation in dopamine neurons affects their neuronal activity and increases AMPA-mediated over NMDA-mediated excitatory synaptic currents. These changes are associated with lower ventral striatum dopamine activity and blunted cocaine self-administration. These data identify the 5-HT 2B receptor as a pharmacological intermediate and provide mechanistic insight into attenuated dopamine tone following exposure to drugs of abuse. SIGNIFICANCE STATEMENT Here we report that mice lacking 5-HT 2B receptors totally or exclusively in dopamine neurons exhibit heightened cocaine-induced locomotor responses. Despite the sensitized state of these mice, we found that associated changes include lower ventral striatum dopamine activity and lower cocaine operant self-administration. We described the selective expression of 5-HT 2B receptors in a subpopulation of

  17. Increased dopamine turnover in the prefrontal cortex impairs spatial working memory performance in rats and monkeys.

    Science.gov (United States)

    Murphy, B L; Arnsten, A F; Goldman-Rakic, P S; Roth, R H

    1996-01-01

    The selective activation of the prefrontal cortical dopamine system by mild stress can be mimicked by anxiogenic beta-carbolines such as FG7142. To investigate the functional relevance of elevated levels of dopamine turnover in the prefrontal cortex, the current study examined the effects of FG7142 on the performance of spatial working memory tasks in the rat and monkey. FG7142 selectively increased prefrontal cortical dopamine turnover in rats and significantly impaired performance on spatial working memory tasks in both rats and monkeys. Spatial discrimination, a task with similar motor and motivational demands (rats), or delayed response performance following zero-second delays (monkeys) was unaffected by FG7142. Further, biochemical analysis in rats revealed a significant positive correlation between dopamine turnover in the prefrontal cortex and cognitive impairment on the delayed alternation task. The cognitive deficits in both rats and monkeys were prevented by pretreatment with the benzodiazepine receptor antagonist, RO15-1788, which blocked the increase in dopamine turnover and by the dopamine receptor antagonists, haloperidol, clozapine, and SCH23390. These findings indicate that excessive dopamine activity in the prefrontal cortex is detrimental to cognitive functions mediated by the prefrontal cortex. PMID:8577763

  18. 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.

  19. The Dopamine D2 Receptor Gene, Perceived Parental Support, and Adolescent Loneliness: Longitudinal Evidence for Gene-Environment Interactions

    Science.gov (United States)

    van Roekel, Eeske; Goossens, Luc; Scholte, Ron H. J.; Engels, Rutger C. M. E.; Verhagen, Maaike

    2011-01-01

    Background: Loneliness is a common problem in adolescence. Earlier research focused on genes within the serotonin and oxytocin systems, but no studies have examined the role of dopamine-related genes in loneliness. In the present study, we focused on the dopamine D2 receptor gene (DRD2). Methods: Associations among the DRD2, sex, parental support,…

  20. The renal and neurohumoral effects of the addition of low-dose dopamine in septic critically ill patients

    NARCIS (Netherlands)

    Girbes, ARJ; Patten, MT; McCloskey, BV; Groeneveld, ABJ; Hoogenberg, K

    2000-01-01

    Objectives: Dopamine exerts a complicated action on the cardiovascular-renal and neurohumoral systems. We evaluated the effects of the addition of different doses of dopamine on top of treatment with norepinephrine on the haemodynamics, renal function and neurohormones of septic shock patients.

  1. The dopamine D2 receptor gene, perceived parental support, and adolescent loneliness : longitudinal evidence for gene-environment interactions

    NARCIS (Netherlands)

    van Roekel, Eeske; Goossens, Luc; Scholte, Ron H. J.; Engels, Rutger C. M. E.; Verhagen, Maaike

    2011-01-01

    Background: Loneliness is a common problem in adolescence. Earlier research focused on genes within the serotonin and oxytocin systems, but no studies have examined the role of dopamine-related genes in loneliness. In the present study, we focused on the dopamine D2 receptor gene (DRD2). Methods:

  2. Determinação enzimática de dopamina em formulações farmacêuticas utilizando sistema de análise por injeção em fluxo com extrato bruto de abacate (Persea americana Enzimatic determination of dopamine in pharmaceutical formulations using a flow injection analysis system with avocado (Persea americana crude extract

    Directory of Open Access Journals (Sweden)

    Karina Omuro Lupetti

    2003-03-01

    Full Text Available In this work, a spectrophotometric flow injection analysis system using a crude extract of avocado (Persea americana as a source of polyphenol oxidase to dopamine determination was developed. The substrates and enzyme concentrations from 2.4x10-7 to 5.3x10-4 mol L-1 and 28 to 332 units mL-1 were evaluated, respectively. In addition, the FIA parameters such as sample loop (50 to 500 µL, flow rate (1.4 to 4.3 mL min-1 and reactor length (100 to 500 cm were also evaluated in a 0.1 mol L-1 phosphate buffer solution (pH 7.0. Dopamine solution concentrations were determined using 277 units mL-1 enzyme solution, 400 mL enzyme loop, 375 µL sample loop, 2.2 mL min-1 flow rate and a reactor of 350 cm. The analytical curve showed a linearity from 5.3x10-5 to 5.3x10-4 mol L-1 dopamine with a detection limit of 1.3x10-5 mol L-1. The analytical frequency was 46 h-1 and the RSD lower than 0.5% for 5.3x10-4 mol L-1 dopamine solution (n=10. A paired t-test showed that all results obtained for dopamine in commercial formulations using the proposed flow injection procedure and a spectrophotometric procedure agree at the 95% confidence level.

  3. Prefrontal cortical dopamine from an evolutionary perspective.

    Science.gov (United States)

    Lee, Young-A; Goto, Yukiori

    2015-04-01

    In this article, we propose the hypothesis that the prefrontal cortex (PFC) acquired neotenic development as a consequence of mesocortical dopamine (DA) innervation, which in turn drove evolution of the PFC into becoming a complex functional system. Accordingly, from the evolutionary perspective, decreased DA signaling in the PFC associated with such adverse conditions as chronic stress may be considered as an environmental adaptation strategy. Psychiatric disorders such as schizophrenia and attention deficit/hyperactivity disorder may also be understood as environmental adaptation or a by-product of such a process that has emerged through evolution in humans. To investigate the evolutionary perspective of DA signaling in the PFC, domestic animals such as dogs may be a useful model.

  4. Dopamine Modulates the Activity of Sensory Hair Cells.

    Science.gov (United States)

    Toro, Cecilia; Trapani, Josef G; Pacentine, Itallia; Maeda, Reo; Sheets, Lavinia; Mo, Weike; Nicolson, Teresa

    2015-12-16

    The senses of hearing and balance are subject to modulation by efferent signaling, including the release of dopamine (DA). How DA influences the activity of the auditory and vestibular systems and its site of action are not well understood. Here we show that dopaminergic efferent fibers innervate the acousticolateralis epithelium of the zebrafish during development but do not directly form synapses with hair cells. However, a member of the D1-like receptor family, D1b, tightly localizes to ribbon synapses in inner ear and lateral-line hair cells. To assess modulation of hair-cell activity, we reversibly activated or inhibited D1-like receptors (D1Rs) in lateral-line hair cells. In extracellular recordings from hair cells, we observed that D1R agonist SKF-38393 increased microphonic potentials, whereas D1R antagonist SCH-23390 decreased microphonic potentials. Using ratiometric calcium imaging, we found that increased D1R activity resulted in larger calcium transients in hair cells. The increase of intracellular calcium requires Cav1.3a channels, as a Cav1 calcium channel antagonist, isradipine, blocked the increase in calcium transients elicited by the agonist SKF-38393. Collectively, our results suggest that DA is released in a paracrine fashion and acts at ribbon synapses, likely enhancing the activity of presynaptic Cav1.3a channels and thereby increasing neurotransmission. The neurotransmitter dopamine acts in a paracrine fashion (diffusion over a short distance) in several tissues and bodily organs, influencing and regulating their activity. The cellular target and mechanism of the action of dopamine in mechanosensory organs, such as the inner ear and lateral-line organ, is not clearly understood. Here we demonstrate that dopamine receptors are present in sensory hair cells at synaptic sites that are required for signaling to the brain. When nearby neurons release dopamine, activation of the dopamine receptors increases the activity of these mechanosensitive

  5. Dopamine and glucose, obesity, and reward deficiency syndrome.

    Science.gov (United States)

    Blum, Kenneth; Thanos, Panayotis K; Gold, Mark S

    2014-01-01

    Obesity as a result of overeating as well as a number of well described eating disorders has been accurately considered to be a world-wide epidemic. Recently a number of theories backed by a plethora of scientifically sound neurochemical and genetic studies provide strong evidence that food addiction is similar to psychoactive drug addiction. Our laboratory has published on the concept known as Reward Deficiency Syndrome (RDS) which is a genetic and epigenetic phenomena leading to impairment of the brain reward circuitry resulting in a hypo-dopaminergic function. RDS involves the interactions of powerful neurotransmitters and results in abnormal craving behavior. A number of important facts which could help translate to potential therapeutic targets espoused in this focused review include: (1) consumption of alcohol in large quantities or carbohydrates binging stimulates the brain's production of and utilization of dopamine; (2) in the meso-limbic system the enkephalinergic neurons are in close proximity, to glucose receptors; (3) highly concentrated glucose activates the calcium channel to stimulate dopamine release from P12 cells; (4) a significant correlation between blood glucose and cerebrospinal fluid concentrations of homovanillic acid the dopamine metabolite; (5) 2-deoxyglucose (2DG), the glucose analog, in pharmacological doses is associated with enhanced dopamine turnover and causes acute glucoprivation. Evidence from animal studies and fMRI in humans support the hypothesis that multiple, but similar brain circuits are disrupted in obesity and drug dependence and for the most part, implicate the involvement of DA-modulated reward circuits in pathologic eating behaviors. Based on a consensus of neuroscience research treatment of both glucose and drug like cocaine, opiates should incorporate dopamine agonist therapy in contrast to current theories and practices that utilizes dopamine antagonistic therapy. Considering that up until now clinical utilization

  6. Activation of fronto-limbic system in the human brain by cigarette smoking: evaluated by a CBF measurement.

    Science.gov (United States)

    Nakamura, H; Tanaka, A; Nomoto, Y; Ueno, Y; Nakayama, Y

    2000-02-01

    Nicotine produces profound behavioral effects in humans, but little is known about the sites of its action. There is a hypothesis that frontal lobe and limbic/cingulate cortical structures might be the sites. In this study, we examined the effects of cigarette smoking on feeling and cerebral blood flow (CBF) in human subjects. Young and healthy 9 cigarette smokers (all males, 24-33 years, average, 26.4) were included. After prohibiting them from smoking for 15 hours, CBF was measured using a Xenon CT-CBF system. Fifteen minutes later after allowing them to smoke two pieces of cigarette, the second CBF measurement was performed. Subtraction CBF map was created to display the changes after smoking. CT images were taken at three levels so as to include the cerebral lobes, basal ganglia, limbic system, brainstem and cerebellum. Arterial nicotine increased up to the levels 8 times higher than before smoking. The increases of blood pressure and pulse rate were minimal. Arterial carbon dioxide level and hematocrit did not change. Feeling after smoking was variable in individual subject. In 8 subjects with a relatively high feeling, CBF increased mainly in the frontal lobe, hippocampus, uncus, thalamus and caudate nucleus. CBF did not change in the parietal, temporal and occipital lobes, and in the putamen, insula, brainstem and cerebellum. In two subjects with uncomfortable feeling, CBF did reduce in the whole brain. The CBF increase in frontal lobe and limbic structures seems to be secondary to nicotine-induced neuronal activation in each structure. Mesocorticolimbic dopamine system, which is believed to influence learning, memory or emotional performance, appears to be a target for nicotine. The CBF reduction in the whole brain might be due to cerebral vasoconstriction or be secondary to a systemic hypotension.

  7. Dopamine stimulates snail albumen gland glycoprotein secretion through the activation of a D1-like receptor.

    Science.gov (United States)

    Mukai, S T; Kiehn, L; Saleuddin, A S M

    2004-06-01

    The catecholamine dopamine is present in both the central nervous system and in the peripheral tissues of molluscs, where it is involved in regulating reproduction. Application of exogenous dopamine to the isolated albumen gland of the freshwater pulmonate snail Helisoma duryi (Wetherby) induces the secretion (release) of perivitelline fluid. The major protein component of the perivitelline fluid of Helisoma duryi is a native 288 kDa glycoprotein that is secreted around individual eggs and serves as an important source of nutrients for the developing embryos. The secretion of glycoprotein by the albumen gland is a highly regulated event that must be coordinated with the arrival of the fertilized ovum at the carrefour (the region where the eggs receive albumen gland secretory products). In order to elucidate the intracellular signalling pathway(s) mediating dopamine-induced glycoprotein secretion, albumen gland cAMP production and glycoprotein secretion were measured in the presence/absence of selected dopamine receptor agonists and antagonists. Dopamine D1-selective agonists dihydrexidine, 6,7-ADTN and SKF81297 stimulated cAMP production and glycoprotein secretion from isolated albumen glands whereas D1-selective antagonists SCH23390 and SKF83566 suppressed dopamine-stimulated cAMP production. Dopamine D2-selective agonists and antagonists generally had no effect on cAMP production or protein secretion. Based on the effects of these compounds, a pharmacological profile was obtained that strongly suggests the presence of a dopamine D1-like receptor in the albumen gland of Helisoma duryi. In addition, secretion of albumen gland glycoprotein was not inhibited by protein kinase A inhibitors, suggesting that dopamine-stimulated protein secretion might occur through a protein kinase A-independent pathway.

  8. The Role of Genes, Stress, and Dopamine in the Development of Schizophrenia.

    Science.gov (United States)

    Howes, Oliver D; McCutcheon, Robert; Owen, Michael J; Murray, Robin M

    2017-01-01

    The dopamine hypothesis is the longest standing pathoetiologic theory of schizophrenia. Because it was initially based on indirect evidence and findings in patients with established schizophrenia, it was unclear what role dopamine played in the onset of the disorder. However, recent studies in people at risk of schizophrenia have found elevated striatal dopamine synthesis capacity and increased dopamine release to stress. Furthermore, striatal dopamine changes have been linked to altered cortical function during cognitive tasks, in line with preclinical evidence that a circuit involving cortical projections to the striatum and midbrain may underlie the striatal dopamine changes. Other studies have shown that a number of environmental risk factors for schizophrenia, such as social isolation and childhood trauma, also affect presynaptic dopaminergic function. Advances in preclinical work and genetics have begun to unravel the molecular architecture linking dopamine, psychosis, and psychosocial stress. Included among the many genes associated with risk of schizophrenia are the gene encoding the dopamine D 2 receptor and those involved in the upstream regulation of dopaminergic synthesis, through glutamatergic and gamma-aminobutyric acidergic pathways. A number of these pathways are also linked to the stress response. We review these new lines of evidence and present a model of how genes and environmental factors may sensitize the dopamine system so that it is vulnerable to acute stress, leading to progressive dysregulation and the onset of psychosis. Finally, we consider the implications for rational drug development, in particular regionally selective dopaminergic modulation, and the potential of genetic factors to stratify patients. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  9. Limited Associations of Dopamine System Genes With Alcohol Dependence and Related Traits in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD)

    Science.gov (United States)

    Hack, Laura M.; Kalsi, Gursharan; Aliev, Fazil; Kuo, Po-Hsiu; Prescott, Carol A.; Patterson, Diana G.; Walsh, Dermot; Dick, Danielle M.; Riley, Brien P.; Kendler, Kenneth S.

    2012-01-01

    Background Over 50 years of evidence from research has established that the central dopaminergic reward pathway is likely involved in alcohol dependence (AD). Additional evidence supports a role for dopamine (DA) in other disinhibitory psychopathology, which is often comorbid with AD. Family and twin studies demonstrate that a common genetic component accounts for most of the genetic variance in these traits. Thus, DA-related genes represent putative candidates for the genetic risk that underlies not only AD but also behavioral disinhibition. Many linkage and association studies have examined these relationships with inconsistent results, possibly because of low power, poor marker coverage, and/or an inappropriate correction for multiple testing. Methods We conducted an association study on the products encoded by 10 DA-related genes (DRD1-D5, SLC18A2, SLC6A3, DDC, TH, COMT) using a large, ethnically homogeneous sample with severe AD (n = 545) and screened controls (n = 509). We collected genotypes from linkage disequilibrium (LD)-tagging single nucleotide polymorphisms (SNPs) and employed a gene-based method of correction. We tested for association with AD diagnosis in cases and controls and with a variety of alcohol-related traits (including age-at-onset, initial sensitivity, tolerance, maximum daily drinks, and a withdrawal factor score), disinhibitory symptoms, and a disinhibitory factor score in cases only. A total of 135 SNPs were genotyped using the Illumina GoldenGate and Taqman Assays-on-Demand protocols. Results Of the 101 SNPs entered into standard analysis, 6 independent SNPs from 5 DA genes were associated with AD or a quantitative alcohol-related trait. Two SNPs across 2 genes were associated with a disinhibitory symptom count, while 1 SNP in DRD5 was positive for association with the general disinhibitory factor score. Conclusions Our study provides evidence of modest associations between a small number of DA-related genes and AD as well as a range

  10. Long-term controlled GDNF over-expression reduces dopamine transporter activity without affecting tyrosine hydroxylase expression in the rat mesostriatal system.

    Science.gov (United States)

    Barroso-Chinea, Pedro; Cruz-Muros, Ignacio; Afonso-Oramas, Domingo; Castro-Hernández, Javier; Salas-Hernández, Josmar; Chtarto, Abdelwahed; Luis-Ravelo, Diego; Humbert-Claude, Marie; Tenenbaum, Liliane; González-Hernández, Tomás

    2016-04-01

    The dopamine (DA) transporter (DAT) is a plasma membrane glycoprotein expressed in dopaminergic (DA-) cells that takes back DA into presynaptic neurons after its release. DAT dysfunction has been involved in different neuro-psychiatric disorders including Parkinson's disease (PD). On the other hand, numerous studies support that the glial cell line-derived neurotrophic factor (GDNF) has a protective effect on DA-cells. However, studies in rodents show that prolonged GDNF over-expression may cause a tyrosine hydroxylase (TH, the limiting enzyme in DA synthesis) decline. The evidence of TH down-regulation suggests that another player in DA handling, DAT, may also be regulated by prolonged GDNF over-expression, and the possibility that this effect is induced at GDNF expression levels lower than those inducing TH down-regulation. This issue was investigated here using intrastriatal injections of a tetracycline-inducible adeno-associated viral vector expressing human GDNF cDNA (AAV-tetON-GDNF) in rats, and doxycycline (DOX; 0.01, 0.03, 0.5 and 3mg/ml) in the drinking water during 5weeks. We found that 3mg/ml DOX promotes an increase in striatal GDNF expression of 12× basal GDNF levels and both DA uptake decrease and TH down-regulation in its native and Ser40 phosphorylated forms. However, 0.5mg/ml DOX promotes a GDNF expression increase of 3× basal GDNF levels with DA uptake decrease but not TH down-regulation. The use of western-blot under non-reducing conditions, co-immunoprecipitation and in situ proximity ligation assay revealed that the DA uptake decrease is associated with the formation of DAT dimers and an increase in DAT-α-synuclein interactions, without changes in total DAT levels or its compartmental distribution. In conclusion, at appropriate GDNF transduction levels, DA uptake is regulated through DAT protein-protein interactions without interfering with DA synthesis. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Cocaine Self-Administration Produces Long-Lasting Alterations in Dopamine Transporter Responses to Cocaine

    OpenAIRE

    Siciliano, Cody A.; Fordahl, Steve C.; Jones, Sara R.

    2016-01-01

    Cocaine addiction is a debilitating neuropsychiatric disorder characterized by uncontrolled cocaine intake, which is thought to be driven, at least in part, by cocaine-induced deficits in dopamine system function. A decreased ability of cocaine to elevate dopamine levels has been repeatedly observed as a consequence of cocaine use in humans, and preclinical work has highlighted tolerance to cocaine's effects as a primary determinant in the development of aberrant cocaine taking behaviors. Her...

  12. The treatment of Parkinson's disease with dopamine agonists

    Directory of Open Access Journals (Sweden)

    Frank, Wilhelm

    2008-06-01

    Full Text Available Parkinson’s disease is a chronic degenerative organic disease with unknown causes. A disappearance of cells with melanin in the substantia nigra is considered as biological artefact of the disease, which causes a degenerative loss of neurons in the corpus striatum of mesencephalon. This structure produces also the transmitter substance dopamine. Due to this disappearance of cells dopamine is not produced in a sufficient quantity which is needed for movement of the body. The questions of this report are concerned the efficiency and safety of a treatment with dopamine agonists. Furthermore the cost-effectiveness is investigated as well as ethic questions. The goal is to give recommendation for the use of dopamine agonists to the German health system. A systematic literature search was done. The identified studies have different methodological quality and investigate different hypothesis and different outcome criteria. Therefore a qualitative method of information synthesis was chosen. Since the introduction of L-Dopa in the 1960´s it is considered as the most effective substance to reduce all the cardinal symptoms of Parkinson disease. This substance was improved in the course of time. Firstly some additional substances were given (decarbonxylase inhibitors, catechol-o-transferase inhibitors (COMT-inhibitors, monoaminoxydase-inhibitors (MAO-inhibitors and NMDA-antagonists (N-Methyl-d-aspartat-antagonists. In the practical therapy of Parkinson dopamine agonists play an important role, because they directly use the dopamine receptors. The monotherapy of Parkinson disease is basically possible and is used in early stages of the disease. Clinical practise has shown, that an add on therapy with dopamine agonists can led to a reduction of the dose of L-dopa and a reduction of following dyskinesia. The studies for effectiveness include studies for the initial therapy, monotherapy and add-on-therapy. Basically there is a good effectiveness of dopamine

  13. Anhedonia, Reduced Cocaine Reward, and Dopamine Dysfunction in a Rat Model of Posttraumatic Stress Disorder.

    Science.gov (United States)

    Enman, Nicole M; Arthur, Kayti; Ward, Sara J; Perrine, Shane A; Unterwald, Ellen M

    2015-12-15

    Posttraumatic stress disorder (PTSD) co-occurs with substance use disorders at high rates, but the neurobiological basis of this relationship is largely unknown. PTSD and drug addiction each involve dysregulation of brain reward circuitry; therefore, the identification of pathology of the mesolimbic dopamine system may aid in understanding their functional relationship. Dopamine reward dysfunction also may be relevant to the mechanisms underlying the PTSD symptoms of anhedonia and emotional numbing. Single-prolonged stress (SPS) was used as a rat model of PTSD, and a series of behavioral and neuropharmacologic assays were applied to assess the impact of SPS on reward, cocaine intake, and components of the striatal dopamine system. Exposure to SPS increased anhedonia-like behaviors and decreased the rewarding properties of cocaine compared with control handling. Altered cocaine intake during extended access self-administration sessions was observed in rats exposed to SPS, further suggesting a difference in the reinforcing properties of cocaine following severe stress. SPS reduced tissue content of dopamine and its metabolites in the striatum, as well as altered striatal dopamine transporter and D2, but not D1, receptor densities. These results support a role for altered dopaminergic transmission in reduced reward function in PTSD. Pathology of the dopamine system and the degradation of reward processes may contribute to PTSD symptomology and have implications for co-occurring psychiatric disorders such as substance abuse or depression. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  14. Glutamate stimulation of (/sup 3/H)dopamine release from dissociated cell cultures of rat ventral mesencephalon

    Energy Technology Data Exchange (ETDEWEB)

    Mount, H.; Welner, S.; Quirion, R.; Boksa, P.

    1989-04-01

    In dissociated cell cultures of fetal rat ventral mesencephalon preloaded with (3H)dopamine, glutamate (10(-5)-10(-3) M) stimulated the release of (3H)dopamine. Glutamate stimulation of (3H)dopamine release was Ca2+ dependent and was blocked by the glutamate antagonist, cis-2,3-piperidine dicarboxylic acid. Glutamate stimulation of (3H)dopamine release was not due to glutamate neurotoxicity because (1) glutamate did not cause release of a cytosolic marker, lactate dehydrogenase, and (2) preincubation of cultures with glutamate did not impair subsequent ability of the cells to take up or release (3H)dopamine. Thus, these dissociated cell cultures appear to provide a good model system to characterize glutamate stimulation of dopamine release. Release of (3H)dopamine from these cultures was stimulated by veratridine, an activator of voltage-sensitive Na+ channels, and this stimulation was blocked by tetrodotoxin. However, glutamate-stimulated (3H)dopamine release was not blocked by tetrodotoxin or Zn2+. Substitution of NaCl in the extracellular medium by sucrose, LiCl, or Na2SO4 had no effect on glutamate stimulation of (3H)dopamine release; however, release was inhibited when NaCl was replaced by choline chloride or N-methyl-D-glucamine HCl. Glutamate-stimulated (3H)-dopamine release was well maintained (60-82% of control) in the presence of Co2+, which blocks Ca2+ action potentials, and was unaffected by the local anesthetic, lidocaine. These results are discussed in terms of the receptor and ionic mechanisms involved in the stimulation of dopamine release by excitatory amino acids.

  15. Dopamine beta-hydroxylase deficiency

    Directory of Open Access Journals (Sweden)

    Senard Jean-Michel

    2006-03-01

    Full Text Available Abstract Dopamine beta-hydroxylase (DβH deficiency is a very rare form of primary autonomic failure characterized by a complete absence of noradrenaline and adrenaline in plasma together with increased dopamine plasma levels. The prevalence of DβH deficiency is unknown. Only a limited number of cases with this disease have been reported. DβH deficiency is mainly characterized by cardiovascular disorders and severe orthostatic hypotension. First symptoms often start during a complicated perinatal period with hypotension, muscle hypotonia, hypothermia and hypoglycemia. Children with DβH deficiency exhibit reduced ability to exercise because of blood pressure inadaptation with exertion and syncope. Symptoms usually worsen progressively during late adolescence and early adulthood with severe orthostatic hypotension, eyelid ptosis, nasal stuffiness and sexual disorders. Limitation in standing tolerance, limited ability to exercise and traumatic morbidity related to falls and syncope may represent later evolution. The syndrome is caused by heterogeneous molecular alterations of the DBH gene and is inherited in an autosomal recessive manner. Restoration of plasma noradrenaline to the normal range can be achieved by therapy with the synthetic precursor of noradrenaline, L-threo-dihydroxyphenylserine (DOPS. Oral administration of 100 to 500 mg DOPS, twice or three times daily, increases blood pressure and reverses the orthostatic intolerance.

  16. Dopamine-transporter SPECT and Dopamine-D2-receptor SPECT in basal ganglia diseases

    International Nuclear Information System (INIS)

    Hesse, S.; Barthel, H.; Seese, A.; Sabri, O.

    2007-01-01

    The basal ganglia comprise a group of subcortical nuclei, which are essential for motor control. Dysfunction of these areas, especially in dopaminergic transmission, results in disordered movement and neurological diseases such as Parkinson's disease, Wilson's disease, or Huntington disease. Positron emission tomography and single photon emission computed tomography (SPECT) have enhanced the understanding of the underlying pathophysiology, but they much more contribute to the early differential diagnosis of patients suffering from Parkinsonian syndrome in routine care. The present article provides dopamine transporter and D 2 receptor SPECT findings in selected movement disorders. (orig.)

  17. Decreased prefrontal cortical dopamine transmission in alcoholism.

    Science.gov (United States)

    Narendran, Rajesh; Mason, Neale Scott; Paris, Jennifer; Himes, Michael L; Douaihy, Antoine B; Frankle, W Gordon

    2014-08-01

    Basic studies have demonstrated that optimal levels of prefrontal cortical dopamine are critical to various executive functions such as working memory, attention, inhibitory control, and risk/reward decisions, all of which are impaired in addictive disorders such as alcoholism. Based on this and imaging studies of alcoholism that have demonstrated less dopamine in the striatum, the authors hypothesized decreased dopamine transmission in the prefrontal cortex in persons with alcohol dependence. To test this hypothesis, amphetamine and [11C]FLB 457 positron emission tomography were used to measure cortical dopamine transmission in 21 recently abstinent persons with alcohol dependence and 21 matched healthy comparison subjects. [11C]FLB 457 binding potential, specific compared to nondisplaceable uptake (BPND), was measured in subjects with kinetic analysis using the arterial input function both before and after 0.5 mg kg-1 of d-amphetamine. Amphetamine-induced displacement of [11C]FLB 457 binding potential (ΔBPND) was significantly smaller in the cortical regions in the alcohol-dependent group compared with the healthy comparison group. Cortical regions that demonstrated lower dopamine transmission in the alcohol-dependent group included the dorsolateral prefrontal cortex, medial prefrontal cortex, orbital frontal cortex, temporal cortex, and medial temporal lobe. The results of this study, for the first time, unambiguously demonstrate decreased dopamine transmission in the cortex in alcoholism. Further research is necessary to understand the clinical relevance of decreased cortical dopamine as to whether it is related to impaired executive function, relapse, and outcome in alcoholism.

  18. Stereoselectivity of presynaptic autoreceptors modulating dopamine release

    International Nuclear Information System (INIS)

    Arbilla, S.; Langer, S.Z.

    1981-01-01

    The effects of the (R)- and (S)-enantiomers of sulpiride and butaclamol were studied on the spontaneous and field stimulation-evoked release of total radioactivity from slices of rabbit caudate nucleus prelabelled with [ 3 H]dopamine. (S)-Sulpiride in concentrations ranging from 0.01-1μM enhanced the electrically evoked release of [ 3 H]dopamine while (R)-sulpiride was 10 times less potent than (S)-sulpiride. Exposure to (S)-butaclamol (0.1-1 μM) but not to (R)-butaclamol (0.1-10μM) enhanced the field-stimulated release of [ 3 H]dopamine. The facilitatory effects of (S)- and (R)-sulpiride and (S)-butaclamol on the stimulated release of the labelled neurotransmitter were observed under conditions in which these drugs did not modify the spontaneous outflow of radioactivity. Only the active enantiomers of sulpiride and butaclamol antagonized the inhibition by apomorphine (1μM) of the stimulated release of [ 3 H]dopamine. Our results indicate that the presynaptic inhibitory dopamine autoreceptors modulating the stimulation-evoked release of [ 3 H]dopamine in the caudate nucleus are, like the classical postsynaptic dopamine receptors, chemically stereoselective. (Auth.)

  19. Dopamine agonist suppression of rapid-eye-movement sleep is secondary to sleep suppression mediated via limbic structures

    International Nuclear Information System (INIS)

    Miletich, R.S.

    1985-01-01

    The effects of pergolide, a direct dopamine receptor agonist, on sleep and wakefulness, motor behavior and 3 H-spiperone specific binding in limbic structures and striatum in rats was studied. The results show that pergolide induced a biphasic dose effect, with high doses increasing wakefulness and suppressing sleep while low dose decreased wakefulness, but increased sleep. It was shown that pergolide-induced sleep suppression was blocked by α-glupenthixol and pimozide, two dopamine receptor antagonists. It was further shown that pergolide merely delayed the rebound resulting from rapid-eye-movement (REM) sleep deprivation, that dopamine receptors stimulation had no direct effect on the period, phase or amplitude of the circadian rhythm of REM sleep propensity and that there was no alteration in the coupling of REM sleep episodes with S 2 episodes. Rapid-eye-movement sleep deprivation resulted in increased sensitivity to the pergolide-induced wakefulness stimulation and sleep suppression and pergolide-induced motor behaviors of locomotion and head bobbing. 3 H-spiperone specific binding to dopamine receptors was shown to be altered by REM sleep deprivation in the subcortical limbic structures. It is concluded that the REM sleep suppressing action of dopamine receptor stimulation is secondary to sleep suppression per se and not secondary to a unique effect on the REM sleep. Further, it is suggested that the wakefulness stimulating action of dopamine receptor agonists is mediated by activation of the dopamine receptors in the terminal areas of the mesolimbocortical dopamine projection system

  20. 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.

  1. Human dopamine receptor and its uses

    Energy Technology Data Exchange (ETDEWEB)

    Civelli, Olivier (Portland, OR); Van Tol, Hubert Henri-Marie (Toronto, CA)

    1999-01-01

    The present invention is directed toward the isolation, characterization and pharmacological use of the human D4 dopamine receptor. The nucleotide sequence of the gene corresponding to this receptor and alleleic variant thereof are provided by the invention. The invention also includes recombinant eukaryotic expression constructs capable of expressing the human D4 dopamine receptor in cultures of transformed eukaryotic cells. The invention provides cultures of transformed eukaryotic cells which synthesize the human D4 dopamine receptor, and methods for characterizing novel psychotropic compounds using such cultures.

  2. Cellular regulation of the dopamine transporter

    DEFF Research Database (Denmark)

    Eriksen, Jacob

    2010-01-01

    The dopamine transporter (DAT) mediates reuptake of dopamine from the synaptic cleft and is a target for widely abused psychostimulants such as cocaine and amphetamine. Nonetheless, little is known about the cellular distribution and trafficking of natively expressed DAT. DAT and its trafficking...... in heterologous cells and in cultured DA neurons. DAT has been shown to be regulated by the dopamine D2 receptor (D2R), the primary target foranti-psychotics, through a direct interaction. D2R is among other places expressed as an autoreceptor in DA neurons. Transient over-expression of DAT with D2R in HEK293...

  3. Action of dopamine in radiation protection

    International Nuclear Information System (INIS)

    Gupta, G.S.

    1983-01-01

    Administration of dopamine prior to irradiation modified biochemical processes in testes and other radioresponsive tissues. Results suggested that dopamine exerts its radio-protection which may be direct or indirect at molecular level in the tissues. At molecular level it protects cell injury by inhibiting DNA replication and acting as a lipotropic agent. Coincidently it protects the activity of -SH group containing enzymes such as inorganic pyrophosphatase which is sensitive index of tissue injury. Moreover, dopamine modifies the levels of phosphorylase and glycogen in testes indicating that its action is similar to epinephrine

  4. Regional influence of cocaine on evoked dopamine release in the nucleus accumbens core: A role for the caudal brainstem.

    Science.gov (United States)

    Gerth, Ashlynn I; Alhadeff, Amber L; Grill, Harvey J; Roitman, Mitchell F

    2017-01-15

    Cocaine increases dopamine concentration in the nucleus accumbens through competitive binding to the dopamine transporter (DAT). However, it also increases the frequency of dopamine release events, a finding that cannot be explained by action at the DAT alone. Rather, this effect may be mediated by cocaine-induced modulation of brain regions that project to dopamine neurons. To explore regional contributions of cocaine to dopamine signaling, we administered cocaine to the lateral or fourth ventricles and compared the effects on dopamine release in the nucleus accumbens evoked by electrical stimulation of the ventral tegmental area to that of systemically-delivered cocaine. Stimulation trains caused a sharp rise in dopamine followed by a slower return to baseline. The magnitude of dopamine release ([DA]max) as well as the latency to decay to fifty percent of the maximum (t(1/2); index of DAT activity) by each stimulation train were recorded. All routes of cocaine delivery caused an increase in [DA]max; only systemic cocaine caused an increase in t(1/2). Importantly, these data are the first to show that hindbrain (fourth ventricle)-delivered cocaine modulates phasic dopamine signaling. Fourth ventricular cocaine robustly increased cFos immunoreactivity in the nucleus of the solitary tract (NTS), suggesting a neural substrate for hindbrain cocaine-mediated effects on [DA]max. Together, the data demonstrate that cocaine-induced effects on phasic dopamine signaling are mediated via actions throughout the brain including the hindbrain. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  5. Kinetic diversity of dopamine transmission in the dorsal striatum.

    Science.gov (United States)

    Taylor, I Mitch; Nesbitt, Kathryn M; Walters, Seth H; Varner, Erika L; Shu, Zhan; Bartlow, Kathleen M; Jaquins-Gerstl, Andrea S; Michael, Adrian C

    2015-05-01

    Dopamine (DA), a highly significant neurotransmitter in the mammalian central nervous system, operates on multiple time scales to affect a diverse array of physiological functions. The significance of DA in human health is heightened by its role in a variety of pathologies. Voltammetric measurements of electrically evoked DA release have brought to light the existence of a patchwork of DA kinetic domains in the dorsal striatum (DS) of the rat. Thus, it becomes necessary to consider how these domains might be related to specific aspects of DA's functions. Responses evoked in the fast and slow domains are distinct in both amplitude and temporal profile. Herein, we report that responses evoked in fast domains can be further classified into four distinct types, types 1-4. The DS, therefore, exhibits a total of at least five distinct evoked responses (four fast types and one slow type). All five response types conform to kinetic models based entirely on first-order rate expressions, which indicates that the heterogeneity among the response types arises from kinetic diversity within the DS terminal field. We report also that functionally distinct subregions of the DS express DA kinetic diversity in a selective manner. Thus, this study documents five response types, provides a thorough kinetic explanation for each of them, and confirms their differential association with functionally distinct subregions of this key DA terminal field. The dorsal striatum is composed of five significantly different dopamine domains (types 1-4 and slow, average ± SEM responses to medial forebrain bundle (MFB) stimulation are shown in the figure). Responses from each of these five domains exhibit significantly different ascending and descending kinetic profiles and return to a long lasting elevated dopamine state, termed the dopamine hang-up. All features of these responses are modeled with high correlation using first-order modeling as well as our recently published restricted diffusion

  6. Cocaine exposure modulates dopamine and adenosine signaling in the fetal brain

    Science.gov (United States)

    Kubrusly, Regina C. C.; Bhide, Pradeep G.

    2009-01-01

    Exposure to cocaine during the fetal period can produce significant lasting changes in the structure and function of the brain. Cocaine exerts its effects on the developing brain by blocking monoamine transporters and impairing monoamine receptor signaling. Dopamine is a major central target of cocaine. In a mouse model, we show that cocaine exposure from embryonic day 8 (E8) to E14 produces significant reduction in dopamine transporter activity, attenuation of dopamine D1-receptor function and upregulation of dopamine D2-receptor function. Cocaine’s effects on the D1-receptor are at the level of protein expression as well as activity. The cocaine exposure also produces significant increases in basal cAMP levels in the striatum and cerebral cortex. The increase in the basal cAMP levels was independent of dopamine receptor activity. In contrast, blocking the adenosine A2a receptor downregulated of the basal cAMP levels in the cocaine-exposed brain to physiological levels, suggesting the involvement of adenosine receptors in mediating cocaine’s effects on the embryonic brain. In support of this suggestion, we found that the cocaine exposure downregulated adenosine transporter function. We also found that dopamine D2- and adenosine A2a-receptors antagonize each other’s function in the embryonic brain in a manner consistent with their interactions in the mature brain. Thus, our data show that prenatal cocaine exposure produces direct effects on both the dopamine and adenosine systems. Furthermore, the dopamine D2 and adenosine A2a receptor interactions in the embryonic brain discovered in this study unveil a novel substrate for cocaine’s effects on the developing brain. PMID:19765599

  7. Beyond the Dopamine Receptor: Regulation and Roles of Serine/Threonine Protein Phosphatases

    Directory of Open Access Journals (Sweden)

    Sven I Walaas

    2011-08-01

    Full Text Available Dopamine plays an important modulatory role in the central nervous system, helping to control critical aspects of motor function and reward learning. Alteration in normal dopaminergic neurotransmission underlies multiple neurological diseases including schizophrenia, Huntington's disease and Parkinson's disease. Modulation of dopamine-regulated signaling pathways is also important in the addictive actions of most drugs of abuse. Our studies over the last 30 years have focused on the molecular actions of dopamine acting on medium spiny neurons, the predominant neurons of the neostriatum. Striatum-enriched phosphoproteins, particularly DARPP-32, RCS (Regulator of Calmodulin Signaling and ARPP-16, mediate pleiotropic actions of dopamine. Notably, each of these proteins, either directly or indirectly, regulates the activity of one of the three major subclasses of serine/threonine protein phosphatases, PP1, PP2B and PP2A, respectively. For example, phosphorylation of DARPP-32 at Thr34 by protein kinase A results in potent inhibition of PP1, leading to potentiation of dopaminergic signaling at multiple steps from the dopamine receptor to the nucleus. The discovery of DARPP-32 and its emergence as a critical molecular integrator of striatal signaling will be discussed, as will more recent studies that highlight novel roles for RCS and ARPP-16 in dopamine-regulated striatal signaling pathways.

  8. Dopamine versus noradrenaline in septic shock

    Directory of Open Access Journals (Sweden)

    Bo Xu

    2011-10-01

    Full Text Available BackgroundThe ‘Surviving Sepsis’ Campaign guidelines recommend theuse of dopamine or noradrenaline as the first vasopressor inseptic shock. However, information that guides clinicians inchoosing between dopamine and noradrenaline as the firstvasopressor in patients with septic shock is limited.ObjectiveThis article presents a review of the literature regarding theuse of dopamine versus noradrenaline in patients with septicshock.ResultsTwo randomised controlled trials (RCT and two largeprospective cohort studies were analysed. RCT data showeddopamine was associated with increased arrhythmic events.One cohort study found dopamine was associated with higher30-day mortality. The other cohort study found noradrenalinewas associated with higher 28-day mortality.DiscussionData on the use of dopamine versus noradrenaline in patientswith septic shock is limited. Following the recent SOAP IIstudy, there is now strong evidence that the use of dopaminein septic shock is associated with significantly morecardiovascular adverse events, compared tonoradrenaline.ConclusionNoradrenaline should be used as the initial vasopressor inseptic shock to avoid the arrhythmic events associatedwith dopamine.

  9. Tonic dopamine modulates exploitation of reward learning

    Directory of Open Access Journals (Sweden)

    Jeff A Beeler

    2010-11-01

    Full Text Available The impact of dopamine on adaptive behavior in a naturalistic environment is largely unexamined. Experimental work suggests that phasic dopamine is central to reinforcement learning whereas tonic dopamine may modulate performance without altering learning per se; however, this idea has not been developed formally or integrated with computational models of dopamine function. We quantitatively evaluate the role of tonic dopamine in these functions by studying the behavior of hyperdopaminergic DAT knockdown mice in an instrumental task in a semi-naturalistic homecage environment. In this closed economy paradigm, subjects earn all of their food by pressing either of two levers, but the relative cost for food on each lever shifts frequently. Compared to wild-type mice, hyperdopaminergic mice allocate more lever presses on high-cost levers, thus working harder to earn a given amount of food and maintain their body weight. However, both groups show a similarly quick reaction to shifts in lever cost, suggesting that the hyperdominergic mice are not slower at detecting changes, as with a learning deficit. We fit the lever choice data using reinforcement learning models to assess the distinction between acquisition and expression the models formalize. In these analyses, hyperdopaminergic mice displayed normal learning from recent reward history but diminished capacity to exploit this learning: a reduced coupling between choice and reward history. These data suggest that dopamine modulates the degree to which prior learning biases action selection and consequently alters the expression of learned, motivated behavior.

  10. Dopamine dysregulation syndrome, addiction and behavioral changes in Parkinson's disease.

    Science.gov (United States)

    Merims, Doron; Giladi, Nir

    2008-01-01

    Degeneration of the dopaminergic system in Parkinson's disease and longstanding exposure to dopaminergic drugs may cause reward system malfunction. This may manifest as addiction to l-dopa and behavioral disturbances associated with the impulse control system. These disturbances include: gambling, excessive spending (shopping), hypersexuality and binge eating. We included one such patient's personal story to emphasize the devastating consequences of these potentially reversible phenomena: the patient describes in his own words how gambling induced by an exposure dopamine agonist therapy significantly worsened his disease-related difficulties.

  11. Dopamine genes and pathological gambling in discordant sib-pairs.

    Science.gov (United States)

    da Silva Lobo, Daniela Sabbatini; Vallada, Homero P; Knight, Joanne; Martins, Silvia S; Tavares, Hermano; Gentil, Valentim; Kennedy, James L

    2007-12-01

    Pathological gambling (PG) is an impulse control disorder that has been considered as a behavioral addiction. Recent studies have suggested the involvement of the dopaminergic system in addictions and impulse control disorders and associations of dopamine receptor genes (DRD1, DRD2, and DRD4) and PG have been reported. In the present study, 140 sib-pairs discordant for the diagnosis of PG (70 males and 70 females on each group) were recruited through the Gambling Outpatient Unit at the Institute of Psychiatry, University of Sao Paulo and were assessed by trained psychiatrists. A family-based association design was chosen to prevent population stratification. All subjects were genotyped for dopamine receptor genes (DRD1 -800 T/C, DRD2 TaqIA RFLP, DRD3 Ser9Gly, DRD4 48bp exon III VNTR, DRD5 (CA) repeat) and the dopamine transporter gene (SCL6A3 40 bp VNTR). Our results suggest the association of PG with DRD1 -800 T/C allele T (P = .03).

  12. Dopamine-Induced Nonmotor Symptoms of Parkinson's Disease

    Directory of Open Access Journals (Sweden)

    Ariane Park

    2011-01-01

    Full Text Available Nonmotor symptoms of Parkinson's disease (PD may emerge secondary to the underlying pathogenesis of the disease, while others are recognized side effects of treatment. Inevitably, there is an overlap as the disease advances and patients require higher dosages and more complex medical regimens. The non-motor symptoms that emerge secondary to dopaminergic therapy encompass several domains, including neuropsychiatric, autonomic, and sleep. These are detailed in the paper. Neuropsychiatric complications include hallucinations and psychosis. In addition, compulsive behaviors, such as pathological gambling, hypersexuality, shopping, binge eating, and punding, have been shown to have a clear association with dopaminergic medications. Dopamine dysregulation syndrome (DDS is a compulsive behavior that is typically viewed through the lens of addiction, with patients needing escalating dosages of dopamine replacement therapy. Treatment side effects on the autonomic system include nausea, orthostatic hypotension, and constipation. Sleep disturbances include fragmented sleep, nighttime sleep problems, daytime sleepiness, and sleep attacks. Recognizing the non-motor symptoms that can arise specifically from dopamine therapy is useful to help optimize treatment regimens for this complex disease.

  13. On the role of subsecond dopamine release in conditioned avoidance

    Directory of Open Access Journals (Sweden)

    Erik B Oleson

    2013-06-01

    Full Text Available Using shock avoidance procedures to study conditioned behavioral responses has a rich history within the field of experimental psychology. Such experiments led to the formulation of the general concept of negative reinforcement and specific theories attempting to explain escape and avoidance behavior, or why animals choose to either terminate or prevent the presentation of an aversive event. For example, the two-factor theory of avoidance holds that cues preceding an aversive event begin to evoke conditioned fear responses, and these conditioned fear responses reinforce the instrumental avoidance response. Current neuroscientific advances are providing new perspectives into this historical literature. Due to its well-established role in reinforcement processes and behavioral control, the mesolimbic dopamine system presented itself as a logical starting point in the search for neural correlates of avoidance and escape behavior. We recently demonstrated that phasic dopamine release events are inhibited by stimuli associated with aversive events but increased by stimuli preceding the successful avoidance of the aversive event. The latter observation is inconsistent with the second component of the two-factor theory of avoidance and; therefore, led us propose a new theoretical explanation of conditioned avoidance: 1 fear is initially conditioned to the warning signal and dopamine computes this fear association as a decrease in release, 2 the warning signal, now capable of producing a negative emotional state, suppresses dopamine release and behavior, 3 over repeated trials the warning signal becomes associated with safety rather than fear; dopaminergic neurons already compute safety as an increase in release and begin to encode the warning signal as the earliest predictor of safety 4 the warning signal now promotes conditioned avoidance via dopaminergic modulation of the brain’s incentive-motivational circuitry.

  14. Dopamine release in organotypic cultures of foetal mouse mesencephalon: effects of depolarizing agents, pargyline, nomifensine, tetrodotoxin and calcium

    DEFF Research Database (Denmark)

    Larsen, Trine R; Rossen, Sine; Gramsbergen, Jan B

    2008-01-01

    Organotypic mesencephalic cultures provide an attractive in vitro alternative to study development of the nigrostriatal system and pathophysiological mechanisms related to Parkinson's disease. However, dopamine (DA) release mechanisms have been poorly characterized in such cultures. We report here...

  15. Dopamine signaling in food addiction: role of dopamine D2 receptors

    Directory of Open Access Journals (Sweden)

    Ja-Hyun Baik

    2013-11-01

    Full Text Available Dopamine (DA regulates emotional and motivationalbehavior through the mesolimbic dopaminergic pathway.Changes in DA signaling in mesolimbic neurotransmission arewidely believed to modify reward-related behaviors and aretherefore closely associated with drug addiction. Recentevidence now suggests that as with drug addiction, obesitywith compulsive eating behaviors involves reward circuitry ofthe brain, particularly the circuitry involving dopaminergicneural substrates. Increasing amounts of data from humanimaging studies, together with genetic analysis, havedemonstrated that obese people and drug addicts tend to showaltered expression of DA D2 receptors in specific brain areas,and that similar brain areas are activated by food-related anddrug-related cues. This review focuses on the functions of theDA system, with specific focus on the physiological interpretationand the role of DA D2 receptor signaling in foodaddiction. [BMB Reports 2013; 46(11: 519-526

  16. [11]Cocaine: PET studies of cocaine pharmacokinetics, dopamine transporter availability and dopamine transporter occupancy

    International Nuclear Information System (INIS)

    Fowler, Joanna S.; Volkow, Nora D.; Wang, Gene-Jack; Gatley, S. John; Logan, Jean

    2001-01-01

    Cocaine was initially labeled with carbon-11 in order to track the distribution and pharmacokinetics of this powerful stimulant and drug of abuse in the human brain and body. It was soon discovered that [ 11 C]cocaine was not only useful for measuring cocaine pharmacokinetics and its relationship to behavior but that it is also a sensitive radiotracer for dopamine transporter (DAT) availability. Measures of DAT availability were facilitated by the development of a graphical analysis method (Logan Plot) for reversible systems which streamlined kinetic analysis. This expanded the applications of [ 11 C]cocaine to studies of DAT availability in the human brain and allowed the first comparative measures of the degree of DAT occupancy by cocaine and another stimulant drug methylphenidate. This article will summarize preclinical and clinical research with [ 11 C]cocaine

  17. [{sup 11}]Cocaine: PET studies of cocaine pharmacokinetics, dopamine transporter availability and dopamine transporter occupancy

    Energy Technology Data Exchange (ETDEWEB)

    Fowler, Joanna S. E-mail: fowler@bnl.gov; Volkow, Nora D.; Wang, Gene-Jack; Gatley, S. John; Logan, Jean

    2001-07-01

    Cocaine was initially labeled with carbon-11 in order to track the distribution and pharmacokinetics of this powerful stimulant and drug of abuse in the human brain and body. It was soon discovered that [{sup 11}C]cocaine was not only useful for measuring cocaine pharmacokinetics and its relationship to behavior but that it is also a sensitive radiotracer for dopamine transporter (DAT) availability. Measures of DAT availability were facilitated by the development of a graphical analysis method (Logan Plot) for reversible systems which streamlined kinetic analysis. This expanded the applications of [{sup 11}C]cocaine to studies of DAT availability in the human brain and allowed the first comparative measures of the degree of DAT occupancy by cocaine and another stimulant drug methylphenidate. This article will summarize preclinical and clinical research with [{sup 11}C]cocaine.

  18. Cocaine sensitization increases subthreshold activity in dopamine neurons from the ventral tegmental area.

    Science.gov (United States)

    Arencibia-Albite, Francisco; Vázquez-Torres, Rafael; Jiménez-Rivera, Carlos A

    2017-02-01

    The progressive escalation of psychomotor responses that results from repeated cocaine administration is termed sensitization. This phenomenon alters the intrinsic properties of dopamine (DA) neurons from the ventral tegmental area (VTA), leading to enhanced dopaminergic transmission in the mesocorticolimbic network. The mechanisms underlying this augmented excitation are nonetheless poorly understood. DA neurons display the hyperpolarization-activated, nonselective cation current, dubbed I h We recently demonstrated that I h and membrane capacitance are substantially reduced in VTA DA cells from cocaine-sensitized rats. The present study shows that 7 days of cocaine withdrawal did not normalize I h and capacitance. In cells from cocaine-sensitized animals, the amplitude of excitatory synaptic potentials, at -70 mV, was ∼39% larger in contrast to controls. Raise and decay phases of the synaptic signal were faster under cocaine, a result associated with a reduced membrane time constant. Synaptic summation was paradoxically elevated by cocaine exposure, as it consisted of a significantly reduced summation indexed but a considerably increased depolarization. These effects are at least a consequence of the reduced capacitance. I h attenuation is unlikely to explain such observations, since at -70 mV, no statistical differences exist in I h or input resistance. The neuronal shrinkage associated with a diminished capacitance may help to understand two fundamental elements of drug addiction: incentive sensitization and negative emotional states. A reduced cell size may lead to substantial enhancement of cue-triggered bursting, which underlies drug craving and reward anticipation, whereas it could also result in DA depletion, as smaller neurons might express low levels of tyrosine hydroxylase. This work uses a new approach that directly extracts important biophysical parameters from alpha function-evoked synaptic potentials. Two of these parameters are the cell membrane

  19. Membrane permeable C-terminal dopamine transporter peptides attenuate amphetamine-evoked dopamine release

    DEFF Research Database (Denmark)

    Rickhag, Karl Mattias; Owens, WA; Winkler, Marie-Therese

    2013-01-01

    The dopamine transporter (DAT) is responsible for sequestration of extracellular dopamine (DA). The psychostimulant amphetamine (AMPH) is a DAT substrate, which is actively transported into the nerve terminal, eliciting vesicular depletion and reversal of DA transport via DAT. Here, we investigate...

  20. Dopamine D2/3 receptor availability and amphetamine-induced dopamine release in obesity

    NARCIS (Netherlands)

    van de Giessen, Elsmarieke; Celik, Funda; Schweitzer, Dave H.; van den Brink, Wim; Booij, Jan

    2014-01-01

    The neurotransmitter dopamine is important in the regulation of food intake. It is hypothesised that obese people experience less reward from food due to lower striatal dopamine release, which consequently leads to overeating. This study is the first to assess whether obese subjects have blunted

  1. Gestational lead exposure selectively decreases retinal dopamine amacrine cells and dopamine content in adult mice

    Energy Technology Data Exchange (ETDEWEB)

    Fox, Donald A., E-mail: dafox@uh.edu [College of Optometry, University of Houston, Houston, TX (United States); Department of Biology and Biochemistry, University of Houston, Houston, TX (United States); Department of Pharmacology and Pharmaceutical Sciences, University of Houston, Houston, TX (United States); Hamilton, W. Ryan [Department of Biology and Biochemistry, University of Houston, Houston, TX (United States); Johnson, Jerry E. [Department of Natural Sciences, University of Houston-Downtown, Houston, TX (United States); Xiao, Weimin [College of Optometry, University of Houston, Houston, TX (United States); Chaney, Shawntay; Mukherjee, Shradha [Department of Biology and Biochemistry, University of Houston, Houston, TX (United States); Miller, Diane B.; O' Callaghan, James P. [Toxicology and Molecular Biology Branch, Health Effects Research Laboratory, Centers for Disease Control and Prevention-NIOSH, Morgantown, WV USA (United States)

    2011-11-15

    Gestational lead exposure (GLE) produces supernormal scotopic electroretinograms (ERG) in children, monkeys and rats, and a novel retinal phenotype characterized by an increased number of rod photoreceptors and bipolar cells in adult mice and rats. Since the loss of dopaminergic amacrine cells (DA ACs) in GLE monkeys and rats contributes to supernormal ERGs, the retinal DA system was analyzed in mice following GLE. C57BL/6 female mice were exposed to low (27 ppm), moderate (55 ppm) or high (109 ppm) lead throughout gestation and until postnatal day 10 (PN10). Blood [Pb] in control, low-, moderate- and high-dose GLE was {<=} 1, {<=} 10, {approx} 25 and {approx} 40 {mu}g/dL, respectively, on PN10 and by PN30 all were {<=} 1 {mu}g/dL. At PN60, confocal-stereology studies used vertical sections and wholemounts to characterize tyrosine hydroxylase (TH) expression and the number of DA and other ACs. GLE dose-dependently and selectively decreased the number of TH-immunoreactive (IR) DA ACs and their synaptic plexus without affecting GABAergic, glycinergic or cholinergic ACs. Immunoblots and confocal revealed dose-dependent decreases in retinal TH protein expression and content, although monoamine oxidase-A protein and gene expression were unchanged. High-pressure liquid chromatography showed that GLE dose-dependently decreased retinal DA content, its metabolites and DA utilization/release. The mechanism of DA selective vulnerability is unknown. However, a GLE-induced loss/dysfunction of DA ACs during development could increase the number of rods and bipolar cells since DA helps regulate neuronal proliferation, whereas during adulthood it could produce ERG supernormality as well as altered circadian rhythms, dark/light adaptation and spatial contrast sensitivity. -- Highlights: Black-Right-Pointing-Pointer Peak [BPb] in control, low-, moderate- and high-dose newborn mice with gestational lead exposure: {<=} 1, {<=} 10, 25 and 40 {mu}g/dL Black

  2. Raman Spectroscopic Signature Markers of Dopamine-Human Dopamine Transporter Interaction in Living Cells.

    Science.gov (United States)

    Silwal, Achut P; Yadav, Rajeev; Sprague, Jon E; Lu, H Peter

    2017-07-19

    Dopamine (DA) controls many psychological and behavioral activities in the central nervous system (CNS) through interactions with the human dopamine transporter (hDAT) and dopamine receptors. The roles of DA in the function of the CNS are affected by the targeted binding of drugs to hDAT; thus, hDAT plays a critical role in neurophysiology and neuropathophysiology. An effective experimental method is necessary to study the DA-hDAT interaction and effects of variety of drugs like psychostimulants and antidepressants that are dependent on this interaction. In searching for obtaining and identifying the Raman spectral signatures, we have used surface enhanced Raman scattering (SERS) spectroscopy to record SERS spectra from DA, human embryonic kidney 293 cells (HEK293), hDAT-HEK293, DA-HEK293, and DA-hDAT-HEK293. We have demonstrated a specific 2D-distribution SERS spectral analytical approach to analyze DA-hDAT interaction. Our study shows that the Raman modes at 807, 839, 1076, 1090, 1538, and 1665 cm -1 are related to DA-hDAT interaction, where Raman shifts at 807 and 1076 cm -1 are the signature markers for the bound state of DA to probe DA-hDAT interaction. On the basis of density function theory (DFT) calculation, Raman shift of the bound state of DA at 807 cm -1 is related to combination of bending modes α(C3-O10-H21), α(C2-O11-H22), α(C7-C8-H18), α(C6-C4-H13), α(C7-C8-H19), and α(C7-C8-N9), and Raman shift at 1076 cm -1 is related to combination of bending modes α(H19-N9-C8), γ(N9-H19), γ(C8-H19), γ(N9-H20), γ(C8-H18), and α(C7-C8-H18). These findings demonstrate that protein-ligand interactions can be confirmed by probing change in Raman shift of ligand molecules, which could be crucial to understanding molecular interactions between neurotransmitters and their receptors or transporters.

  3. Neuroprotective Properties of Endocannabinoids N-Arachidonoyl Dopamine and N-Docosahexaenoyl Dopamine Examined in Neuronal Precursors Derived from Human Pluripotent Stem Cells.

    Science.gov (United States)

    Novosadova, E V; Arsenyeva, E L; Manuilova, E S; Khaspekov, L G; Bobrov, M Yu; Bezuglov, V V; Illarioshkin, S N; Grivennikov, I A

    2017-11-01

    Neuroprotective properties of endocannabinoids N-arachidonoyl dopamine (NADA) and N-docosahexaenoyl dopamine (DHDA) were examined in neuronal precursor cells differentiated from human induced pluripotent stem cells and subjected to oxidative stress. Both compounds exerted neuroprotective activity, which was enhanced by elevating the concentration of the endocannabinoids within the 0.1-10 µM range. However, both agents at 10 µM concentration showed a marked toxic effect resulting in death of ~30% of the cells. Finally, antagonists of cannabinoid receptors as well as the receptor of the TRPV1 endovanilloid system did not hamper the neuroprotective effects of these endocannabinoids.

  4. Dopamine D(1) receptor-mediated control of striatal acetylcholine release by endogenous dopamine.

    Science.gov (United States)

    Acquas, E; Di Chiara, G

    1999-10-27

    The role of dopamine D(1) and D(2) receptors in the control of acetylcholine release in the dorsal striatum by endogenous dopamine was investigated by monitoring with microdialysis the effect of the separate or combined administration of the dopamine D(1) receptor antagonist, SCH 39166 ¿(-)-trans-6,7,7a,8,9, 13b-exahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo-[d]-nap hto-[2, 1b]-azepine hydrochloride¿ (50 microg/kg subcutaneous (s.c.)), of the dopamine D(2)/D(3) receptor agonist, quinpirole (trans-(-)-4aR, 4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo-(3,4-g)-quinoline hydrochloride) (5 and 10 microg/kg s.c.), and of the D(3) receptor selective agonist, PD 128,907 [S(+)-(4aR,10bR)-3,4,4a, 10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin -9-ol hydrochloride] (50 microg/kg s.c.), on in vivo dopamine and acetylcholine release. Microdialysis was performed with a Ringer containing low concentrations (0.01 microM) of the acetylcholinesterase inhibitor, neostigmine. Quinpirole (10 microg/kg s.c.) decreased striatal dopamine and acetylcholine release. Administration of PD 128,907 (50 microg/kg) decreased dopamine but failed to affect acetylcholine release. SCH 39166 (50 microg/kg s.c.) stimulated dopamine release and reduced acetylcholine release. Pretreatment with quinpirole reduced (5 microg/kg s.c.) or completely prevented (10 microg/kg s.c.) the stimulation of dopamine release elicited by SCH 39166 (50 microg/kg s.c.); on the other hand, pretreatment with quinpirole (5 and 10 microg/kg) potentiated the reduction of striatal acetylcholine release induced by SCH 39166 (50 microg/kg s.c.). Similarly, pretreatment with PD 128,907 (50 microg/kg) which prevented the increase of dopamine release induced by SCH 39166 (50 microg/kg), potentiated the reduction of striatal acetylcholine transmission elicited by SCH 39166. Thus, pretreatment with low doses of quinpirole or PD 128,907 influences in opposite manner the effect of SCH 39166 on striatal dopamine and

  5. Prefrontal Dopamine in Associative Learning and Memory

    Science.gov (United States)

    Puig, M. Victoria; Antzoulatos, Evan G.; Miller, Earl K.

    2014-01-01

    Learning to associate specific objects or actions with rewards and remembering the associations are everyday tasks crucial for our flexible adaptation to the environment. These higher-order cognitive processes depend on the prefrontal cortex (PFC) and frontostriatal circuits that connect areas in the frontal lobe with the striatum in the basal ganglia. Both structures are densely innervated by dopamine (DA) afferents that originate in the midbrain. Although the activity of DA neurons is thought to be important for learning, the exact role of DA transmission in frontostriatal circuits during learning-related tasks is still unresolved. Moreover, the neural substrates of this modulation are poorly understood. Here, we review our recent work in monkeys utilizing local pharmacology of DA agents in the PFC to investigate the cellular mechanisms of DA modulation of associative learning and memory. We show that blocking both D1 and D2 receptors in the lateral PFC impairs learning of new stimulus-response associations and cognitive flexibility, but not the memory of highly familiar associations. In addition, D2 receptors may also contribute to motivation. The learning deficits correlated with reductions of neural information about the associations in PFC neurons, alterations in global excitability and spike synchronization, and exaggerated alpha and beta neural oscillations. Our findings provide new insights into how DA transmission modulate associative learning and memory processes in frontostriatal systems. PMID:25241063

  6. Measuring dopamine release in the human brain with PET

    Energy Technology Data Exchange (ETDEWEB)

    Volkow, N.D. [Brookhaven National Lab., Upton, NY (United States)]|[State Univ. of New York at Stony Brook, Stony Brook, NY (United States). Dept. of Psychiatry; Fowler, J.S.; Logan, J.; Wang, G.J. [Brookhaven National Lab., Upton, NY (United States)

    1995-12-01

    The dopamine system is involved in the regulation of brain regions that subserve motor, cognitive and motivational behaviors. Disruptions of dopamine (DA) function have ben implicated in neurological and psychiatric illnesses including substance abuse as well as on some of the deficits associated with aging of the human brain. This has made the DA system an important topic in research in the neurosciences and neuroimaging as well as an important molecular target for drug development. Positron Emission Tomography (PET), was the first technology that enabled direct measurement of components of the DA system in the living human brain. Imaging studies of DA in the living brain have been indirect, relying on the development of radiotracers to label DA receptors, DA transporters, compounds which have specificity for the enzymes which degrade synaptic DA. Additionally, through the use of tracers that provide information on regional brain activity (ie brain glucose metabolism and cerebral blood flow) and of appropriate pharmacological interventions, it has been possible to assess the functional consequences of changes in brain DA activity. DA specific ligands have been useful in the evaluation of patients with neuropsychiatric illnesses as well as to investigate receptor blockade by antipsychotic drugs. A limitation of strategies that rely on the use of DA specific ligands is that the measures do not necessarily reflect the functional state of the dopaminergic system and that there use to study the effects of drugs is limited to the investigation of receptor or transporter occupancy. Newer strategies have been developed in an attempt to provide with information on dopamine release and on the functional responsivity of the DA system in the human brain. This in turn allows to investigate the effects of pharmacological agent in an analogous way to what is done with microdialysis techniques.

  7. Rab3A Inhibition of Ca2+-Dependent Dopamine Release From PC12 Cells Involves Interaction With Synaptotagmin I.

    Science.gov (United States)

    Dai, Zhipan; Tang, Xia; Chen, Jia; Tang, Xiaochao; Wang, Xianchun

    2017-11-01

    Rab3 and synaptotagmin have been suggested to play important roles in the regulation of neurotransmitter release and, however, the molecular mechanism has not been completely clear. Here, we studied the effects of Rab3A and synaptotagmin I (Syt I) on dopamine release using PC12 cells as a model system. Rab3A was demonstrated to have effects on both Ca 2+ -independent and Ca 2+ -dependent dopamine releases from the PC12 cells. Application of Rab3A (up to 2500 nM) gradually decreased the amount of Ca 2+ -dependently released dopamine, indicating that Rab3A is a negative modulator that was further supported by the increase in dopamine release caused by Rab3A knockdown. Syt I knockdown weakened the Ca 2+ -dependent dopamine release, suggesting that Syt I plays a positive regulatory role in the cellular process. Treatment of the Syt I-knocked down PC12 cells with Rab3A further decreased Ca 2+ -dependent dopamine release and, however, the decrease magnitude was significantly reduced compared with that before Syt I knockdown, thus for the first time demonstrating that the inhibitory effect of Rab3A on Ca 2+ -dependent dopamine release involves the interaction with Syt I. This work has shed new light on the molecular mechanism for Rab3 and synaptotamin regulation of neurotransmitter release. J. Cell. Biochem. 118: 3696-3705, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  8. D-2 dopamine receptor activation reduces free [3H]arachidonate release induced by hypophysiotropic peptides in anterior pituitary cells

    International Nuclear Information System (INIS)

    Canonico, P.L.

    1989-01-01

    Dopamine reduces the stimulation of intracellular [ 3 H]arachidonate release produced by the two PRL-stimulating peptides angiotensin-II and TRH. This effect is concentration dependent and is mediated by stimulation of D-2 dopamine receptors. D-2 receptor agonists (bromocriptine, dihydroergocryptine, and dihydroergocristine) inhibit the release of fatty acid induced by angiotensin-II with a potency that parallels their ability to inhibit PRL release in vitro. Conversely, the selective D-2 receptor antagonist L-sulpiride completely prevents dopamine's effect, whereas SCH 23390 (a D-1 receptor antagonist) is ineffective. The inhibitory action of dopamine does not seem to be consequent to an action on the adenylate cyclase-cAMP system, as 8-bromo-cAMP (1 mM) does not affect either basal or dopamine-inhibited [ 3 H]arachidonate release. However, a 24-h pertussis toxin pretreatment significantly reduces the action of dopamine on fatty acid release. Collectively, these results suggest that D-2 dopamine receptor-mediated inhibition of intracellular [ 3 H]arachidonate release requires the action of a GTP-binding protein, but is not a consequence of an inhibitory action on cAMP levels

  9. Detecting associations between behavioral addictions and dopamine agonists in the Food & Drug Administration's Adverse Event database.

    Science.gov (United States)

    Gendreau, Katherine E; Potenza, Marc N

    2014-03-01

    Studies have reported higher prevalences of four behavioral addictions (binge eating, compulsive shopping, hypersexuality, and pathological gambling) in dopamine agonist-treated Parkinson's disease relative to non-dopamine agonist-treated Parkinson's. However, recent case-control and epidemiological studies suggest that prevalences of behavioral addictions in dopamine agonist-treated Parkinson's may be similar to background population rates. This study tests that hypothesis by examining the FDA Adverse Event Reporting System (FAERS) for evidence of these associations, taking into account the potential impact of publicity on reporting rates. FAERS reports in 2004 (pre-publicity for all but pathological gambling) and 2007 (post-publicity for all four behaviors) were analyzed. A threshold consisting of ≥3 cases, proportional reporting ratio ≥2, and χ (2) with Yates' correction ≥4 was used to detect signals (drug-associated adverse reactions) involving any of five dopamine agonists and any of four behavioral addictions. No reports containing compulsive shopping and no signal for binge eating and dopamine agonists were found in either year. A weak signal was found for hypersexuality in 2004, with a stronger signal in 2007. A robust signal was found for pathological gambling in 2004, with a more robust signal in 2007. These results suggest that publicity may increase reporting rates in the FAERS. Findings for binge eating, compulsive shopping, and hypersexuality suggest that prevalences of these behaviors among those treated with dopamine agonists may be similar to background population rates and thus may not reflect an adverse safety signal. Further investigation of the relationship between dopamine agonists and behavioral addictions is warranted.

  10. Apo-ghrelin receptor (apo-GHSR1a Regulates Dopamine Signaling in the Brain

    Directory of Open Access Journals (Sweden)

    Andras eKern

    2014-08-01

    Full Text Available The orexigenic peptide hormone ghrelin is synthesized in the stomach and its receptor growth hormone secretagogue receptor (GHSR1a is expressed mainly in the central nervous system (CNS. In this review we confine our discussion to the physiological role of GHSR1a in the brain. Paradoxically, despite broad expression of GHSR1a in the CNS, other than trace amounts in the hypothalamus, ghrelin is undetectable in the brain. In our efforts to elucidate the function of the ligand-free ghrelin receptor (apo-GHSR1a we identified subsets of neurons that co-express GHSR1a and dopamine receptors. In this review we focus on interactions between apo-GHSR1a and dopamine-2 receptor (DRD2 and formation of GHSR1a:DRD2 heteromers in hypothalamic neurons that regulate appetite, and discuss implications for the treatment of Prader-Willi syndrome. GHSR1a antagonists of distinct chemical structures, a quinazolinone and a triazole, respectively enhance and inhibit dopamine signaling through GHSR1a:DRD2 heteromers by an allosteric mechanism. This finding illustrates a potential strategy for designing the next generation of drugs for treating eating disorders as well as psychiatric disorders caused by abnormal dopamine signaling. Treatment with a GHSR1a antagonist that enhances dopamine/DRD2 activity in GHSR1a:DRD2 expressing hypothalamic neurons has the potential to inhibit the uncontrollable hyperphagia associated with Prader-Willi syndrome. DRD2 antagonists are prescribed for treating schizophrenia, but these block dopamine signaling in all DRD2 expressing neurons and are associated with adverse side effects, including enhanced appetite and excessive weight gain. A GHSR1a antagonist of structural class that allosterically blocks dopamine/DRD2 action in GHSR1a:DRD2 expressing neurons would have no effect on neurons expressing DRD2 alone; therefore, the side effects of DRD2 antagonists would potentially be reduced thereby enhancing patient compliance.

  11. Altered dopamine ontogeny in the developmentally vitamin D deficient rat and its relevance to schizophrenia

    Directory of Open Access Journals (Sweden)

    James P. Kesby

    2013-07-01

    Full Text Available Schizophrenia is a heterogeneous group of disorders with unknown aetiology. Although abnormalities in multiple neurotransmitter systems have been linked to schizophrenia, alterations in dopamine neurotransmission remain central to the treatment of this disorder. Given that schizophrenia is considered a neurodevelopmental disorder we have hypothesised that abnormal dopamine signalling in the adult patient may result from altered dopamine signalling during foetal brain development. Environmental and genetic risk factors can be modelled in rodents to allow for the investigation of early neurodevelopmental pathogenesis that may lead to clues into the aetiology of schizophrenia. To address this we created an animal model of one such risk factor, developmental vitamin D (DVD deficiency. DVD-deficient adult rats display an altered behavioural profile in response to dopamine releasing and blocking agents that are reminiscent of that seen in schizophrenia patients. Furthermore, developmental studies revealed that DVD deficiency also altered cell proliferation, apoptosis and neurotransmission across the embryonic brain. In particular, DVD deficiency reduces the expression of crucial dopaminergic specification factors and alters dopamine metabolism in the developing brain. We speculate such alterations in foetal brain development may change the trajectory of dopamine neuron ontogeny to induce the behavioural abnormalities observed in adult offspring. The widespread evidence that both dopaminergic and structural changes are present in people who develop schizophrenia prior to onset also suggest that early alterations in development are central to the disease. Taken together, early alterations in dopamine ontogeny may represent a core feature in the pathology of schizophrenia. Such a mechanism could bring together evidence from multiple risk factors and genetic vulnerabilities to form a convergent pathway in disease pathophysiology.

  12. Effect of mazindol on extracellular dopamine concentration in human brain measured by PET.

    Science.gov (United States)

    Sakayori, Takeshi; Tateno, Amane; Arakawa, Ryosuke; Ikeda, Yumiko; Suzuki, Hidenori; Okubo, Yoshiro

    2014-06-01

    Mazindol, an appetite suppressant, inhibits the reuptake of dopamine in the synaptic cleft. It has been considered that mazindol might enhance dopamine transmission in the human brain. However, there has been no study that investigated the extracellular dopamine concentration in vivo. Using positron emission tomography (PET), we aimed to measure the effect of mazindol on the extracellular dopamine concentration and to evaluate how mazindol affects the dopamine system in the healthy human brain. Eleven healthy individuals (six males, five females, age 30.9 ± 4.9 years) were enrolled in this study. Each participant was scanned with [(11)C]raclopride on 1 day without any medicine as baseline condition, and on another day with mazindol as drug condition. In the drug condition, participants took mazindol 0.5 mg (N = 5) or 1.5 mg (N = 6) 2 h before the PET scan. Plasma concentrations of mazindol were measured before the injection of [(11)C]raclopride, and urine concentrations of mazindol were measured after the scan. After taking mazindol, the calculated decrease in binding potential (ΔBP) in the striatum was 1.74 % for 0.5 mg and 8.14 for 1.5 mg, and the correlation with the blood concentration of mazindol was significant (P = 0.0016, R (2) = 0.69). ΔBP was not significantly correlated with the urine concentration of mazindol (P = 0.84, R (2) = 0.005). Mazindol increased the extracellular concentration of dopamine in the human brain, and its effect was dose dependent. A single administration of mazindol, even at usual dosage, elevated dopamine concentration similarly to other addictive drugs, suggesting that the risk of dependence may increase with the mazindol dose.

  13. Distribution of dopamine transporter immunoreactive fibers in the human amygdaloid complex.

    Science.gov (United States)

    García-Amado, María; Prensa, Lucía

    2013-12-01

    The nuclei of the human amygdaloid complex can be distinguished from each other on the basis of their cytoarchitecture, chemistry and connections, all of which process the information needed for the different functions (ranging from attention to memory and emotion) of the amygdala. This complex receives dopaminergic input that exerts modulatory effects over its intrinsic network and is critical for reward-related learning and fear conditioning. To determine the specific distribution of the dopaminergic input through the different nuclei and nuclear subdivisions of this structure we used stereological tools to quantify the fibers containing the dopamine transporter (used to signal the dopaminergic phenotype) in post-mortem samples from control individuals. Dopaminergic axons targeted every nucleus of the amygdaloid complex, and the density of dopamine transporter-containing axons varied considerably among its nuclear groups. The central group showed the greatest density of dopamine transporter-positive fibers, more than double the density of the basolateral group, the second most densely innervated structure. The dopamine transporter-positive innervation is very scant in the corticomedial group. The density of dopamine transporter-positive fibers did not vary among the nuclei of the basolateral group - i.e. basal, lateral and accessory basal nuclei - although there were significant density gradients among the subdivisions of these nuclei. These detailed quantitative data on dopamine transporter-positive innervation in the human amygdaloid complex can offer a useful reference in future studies aimed at analysing putative dysfunctions of this system in diseases involving brain dopamine, such as certain anxiety disorders, Parkinson's disease and schizophrenia. © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  14. Characterization of alternate reductant binding and electron transfer in the dopamine β-monooxygenase reaction

    International Nuclear Information System (INIS)

    Stewart, L.C.; Klinman, J.P.

    1987-01-01

    The steady-state limiting kinetic parameters V/sub max/, V/K/sub DA/, and V/K/sub O 2 /, together with deuterium isotope effects on these parameters, have been determined for the dopamine β-monooxygenase (DβM) reaction in the presence of structurally distinct reductants. The results show the one-electron reductant ferrocyanide to be nearly as kinetically competent as the presumed in vivo reductant ascrobate. Further, a reductant system of ferricyanide plus substrate dopamine yields steady-state kinetic parameters and isotope effects very similar to those measured solely in the presence of ferrocyanide, indicating a role for catecholamine in the rapid recycling of oxidized ferrocyanide. Use of substrate dopamine as the sole reductant is found to lead to a highly unusual kinetic independence of oxygen concentration, as well as significantly reduced values of V/sub max/ and V/K/sub DA/, and the authors conclude that dopamine reduces enzymic copper in a rate-limiting step that is 40-fold slower than with ascorbate. The near-identical kinetic parameters measured in the presence of either ascorbate or ferrocyanide, together with markedly reduced rates with dopamine, are interpreted in terms of a binding site for reductant that is physically distinct from the substrate binding site. This view is supported by molecular modeling, which reveals ascorbate and ferrocyanide to possess an unexpected similarity in potential sites for interaction with enzymic residues. With regard to electron flux, identical values of V/K/sub O 2 / have been measured with [2,2- 2 H 2 ]dopamine as substrate both in the presence and in the absence of added ascorbate. This key result unambiguously rules out an entry of electrons to enzyme forms leading from the enzyme-dopamine complex to enzyme-bound product and, hence, reaction mechanisms involving a reductive activation of the putative Cu(II)-OOH prior to substrate hydroxylation

  15. Glutamate and dopamine in schizophrenia: an update for the 21st century

    Science.gov (United States)

    Howes, Oliver; McCutcheon, Rob; Stone, James

    2016-01-01

    The glutamate and dopamine hypotheses are leading theories of the pathoaetiology of schizophrenia. Both were initially based on indirect evidence from pharmacological studies supported by post-mortem findings, but have since been substantially advanced by new lines of evidence from in vivo imaging studies. This review provides an up- date on the latest findings on dopamine and glutamate abnormalities in schizophrenia, focusing on the in vivo neuroimaging studies in patients and clinical high risk groups, and considers their implications for understanding the biology and treatment of schizophrenia. These findings have refined both the dopamine and glutamate hypotheses, enabling greater anatomical and functional specificity, and have been complemented by preclinical evidence showing how the risk factors for schizophrenia impact on the dopamine and glutamate systems. The implications of this new evidence for understanding the development and treatment of schizophrenia are considered, and the gaps in current knowledge highlighted. Finally the evidence for an integrated model of the interactions between the glutamate and dopamine systems is reviewed, and future directions discussed. PMID:25586400

  16. Effects of asarinin on dopamine biosynthesis and 6-hydroxydopamine-induced cytotoxicity in PC12 cells.

    Science.gov (United States)

    Park, Hyun Jin; Lee, Kyung Sook; Zhao, Ting Ting; Lee, Kyung Eun; Lee, Myung Koo

    2017-05-01

    This study investigated the effects of asarinin on dopamine biosynthesis and 6-hydroxydopamine (6-OHDA)-induced cytotoxicity in rat adrenal pheochromocytoma (PC12) cells. Treatment with asarinin (25-50 μM) increased intracellular dopamine levels and enhanced L-DOPA-induced increases in dopamine levels. Asarinin (25 μM) induced cyclic AMP-dependent protein kinase A (PKA) signaling, leading to increased cyclic AMP-response element binding protein (CREB) and tyrosine hydroxylase (TH) phosphorylation, which in turn stimulated dopamine production. Asarinin (25 μM) also activated transient phosphorylation of extracellular signal-regulated kinase (ERK1/2) and Bad phosphorylation at Ser 112, both of which have been shown to promote cell survival. In contrast, asarinin (25 μM) inhibited sustained ERK1/2, Bax, c-Jun N-terminal kinase (JNK1/2) and p38 mitogen-activated protein kinase (p38MAPK) phosphorylation and caspase-3 activity, which were induced by 6-OHDA (100 μM). These results suggest that asarinin induces dopamine biosynthesis via activation of the PKA-CREB-TH system and protects against 6-OHDA-induced cytotoxicity by inhibiting the sustained activation of the ERK-p38MAPK-JNK1/2-caspase-3 system in PC12 cells.

  17. Dopamine genes are linked to Extraversion and Neuroticism personality traits, but only in demanding climates.

    Science.gov (United States)

    Fischer, Ronald; Lee, Anna; Verzijden, Machteld N

    2018-01-29

    Cross-national differences in personality have long been recognized in the behavioural sciences. However, the origins of such differences are debated. Building on reinforcement sensitivity theories and gene-by-environment interactions, we predict that personality trait phenotypes linked to dopaminergic brain functions (centrally involved in reward processing) diverge most strongly in climatically stressful environments, due to shifts in perceived rewards vs risks. Individuals from populations with a highly efficient dopamine system are biased towards behavioural approach traits (Extraversion and Emotional Stability) due to higher perceived reward values, whereas individuals from populations with a less efficient dopaminergic system are biased towards risk avoidance. In temperate climates, we predict smaller phenotypic differences due to overall weakened reward and risk ratios. We calculated a population-level index of dopamine functioning using 9 commonly investigated genetic polymorphisms encoding dopamine transporters and receptors, derived from a meta-analysis with data from 805 independent samples involving 127,685 participants across 73 societies or territories. We found strong support for the dopamine gene by climatic stress interaction: Population genetic differences in dopamine predicted personality traits at the population level in demanding climates, but not in temperate, less demanding climates, even when controlling for known correlates of personality including wealth and parasite stress.

  18. Dopamine-induced apoptosis in human neuronal cells: inhibition by nucleic acides antisense to the dopamine transporter

    International Nuclear Information System (INIS)

    Porat, S.; Gabbay, M.; Tauber, M.; Ratovitski, T.; Blinder, E.; Simantov, R.

    1996-01-01

    Human neuroblastoma NMB cells take up [ 3 H]dopamine in a selective manner indicating that dopamine transporters are responsible for this uptake. These cells were therefore used as a model to study dopamine neurotoxicity, and to elucidate the role of dopamine transporters in controlling cell death. Treatment with 0.05-0.4 mM dopamine changed cells' morphology within 4 h, accompanied by retraction of processes, shrinkage, apoptosis-like atrophy, accumulation of apoptotic particles, DNA fragmentation and cell death. Cycloheximide inhibited dopamine's effect, suggesting that induction of apoptosis by dopamine was dependent upon protein synthesis. Dopamine cytotoxicity, monitored morphologically by flow cytometric analysis, and by lactate dehydrogenase released, was blocked by cocaine but not by the noradrenaline and serotonin uptake blockers desimipramine and imipramine, respectively. Attempting to inhibit dopamine transport and toxicity in a drug-free and highly selective way, three 18-mer dopamine transporter antisense phosphorothioate oligonucleotides (numbers 1, 2 and 3) and a new plasmid vector expressing the entire rat dopamine transporter complementary DNA in the antisense orientation were prepared and tested. Antisense phosphorothioate oligonucleotide 3 inhibited [ 3 H]dopamine uptake in a time- and dose-dependent manner. Likewise, transient transfection of NMB cells with the plasmid expressing dopamine transporter complementary DNA in the antisense orientation partially blocked [ 3 H]dopamine uptake. Antisense phosphorothioate oligonucleotide 3 also decreased, dose-dependently, the toxic effect of dopamine and 6-hydroxydopamine. Western blot analysis with newly prepared anti-human dopamine transporter antibodies showed that antisense phosphorothioate oligonucleotide 3 decreased the transporter protein level. These studies contribute to better understand the mechanism of dopamine-induced apoptosis and neurotoxicity. (Copyright (c) 1996 Elsevier Science B

  19. Neurotoxic profiles of HIV, psychostimulant drugs of abuse, and their concerted effect on the brain: current status of dopamine system vulnerability in NeuroAIDS.

    Science.gov (United States)

    Ferris, Mark J; Mactutus, Charles F; Booze, Rosemarie M

    2008-07-01

    There are roughly 30-40 million HIV-infected individuals in the world as of December 2007, and drug abuse directly contributes to one-third of all HIV infections in the United States. Antiretroviral therapy has increased the lifespan of HIV-seropositives, but CNS function often remains diminished, effectively decreasing quality of life. A modest proportion may develop HIV-associated dementia, the severity and progression of which is increased with drug abuse. HIV and drugs of abuse in the CNS target subcortical brain structures and DA systems in particular. This toxicity is mediated by a number of neurotoxic mechanisms, including but not limited to, aberrant immune response and oxidative stress. Therefore, novel therapeutic strategies must be developed that can address a wide variety of disparate neurotoxic mechanisms and apoptotic cascades. This paper reviews the research pertaining to the where, what, and how of HIV and cocaine/methamphetamine toxicity in the CNS. Specifically, where these toxins most affect the brain, what aspects of the virus are neurotoxic, and how these toxins mediate neurotoxicity.

  20. Greater ethanol-induced locomotor activation in DBA/2J versus C57BL/6J mice is not predicted by presynaptic striatal dopamine dynamics.

    Directory of Open Access Journals (Sweden)

    Jamie H Rose

    Full Text Available A large body of research has aimed to determine the neurochemical factors driving differential sensitivity to ethanol between individuals in an attempt to find predictors of ethanol abuse vulnerability. Here we find that the locomotor activating effects of ethanol are markedly greater in DBA/2J compared to C57BL/6J mice, although it is unclear as to what neurochemical differences between strains mediate this behavior. Dopamine elevations in the nucleus accumbens and caudate-putamen regulate locomotor behavior for most drugs, including ethanol; thus, we aimed to determine if differences in these regions predict strain differences in ethanol-induced locomotor activity. Previous studies suggest that ethanol interacts with the dopamine transporter, potentially mediating its locomotor activating effects; however, we found that ethanol had no effects on dopamine uptake in either strain. Ex vivo voltammetry allows for the determination of ethanol effects on presynaptic dopamine terminals, independent of drug-induced changes in firing rates of afferent inputs from either dopamine neurons or other neurotransmitter systems. However, differences in striatal dopamine dynamics did not predict the locomotor-activating effects of ethanol, since the inhibitory effects of ethanol on dopamine release were similar between strains. There were differences in presynaptic dopamine function between strains, with faster dopamine clearance in the caudate-putamen of DBA/2J mice; however, it is unclear how this difference relates to locomotor behavior. Because of the role of the dopamine system in reinforcement and reward learning, differences in dopamine signaling between the strains could have implications for addiction-related behaviors that extend beyond ethanol effects in the striatum.

  1. Reduced striatal dopamine D2/3 receptor availability in Body Dysmorphic Disorder

    NARCIS (Netherlands)

    Vulink, Nienke C; Planting, Robin S; Figee, Martijn; Booij, Jan; Denys, D.

    Though the dopaminergic system is implicated in Obsessive Compulsive and Related Disorders (OCRD), the dopaminergic system has never been investigated in-vivo in Body Dysmorphic Disorder (BDD). In line with consistent findings of reduced striatal dopamine D2/3 receptor availability in Obsessive

  2. Reduced striatal dopamine D2/3 receptor availability in Body Dysmorphic Disorder

    NARCIS (Netherlands)

    Vulink, Nienke C.; Planting, Robin S.; Figee, Martijn; Booij, Jan; Denys, Damiaan

    2016-01-01

    Though the dopaminergic system is implicated in Obsessive Compulsive and Related Disorders (OCRD), the dopaminergic system has never been investigated in-vivo in Body Dysmorphic Disorder (BDD). In line with consistent findings of reduced striatal dopamine D2/3 receptor availability in Obsessive

  3. Sleep patterns in congenital dopamine beta-hydroxylase deficiency

    OpenAIRE

    Tulen, Joke; Man in't Veld, A.; Mechelse, Karel; Boomsma, Frans

    1990-01-01

    textabstractSleep patterns of two young female patients with congenital dopamine beta-hydroxylase deficiency are described. In this orthostatic syndrome central and peripheral noradrenergic failure occurs as a result of impaired beta-hydroxylation of dopamine. Consequently, the levels of dopamine and its metabolites are elevated. The relative importance of noradrenaline deficit in the face of dopamine excess for sleep-regulatory mechanisms can be inferred from the sleep pattern of these patie...

  4. Cerebral vascular effects of hypovolemia and dopamine infusions

    DEFF Research Database (Denmark)

    Holst Hahn, Gitte; Heiring, Christian; Pryds, Ole

    2012-01-01

    Despite widespread use, effects of volume boluses and dopamine in hypotensive newborn infants remain controversial. We aimed to elucidate if hypovolemia alone impairs cerebral autoregulation (CA) and if dopamine affects cerebral vasculature.......Despite widespread use, effects of volume boluses and dopamine in hypotensive newborn infants remain controversial. We aimed to elucidate if hypovolemia alone impairs cerebral autoregulation (CA) and if dopamine affects cerebral vasculature....

  5. Behavioral responses of dopamine β-hydroxylase knockout mice to modafinil suggest a dual noradrenergic-dopaminergic mechanism of action

    OpenAIRE

    Mitchell, Heather A.; Bogenpohl, James W.; Liles, L. Cameron; Epstein, Michael P.; Bozyczko-Coyne, Donna; Williams, Michael; Weinshenker, David

    2008-01-01

    Modafinil is approved for use in the treatment of excessive daytime sleepiness. The precise mechanism of modafinil action has not been elucidated, although both dopamine (DA) and norepinephrine (NE) systems have been implicated. To explore the roles of DA and NE in the mechanism of modafinil-induced arousal, dopamine β-hydroxylase knockout (Dbh −/−) mice were examined in behavioral paradigms of arousal (photobeam breaks and behavioral scoring of sleep latency). Dbh −/− mice completely lack NE...

  6. Progressive supranuclear palsy dopamine D2 receptor tomoscintigraphy to detect L-dopamine efficiency

    International Nuclear Information System (INIS)

    Tranquart, F.; Henry Le Bras, F.; Toffol, B. de; Autret, A.; Guilloteau, D.; Baulieu, J.L.

    1994-01-01

    Progressive supranuclear palsy (PSP) may sometimes be misdiagnosed as Parkinson's disease in its early stages, hence an early positive diagnosis of PSP based on dopamine D2 receptor density could be extremely valuable. In the present case report, the absence of dopamine D2 receptors was clearly demonstrated in the striatum using 123 I-iodobenzamide (IBZM) tomoscintigraphy. This illustrates the potential use of IBZM tomoscintigraphy to identify Parkinson-like's disease presenting with decreased dopamine D2 receptor density; and hence to predict L-Dopa effectiveness. Further studies are needed to evaluate the value of IBZM tomoscintigraphy in the different Parkinson's like diseases. (authors). 11 refs., 2 figs

  7. Sleep patterns in congenital dopamine beta-hydroxylase deficiency

    NARCIS (Netherlands)

    J.H.M. Tulen (Joke); A.J. Man in't Veld (A.); K. Mechelse (Karel); F. Boomsma (Frans)

    1990-01-01

    textabstractSleep patterns of two young female patients with congenital dopamine beta-hydroxylase deficiency are described. In this orthostatic syndrome central and peripheral noradrenergic failure occurs as a result of impaired beta-hydroxylation of dopamine. Consequently, the levels of dopamine

  8. ORAL IBOPAMINE SUBSTITUTION IN PATIENTS WITH INTRAVENOUS DOPAMINE DEPENDENCE

    NARCIS (Netherlands)

    GIRBES, ARJ; MILNER, AR; MCCLOSKEY, BV; ZWAVELING, JH; VANVELDHUISEN, DJ; ZIJLSTRA, JG; LIE, KI

    1995-01-01

    In a prospective open study we evaluated whether intravenous dopamine infusions can be safely switched to enterally administered ibopamine in dopamine-dependent patients. Six patients defined as being clinically stable, normovolaemic, but dopamine dependent, i.e. with repeated inability to stop

  9. High fructose corn syrup induces metabolic dysregulation and altered dopamine signaling in the absence of obesity

    Science.gov (United States)

    2017-01-01

    The contribution of high fructose corn syrup (HFCS) to metabolic disorder and obesity, independent of high fat, energy-rich diets, is controversial. While high-fat diets are widely accepted as a rodent model of diet-induced obesity (DIO) and metabolic disorder, the value of HFCS alone as a rodent model of DIO is unclear. Impaired dopamine function is associated with obesity and high fat diet, but the effect of HFCS on the dopamine system has not been investigated. The objective of this study was to test the effect of HFCS on weight gain, glucose regulation, and evoked dopamine release using fast-scan cyclic voltammetry. Mice (C57BL/6) received either water or 10% HFCS solution in combination with ad libitum chow for 15 weeks. HFCS consumption with chow diet did not induce weight gain compared to water, chow-only controls but did induce glucose dysregulation and reduced evoked dopamine release in the dorsolateral striatum. These data show that HFCS can contribute to metabolic disorder and altered dopamine function independent of weight gain and high-fat diets. PMID:29287121

  10. Modulatory Effects of Dopamine D2 Receptors on Spreading Depression in Rat Somatosensory Neocortex

    Directory of Open Access Journals (Sweden)

    Anna Maria Haarmann

    2014-11-01

    Full Text Available Introduction: Spreading depression (SD is a propagating wave of depolarization followed by depression of the neuroglial activities and can modulate extracellular dopamine concentrations in the neocortex. It has been shown that the dopaminergic system plays a role in migraine. SD has been suggested as a critical phenomenon in the pathophysiology of migraine. The aim of this study was to investigate the effect of dopamine D2 receptors on the characteristic features of SD in rat neocortical tissues. Methods: The effect of dopamine D2 receptor agonist quinpirole and D2 receptor antagonist sulpiride was tested on different characteristic features (amplitude, duration and velocity of KCl-induced SD in somatosensory neocortical slices of adult rats. The effect of above-mentioned substances on production of long-term potentiation (LTP in the neocortex was also evaluated. Results: The present data revealed a dose-dependent suppression of the amplitude and duration of SD in the presence of the dopamine D2 receptor antagonist sulpiride in the neocortex. D2 dopamine receptor agonist quinpirole dose-dependently enhanced the amplitude and duration of the neocortical SD. Furthermore, application of D2 receptor antagonist significantly suppressed induction of LTP. Discussion: These results indicate that D2 receptors modulate the initiation of SD in the neocortex. This finding refers to the potential role of D2 receptor antagonist in treatment of migraine pain.

  11. Intracellular Methamphetamine Prevents the Dopamine-induced Enhancement of Neuronal Firing*

    Science.gov (United States)

    Saha, Kaustuv; Sambo, Danielle; Richardson, Ben D.; Lin, Landon M.; Butler, Brittany; Villarroel, Laura; Khoshbouei, Habibeh

    2014-01-01

    The dysregulation of the dopaminergic system is implicated in multiple neurological and neuropsychiatric disorders such as Parkinson disease and drug addiction. The primary target of psychostimulants such as amphetamine and methamphetamine is the dopamine transporter (DAT), the major regulator of extracellular dopamine levels in the brain. However, the behavioral and neurophysiological correlates of methamphetamine and amphetamine administration are unique from one another, thereby suggesting these two compounds impact dopaminergic neurotransmission differentially. We further examined the unique mechanisms by which amphetamine and methamphetamine regulate DAT function and dopamine neurotransmission; in the present study we examined the impact of extracellular and intracellular amphetamine and methamphetamine on the spontaneous firing of cultured midbrain dopaminergic neurons and isolated DAT-mediated current. In dopaminergic neurons the spontaneous firing rate was enhanced by extracellular application of amphetamine > dopamine > methamphetamine and was DAT-dependent. Amphetamine > methamphetamine similarly enhanced DAT-mediated inward current, which was sensitive to isosmotic substitution of Na+ or Cl− ion. Although isosmotic substitution of extracellular Na+ ions blocked amphetamine and methamphetamine-induced DAT-mediated inward current similarly, the removal of extracellular Cl− ions preferentially blocked amphetamine-induced inward current. The intracellular application of methamphetamine, but not amphetamine, prevented the dopamine-induced increase in the spontaneous firing of dopaminergic neurons and the corresponding DAT-mediated inward current. The results reveal a new mechanism for methamphetamine-induced dysregulation of dopaminergic neurons. PMID:24962577

  12. Cortico-striatal oxidative status, dopamine turnover and relation with stereotypy in the deer mouse.

    Science.gov (United States)

    Güldenpfennig, Marianne; Wolmarans, De Wet; du Preez, Jan L; Stein, Dan J; Harvey, Brian H

    2011-06-01

    The deer mouse presents with spontaneous stereotypic movements that resemble the repetitive behaviours of obsessive-compulsive disorder (OCD), and demonstrates a selective response to serotonin reuptake inhibitors. OCD has been linked to altered redox status and since increased dopamine signalling can promote stereotypies as well as oxidative stress, we investigated whether the severity of deer mouse stereotypy may be associated with altered dopamine turnover and cortico-striatal redox status. Deer mice were separated into high (HSB), low (LSB) and non-stereotypy (NS) groups. Frontal cortical and striatal dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), as well as superoxide dismutase (SOD) activity, reduced (GSH) and oxidised (GSSG) glutathione and glutathione redox index, were analysed as markers for regional dopamine turnover and oxidative stress, respectively. Dopamine and its metabolites and SOD activity did not differ across the stereotypy groups. Significantly reduced GSH and GSSG and increased glutathione redox index were only observed in the frontal cortex of HSB animals. Frontal cortical GSH and GSSG were inversely correlated while glutathione redox index was positively correlated with stereotypy. Deer mouse stereotypy is thus characterised by a deficient glutathione system in the frontal cortex but not striatum, and provides a therapeutic rationale for using glutathione-active antioxidants in OCD. The evidence for a primary frontal lesion has importance for future OCD research. Copyright © 2011 Elsevier Inc. All rights reserved.

  13. At-risk for pathological gambling: imaging neural reward processing under chronic dopamine agonists.

    Science.gov (United States)

    Abler, Birgit; Hahlbrock, Roman; Unrath, Alexander; Grön, Georg; Kassubek, Jan

    2009-09-01

    Treatment with dopamine receptor agonists has been associated with impulse control disorders and pathological gambling (PG) secondary to medication in previously unaffected patients with Parkinson's disease or restless legs syndrome (RLS). In a within-subjects design, we investigated the underlying neurobiology in RLS patients using functional magnetic resonance imaging. We scanned 12 female RLS patients without a history of PG. All patients were scanned twice: once whilst taking their regular medication with low dose dopamine receptor agonists and once after a washout phase interval. They performed an established gambling game task involving expectation and receipt or omission of monetary rewards at different levels of probabilities. Upon expectation of rewards, reliable ventral striatal activation was detected only when patients were on, but not when patients were off medication. Upon receipt or omission of rewards, the observed ventral striatal signal under medication differed markedly from its predicted pattern which by contrast was apparent when patients were off medication. Orbitofrontal activation was not affected by medication. Chronic dopamine receptor agonist medication changed the neural signalling of reward expectation predisposing the dopaminergic reward system to mediate an increased appetitive drive. Even without manifest PG, chronic medication with dopamine receptor agonists led to markedly changed neural processing of negative consequences probably mediating dysfunctional learning of contingencies. Intact orbitofrontal functioning, potentially moderating impulse control, may explain why none of the patients actually developed PG. Our results support the notion of a general medication effect in patients under dopamine receptor agonists in terms of a sensitization towards impulse control disorders.

  14. Drug induced increases in CNS dopamine alter monocyte, macrophage and T cell functions: implications for HAND

    Science.gov (United States)

    Gaskill, Peter J.; Calderon, Tina M.; Coley, Jacqueline S.; Berman, Joan W.

    2013-01-01

    Central nervous system (CNS) complications resulting from HIV infection remain a major public health problem as individuals live longer due to the success of combined antiretroviral therapy (cART). As many as 70% of HIV infected people have HIV associated neurocognitive disorders (HAND). Many HIV infected individuals abuse drugs, such as cocaine, heroin or methamphetamine, that may be important cofactors in the development of HIV CNS disease. Despite different mechanisms of action, all drugs of abuse increase extracellular dopamine in the CNS. The effects of dopamine on HIV neuropathogenesis are not well understood, and drug induced increases in CNS dopamine may be a common mechanism by which different types of drugs of abuse impact the development of HAND. Monocytes and macrophages are central to HIV infection of the CNS and to HAND. While T cells have not been shown to be a major factor in HIV-associated neuropathogenesis, studies indicate that T cells may play a larger role in the development of HAND in HIV infected drug abusers. Drug induced increases in CNS dopamine may dysregulate functions of, or increase HIV infection in, monocytes, macrophages and T cells in the brain. Thus, characterizing the effects of dopamine on these cells is important for understanding the mechanisms that mediate the development of HAND in drug abusers. PMID:23456305

  15. Declines in stimulated striatal dopamine release over the first 32 h following microdialysis probe insertion: generalization across releasing mechanisms.

    Science.gov (United States)

    Holson, R R; Gazzara, R A; Gough, B

    1998-10-19

    conclude that there is a general decline over time post-probe implantation in the ability of the striatal dopamine system to release dopamine, and perhaps to increase dopamine synthesis, in response to pharmacological challenges. Copyright 1998 Elsevier Science B.V.

  16. Contribution of vesicular and cytosolic dopamine to the increased striatal dopamine efflux elicited by intrastriatal injection of SKF38393.

    NARCIS (Netherlands)

    Saigusa, T.; Aono, Y.; Sekino, R.; Uchida, T.; Takada, K.; Oi, Y.; Koshikawa, N.; Cools, A.R.

    2009-01-01

    Like dexamphetamine, SKF38393 induces an increase in striatal dopamine efflux which is insensitive for tetrodotoxin, Ca(2+) independent and prevented by a dopamine transporter inhibitor. The dexamphetamine-induced striatal dopamine efflux originates from both the reserpine-sensitive vesicular

  17. TRPV1 on astrocytes rescues nigral dopamine neurons in Parkinson’s disease via CNTF

    Science.gov (United States)

    Nam, Jin H.; Park, Eun S.; Won, So-Yoon; Lee, Yu A.; Kim, Kyoung I.; Jeong, Jae Y.; Baek, Jeong Y.; Cho, Eun J.; Jin, Minyoung; Chung, Young C.; Lee, Byoung D.; Kim, Sung Hyun; Kim, Eung-Gook; Byun, Kyunghee; Lee, Bonghee; Woo, Dong Ho; Lee, C. Justin; Kim, Sang R.; Bok, Eugene; Kim, Yoon-Seong; Ahn, Tae-Beom; Ko, Hyuk Wan; Brahmachari, Saurav; Pletinkova, Olga; Troconso, Juan C.; Dawson, Valina L.; Dawson, Ted M.

    2015-01-01

    Currently there is no neuroprotective or neurorestorative therapy for Parkinson’s disease. Here we report that transient receptor potential vanilloid 1 (TRPV1) on astrocytes mediates endogenous production of ciliary neurotrophic factor (CNTF), which prevents the active degeneration of dopamine neurons and leads to behavioural recovery through CNTF receptor alpha (CNTFRα) on nigral dopamine neurons in both the MPP+-lesioned or adeno-associated virus α-synuclein rat models of Parkinson’s disease. Western blot and immunohistochemical analysis of human post-mortem substantia nigra from Parkinson’s disease suggests that this endogenous neuroprotective system (TRPV1 and CNTF on astrocytes, and CNTFRα on dopamine neurons) might have relevance to human Parkinson’s disease. Our results suggest that activation of astrocytic TRPV1 activates endogenous neuroprotective machinery in vivo and that it is a novel therapeutic target for the treatment of Parkinson’s disease. PMID:26490328

  18. Hypocretin/orexin regulation of dopamine signaling: implications for reward and reinforcement mechanisms

    Directory of Open Access Journals (Sweden)

    Rodrigo eEspaña

    2012-08-01

    Full Text Available The hypocretins/orexins are comprised of two neuroexcitatory peptides that are synthesized exclusively within a circumscribed region of the lateral hypothalamus. These peptides project widely throughout the brain and interact with a variety of regions involved in the regulation of arousal-related processes including those associated with motivated behavior. The current review focuses on emerging evidence indicating that the hypocretins influence reward and reinforcement processing via actions on the mesolimbic dopamine system. We discuss contemporary perspectives of hypocretin regulation of mesolimbic dopamine signaling in both drug free and drug states, as well as hypocretin regulation of behavioral responses to drugs of abuse, particularly as it relates to cocaine.

  19. Hypocretin/orexin regulation of dopamine signaling: implications for reward and reinforcement mechanisms

    Science.gov (United States)

    Calipari, Erin S.; España, Rodrigo A.

    2012-01-01

    The hypocretins/orexins are comprised of two neuroexcitatory peptides that are synthesized exclusively within a circumscribed region of the lateral hypothalamus. These peptides project widely throughout the brain and interact with a variety of regions involved in the regulation of arousal-related processes including those associated with motivated behavior. The current review focuses on emerging evidence indicating that the hypocretins influence reward and reinforcement processing via actions on the mesolimbic dopamine system. We discuss contemporary perspectives of hypocretin regulation of mesolimbic dopamine signaling in both drug free and drug states, as well as hypocretin regulation of behavioral responses to drugs of abuse, particularly as it relates to cocaine. PMID:22933994

  20. Dopamine-based reward circuitry responsivity, genetics, and overeating.

    Science.gov (United States)

    Stice, Eric; Yokum, Sonja; Zald, David; Dagher, Alain

    2011-01-01

    Data suggest that low levels of dopamine D2 receptors and attenuated responsivity of dopamine-target regions to food intake is associated with increased eating and elevated weight. There is also growing (although mixed) evidence that genotypes that appear to lead to reduced dopamine signaling (e.g., DRD2, DRD4, and DAT) and certain appetite-related hormones and peptides (e.g., ghrelin, orexin A, leptin) moderate the relation between dopamine signaling, overeating, and obesity. This chapter reviews findings from studies that have investigated the relation between dopamine functioning and food intake and how certain genotypes and appetite-related hormones and peptides affect this relation.

  1. The binding sites for benztropines and dopamine in the dopamine transporter overlap

    DEFF Research Database (Denmark)

    Jensen, Heidi Bisgaard; Larsen, M Andreas B; Mazier, Sonia

    2011-01-01

    Analogs of benztropines (BZTs) are potent inhibitors of the dopamine transporter (DAT) but are less effective than cocaine as behavioral stimulants. As a result, there have been efforts to evaluate these compounds as leads for potential medication for cocaine addiction. Here we use computational...... with a larger decrease in the affinity for BZT than for JHW007. Summarized, our data suggest that BZTs display a classical competitive binding mode with binding sites overlapping those of cocaine and dopamine....

  2. Stress in adolescence and drugs of abuse in rodent models: Role of dopamine, CRF, and HPA axis

    Science.gov (United States)

    Burke, Andrew R.; Miczek, Klaus A.

    2014-01-01

    Rationale Research on adolescence and drug abuse increased substantially in the past decade. However, drug-addiction related behaviors following stressful experiences during adolescence are less studied. We focus on rodent models of adolescent stress cross-sensitization to drugs of abuse. Objectives Review the ontogeny of behavior, dopamine, corticotropin-releasing factor (CRF), and the hypothalamic pituitary adrenal (HPA) axis in adolescent rodents. We evaluate evidence that stressful experiences during adolescence engender hypersensitivity to drugs of abuse and offer potential neural mechanisms. Results and Conclusions Much evidence suggests that final maturation of behavior, dopamine systems, and HPA axis occurs during adolescence. Stress during adolescence increases amphetamine- and ethanol-stimulated locomotion, preference, and self-administration under many conditions. The influence of adolescent stress on subsequent cocaine- and nicotine-stimulated locomotion and preference is less clear. The type of adolescent stress, temporal interval between stress and testing, species, sex, and the drug tested are key methodological determinants for successful cross-sensitization procedures. The sensitization of the mesolimbic dopamine system is proposed to underlie stress cross-sensitization to drugs of abuse in both adolescents and adults through modulation by CRF. Reduced levels of mesocortical dopamine appear to be a unique consequence of social stress during adolescence. Adolescent stress may reduce the final maturation of cortical dopamine through D2 dopamine receptor regulation of dopamine synthesis or glucocorticoid-facilitated pruning of cortical dopamine fibers. Certain rodent models of adolescent adversity are useful for determining neural mechanisms underlying the cross-sensitization to drugs of abuse. PMID:24370534

  3. Vagally mediated effects of brain stem dopamine on gastric tone and phasic contractions of the rat.

    Science.gov (United States)

    Anselmi, L; Toti, L; Bove, C; Travagli, R A

    2017-11-01

    Dopamine (DA)-containing fibers and neurons are embedded within the brain stem dorsal vagal complex (DVC); we have shown previously that DA modulates the membrane properties of neurons of the dorsal motor nucleus of the vagus (DMV) via DA1 and DA2 receptors. The vagally dependent modulation of gastric tone and phasic contractions, i.e., motility, by DA, however, has not been characterized. With the use of microinjections of DA in the DVC while recording gastric tone and motility, the aims of the present study were 1 ) assess the gastric effects of brain stem DA application, 2 ) identify the DA receptor subtype, and, 3 ) identify the postganglionic pathway(s) activated. Dopamine microinjection in the DVC decreased gastric tone and motility in both corpus and antrum in 29 of 34 rats, and the effects were abolished by ipsilateral vagotomy and fourth ventricular treatment with the selective DA2 receptor antagonist L741,626 but not by application of the selective DA1 receptor antagonist SCH 23390. Systemic administration of the cholinergic antagonist atropine attenuated the inhibition of corpus and antrum tone in response to DA microinjection in the DVC. Conversely, systemic administration of the nitric oxide synthase inhibitor nitro-l-arginine methyl ester did not alter the DA-induced decrease in gastric tone and motility. Our data provide evidence of a dopaminergic modulation of a brain stem vagal neurocircuit that controls gastric tone and motility. NEW & NOTEWORTHY Dopamine administration in the brain stem decreases gastric tone and phasic contractions. The gastric effects of dopamine are mediated via dopamine 2 receptors on neurons of the dorsal motor nucleus of the vagus. The inhibitory effects of dopamine are mediated via inhibition of the postganglionic cholinergic pathway. Copyright © 2017 the American Physiological Society.

  4. Dopamine 3 or 4 phosphate: pharmacologic properties

    International Nuclear Information System (INIS)

    Byington, K.H.

    1986-01-01

    The 3 or 4 phosphate ester of dopamine (PD) is being used to test the hypothesis that PD, as well as phosphate esters of other catecholamines, occur and function physiologically. In 1.00 mM PD-20 mM NaHEPES, pH 7.15 - 5.00 mM MgCl 2 (PDase conditions) the order of the rates at which homogenates of rat tissues catalyzed the hydrolysis of PD to give Pi at 37 0 were: kidney > brain > liver > heart > blood. Recoveries of dopamine and PD showed that dopamine and Pi are the main products generated when PD was incubated with 1% homogenates of brain, heart, kidney and liver. Purine nucleotides inhibited the hydrolysis of 32 PD to give 32 Pi with the following order of activity: ATP 32 PD could be recovered as dopamine and 32 PD after incubation with kidney homogenate under PDase conditions with 5 mM ATP. Incubation of 1% tissue homogenates with 32 PD under PDase conditions resulted in accumulation of acid precipitable label as follows: kidney 19, heart 11, liver 10, brain 6 nmole label/g tissue. The results suggest that specific enzymes exist to metabolize PD and support the hypothesis that PD and related phosphate esters are physiologic. In addition, the results indicate that PD may be useful as a prodrug for catecholamines

  5. Dopamine in heart failure and critical care

    NARCIS (Netherlands)

    Smit, AJ

    Dopamine is widely used in critical care to prevent renal function loss. Nevertheless sufficient evidence is still lacking of reduction in end points like mortality or renal replacement therapy. Dopaminergic treatment in chronic heart failure (CHF) has provided an example of unexpected adverse

  6. Oscillating from Neurosecretion to Multitasking Dopamine Neurons

    Directory of Open Access Journals (Sweden)

    David R. Grattan

    2016-04-01

    Full Text Available In this issue of Cell Reports, Stagkourakis et al. (2016 report that oscillating hypothalamic TIDA neurons, previously thought to be simple neurosecretory neurons controlling pituitary prolactin secretion, control dopamine output via autoregulatory mechanisms and thus could potentially regulate other physiologically important hypothalamic neuronal circuits.

  7. Impulse control disorders and dopamine dysregulation syndrome associated with dopamine agonist therapy in Parkinson's disease.

    Science.gov (United States)

    Fenu, Sandro; Wardas, Jadwiga; Morelli, Micaela

    2009-09-01

    Over the last decade, evidence has emerged linking disorders in the impulsive-compulsive spectrum in Parkinson's disease to dopamine receptor agonist treatment. These disorders include hypersexuality, gambling and, to a minor extent, compulsive shopping and eating, as well as dopamine dysregulation syndrome, characterized by an addictive pattern toward dopamine replacement therapy and stereotyped behaviors, such as punding. These syndromes, which have only recently been recognized and are still underdiagnosed, have deleterious social consequences that warrant interventions at the clinical level and promotion of research at the preclinical level. In this review, we first provide a summary of features of Parkinson's disease and current pharmacological therapies associated with the development of dopamine dysregulation syndrome and impulsive-compulsive disorders. We also examine the dopamine receptors and brain areas important in reward and compulsive behaviors. We then critically examine the neuroadaptations in dopaminergic circuitries and the literature concerning gambling, hypersexuality, and other addictive behaviors in parkinsonian patients. Finally, we focus on suggestions pointing to a role for dopamine D(3) receptors and sensitization phenomena as the main factors which may be the origin of these disorders.

  8. Regulation of Dopamine Uptake by Vasoactive Peptides in the Kidney

    Directory of Open Access Journals (Sweden)

    N. L. Rukavina Mikusic

    2016-01-01

    Full Text Available Considering the key role of renal dopamine in tubular sodium handling, we hypothesized that c-type natriuretic peptide (CNP and Ang-(1-7 may regulate renal dopamine availability in tubular cells, contributing to Na+, K+-ATPase inhibition. Present results show that CNP did not affect either 3H-dopamine uptake in renal tissue or Na+, K+-ATPase activity; meanwhile, Ang-(1-7 was able to increase 3H-dopamine uptake and decreased Na+, K+-ATPase activity in renal cortex. Ang-(1-7 and dopamine together decreased further Na+, K+-ATPase activity showing an additive effect on the sodium pump. In addition, hydrocortisone reversed Ang-(1-7-dopamine overinhibition on the enzyme, suggesting that this inhibition is closely related to Ang-(1-7 stimulation on renal dopamine uptake. Both anantin and cANP (4-23-amide did not modify CNP effects on 3H-dopamine uptake by tubular cells. The Mas receptor antagonist, A-779, blocked the increase elicited by Ang-(1-7 on 3H-dopamine uptake. The stimulatory uptake induced by Ang-(1-7 was even more pronounced in the presence of losartan, suggesting an inhibitory effect of Ang-(1-7 on AT1 receptors on 3H-dopamine uptake. By increasing dopamine bioavailability in tubular cells, Ang-(1-7 enhances Na+, K+-ATPase activity inhibition, contributing to its natriuretic and diuretic effects.

  9. Single photon emission tomography (SPET) imaging of dopamine D2 receptors in the course of dopamine replacement therapy in patients with nocturnal myoclonus syndrome (NMS)

    International Nuclear Information System (INIS)

    Staedt, J.; Stoppe, G.; Riemann, H.; Hajak, G.; Ruether, E.; Koegler, A.; Emrich, D.

    1995-01-01

    Single photon emission tomography (SPET) permits the in vivo measurements of regional cerebral radioactivity in the human brain following the administration of compounds labeled with photon-emitting isotopes. According to our SPET findings of a reduced binding of [ 123 I]labeled (S)-2-hydroxy-3-iodo-6-methoxy-([1-ethyl-2-pyrrolidinyl]methyl) benzamide (IBZM) (a highly selective CNS D 2 dopamine receptor ligand) to D 2 dopamine receptors in striatal structures in untreated patients with nocturnal myoclonus syndrome (NMS) it seemed to be of interest to investigate whether there are changes in D 2 receptor binding under dopamine replacement therapy or not. We studied the uptake and distribution of [ 123 I]IBZM before and in the course of dopamine replacement therapy in four patients with severe insomnia caused by nocturnal myoclonus syndrome (NMS). We found an increase of the IBZM binding to D 2 receptors in the course of treatment, which was associated with an improvement of sleep quality. Reasons for this are discussed. The [ 123 I]IBZM SPET technique in conclusion offers an interesting tool for in vivo investigations of functional changes in the dopaminergic neurotransmitter system in longitudinal studies. (author)

  10. Increased expression of the dopamine transporter leads to loss of dopamine neurons, oxidative stress and L-DOPA reversible motor deficits

    OpenAIRE

    Masoud, ST; Vecchio, LM; Bergeron, Y; Hossain, MM; Nguyen, LT; Bermejo, MK; Kile, B; Sotnikova, TD; Siesser, WB; Gainetdinov, RR; Wightman, RM; Caron, MG; Richardson, JR; Miller, GW; Ramsey, AJ

    2014-01-01

    The dopamine transporter is a key protein responsible for regulating dopamine homeostasis. Its function is to transport dopamine from the extracellular space into the presynaptic neuron. Studies have suggested that accumulation of dopamine in the cytosol can trigger oxidative stress and neurotoxicity. Previously, ectopic expression of the dopamine transporter was shown to cause damage in non-dopaminergic neurons due to their inability to handle cytosolic dopamine. However, it is unknown wheth...

  11. Imaging of dopamine transporters in rats using high-resolution pinhole single-photon emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Booij, Jan; Bruin, Kora de; Habraken, Jan B.A. [Department of Nuclear Medicine, F2N, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam (Netherlands); Voorn, Pieter [Department of Anatomy, Vrije Universiteit Medical Center, Amsterdam (Netherlands)

    2002-09-01

    To date, the vast majority of investigations on the dopaminergic system in small animals have been in vitro studies. In comparison with in vitro studies, single-photon emission tomography (SPET) or positron emission tomography (PET) imaging of the dopaminergic system in small animals has the advantage of permitting repeated studies within the same group of animals. Dopamine transporter imaging is a valuable non-invasive tool with which to investigate the integrity of dopaminergic neurons. The purpose of this study was to investigate the feasibility of assessing dopamine transporter density semi-quantitatively in rats using a recently developed high-resolution pinhole SPET system. This system was built exclusively for imaging of small animals. In this unique single-pinhole system, the animal rotates instead of the collimated detector. The system has proven to have a high spatial resolution. We performed SPET imaging with [{sup 123}I]FP-CIT to quantify striatal dopamine transporters in rat brain. In all seven studied control rats, symmetrical striatal binding to dopamine transporters was seen 2 h after injection of the radiotracer, with striatal-to-cerebellar binding ratios of approximately 3.5. In addition, test/retest variability of the striatal-to-cerebellar binding ratios was studied and found to be 14.5%. Finally, in unilaterally 6-hydroxydopamine-lesioned rats, striatal binding was only visible on the non-lesioned side. Quantitative analysis revealed that striatal-to-cerebellar SPET ratios were significantly lower on the lesioned (mean binding ratio 2.2{+-}0.2) than on the non-lesioned (mean ratio 3.1{+-}0.4) side. The preliminary results of this study indicate that semi-quantitative assessment of striatal dopamine transporter density using our recently developed high-resolution single-pinhole SPET system is feasible in living rat brain. (orig.)

  12. Opposite Actions of Dopamine on Aversive and Appetitive Memories in the Crab

    Science.gov (United States)

    Klappenbach, Martin; Maldonado, Hector; Locatelli, Fernando; Kaczer, Laura

    2012-01-01

    The understanding of how the reinforcement is represented in the central nervous system during memory formation is a current issue in neurobiology. Several studies in insects provide evidence of the instructive role of biogenic amines during the learning and memory process. In insects it was widely accepted that dopamine (DA) mediates aversive…

  13. Pharmacological characterization of the dopamine-sensitive adenylate cyclase in cockroach brain: evidence for a distinct dopamine receptor

    Energy Technology Data Exchange (ETDEWEB)

    Orr, G.L.; Gole, J.W.D.; Notman, H.J.; Downer, R.G.H.

    1987-12-21

    Dopamine increases cyclic AMP production in crude membrane preparations of cockroach brain with plateaus in cyclic AMP production occurring between 1-10 ..mu..M and 10 mM. Maximal production of cyclic AMP is 2.25 fold greater than that of control values. Octopamine also increases cyclic AMP production with a Ka of 1.4 ..mu..M and maximal production 3.5 fold greater than that of control. 5-Hydroxytryptamine does not increase cyclic AMP production. The effects of octopamine and dopamine are fully additive. The vertebrate dopamine agonists ADTN and epinine stimulate the dopamine-sensitive adenylate cyclase (AC) with Ka values of 4.5 and 0.6 ..mu..M respectively and with maximal effectiveness 1.7 fold greater than that of control. The selective D/sub 2/-dopamine agonist LY-171555 stimulates cyclic AMP production to a similar extent with a Ka of 50 ..mu..M. Other dopamine agonists have no stimulatory effects. With the exception of mianserin, /sup 3/H-piflutixol is displaced from brain membranes by dopamine antagonists with an order of potency similar to that observed for the inhibition of dopamine-sensitive AC. The results indicate that the octopamine- and dopamine-sensitive AC in cockroach brain can be distinguished pharmacologically and the dopamine receptors coupled to AC have pharmacological characteristics distinct from vertebrate D/sup 1/- and D/sup 2/-dopamine receptors. 33 references, 3 figures, 2 tables.

  14. Pharmacological characterization of the dopamine-sensitive adenylate cyclase in cockroach brain: evidence for a distinct dopamine receptor

    International Nuclear Information System (INIS)

    Orr, G.L.; Gole, J.W.D.; Notman, H.J.; Downer, R.G.H.

    1987-01-01

    Dopamine increases cyclic AMP production in crude membrane preparations of cockroach brain with plateaus in cyclic AMP production occurring between 1-10 μM and 10 mM. Maximal production of cyclic AMP is 2.25 fold greater than that of control values. Octopamine also increases cyclic AMP production with a Ka of 1.4 μM and maximal production 3.5 fold greater than that of control. 5-Hydroxytryptamine does not increase cyclic AMP production. The effects of octopamine and dopamine are fully additive. The vertebrate dopamine agonists ADTN and epinine stimulate the dopamine-sensitive adenylate cyclase (AC) with Ka values of 4.5 and 0.6 μM respectively and with maximal effectiveness 1.7 fold greater than that of control. The selective D 2 -dopamine agonist LY-171555 stimulates cyclic AMP production to a similar extent with a Ka of 50 μM. Other dopamine agonists have no stimulatory effects. With the exception of mianserin, 3 H-piflutixol is displaced from brain membranes by dopamine antagonists with an order of potency similar to that observed for the inhibition of dopamine-sensitive AC. The results indicate that the octopamine- and dopamine-sensitive AC in cockroach brain can be distinguished pharmacologically and the dopamine receptors coupled to AC have pharmacological characteristics distinct from vertebrate D 1 - and D 2 -dopamine receptors. 33 references, 3 figures, 2 tables

  15. Endocannabinoid-dopamine interactions in striatal synaptic plasticity

    Directory of Open Access Journals (Sweden)

    Brian Neil Mathur

    2012-04-01

    Full Text Available The nigrostriatal dopaminergic system is implicated in action control and learning. A large body of work has focused on the contribution of this system to modulation of the corticostriatal synapse, the predominant synapse type in the striatum. Signaling through the D2 dopamine receptor is necessary for endocannabinoid-mediated depression of corticostriatal glutamate release. Here we review the known details of this mechanism and discuss newly discovered signaling pathways interacting with this system that ultimately exert dynamic control of cortical input to the striatum and striatal output. This topic is timely with respect to Parkinson’s disease given recent data indicating changes in the striatal endocannabinoid system in patients with this disorder.

  16. Maternal separation affects dopamine transporter function in the Spontaneously Hypertensive Rat: An in vivo electrochemical study

    Directory of Open Access Journals (Sweden)

    Womersley Jacqueline S

    2011-12-01

    Full Text Available Abstract Background Attention-deficit/hyperactivity disorder (ADHD is a developmental disorder characterised by symptoms of inattention, impulsivity and hyperactivity. The spontaneously hypertensive rat (SHR is a well-characterised model of this disorder and has been shown to exhibit dopamine dysregulation, one of the hypothesised causes of ADHD. Since stress experienced in the early stages of life can have long-lasting effects on behaviour, it was considered that early life stress may alter development of the dopaminergic system and thereby contribute to the behavioural characteristics of SHR. It was hypothesized that maternal separation would alter dopamine regulation by the transporter (DAT in ways that distinguish SHR from control rat strains. Methods SHR and control Wistar-Kyoto (WKY rats were subjected to maternal separation for 3 hours per day from postnatal day 2 to 14. Rats were tested for separation-induced anxiety-like behaviour followed by in vivo chronoamperometry to determine whether changes had occurred in striatal clearance of dopamine by DAT. The rate of disappearance of ejected dopamine was used as a measure of DAT function. Results Consistent with a model for ADHD, SHR were more active than WKY in the open field. SHR entered the inner zone more frequently and covered a significantly greater distance than WKY. Maternal separation increased the time that WKY spent in the closed arms and latency to enter the open arms of the elevated plus maze, consistent with other rat strains. Of note is that, maternal separation failed to produce anxiety-like behaviour in SHR. Analysis of the chronoamperometric data revealed that there was no difference in DAT function in the striatum of non-separated SHR and WKY. Maternal separation decreased the rate of dopamine clearance (k-1 in SHR striatum. Consistent with this observation, the dopamine clearance time (T100 was increased in SHR. These results suggest that the chronic mild stress of

  17. Simultaneous 99mTC and 123I Dual-Isotope Brain Striatal Phantom Single Photon Emission Computed Tomography: Validation of 99mTC-Trodat-1 and 123I-IBZM Simultaneous Dopamine System Brain Imaging

    OpenAIRE

    Pan-Fu Kao; Shiaw-Pyng Wey; An-Shoei Yang

    2009-01-01

    [2[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3,2,1]-oct-2-yl]-methyl](2-mercaptoethyl)amino]ethyl]amino]ethanethiolato(3-)-N2,N2′,S2,S2]oxo-[1R-exo-exo)])-[99mTc]-technetium (99mTc-TRODAT-1) and 123I-iodobenzamide (123I-IBZM) are radiotracers for brain dopamine preand postsynaptic neuron imaging. The purpose of this study was to evaluate imaging parameters and crossed energy interference using simultaneous single photon emission computed tomography (SPECT) 99mTc and 123I data acquisition...

  18. Further human evidence for striatal dopamine release induced by administration of ∆9-tetrahydrocannabinol (THC): selectivity to limbic striatum.

    Science.gov (United States)

    Bossong, Matthijs G; Mehta, Mitul A; van Berckel, Bart N M; Howes, Oliver D; Kahn, René S; Stokes, Paul R A

    2015-08-01

    Elevated dopamine function is thought to play a key role in both the rewarding effects of addictive drugs and the pathophysiology of schizophrenia. Accumulating epidemiological evidence indicates that cannabis use is a risk factor for the development of schizophrenia. However, human neurochemical imaging studies that examined the impact of ∆9-tetrahydrocannabinol (THC), the main psychoactive component in cannabis, on striatal dopamine release have provided inconsistent results. The objective of this study is to assess the effect of a THC challenge on human striatal dopamine release in a large sample of healthy participants. We combined human neurochemical imaging data from two previous studies that used [(11)C]raclopride positron emission tomography (PET) (n = 7 and n = 13, respectively) to examine the effect of THC on striatal dopamine neurotransmission in humans. PET images were re-analysed to overcome differences in PET data analysis. THC administration induced a significant reduction in [(11)C]raclopride binding in the limbic striatum (-3.65 %, from 2.39 ± 0.26 to 2.30 ± 0.23, p = 0.023). This is consistent with increased dopamine levels in this region. No significant differences between THC and placebo were found in other striatal subdivisions. In the largest data set of healthy participants so far, we provide evidence for a modest increase in human striatal dopamine transmission after administration of THC compared to other drugs of abuse. This finding suggests limited involvement of the endocannabinoid system in regulating human striatal dopamine release and thereby challenges the hypothesis that an increase in striatal dopamine levels after cannabis use is the primary biological mechanism underlying the associated higher risk of schizophrenia.

  19. Dopamine agonist suppression of rapid-eye-movement sleep is secondary to sleep suppression mediated via limbic structures

    Energy Technology Data Exchange (ETDEWEB)

    Miletich, R.S.

    1985-01-01

    The effects of pergolide, a direct dopamine receptor agonist, on sleep and wakefulness, motor behavior and /sup 3/H-spiperone specific binding in limbic structures and striatum in rats was studied. The results show that pergolide induced a biphasic dose effect, with high doses increasing wakefulness and suppressing sleep while low dose decreased wakefulness, but increased sleep. It was shown that pergolide-induced sleep suppression was blocked by ..cap alpha..-glupenthixol and pimozide, two dopamine receptor antagonists. It was further shown that pergolide merely delayed the rebound resulting from rapid-eye-movement (REM) sleep deprivation, that dopamine receptors stimulation had no direct effect on the period, phase or amplitude of the circadian rhythm of REM sleep propensity and that there was no alteration in the coupling of REM sleep episodes with S/sub 2/ episodes. Rapid-eye-movement sleep deprivation resulted in increased sensitivity to the pergolide-induced wakefulness stimulation and sleep suppression and pergolide-induced motor behaviors of locomotion and head bobbing. /sup 3/H-spiperone specific binding to dopamine receptors was shown to be altered by REM sleep deprivation in the subcortical limbic structures. It is concluded that the REM sleep suppressing action of dopamine receptor stimulation is secondary to sleep suppression per se and not secondary to a unique effect on the REM sleep. Further, it is suggested that the wakefulness stimulating action of dopamine receptor agonists is mediated by activation of the dopamine receptors in the terminal areas of the mesolimbocortical dopamine projection system.

  20. Reduced striatal dopamine D2/3 receptor availability in Body Dysmorphic Disorder.

    Science.gov (United States)

    Vulink, Nienke C; Planting, Robin S; Figee, Martijn; Booij, Jan; Denys, Damiaan

    2016-02-01

    Though the dopaminergic system is implicated in Obsessive Compulsive and Related Disorders (OCRD), the dopaminergic system has never been investigated in-vivo in Body Dysmorphic Disorder (BDD). In line with consistent findings of reduced striatal dopamine D2/3 receptor availability in Obsessive Compulsive Disorder (OCD), we hypothesized that the dopamine D2/3 receptor availability in the striatum will be lower in patients with BDD in comparison to healthy subjects. Striatal dopamine D2/3 receptor Binding Potential (BPND) was examined in 12 drug-free BDD patients and 12 control subjects pairwise matched by age, sex, and handedness using [(123)I]iodobenzamide Single Photon Emission Computed Tomography (SPECT; bolus/constant infusion technique). Regions of interest were the caudate nucleus and the putamen. BPND was calculated as the ratio of specific striatal to binding in the occipital cortex (representing nonspecific binding). Compared to controls, dopamine D2/3 receptor BPND was significantly lower in BDD, both in the putamen (p=0.017) and caudate nucleus (p=0.022). This study provides the first evidence of a disturbed dopaminergic system in BDD patients. Although previously BDD was classified as a separate disorder (somatoform disorder), our findings give pathophysiological support for the recent reclassification of BDD to the OCRD in DSM-5. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  1. The effect of modafinil on the rat dopamine transporter and dopamine receptors D1-D3 paralleling cognitive enhancement in the radial arm maze

    Directory of Open Access Journals (Sweden)

    Yasemin eKarabacak

    2015-08-01

    Full Text Available A series of drugs have been reported to increase memory performance modulating the dopaminergic system and herein modafinil was tested for its working memory (WM enhancing properties. Reuptake inhibition of dopamine, serotonin (SERT and norepinephrine (NET by modafinil was tested. 60 male Sprague Dawley rats were divided into six groups (modafinil-treated 1-5-10 mg/kg body weight, trained and untrained and vehicle treated trained and untrained rats; daily injected intraperitoneally for a period of 10 days and tested in a radial arm maze (RAM, a paradigm for testing spatial WM. Hippocampi were taken six hours following the last day of training and complexes containing the unphosphorylated or phosphorylated dopamine transporter (DAT-CC and pDAT-CC and complexes containing the D1-3 dopamine receptor subunits (D1-D3-CC were determined. Modafinil was binding to the DAT but insignificantly to SERT or NET and dopamine reuptake was blocked specifically (IC50=11.11; SERT 1547; NET 182. From day 8 (day 9 for 1 mg/kg body weight modafinil was decreasing WM errors in the RAM significantly and remarkably at all doses tested as compared to the vehicle controls. WMEs were linked to the D2R-CC and the pDAT-CC. pDAT and D1-D3-CC levels were modulated significantly and modafinil was shown to enhance spatial WM in the rat in a well-documented paradigm at all the three doses and dopamine reuptake inhibition with subsequent modulation of D1-3-CC is proposed as a possible mechanism of action.

  2. Optical suppression of drug-evoked phasic dopamine release

    Directory of Open Access Journals (Sweden)

    James Edgar Mccutcheon

    2014-09-01

    Full Text Available Brief fluctuations in dopamine concentration (dopamine transients play a key role in behavior towards rewards, including drugs of abuse. Drug-evoked dopamine transients may result from actions at both dopamine cell bodies and dopamine terminals. Inhibitory opsins can be targeted to dopamine neurons permitting their firing activity to be suppressed. However, as dopamine transients can become uncoupled from firing, it is unknown whether optogenetic hyperpolarization at the level of the soma is able to suppress dopamine transients. Here, we used in vivo fast-scan cyclic voltammetry to record transients evoked by cocaine and raclopride in nucleus accumbens (NAc of urethane-anesthetized rats. We targeted halorhodopsin (NpHR specifically to dopamine cells by injecting Cre-inducible virus into ventral tegmental area (VTA of transgenic rats that expressed Cre recombinase under control of the tyrosine hydroxylase promoter (TH-Cre+ rats. Consistent with previous work, co-administration of cocaine and raclopride led to the generation of dopamine transients in NAc shell. Illumination of VTA with laser strongly suppressed the frequency of transients in NpHR-expressing rats, but not in control rats. Laser did not have any effect on amplitude of transients. Thus, optogenetics can effectively reduce the occurrence of drug-evoked transients and is therefore a suitable approach for studying the functional role of such transients in drug-associated behavior.

  3. Impedimetric biosensor based on magnetic nanoparticles for electrochemical detection of dopamine

    International Nuclear Information System (INIS)

    Chandra, Sudeshna; Arora, Kunal; Bahadur, D.

    2012-01-01

    Highlights: ► Fabrication of dopamine biosensor based on magnetic nanoparticles (MNPs). ► Elimination of interference from ascorbic acid using the negatively charged MNPs. ► Amperometric detection of dopamine (DA) with a detection limit of 7.25 μM. ► Impedance spectroscopy revealed the interfacial properties of modified electrodes. ► Biosensor suitably designed for screening and determination of DA. - Abstract: One of the difficulties which limit the use of electrochemical sensors for detection of dopamine is the interference from ascorbic acid. We have sought to address this problem through the synthesis and characterization of a suitable electrode material based on magnetic nanoparticles. The interference from the ascorbic acid was overcome by fabricating a negatively charged electrode surface using PEGylated arginine functionalized magnetic nanoparticles (PA-MNPs). The nanoparticles were characterized by various techniques viz., X-ray diffraction, FT-Infrared spectroscopy, transmission electron microscopy and vibrating sample magnetometer. The electrochemical behavior of the proposed sensor was investigated by cyclic voltammetry and the sensor showed high sensitivity and selectivity for dopamine. The response mechanism of the modified electrode is based on the interaction between the negatively charged electrode and the positively charged dopamine. Under optimized conditions, linear calibration plots were obtained for amperometric detection of dopamine (DA) over the concentration range of 1–9 mM dopamine, with a linear correlation coefficient of 0.9836, sensitivity of 121 μA/mM and a detection limit of 7.25 μM. Electrochemical impedance spectroscopy (EIS) has been used to study the interface properties of modified electrodes. The value of the polarization resistance (R p ) increases linearly with dopamine concentration in the range of 10 μM to 1 mM and the limit of detection (LOD) was calculated to be 14.1 μM. High sensitivity and selectivity

  4. Dopamine regulation of social choice in a monogamous rodent species

    Directory of Open Access Journals (Sweden)

    Brandon J Aragona

    2009-08-01

    Full Text Available There is growing appreciation that social decision making in humans is strongly influenced by hedonic and emotional processing. The field of social neuroeconomics has shown that neural systems important for reward are associated with social choice and social preferences in humans. Here, we show that the neurobiology of social preferences in a monogamous rodent species, the prairie vole, is also regulated by neural systems involved in reward and emotional processing. Specifically, we describe how mesolimbic dopamine transmission differentially mediates the formation and maintenance of monogamous pair bonds in this species. Thus, reward processing exerts tremendous regulation over social choice behaviors that serve as the foundation of a rather complex social organization. We conclude that prairie voles are an excellent model system for the neuroscience of social choice and that complex social decision-making can be robustly explained by reward and hedonic processing.

  5. Dopamine-beta hydroxylase polymorphism and cocaine addiction

    Directory of Open Access Journals (Sweden)

    Collier David

    2008-01-01

    Full Text Available Abstract Cocaine addiction involves a number of medical, psychological and social problems. Understanding the genetic aetiology of this disorder will be essential for design of effective treatments. Dopamine-beta hydroxylase (DbH catalyzes the conversion of dopamine to norepinephrine and could, therefore, have an influence on both cocaine action and the basal sensitivity of neurotransmitter systems to cocaine. Recently, the -1021C>T polymorphism have been found to strongly correlated with individual variation in plasma DbH activity. To test the influence of this polymorphism on the susceptibility of cocaine addiction, we decided to genotype it in a sample of 689 cocaine addicts and 832 healthy individuals. Genotypic and allelic analyses did not show any evidence of association with cocaine addiction, even after correcting for the effect of population stratification and other possible confounders. Our results do not support a major role of the -1021C>T polymorphism or the gene itself in the development of cocaine addiction but further examination of other variants within this gene will be necessary to completely rule out an effect.

  6. Dopamine Does Not Appear to Affect Mental Rotation in Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Gregory P. Crucian

    2014-10-01

    Full Text Available ObjectivePatients with Parkinson’s disease (PD often have deficits with mental rotation (MR. The neuropathological factors underlying these deficits, however, remain to be elucidated. One hypothesis suggests that dopamine depletion in nigro-striatal systems adversely influences MR. Another hypothesis suggests that deterioration of cortical (fronto-temporo-parietal basal ganglia networks that mediate this function are responsible for this deficit. The goal of this study was to test the dopamine hypothesis by determining if dopamine abstinence negatively influences MR performance. MethodsThirty three non-demented right-handed individuals with PD were assess for their ability to perform a pencil and paper MR test while “on” and “off” dopaminergic medications. Dopamine abstinence followed the typical overnight withdrawal procedures. ResultsNo differences in mental rotation abilities were found between “on” and “off” dopaminergic medications. ConclusionsThese results suggest that other neuropathological factors, such as cortical-basal ganglia neurodegeneration, or dysfunction of other neurotransmitters systems, might account for these cognitive deficits and future research will have to test these alternative hypotheses.

  7. 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.

  8. The Effects of Acute Dopamine Precursor Depletion on the Reinforcing Value of Exercise in Anorexia Nervosa.

    Directory of Open Access Journals (Sweden)

    Caitlin B O'Hara

    Full Text Available This study investigated whether dopaminergic systems are involved in the motivation to engage in behaviours associated with anorexia nervosa (AN, specifically, the drive to exercise. Women recovered from AN (AN REC, n = 17 and healthy controls (HC, n = 15 were recruited. The acute phenylalanine/tyrosine depletion (APTD method was used to transiently decrease dopamine synthesis and transmission. The effect of dopamine precursor depletion on drive to exercise was measured using a progressive ratio (PR exercise breakpoint task. Both groups worked for the opportunity to exercise, and, at baseline, PR breakpoint scores were higher in AN REC than HC. Compared to values on the experimental control session, APTD did not decrease PR breakpoint scores in AN REC, but significantly decreased scores in HC. These data show that women recovered from AN are more motivated to exercise than HC, although in both groups, activity is more reinforcing than inactivity. Importantly, decreasing dopamine does not reduce the motivation to exercise in people recovered from AN, but in contrast, does so in HC. It is proposed that in AN, drive to exercise develops into a behaviour that is largely independent of dopamine mediated reward processes and becomes dependent on cortico-striatal neurocircuitry that regulates automated, habit- or compulsive-like behaviours. These data strengthen the case for the involvement of reward, learning, habit, and dopaminergic systems in the aetiology of AN.

  9. Striatal dopamine D1 and D2 receptors are differentially regulated following buprenorphine or methadone treatment.

    Science.gov (United States)

    Allouche, Stéphane; Le Marec, Thierry; Coquerel, Antoine; Noble, Florence; Marie, Nicolas

    2015-05-01

    Chronic administration of morphine induces adaptations in neurotransmission system such as the dopamine pathway, and these modifications could be influenced by the drug administration pattern. Methadone and buprenorphine are the two main opioid substitution therapies, and despite their protracted use in humans, no study has investigated their ability to regulate dopamine system after chronic exposure/withdrawal. We evaluated the consequences of two administration patterns of methadone and buprenorphine on striatal dopamine D1 (D1R) and D2 (D2R) receptor levels. Mice were treated with escalating doses of methadone or buprenorphine for 5 days either once daily (binge) or three times a day (TTD). D1R and D2R density in striatum was measured by autoradiography using [(3)H]-SCH23390 and [(3)H]-raclopride, respectively, at 1 (WD1), 14 (WD14), and 35 (WD35) days after the last opioid injection. A downregulation of D1R was observed upon TTD administration of buprenorphine and binge methadone treatment while an increase of those receptor levels was detected both with binge buprenorphine and TTD methadone treatments. Concerning the D2R, we rather measured an early or late downregulation with both agonists and administration patterns. Our results demonstrated that methadone and buprenorphine were able to differentially regulate dopamine receptor density depending on the withdrawal period and the administration pattern.

  10. The multiplicity of the D-1 dopamine receptor

    International Nuclear Information System (INIS)

    Mailman, R.B.; Klits, C.D.; Lewis, M.H.; Rollema, H.; Schulz, D.W.; Wyrick, S.

    1986-01-01

    The authors have sought to address two questions of some neuropharmacological importance in this chapter. First, they examine the nature of mechanisms by which dopamine initiates many psychopharmacological effects and, second, they study the possibility of designing highly specific drugs targeted only at a selected subpopulation of dopamine receptors. Effects of SCH23390 and haloperidol on concentrations of dopamine, DOPAC, and HVA in various rat brain regions are shown. In addition, the effects of SCH23390 on the in vivo binding of dipropyl-5, 6-ADTN are shown. Differential distribution of a dopamine sensitive adenylate cyclase and ( 3 H)-SCH23390 binding sites are examined. A model is presented of D 1 dopamine receptors in membrane, illustrating the lack of identity of some of the ( 3 H)-SCH23390 binding sites with the dopamine receptor linked to stimulation of cAMP synthesis

  11. Neuronal Depolarization Drives Increased Dopamine Synaptic Vesicle Loading via VGLUT.

    Science.gov (United States)

    Aguilar, Jenny I; Dunn, Matthew; Mingote, Susana; Karam, Caline S; Farino, Zachary J; Sonders, Mark S; Choi, Se Joon; Grygoruk, Anna; Zhang, Yuchao; Cela, Carolina; Choi, Ben Jiwon; Flores, Jorge; Freyberg, Robin J; McCabe, Brian D; Mosharov, Eugene V; Krantz, David E; Javitch, Jonathan A; Sulzer, David; Sames, Dalibor; Rayport, Stephen; Freyberg, Zachary

    2017-08-30

    The ability of presynaptic dopamine terminals to tune neurotransmitter release to meet the demands of neuronal activity is critical to neurotransmission. Although vesicle content has been assumed to be static, in vitro data increasingly suggest that cell activity modulates vesicle content. Here, we use a coordinated genetic, pharmacological, and imaging approach in Drosophila to study the presynaptic machinery responsible for these vesicular processes in vivo. We show that cell depolarization increases synaptic vesicle dopamine content prior to release via vesicular hyperacidification. This depolarization-induced hyperacidification is mediated by the vesicular glutamate transporter (VGLUT). Remarkably, both depolarization-induced dopamine vesicle hyperacidification and its dependence on VGLUT2 are seen in ventral midbrain dopamine neurons in the mouse. Together, these data suggest that in response to depolarization, dopamine vesicles utilize a cascade of vesicular transporters to dynamically increase the vesicular pH gradient, thereby increasing dopamine vesicle content. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Dopamine supports sentence comprehension in Parkinson's Disease.

    Science.gov (United States)

    Grossman, M; Glosser, G; Kalmanson, J; Morris, J; Stern, M B; Hurtig, H I

    2001-03-01

    To determine the role of dopamine in the executive resource component of sentence comprehension. We studied sentence-picture matching in 20 right-handed, non-demented, native English speakers with mild Parkinson's disease (PD) when 'on' and 'off' their levodopa, taking into account disease duration to control for endogenous dopamine metabolism. We also administered a verbal working memory measure that does not involve specific grammatical manipulations. PD patients 'off' levodopa demonstrated a significant discrepancy in their comprehension of grammatically complex sentences compared to grammatically simpler sentences that was not evident when PD patients were 'on' levodopa. An error analysis demonstrated that impaired comprehension of grammatically complex sentences when 'off' levodopa was associated with poorer performance on foils requiring working memory resources. Performance on an independent measure of verbal working memory correlated only with comprehension of grammatically complex sentences during levodopa supplementation, but working memory according to this measure did not differ during 'on' and 'off' states. Dopamine supports the executive resources contributing to sentence comprehension in PD.

  13. Transcription factors Foxa1 and Foxa2 are required for adult dopamine neurons maintenance

    Directory of Open Access Journals (Sweden)

    Andrii eDomanskyi

    2014-09-01

    Full Text Available The proteins Foxa1 and Foxa2 belong to the forkhead family of transcription factors and are involved in the development of several tissues, including liver, pancreas, lung, prostate, and the neural system. Both Foxa1 and Foxa2 are also crucial for the specification and differentiation of dopamine (DA neurons during embryonic development, while about 30% of mice with an embryonic deletion of a single allele of the Foxa2 gene exhibit an age-related asymmetric loss of DA neurons and develop locomotor symptoms resembling Parkinson’s disease (PD. Notably, both Foxa1 and Foxa2 factors continue to be expressed in the adult dopamine system. To directly assess their functions selectively in adult DA neurons, we induced genetic deletions of Foxa1/2 transcription factors in mice using a tamoxifen inducible tissue-specific CreERT2 recombinase expressed under control of the dopamine transporter (DAT promoter (DATCreERT2. The conditional DA neurons-specific ablation of both genes, but not of Foxa2 alone, in early adulthood, caused a decline of striatal dopamine and its metabolites, along with locomotor deficits. At early pre-symptomatic stages, we observed a decline in aldehyde dehydrogenase family 1, subfamily A1 (Aldh1a1 protein expression in DA neurons. Further analyses revealed a decline of aromatic amino acid decarboxylase (AADC and a complete loss of DAT expression in these neurons. These molecular changes ultimately led to a reduction of DA neuron numbers in the substantia nigra pars compacta (SNpc of aged cFoxa1/2-/- mice, resembling the progressive course of PD in humans. Altogether, in this study, we address the molecular, cellular and functional role of both Foxa1 and Foxa2 factors in the maintenance of the adult dopamine system which may help to find better approaches for PD treatment.

  14. Transcription factors Foxa1 and Foxa2 are required for adult dopamine neurons maintenance.

    Science.gov (United States)

    Domanskyi, Andrii; Alter, Heike; Vogt, Miriam A; Gass, Peter; Vinnikov, Ilya A

    2014-01-01

    The proteins Foxa1 and Foxa2 belong to the forkhead family of transcription factors and are involved in the development of several tissues, including liver, pancreas, lung, prostate, and the neural system. Both Foxa1 and Foxa2 are also crucial for the specification and differentiation of dopamine (DA) neurons during embryonic development, while about 30% of mice with an embryonic deletion of a single allele of the Foxa2 gene exhibit an age-related asymmetric loss of DA neurons and develop locomotor symptoms resembling Parkinson's disease (PD). Notably, both Foxa1 and Foxa2 factors continue to be expressed in the adult dopamine system. To directly assess their functions selectively in adult DA neurons, we induced genetic deletions of Foxa1/2 transcription factors in mice using a tamoxifen inducible tissue-specific CreERT2 recombinase expressed under control of the dopamine transporter (DAT) promoter (DATCreERT2). The conditional DA neurons-specific ablation of both genes, but not of Foxa2 alone, in early adulthood, caused a decline of striatal dopamine and its metabolites, along with locomotor deficits. At early pre-symptomatic stages, we observed a decline in aldehyde dehydrogenase family 1, subfamily A1 (Aldh1a1) protein expression in DA neurons. Further analyses revealed a decline of aromatic amino acid decarboxylase (AADC) and a complete loss of DAT expression in these neurons. These molecular changes ultimately led to a reduction of DA neuron numbers in the substantia nigra pars compacta (SNpc) of aged cFoxa1/2 (-/-) mice, resembling the progressive course of PD in humans. Altogether, in this study, we address the molecular, cellular, and functional role of both Foxa1 and Foxa2 factors in the maintenance of the adult dopamine system which may help to find better approaches for PD treatment.

  15. Practical Approach for the Clinical Use of Dopamine Transporter Imaging

    International Nuclear Information System (INIS)

    Kim, Jae Seung

    2008-01-01

    Dopamine transporter imaging is useful in the diagnosis of Parkinson's disease and the most successful technique in the clinical use of neuroreceptor imaging. Recently, several radiopharmaceuticals including I-123 FP-CIT, Tc-99m TRODAT, and F-18 FP-CIT for dopamine transporter imaging have been approved for the routine clinical use in several European countries, Taiwan and Korea, respectively. This review summarized the practical issue for the routine clinical examination of dopamine transporter imaging

  16. The dopamine transporter: role in neurotoxicity and human disease

    International Nuclear Information System (INIS)

    Bannon, Michael J.

    2005-01-01

    The dopamine transporter (DAT) is a plasma membrane transport protein expressed exclusively within a small subset of CNS neurons. It plays a crucial role in controlling dopamine-mediated neurotransmission and a number of associated behaviors. This review focuses on recent data elucidating the role of the dopamine transporter in neurotoxicity and a number of CNS disorders, including Parkinson disease, drug abuse, and attention deficit hyperactivity disorder (ADHD)

  17. Brain dopamine and serotonin transporter binding are associated with visual attention bias for food in lean men

    NARCIS (Netherlands)

    Koopman, K. E.; Roefs, A.; Elbers, D. C. E.; Fliers, E.; Booij, J.; Serlie, M. J.; La Fleur, S. E.

    2016-01-01

    In rodents, the striatal dopamine (DA) system and the (hypo)thalamic serotonin (5-HT) system are involved in the regulation of feeding behavior. In lean humans, little is known about the relationship between these brain neurotransmitter systems and feeding. We studied the relationship between

  18. Influence of phasic and tonic dopamine release on receptor activation

    DEFF Research Database (Denmark)

    Dreyer, Jakob Kristoffer Kisbye; Herrik, Kjartan F; Berg, Rune W

    2010-01-01

    Tonic and phasic dopamine release is implicated in learning, motivation, and motor functions. However, the relationship between spike patterns in dopaminergic neurons, the extracellular concentration of dopamine, and activation of dopamine receptors remains unresolved. In the present study, we...... develop a computational model of dopamine signaling that give insight into the relationship between the dynamics of release and occupancy of D(1) and D(2) receptors. The model is derived from first principles using experimental data. It has no free parameters and offers unbiased estimation...

  19. Dopamine modulation of learning and memory in the prefrontal cortex: insights from studies in primates, rodents, and birds.

    Science.gov (United States)

    Puig, M Victoria; Rose, Jonas; Schmidt, Robert; Freund, Nadja

    2014-01-01

    In this review, we provide a brief overview over the current knowledge about the role of dopamine transmission in the prefrontal cortex during learning and memory. We discuss work in humans, monkeys, rats, and birds in order to provide a basis for comparison across species that might help identify crucial features and constraints of the dopaminergic system in executive function. Computational models of dopamine function are introduced to provide a framework for such a comparison. We also provide a brief evolutionary perspective showing that the dopaminergic system is highly preserved across mammals. Even birds, following a largely independent evolution of higher cognitive abilities, have evolved a comparable dopaminergic system. Finally, we discuss the unique advantages and challenges of using different animal models for advancing our understanding of dopamine function in the healthy and diseased brain.

  20. Dopamine modulation of learning and memory in the prefrontal cortex: insights from studies in primates, rodents, and birds

    Directory of Open Access Journals (Sweden)

    M. Victoria ePuig

    2014-08-01

    Full Text Available In this review, we provide a brief overview over the current knowledge about the role of dopamine transmission in the prefrontal cortex during learning and memory. We discuss work in humans, monkeys, rats, and birds in order to provide a basis for comparison across species that might help identify crucial features and constraints of the dopaminergic system in executive function. Computational models of dopamine function are introduced to provide a framework for such a comparison. We also provide a brief evolutionary perspective showing that the dopaminergic system is highly preserved across mammals. Even birds, following a largely independent evolution of higher cognitive abilities, have evolved a comparable dopaminergic system. Finally, we discuss the unique advantages and challenges of using different animal models for advancing our understanding of dopamine function in the healthy and diseased brain.

  1. Dopamine modulation of learning and memory in the prefrontal cortex: insights from studies in primates, rodents, and birds

    Science.gov (United States)

    Puig, M. Victoria; Rose, Jonas; Schmidt, Robert; Freund, Nadja

    2014-01-01

    In this review, we provide a brief overview over the current knowledge about the role of dopamine transmission in the prefrontal cortex during learning and memory. We discuss work in humans, monkeys, rats, and birds in order to provide a basis for comparison across species that might help identify crucial features and constraints of the dopaminergic system in executive function. Computational models of dopamine function are introduced to provide a framework for such a comparison. We also provide a brief evolutionary perspective showing that the dopaminergic system is highly preserved across mammals. Even birds, following a largely independent evolution of higher cognitive abilities, have evolved a comparable dopaminergic system. Finally, we discuss the unique advantages and challenges of using different animal models for advancing our understanding of dopamine function in the healthy and diseased brain. PMID:25140130

  2. Conditioned Contribution of Peripheral Cocaine Actions to Cocaine Reward and Cocaine-Seeking

    OpenAIRE

    Wang, Bin; You, Zhi-Bing; Oleson, Erik B; Cheer, Joseph F; Myal, Stephanie; Wise, Roy A

    2013-01-01

    Cocaine has actions in the peripheral nervous system that reliably precede—and thus predict—its soon-to-follow central rewarding effects. In cocaine-experienced animals, the peripheral cocaine signal is relayed to the central nervous system, triggering excitatory input to the ventral tegmental origin of the mesocorticolimbic dopamine system, the system that mediates the rewarding effects of the drug. We used cocaine methiodide, a cocaine analog that does not cross the blood–brain barrier, to ...

  3. 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

  4. Measurement of striatal dopamine metabolism with 6-[18F]-fluoro-L-dopa and PET

    International Nuclear Information System (INIS)

    Kuwabara, Y.; Otsuka, M.; Ichiya, Y.; Yoshikai, T.; Fukumura, T.; Masuda, K.; Kato, M.; Taniwaki, T.

    1992-01-01

    Striatal dopamine metabolism was studied with 6-[ 18 F]-fluoro-L-dopa ( 18 F-DOPA) and PET. The subjects were normal controls, and patients with Parkinson's disease (PD), parkinsonism, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), Alzheimer's disease (AD), Huntington's disease (HD) and other cerebral disorders. Cerebral glucose metabolism (CMRGlc) was also measured in these patients. Striatal dopamine metabolism was evaluated by the relative striatal uptake of 18 F-DOPA referring cerebellum (S/C ratio). In normal controls, the S/C ratio was 2.82 ± 0.32 (n = 6, mean ± SD) at 120 min after injection of 18 F-DOPA. The S/C ratio was low in patients with PD, parkinsonism, MSA and PSP compared to the normal controls and thus coincident with the symptoms of parkinsonism due to decrease in striatal dopamine concentration. The decrease in the striatal CMRGlc was also observed in patients with parkinsonism and PSP, and it was preserved in patients with PD, thus representing that more neurons were damaged in patients with parkinsonism and PSP than in patients with PD. A patient with AD having symptoms of parkinsonism also showed a decrease in S/C ratio. In a patient with HD, the striatal CMRGlc sharply decreased, but the S/C ratio was normal. The measurements of striatal dopamine and glucose metabolism with PET may be useful for studying the pathophysiological mechanism in patients with cerebral disorders. (author)

  5. Data on overlapping brain disorders and emerging drug targets in human Dopamine Receptors Interaction Network

    Directory of Open Access Journals (Sweden)

    Avijit Podder

    2017-06-01

    Full Text Available Intercommunication of Dopamine Receptors (DRs with their associate protein partners is crucial to maintain regular brain function in human. Majority of the brain disorders arise due to malfunctioning of such communication process. Hence, contributions of genetic factors, as well as phenotypic indications for various neurological and psychiatric disorders are often attributed as sharing in nature. In our earlier research article entitled “Human Dopamine Receptors Interaction Network (DRIN: a systems biology perspective on topology, stability and functionality of the network” (Podder et al., 2014 [1], we had depicted a holistic interaction map of human Dopamine Receptors. Given emphasis on the topological parameters, we had characterized the functionality along with the vulnerable properties of the network. In support of this, we hereby provide an additional data highlighting the genetic overlapping of various brain disorders in the network. The data indicates the sharing nature of disease genes for various neurological and psychiatric disorders in dopamine receptors connecting protein-protein interactions network. The data also indicates toward an alternative approach to prioritize proteins for overlapping brain disorders as valuable drug targets in the network.

  6. Dopamine modulates acetylcholine release via octopamine and CREB signaling in Caenorhabditis elegans.

    Directory of Open Access Journals (Sweden)

    Satoshi Suo

    Full Text Available Animals change their behavior and metabolism in response to external stimuli. cAMP response element binding protein (CREB is a signal-activated transcription factor that enables the coupling of extracellular signals and gene expression to induce adaptive changes. Biogenic amine neurotransmitters regulate CREB and such regulation is important for long-term changes in various nervous system functions, including learning and drug addiction. In Caenorhabditis elegans, the amine neurotransmitter octopamine activates a CREB homolog, CRH-1, in cholinergic SIA neurons, whereas dopamine suppresses CREB activation by inhibiting octopamine signaling in response to food stimuli. However, the physiological role of this activation is unknown. In this study, the effect of dopamine, octopamine, and CREB on acetylcholine signaling was analyzed using the acetylcholinesterase inhibitor aldicarb. Mutants with decreased dopamine signaling exhibited reduced acetylcholine signaling, and octopamine and CREB functioned downstream of dopamine in this regulation. This study demonstrates that the regulation of CREB by amine neurotransmitters modulates acetylcholine release from the neurons of C. elegans.

  7. Selective electrochemical detection of dopamine in a microfluidic channel on carbon nanoparticulate electrodes.

    Science.gov (United States)

    Rozniecka, Ewa; Jonsson-Niedziolka, Martin; Celebanska, Anna; Niedziolka-Jonsson, Joanna; Opallo, Marcin

    2014-06-07

    There is a continuous need for the construction of detection systems in microfluidic devices. In particular, electrochemical detection allows the separation of signals from the analyte and interfering substances in the potential domain. Here, a simple microfluidic device for the sensitive and selective determination of dopamine in the presence of interfering substances was constructed and tested. It employs a carbon nanoparticulate electrode allowing the separation of voltammetric signals of dopamine and common interfering substances (ascorbic acid and acetaminophen) both in quiescent conditions and in flow due to the electrocatalytic effect. These voltammograms were also successfully simulated. The limit of detection of dopamine detected by square wave voltammetry in 1 mM solutions of interfering substances in phosphate buffered saline is about 100 nM. In human serum a clear voltammetric signal could be seen for a 200 nM solution, sufficient to detect dopamine in the cerebral fluid. Flow injection analysis allows a decrease in the limit of detection down to 3.5 nM.

  8. Apathy and striatal dopamine transporter levels in de-novo, untreated Parkinson's disease patients.

    Science.gov (United States)

    Santangelo, Gabriella; Vitale, Carmine; Picillo, Marina; Cuoco, Sofia; Moccia, Marcello; Pezzella, Domenica; Erro, Roberto; Longo, Katia; Vicidomini, Caterina; Pellecchia, Maria Teresa; Amboni, Marianna; Brunetti, Arturo; Salvatore, Marco; Barone, Paolo; Pappatà, Sabina

    2015-05-01

    Apathy is a neuropsychiatric symptom in Parkinson's Disease (PD) which has a negative impact on quality of life and might be related in part to damage of presynaptic dopaminergic system. Little is known about relationship between striatal dopamine levels and apathy in PD patients without dementia and/or depression. The aim of the present study was to investigate the relationship between "pure apathy" and striatal dopamine uptake in untreated, drug-naïve PD patients without clinically significant dementia and/or depression. Fourteen PD patients with pure apathy and 14 PD patients without apathy, matched for age, side of motor symptoms at onset, motor disability and disease duration, underwent both neuropsychological and behavioral examination including self-rated version of the Apathy Evaluation Scale (AES-S). All patients underwent 123 I-FP-CIT (DaT-SCAN) SPECT to assess dopamine transporter (DAT) striatal uptake. PD patients with apathy showed lower DAT levels in the striatum than non-apathetic patients. After Bonferroni correction the difference between groups was significant in the right caudate. Apathy is associated with reduced striatal dopamine transporter levels, independent of motor disability and depression in non-demented PD patients. These findings suggest that dysfunction of dopaminergic innervation in the striatum and particularly in the right caudate may contribute to development of apathy in early PD. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. The Role of Dopamine in Anticipatory Pursuit Eye Movements: Insights from Genetic Polymorphisms in Healthy Adults.

    Science.gov (United States)

    Billino, Jutta; Hennig, Jürgen; Gegenfurtner, Karl R

    2016-01-01

    There is a long history of eye movement research in patients with psychiatric diseases for which dysfunctions of neurotransmission are considered to be the major pathologic mechanism. However, neuromodulation of oculomotor control is still hardly understood. We aimed to investigate in particular the impact of dopamine on smooth pursuit eye movements. Systematic variability in dopaminergic transmission due to genetic polymorphisms in healthy subjects offers a noninvasive opportunity to determine functional associations. We measured smooth pursuit in 110 healthy subjects genotyped for two well-documented polymorphisms, the COMT Val 158 Met polymorphism and the SLC6A3 3'-UTR-VNTR polymorphism. Pursuit paradigms were chosen to particularly assess the ability of the pursuit system to initiate tracking when target motion onset is blanked, reflecting the impact of extraretinal signals. In contrast, when following a fully visible target sensory, retinal signals are available. Our results highlight the crucial functional role of dopamine for anticipatory, but not for sensory-driven, pursuit processes. We found the COMT Val 158 Met polymorphism specifically associated with anticipatory pursuit parameters, emphasizing the dominant impact of prefrontal dopamine activity on complex oculomotor control. In contrast, modulation of striatal dopamine activity by the SLC6A3 3'-UTR-VNTR polymorphism had no significant functional effect. Though often neglected so far, individual differences in healthy subjects provide a promising approach to uncovering functional mechanisms and can be used as a bridge to understanding deficits in patients.

  10. Dopamine and paraquat enhance α-synuclein-induced alterations in membrane conductance

    Science.gov (United States)

    Feng, Li Rebekah; Maguire-Zeiss, Kathleen A.

    2011-01-01

    We have previously demonstrated that α-synuclein overexpression increases the membrane conductance of dopaminergic-like cells. Although α-synuclein is thought to play a central role in the pathogenesis of several neurodegenerative diseases including Parkinson’s disease, multiple system atrophy and diffuse Lewy body disease the mechanism of action is not completely understood. In this study we sought to determine whether multiple factors act together with α-synuclein to engender cell vulnerability through an augmentation of membrane conductance. Here we employed a cell model that mimics dopaminergic neurons coupled with α-synuclein overexpression and oxidative stressors. We demonstrate an enhancement of α-synuclein-induced toxicity in the presence of combined treatment with dopamine and paraquat, two molecules known to incite oxidative stress. In addition we show that combined dopamine and paraquat treatment increases the expression of heme oxygenase-1, an antioxidant response protein. Finally, we demonstrate for the first time that combined treatment of dopaminergic cells with paraquat and dopamine enhances α-synuclein-induced leak channel properties resulting in increased membrane conductance. Importantly, these increases are most robust when both paraquat and dopamine are present suggesting the need for multiple oxidative insults to augment α-synuclein-induced disruption of membrane integrity. PMID:21735318

  11. 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.

  12. Concomitant release of ventral tegmental acetylcholine and accumbal dopamine by ghrelin in rats.

    Directory of Open Access Journals (Sweden)

    Elisabet Jerlhag

    Full Text Available Ghrelin, an orexigenic peptide, regulates energy balance specifically via hypothalamic circuits. Growing evidence suggest that ghrelin increases the incentive value of motivated behaviours via activation of the cholinergic-dopaminergic reward link. It encompasses the cholinergic afferent projection from the laterodorsal tegmental area (LDTg to the dopaminergic cells of the ventral tegmental area (VTA and the mesolimbic dopamine system projecting from the VTA to nucleus accumbens (N.Acc.. Ghrelin receptors (GHS-R1A are expressed in these reward nodes and ghrelin administration into the LDTg increases accumbal dopamine, an effect involving nicotinic acetylcholine receptors in the VTA. The present series of experiments were undertaken directly to test this hypothesis. Here we show that ghrelin, administered peripherally or locally into the LDTg concomitantly increases ventral tegmental acetylcholine as well as accumbal dopamine release. A GHS-R1A antagonist blocks this synchronous neurotransmitter release induced by peripheral ghrelin. In addition, local perfusion of the unselective nicotinic antagonist mecamylamine into the VTA blocks the ability of ghrelin (administered into the LDTg to increase N.Acc.-dopamine, but not VTA-acetylcholine. Collectively our data indicate that ghrelin activates the LDTg causing a release of acetylcholine in the VTA, which in turn activates local nicotinic acetylcholine receptors causing a release of accumbal dopamine. Given that a dysfunction in the cholinergic-dopaminergic reward system is involved in addictive behaviours, including compulsive overeating and alcohol use disorder, and that hyperghrelinemia is associated with such addictive behaviours, ghrelin-responsive circuits may serve as a novel pharmacological target for treatment of alcohol use disorder as well as binge eating.

  13. Responses of in vivo renal microvessels to dopamine.

    Science.gov (United States)

    Steinhausen, M; Weis, S; Fleming, J; Dussel, R; Parekh, N

    1986-09-01

    The split hydronephrotic kidney preparation was used to directly observe the effects of locally applied dopamine on the in vivo diameters of renal vessels. Dopamine (1 X 10(-6) to 3 X 10(-5) M) produced a concentration-dependent dilation of the arcuate and interlobular arteries and afferent arterioles. Efferent arterioles near the glomeruli also dilated to dopamine but the dilation was less than that of the preglomerular vessels. Higher dopamine concentrations (3 X 10(-4) and 1 X 10(-3) M) produced more variable effects, with a tendency for the arcuate and interlobular arteries and the afferent and efferent arterioles away from the glomeruli to decrease in diameter. After pretreatment with haloperidol, dopamine (1 X 10(-6) to 1 X 10(-4) M) did not dilate any pre- or postglomerular vascular segment, but the tendency for pre- and postglomerular constrictions with higher dopamine concentrations were not abolished. Pretreatment with phentolamine and propranolol enhanced the dilator response of the pre- and postglomerular vessels (except the afferent arterioles near glomeruli and efferent arterioles near welling points) to dopamine (3 X 10(-5) and 1 X 10(-4) M), and abolished the reductions in diameter produced by the high dopamine levels. These data indicate that the dilator effect of dopamine is mediated by interactions with specific dopaminergic receptors, while alpha and beta adrenergic receptors appear to mediate a constrictor influence observed with high dopamine concentrations. The overall effect of dopamine on the renal vessel diameters thus appears to depend on the balance of dilator and constrictor stimuli mediated by multiple receptors.

  14. Central actions of a novel and selective dopamine antagonist

    International Nuclear Information System (INIS)

    Schulz, D.W.

    1985-01-01

    Receptors for the neurotransmitter dopamine traditionally have been divided into two subgroups: the D 1 class, which is linked to the stimulation of adenylate cyclase-activity, and the D 2 class which is not. There is much evidence suggesting that it is the D 2 class which is not. There is much evidence suggesting that it is the D 2 dopamine receptor that mediates the physiological and behavioral actions of dopamine in the intact animal. However, the benzazepine SCH23390 is a dopamine antagonist which has potent behavioral actions while displaying apparent neurochemical selectivity for the D 1 class of dopamine receptors. The purpose of this dissertation was to (1) confirm and characterize this selectivity, and (2) test certain hypothesis related to possible modes of action of SCH233390. The inhibition of adenylate cyclase by SCH23390 occurred via an action at the dopamine receptor only. A radiolabeled analog of SCH23390 displayed the receptor binding properties of a specific high-affinity ligand, and regional receptor densities were highly correlated with dopamine levels. The subcellular distribution of [ 3 H]-SCH23390 binding did not correspond completely with that of dopamine-stimulated adenylate cyclase. The neurochemical potency of SCH23390 as a D 1 receptor antagonist was preserved following parental administration. A variety of dopamine agonists and antagonists displayed a high correlation between their abilities to compete for [ 3 H]-SCH23390 binding in vitro and to act at an adenylate cyclase-linked receptor. Finally, the relative affinities of dopamine and SCH23390 for both D 1 receptors and [ 3 H]-SCH23390 binding sites were comparable. It is concluded that the behavioral effects of SCH23390 are mediated by actions at D 1 dopamine receptors only, and that the physiological importance of this class of receptors should be reevaluated

  15. Detecting associations between behavioral addictions and dopamine agonists in the Food & Drug Administration’s Adverse Event database

    Science.gov (United States)

    Gendreau, Katherine E.; Potenza, Marc N.

    2014-01-01

    Background/Aims: Studies have reported higher prevalences of four behavioral addictions (binge eating, compulsive shopping, hypersexuality, and pathological gambling) in dopamine agonist-treated Parkinson’s disease relative to non-dopamine agonist-treated Parkinson’s. However, recent case-control and epidemiological studies suggest that prevalences of behavioral addictions in dopamine agonist-treated Parkinson’s may be similar to background population rates. This study tests that hypothesis by examining the FDA Adverse Event Reporting System (FAERS) for evidence of these associations, taking into account the potential impact of publicity on reporting rates. Methods: FAERS reports in 2004 (pre-publicity for all but pathological gambling) and 2007 (post-publicity for all four behaviors) were analyzed. A threshold consisting of ≥3 cases, proportional reporting ratio ≥2, and χ2 with Yates’ correction ≥4 was used to detect signals (drug-associated adverse reactions) involving any of five dopamine agonists and any of four behavioral addictions. Results: No reports containing compulsive shopping and no signal for binge eating and dopamine agonists were found in either year. A weak signal was found for hypersexuality in 2004, with a stronger signal in 2007. A robust signal was found for pathological gambling in 2004, with a more robust signal in 2007. Discussion/Conclusions: These results suggest that publicity may increase reporting rates in the FAERS. Findings for binge eating, compulsive shopping, and hypersexuality suggest that prevalences of these behaviors among those treated with dopamine agonists may be similar to background population rates and thus may not reflect an adverse safety signal. Further investigation of the relationship between dopamine agonists and behavioral addictions is warranted. PMID:25215211

  16. The Roles of Dopamine and Related Compounds in Reward-Seeking Behavior Across Animal Phyla

    OpenAIRE

    Barron, Andrew B.; S?vik, Eirik; Cornish, Jennifer L.

    2010-01-01

    Motile animals actively seek out and gather resources they find rewarding, and this is an extremely powerful organizer and motivator of animal behavior. Mammalian studies have revealed interconnected neurobiological systems for reward learning, reward assessment, reinforcement and reward-seeking; all involving the biogenic amine dopamine. The neurobiology of reward-seeking behavioral systems is less well understood in invertebrates, but in many diverse invertebrate groups, reward learning and...

  17. Effects of Ketamine and Ketamine Metabolites on Evoked Striatal Dopamine Release, Dopamine Receptors, and Monoamine Transporters

    Science.gov (United States)

    Can, Adem; Zanos, Panos; Moaddel, Ruin; Kang, Hye Jin; Dossou, Katinia S. S.; Wainer, Irving W.; Cheer, Joseph F.; Frost, Douglas O.; Huang, Xi-Ping

    2016-01-01

    Following administration at subanesthetic doses, (R,S)-ketamine (ketamine) induces rapid and robust relief from symptoms of depression in treatment-refractory depressed patients. Previous studies suggest that ketamine’s antidepressant properties involve enhancement of dopamine (DA) neurotransmission. Ketamine is rapidly metabolized to (2S,6S)- and (2R,6R)-hydroxynorketamine (HNK), which have antidepressant actions independent of N-methyl-d-aspartate glutamate receptor inhibition. These antidepressant actions of (2S,6S;2R,6R)-HNK, or other metabolites, as well as ketamine’s side effects, including abuse potential, may be related to direct effects on components of the dopaminergic (DAergic) system. Here, brain and blood distribution/clearance and pharmacodynamic analyses at DA receptors (D1–D5) and the DA, norepinephrine, and serotonin transporters were assessed for ketamine and its major metabolites (norketamine, dehydronorketamine, and HNKs). Additionally, we measured electrically evoked mesolimbic DA release and decay using fast-scan cyclic voltammetry following acute administration of subanesthetic doses of ketamine (2, 10, and 50 mg/kg, i.p.). Following ketamine injection, ketamine, norketamine, and multiple hydroxynorketamines were detected in the plasma and brain of mice. Dehydronorketamine was detectable in plasma, but concentrations were below detectable limits in the brain. Ketamine did not alter the magnitude or kinetics of evoked DA release in the nucleus accumbens in anesthetized mice. Neither ketamine’s enantiomers nor its metabolites had affinity for DA receptors or the DA, noradrenaline, and serotonin transporters (up to 10 μM). These results suggest that neither the side effects nor antidepressant actions of ketamine or ketamine metabolites are associated with direct effects on mesolimbic DAergic neurotransmission. Previously observed in vivo changes in DAergic neurotransmission following ketamine administration are likely indirect. PMID

  18. De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder

    DEFF Research Database (Denmark)

    Hamilton, P J; Campbell, N G; Sharma, S

    2013-01-01

    De novo genetic variation is an important class of risk factors for autism spectrum disorder (ASD). Recently, whole-exome sequencing of ASD families has identified a novel de novo missense mutation in the human dopamine (DA) transporter (hDAT) gene, which results in a Thr to Met substitution...

  19. Effects of alkylating agents on dopamine D(3) receptors in rat brain: selective protection by dopamine.

    Science.gov (United States)

    Zhang, K; Weiss, N T; Tarazi, F I; Kula, N S; Baldessarini, R J

    1999-11-13

    Dopamine D(3) receptors are structurally highly homologous to other D(2)-like dopamine receptors, but differ from them pharmacologically. D(3) receptors are notably resistant to alkylation by 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), which readily alkylates D(2) receptors. We compared EEDQ with N-(p-isothiocyanatophenethyl)spiperone (NIPS), a selective D(2)-like receptor alkylating agent, for effects on D(3) and D(2) receptors in rat brain using autoradiographic analysis. Neither agent occluded D(3) receptors in vivo at doses that produced substantial blockade of D(2) receptors, even after catecholamine-depleting pretreatments. In vitro, however, D(3) receptors were readily alkylated by both NIPS (IC(50)=40 nM) and EEDQ (IC(50)=12 microM). These effects on D(3) sites were blocked by nM concentrations of dopamine, whereas microM concentrations were required to protect D(2) receptors from the alkylating agents. The findings are consistent with the view that alkylation of D(3) receptors in vivo is prevented by its high affinity for even minor concentrations of endogenous dopamine.

  20. Serotonin-S2 and dopamine-D2 receptors are the same size in membranes

    International Nuclear Information System (INIS)

    Brann, M.R.

    1985-01-01

    Target size analysis was used to compare the sizes of serotonin-S2 and dopamine-D2 receptors in rat brain membranes. The sizes of these receptors were standardized by comparison with the muscarinic receptor, a receptor of known size. The number of serotonin-S2 receptors labeled with (3H)ketanserin or (3H)spiperone in frontal cortex decreased as an exponential function of radiation dose, and receptor affinity was not affected. The number of dopamine-D2 receptors labeled with (3H)spiperone in striatum also decreased as an exponential function of radiation dose, and D2 and S2 receptors were equally sensitive to radiation. In both striatum and frontal cortex, the number of muscarinic receptors labeled with (3H)QNB decreased as an exponential function of radiation dose, and were much less sensitive to radiation than S2 and D2 receptors. These data indicate that in rat brain membranes, S2 and D2 receptors are of similar size, and both molecules are much larger than the muscarinic receptor

  1. Dopamine, fronto-striato-thalamic circuits and risk for psychosis.

    Science.gov (United States)

    Dandash, Orwa; Pantelis, Christos; Fornito, Alex

    2017-02-01

    A series of parallel, integrated circuits link distinct regions of prefrontal cortex with specific nuclei of the striatum and thalamus. Dysfunction of these fronto-striato-thalamic systems is thought to play a major role in the pathogenesis of psychosis. In this review, we examine evidence from human and animal investigations that dysfunction of a specific dorsal fronto-striato-thalamic circuit, linking the dorsolateral prefrontal cortex, dorsal (associative) striatum, and mediodorsal nucleus of the thalamus, is apparent across different stages of psychosis, including prior to the onset of a first episode, suggesting that it represents a candidate risk biomarker. We consider how abnormalities at distinct points in the circuit may give rise to the pattern of findings seen in patient populations, and how these changes relate to disruptions in dopamine, glutamate and GABA signaling. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Serotonin transporter and dopamine transporter imaging in the canine brain

    Energy Technology Data Exchange (ETDEWEB)

    Peremans, Kathelijne [Department of Medical Imaging, Faculty of Veterinary Sciences, Ghent University, B-9000 Ghent (Belgium); Goethals, Ingeborg [Division of Nuclear Medicine, University Hospital Ghent, B-9000 Ghent (Belgium); De Vos, Filip [Laboratory of Radiopharmacy, Pharmaceutical Sciences, Ghent University, B-9000 Ghent (Belgium); Dobbeleir, A. [Department of Medical Imaging, Faculty of Veterinary Sciences, Ghent University, B-9000 Ghent (Belgium); Ham, Hamphrey [Division of Nuclear Medicine, University Hospital Ghent, B-9000 Ghent (Belgium); Van Bree, Henri [Department of Medical Imaging, Faculty of Veterinary Sciences, Ghent University, B-9000 Ghent (Belgium); Heeringen, Cees van [Department of Psychiatry and Medical Psychology, Faculty of Medical and Health Sciences, Ghent University, B-9000, Ghent (Belgium); Audenaert, Kurt [Division of Nuclear Medicine, University Hospital Ghent, B-9000 Ghent (Belgium) and Department of Psychiatry and Medical Psychology, Faculty of Medical and Health Sciences, Ghent University, B-9000, Ghent (Belgium)]. E-mail: kurt.audenaert@ugent.be

    2006-10-15

    The serotonergic and dopaminergic systems are involved in a wide range of emotional and behavioral aspects of animals and humans and are involved in many neuropsychiatric disorders. Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are designed to block the 5-HT transporter (SERT), thereby increasing the available 5-HT in the brain. Functional imaging with specific SERT and dopamine transporter (DAT) ligands contributes to the study of the SSRI-transporter interaction. First, we evaluated the feasibility of a canine model in the study of the SERT and DAT with the radioligands [{sup 123}I]-{beta}-CIT and [{sup 123}I]-FP-CIT as well as single-photon emission computed tomography imaging. Second, we studied the effect of SSRIs (sertraline, citalopram and escitalopram) on the SERT and DAT in two dogs. The position of the canine model in the study of the SERT and DAT is discussed and compared with other animal models.

  3. Serotonin transporter and dopamine transporter imaging in the canine brain

    International Nuclear Information System (INIS)

    Peremans, Kathelijne; Goethals, Ingeborg; De Vos, Filip; Dobbeleir, A.; Ham, Hamphrey; Van Bree, Henri; Heeringen, Cees van; Audenaert, Kurt

    2006-01-01

    The serotonergic and dopaminergic systems are involved in a wide range of emotional and behavioral aspects of animals and humans and are involved in many neuropsychiatric disorders. Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are designed to block the 5-HT transporter (SERT), thereby increasing the available 5-HT in the brain. Functional imaging with specific SERT and dopamine transporter (DAT) ligands contributes to the study of the SSRI-transporter interaction. First, we evaluated the feasibility of a canine model in the study of the SERT and DAT with the radioligands [ 123 I]-β-CIT and [ 123 I]-FP-CIT as well as single-photon emission computed tomography imaging. Second, we studied the effect of SSRIs (sertraline, citalopram and escitalopram) on the SERT and DAT in two dogs. The position of the canine model in the study of the SERT and DAT is discussed and compared with other animal models

  4. Dopamine Modulates Adaptive Prediction Error Coding in the Human Midbrain and Striatum.

    Science.gov (United States)

    Diederen, Kelly M J; Ziauddeen, Hisham; Vestergaard, Martin D; Spencer, Tom; Schultz, Wolfram; Fletcher, Paul C

    2017-02-15

    Learning to optimally predict rewards requires agents to account for fluctuations in reward value. Recent work suggests that individuals can efficiently learn about variable rewards through adaptation of the learning rate, and coding of prediction errors relative to reward variability. Such adaptive coding has been linked to midbrain dopamine neurons in nonhuman primates, and evidence in support for a similar role of the dopaminergic system in humans is emerging from fMRI data. Here, we sought to investigate the effect of dopaminergic perturbations on adaptive prediction error coding in humans, using a between-subject, placebo-controlled pharmacological fMRI study with a dopaminergic agonist (bromocriptine) and antagonist (sulpiride). Participants performed a previously validated task in which they predicted the magnitude of upcoming rewards drawn from distributions with varying SDs. After each prediction, participants received a reward, yielding trial-by-trial prediction errors. Under placebo, we replicated previous observations of adaptive coding in the midbrain and ventral striatum. Treatment with sulpiride attenuated adaptive coding in both midbrain and ventral striatum, and was associated with a decrease in performance, whereas bromocriptine did not have a significant impact. Although we observed no differential effect of SD on performance between the groups, computational modeling suggested decreased behavioral adaptation in the sulpiride group. These results suggest that normal dopaminergic function is critical for adaptive prediction error coding, a key property of the brain thought to facilitate efficient learning in variable environments. Crucially, these results also offer potential insights for understanding the impact of disrupted dopamine function in mental illness. SIGNIFICANCE STATEMENT To choose optimally, we have to learn what to expect. Humans dampen learning when there is a great deal of variability in reward outcome, and two brain regions that

  5. Reports of pathological gambling, hypersexuality, and compulsive shopping associated with dopamine receptor agonist drugs.

    Science.gov (United States)

    Moore, Thomas J; Glenmullen, Joseph; Mattison, Donald R

    2014-12-01

    Severe impulse control disorders involving pathological gambling, hypersexuality, and compulsive shopping have been reported in association with the use of dopamine receptor agonist drugs in case series and retrospective patient surveys. These agents are used to treat Parkinson disease, restless leg syndrome, and hyperprolactinemia. To analyze serious adverse drug event reports about these impulse control disorders received by the US Food and Drug Administration (FDA) and to assess the relationship of these case reports with the 6 FDA-approved dopamine receptor agonist drugs. We conducted a retrospective disproportionality analysis based on the 2.7 million serious domestic and foreign adverse drug event reports from 2003 to 2012 extracted from the FDA Adverse Event Reporting System. Cases were selected if they contained any of 10 preferred terms in the Medical Dictionary for Regulatory Activities (MedDRA) that described the abnormal behaviors. We used the proportional reporting ratio (PRR) to compare the proportion of target events to all serious events for the study drugs with a similar proportion for all other drugs. We identified 1580 events indicating impulse control disorders from the United States and 21 other countries:710 fordopamine receptor agonist drugs and 870 for other drugs. The dopamine receptor agonist drugs had a strong signal associated with these impulse control disorders (n = 710; PRR = 277.6, P < .001). The association was strongest for the dopamine agonists pramipexole (n = 410; PRR = 455.9, P < .001) and ropinirole (n = 188; PRR = 152.5, P < .001), with preferential affinity for the dopamine D3 receptor. A signal was also seen for aripiprazole, an antipsychotic classified as a partial agonist of the D3 receptor (n = 37; PRR = 8.6, P < .001). Our findings confirm and extend the evidence that dopamine receptor agonist drugs are associated with these specific impulse control disorders. At present

  6. Dopamine in the Brain: Hypothesizing Surfeit or Deficit Links to Reward and Addiction.

    Science.gov (United States)

    Blum, Kenneth; Thanos, Peter K; Oscar-Berman, Marlene; Febo, Marcelo; Baron, David; Badgaiyan, Rajendra D; Gardner, Eliot; Demetrovics, Zsolt; Fahlke, Claudia; Haberstick, Brett C; Dushaj, Kristina; Gold, Mark S

    Recently there has been debate concerning the role of brain dopamine in reward and addiction. David Nutt and associates eloquently proposed that dopamine (DA) may be central to psycho stimulant dependence and some what important for alcohol, but not important for opiates, nicotine or even cannabis. Others have also argued that surfeit theories can explain for example cocaine seeking behavior as well as non-substance-related addictive behaviors. It seems prudent to distinguish between what constitutes "surfeit" compared to" deficit" in terms of short-term (acute) and long-term (chronic) brain reward circuitry responsivity. In an attempt to resolve controversy regarding the contributions of mesolimbic DA systems to reward, we review the three main competing explanatory categories: "liking", "learning", and "wanting". They are (a) the hedonic impact -liking reward, (b) the ability to predict rewarding effects-learning and (c) the incentive salience of reward-related stimuli -wanting. In terms of acute effects, most of the evidence seems to favor the "surfeit theory". Due to preferential dopamine release at mesolimbic-VTA-caudate-accumbens loci most drugs of abuse and Reward Deficiency Syndrome (RDS) behaviors have been linked to heightened feelings of well-being and hyperdopaminergic states.The "dopamine hypotheses" originally thought to be simple, is now believed to be quite complex and involves encoding the set point of hedonic tone, encoding attention, reward expectancy, and incentive motivation. Importantly, Willuhn et al. shows that in a self-administration paradigm, (chronic) excessive use of cocaine is caused by decreased phasic dopamine signaling in the striatum. In terms of chronic addictions, others have shown a blunted responsivity at brain reward sites with food, nicotine, and even gambling behavior. Finally, we are cognizant of the differences in dopaminergic function as addiction progresses and argue that relapse may be tied to dopamine deficiency

  7. Caste differences in the association between dopamine and reproduction in the bumble bee Bombus ignitus.

    Science.gov (United States)

    Sasaki, Ken; Matsuyama, Hinako; Morita, Naruaki; Ono, Masato

    2017-11-01

    A society of bumble bees is primitively eusocial, with an annual life cycle, and can be used as a physiological model of social bees for comparative studies with highly eusocial hymenopterans. We investigated the dynamics of biogenic amine levels in the brain, meso-metathoracic ganglia, terminal abdominal ganglion, and hemolymph in queens 1 day after mating (1DAM), during diapause (Dp), and during colony founding (CF) in the bumble bee, Bombus ignitus. Dopamine levels in the brain of CF queens were significantly lower than in 1DAM and Dp queens, and the levels in the thoracic ganglia and hemolymph in CF queens were lower than in 1DAM queens, but did not differ from other groups in the abdominal ganglion. Octopamine levels in the brains were higher in Dp queens than in 1DAM queens. Serotonin and tyramine levels did not differ between the groups in different compartments of the central nervous system (CNS) that we examined. The dopamine levels in the brains were significantly positively correlated with those in the thoracic ganglia, abdominal ganglion, and hemolymph, suggesting the regulation of dopamine levels among three different compartments of the CNS. In isolated virgin queens, there were no significant correlations between the brain levels of biogenic amines that we examined and the lengths of the largest terminal oocytes, whereas, in isolated workers, the brain dopamine levels were positively correlated with oocyte lengths. These results suggest that dopamine is associated with ovarian activity in reproductive workers, but not in either virgin or mated queens. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. The roles of dopamine and serotonin in decision making: evidence from pharmacological experiments in humans.

    Science.gov (United States)

    Rogers, Robert D

    2011-01-01

    Neurophysiological experiments in primates, alongside neuropsychological and functional magnetic resonance investigations in humans, have significantly enhanced our understanding of the neural architecture of decision making. In this review, I consider the more limited database of experiments that have investigated how dopamine and serotonin activity influences the choices of human adults. These include those experiments that have involved the administration of drugs to healthy controls, experiments that have tested genotypic influences upon dopamine and serotonin function, and, finally, some of those experiments that have examined the effects of drugs on the decision making of clinical samples. Pharmacological experiments in humans are few in number and face considerable methodological challenges in terms of drug specificity, uncertainties about pre- vs post-synaptic modes of action, and interactions with baseline cognitive performance. However, the available data are broadly consistent with current computational models of dopamine function in decision making and highlight the dissociable roles of dopamine receptor systems in the learning about outcomes that underpins value-based decision making. Moreover, genotypic influences on (interacting) prefrontal and striatal dopamine activity are associated with changes in choice behavior that might be relevant to understanding exploratory behaviors and vulnerability to addictive disorders. Manipulations of serotonin in laboratory tests of decision making in human participants have provided less consistent results, but the information gathered to date indicates a role for serotonin in learning about bad decision outcomes, non-normative aspects of risk-seeking behavior, and social choices involving affiliation and notions of fairness. Finally, I suggest that the role played by serotonin in the regulation of cognitive biases, and representation of context in learning, point toward a role in the cortically mediated cognitive

  9. Unilateral Lesion of Dopamine Neurons Induces Grooming Asymmetry in the Mouse.

    Science.gov (United States)

    Pelosi, Assunta; Girault, Jean-Antoine; Hervé, Denis

    2015-01-01

    Grooming behaviour is the most common innate behaviour in animals. In rodents, it consists of sequences of movements organized in four phases, executed symmetrically on both sides of the animal and creating a syntactic chain of behavioural events. The grooming syntax can be altered by stress and novelty, as well as by several mutations and brain lesions. Grooming behaviour is known to be affected by alterations of the dopamine system, including dopamine receptor modulation, dopamine alteration in genetically modified animals, and after brain lesion. While a lot is known about the initiation and syntactic modifications of this refined sequence of movements, effects of unilateral lesion of dopamine neurons are unclear particularly regarding the symmetry of syntactic chains. In the present work we studied grooming in mice unilaterally lesioned in the medial forebrain bundle by 6-hydroxydopamine. We found a reduction in completion of grooming bouts, associated with reduction in number of transitions between grooming phases. The data also revealed the development of asymmetry in grooming behaviour, with reduced tendency to groom the contralateral side to the lesion. Symmetry was recovered following treatment with L-DOPA. Thus, the present work shows that unilateral lesion of dopamine neurons reduces self-grooming behaviour by affecting duration and numbers of events. It produces premature discontinuation of grooming chains but the sequence syntax remains correct. This deficient grooming could be considered as an intrinsic symptom of Parkinson's disease in animal models and could present some similarities with abnormalities of motor movement sequencing seen in patients. Our study also suggests grooming analysis as an additional method to screen parkinsonism in animal models.

  10. Dopamine modulates hemocyte phagocytosis via a D1-like receptor in the rice stem borer, Chilo suppressalis

    Science.gov (United States)

    Dopamine (DA) is a signal moiety bridging the nervous and immune systems. DA dysregulation is linked to serious human diseases, including addiction, schizophrenia, and Parkinson's disease. However, DA actions in the immune system remain incompletely understood. In this study, we found that DA modula...

  11. Dopamine transporter imaging in rapid eye movement sleep behavior disorder

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Yu Kyeong; Yoon, In Young; Kim, Jong Min; Jeong, Seok Hoon; Kim, Ji Sun; Lee, Byung Chul; Lee, Won Woo; Kim, Sang Eun [Seoul National Univ. College of Medicine, Seoul (Korea, Republic of)

    2007-07-01

    The pathogenesis of rapid eye movement (REM) sleep behavior disorder (RBD) is still unknown. However, involvement of dopaminergic system in RBD has been hypothesized because of frequent association with degenerative movement disorders such as Parkinson's disease. The purpose of this study was to examine the extent and pattern of loss of dopamine transporter in RBD using FP-CIT SPECT. Fourteen patient with idiopathic RBD (mean age:665 yrs, M:F=10:3) participated in this study. Polysonmography confirmed loss of REM atonia and determined RBD severities by amount of tonic/phasic muscle activity during REM sleep in all cases. To compare with RBD, 14 early idiopathic Parkinson's disease rated as Hoehn and Yahr stage 1 (IPD) and 12 healthy controls were also selected. All participants performed single-photon emission computed tomography (SPECT) imaging 3 hours after injection of [123I]FP-CIT. Regions of interest were drawn on bilateral caudate and putamen, whole striatum and occipital cortex. Specific binding for dopamine transporters (DAT) were calculated using region to occipital uptake ratio based on the transient equilibrium method. Overall mean of DAT density in the striatum was lower in RBD group than controls, and higher than IPD group, However, DAT density in most individual RBD was still within normal range, and total striatal DAT density was not correlated with severity of RBD. Meanwhile, the caudate to putamen uptake ratio (C/P ratio) in RBD group was insignificantly higher than those in healthy controls. Nevertheless, C/P ratio within RBD group was reversely correlated with the RBD severity. Our study suggested that nigrostriatal dopaminergic degeneration could be a part of the pathogenesis of RBD, but not essential for the development of RBD. Further longitudinal evaluation of presynaptic dopaminergic system in idiopathic RBD may guarantee the more understanding for RBD and associated neurodegenerative disease.

  12. Dopamine transporter imaging in rapid eye movement sleep behavior disorder

    International Nuclear Information System (INIS)

    Kim, Yu Kyeong; Yoon, In Young; Kim, Jong Min; Jeong, Seok Hoon; Kim, Ji Sun; Lee, Byung Chul; Lee, Won Woo; Kim, Sang Eun

    2007-01-01

    The pathogenesis of rapid eye movement (REM) sleep behavior disorder (RBD) is still unknown. However, involvement of dopaminergic system in RBD has been hypothesized because of frequent association with degenerative movement disorders such as Parkinson's disease. The purpose of this study was to examine the extent and pattern of loss of dopamine transporter in RBD using FP-CIT SPECT. Fourteen patient with idiopathic RBD (mean age:665 yrs, M:F=10:3) participated in this study. Polysonmography confirmed loss of REM atonia and determined RBD severities by amount of tonic/phasic muscle activity during REM sleep in all cases. To compare with RBD, 14 early idiopathic Parkinson's disease rated as Hoehn and Yahr stage 1 (IPD) and 12 healthy controls were also selected. All participants performed single-photon emission computed tomography (SPECT) imaging 3 hours after injection of [123I]FP-CIT. Regions of interest were drawn on bilateral caudate and putamen, whole striatum and occipital cortex. Specific binding for dopamine transporters (DAT) were calculated using region to occipital uptake ratio based on the transient equilibrium method. Overall mean of DAT density in the striatum was lower in RBD group than controls, and higher than IPD group, However, DAT density in most individual RBD was still within normal range, and total striatal DAT density was not correlated with severity of RBD. Meanwhile, the caudate to putamen uptake ratio (C/P ratio) in RBD group was insignificantly higher than those in healthy controls. Nevertheless, C/P ratio within RBD group was reversely correlated with the RBD severity. Our study suggested that nigrostriatal dopaminergic degeneration could be a part of the pathogenesis of RBD, but not essential for the development of RBD. Further longitudinal evaluation of presynaptic dopaminergic system in idiopathic RBD may guarantee the more understanding for RBD and associated neurodegenerative disease

  13. Increased dopamine tone during meditation-induced change of consciousness

    DEFF Research Database (Denmark)

    Kjaer, Troels W; Bertelsen, Camilla; Piccini, Paola

    2002-01-01

    -raclopride PET scans: one while attending to speech with eyes closed, and one during active meditation. The tracer competes with endogenous dopamine for access to dopamine D2 receptors predominantly found in the basal ganglia. During meditation, 11C-raclopride binding in ventral striatum decreased by 7...

  14. Modafinil-Induced Increases in Brain Dopamine Levels

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2009-04-01

    Full Text Available The acute effects of modafinil on extracellular dopamine and on dopamine transporters in the male human brain were measured by PET study in 10 healthy subjects at Brookhaven National Laboratory and National Institute on Drug Abuse, Bethesda, MD.

  15. Dopamine D2 receptors in the pathophysiology of insulin resistance

    NARCIS (Netherlands)

    Leeuw van Weenen, Judith Elisabeth de

    2011-01-01

    Extensive literature links the dopamine receptor D2 to insulin resistance and diabetes mellitus type 2. However, many aspects of the functional relationship remain unclear. In this thesis we focused on unraveling the characteristics of the interplay between dopamine D2 receptors and glucose

  16. CRYSTAL STRUCTURE OF HUMAN DOPAMINE BETA-HYDROXYLASE

    DEFF Research Database (Denmark)

    2017-01-01

    A crystalline form of dopamine β-hydroxylase is provided. X-ray crystallography reveals the space group and cell dimensions, as well as the atomic coordinates. The information can be used for identifying one or more modulators of dopamine β-hydroxylase, which can then be chemically synthesised...

  17. Emerging role of dopamine in neovascularization of pheochromocytoma and paraganglioma

    NARCIS (Netherlands)

    Osinga, Thamara E; Links, Thera P; Dullaart, Robin P F; Pacak, Karel; Horst-Schrivers, van der Anouk; Kerstens, Michiel N.; Kema, Ido P

    Dopamine is a catecholamine that acts both as a neurotransmitter and as a hormone, exerting its functions via dopamine (DA) receptors that are present in a broad variety of organs and cells throughout the body. In the circulation, DA is primarily stored in and transported by blood platelets.

  18. Free and conjugated dopamine in human ventricular fluid

    International Nuclear Information System (INIS)

    Sharpless, N.S.; Thal, L.J.; Wolfson, L.I.; Tabaddor, K.; Tyce, G.M.; Waltz, J.M.

    1981-01-01

    Free dopamine and an acid hydrolyzable conjugate of dopamine were measured in human ventricular fluid specimens with a radioenzymatic assay and by high performance liquid chromatography (HPLC) with electrochemical detection. Only trace amounts of free norepinephrine and dopamine were detected in ventricular fluid from patients with movement disorders. When the ventricular fluid was hydrolyzed by heating in HClO 4 or by lyophilization in dilute HClO 4 , however, a substantial amount of free dopamine was released. Values for free plus conjugated dopamine in ventricular fluid from patients who had never taken L-DOPA ranged from 139 to 340 pg/ml when determined by HPLC and from 223 to 428 pg/ml when measured radioenzymatically. The correlation coefficient for values obtained by the two methods in the same sample of CSF was 0.94 (P<0.001). Patients who had been treated with L-DOPA had higher levels of conjugated dopamine in their ventricular CSF which correlated inversely with the time between the last dose of L-DOPA and withdrawal of the ventricular fluid. Additionally, one patient with acute cerebral trauma had elevated levels of free norepinephrine and both free and conjugated dopamine in his ventricular fluid. Conjugation may be an important inactivation pathway for released dopamine in man. (Auth.)

  19. Modelling the active site properties of dopamine b-hydroxylase

    Indian Academy of Sciences (India)

    Administrator

    Dopamine b-hydroxylase (DbH) is a copper-containing glycoprotein that hydroxylates dopamine to norepinephrine 1,2. Based on spectroscopic studies the active site of the metalloenzyme is proposed to have two copper centres. The enzyme in the oxidized dicopper(II) form gets reduced to the dicopper(I) unit by ascorbate ...

  20. Dopamine agonist: pathological gambling and hypersexuality.

    Science.gov (United States)

    2008-10-01

    (1) Pathological gambling and increased sexual activity can occur in patients taking dopaminergic drugs. Detailed case reports and small case series mention serious familial and social consequences. The frequency is poorly documented; (2) Most affected patients are being treated for Parkinson's disease, but cases have been reported among patients prescribed a dopamine agonist for restless legs syndrome or pituitary adenoma; (3) Patients treated with this type of drug, and their relatives, should be informed of these risks so that they can watch for changes in behaviour. If such disorders occur, it may be necessary to reduce the dose or to withdraw the drug or replace it with another medication.

  1. Dopamine-independent locomotor actions of amphetamines in a novel acute mouse model of Parkinson disease.

    Directory of Open Access Journals (Sweden)

    2005-08-01

    Full Text Available Brain dopamine is critically involved in movement control, and its deficiency is the primary cause of motor symptoms in Parkinson disease. Here we report development of an animal model of acute severe dopamine deficiency by using mice lacking the dopamine transporter. In the absence of transporter-mediated recycling mechanisms, dopamine levels become entirely dependent on de novo synthesis. Acute pharmacological inhibition of dopamine synthesis in these mice induces transient elimination of striatal dopamine accompanied by the development of a striking behavioral phenotype manifested as severe akinesia, rigidity, tremor, and ptosis. This phenotype can be reversed by administration of the dopamine precursor, L-DOPA, or by nonselective dopamine agonists. Surprisingly, several amphetamine derivatives were also effective in reversing these behavioral abnormalities in a dopamine-independent manner. Identification of dopamine transporter- and dopamine-independent locomotor actions of amphetamines suggests a novel paradigm in the search for prospective anti-Parkinsonian drugs.

  2. Dopamine release in ventral striatum of pathological gamblers losing money

    DEFF Research Database (Denmark)

    Linnet, J; Peterson, E; Doudet, D J

    2010-01-01

    Linnet J, Peterson E, Doudet DJ, Gjedde A, Møller A. Dopamine release in ventral striatum of pathological gamblers losing money. Objective: To investigate dopaminergic neurotransmission in relation to monetary reward and punishment in pathological gambling. Pathological gamblers (PG) often continue...... gambling despite losses, known as 'chasing one's losses'. We therefore hypothesized that losing money would be associated with increased dopamine release in the ventral striatum of PG compared with healthy controls (HC). Method: We used Positron Emission Tomography (PET) with [(11)C]raclopride to measure...... dopamine release in the ventral striatum of 16 PG and 15 HC playing the Iowa Gambling Task (IGT). Results: PG who lost money had significantly increased dopamine release in the left ventral striatum compared with HC. PG and HC who won money did not differ in dopamine release. Conclusion: Our findings...

  3. Surface functionalization of polyamide fiber via dopamine polymerization

    Science.gov (United States)

    Kuang, Xiao-Hui; Guan, Jin-Ping; Tang, Ren-Cheng; Chen, Guo-Qiang

    2017-09-01

    The oxidative polymerization of dopamine for the functional surface modification of textile fibers has drawn great attention. In this work, the functionalization of polyamide fiber via dopamine polymerization was studied with the aim of the fabrication of hydrophilic and antistatic surface. The conditions of dopamine application were first discussed in the absence of specific oxidants in terms of the apparent color depth of polyamide fiber. Dopamine concentration, pH and time were found to exert great impact on color depth. The highest color depth was achieved at pH 8.5. In the process of modification, polydopamine was deposited onto the surface of polyamide fiber. The modified polyamide fiber displayed a yellowish brown color with excellent wash and light color fastness, and exhibited good hydrophilic, UV protection and antistatic effects. A disadvantage of the present approach was the slow rate of dopamine polymerization and functionalization.

  4. A causal link between prediction errors, dopamine neurons and learning.

    Science.gov (United States)

    Steinberg, Elizabeth E; Keiflin, Ronald; Boivin, Josiah R; Witten, Ilana B; Deisseroth, Karl; Janak, Patricia H

    2013-07-01

    Situations in which rewards are unexpectedly obtained or withheld represent opportunities for new learning. Often, this learning includes identifying cues that predict reward availability. Unexpected rewards strongly activate midbrain dopamine neurons. This phasic signal is proposed to support learning about antecedent cues by signaling discrepancies between actual and expected outcomes, termed a reward prediction error. However, it is unknown whether dopamine neuron prediction error signaling and cue-reward learning are causally linked. To test this hypothesis, we manipulated dopamine neuron activity in rats in two behavioral procedures, associative blocking and extinction, that illustrate the essential function of prediction errors in learning. We observed that optogenetic activation of dopamine neurons concurrent with reward delivery, mimicking a prediction error, was sufficient to cause long-lasting increases in cue-elicited reward-seeking behavior. Our findings establish a causal role for temporally precise dopamine neuron signaling in cue-reward learning, bridging a critical gap between experimental evidence and influential theoretical frameworks.

  5. Graphene-loaded nanofiber-modified electrodes for the ultrasensitive determination of dopamine

    Energy Technology Data Exchange (ETDEWEB)

    Rodthongkum, Nadnudda, E-mail: Nadnudda.R@chula.ac.th [Metallurgy and Materials Science Research Institute, Chulalongkorn University, Pathumwan, Bangkok 10330 (Thailand); Ruecha, Nipapan [Program in Macromolecular Science, Faculty of Science, Chulalongkorn University, Pathumwan, Bangkok 10330 (Thailand); Rangkupan, Ratthapol [Metallurgy and Materials Science Research Institute, Chulalongkorn University, Pathumwan, Bangkok 10330 (Thailand); Center of Innovative Nanotechnology, Chulalongkorn University, Pathumwan, Bangkok 10330 (Thailand); Vachet, Richard W. [Department of Chemistry, University of Massachusetts Amherst, Amherst, MA 01002 (United States); Chailapakul, Orawon, E-mail: corawon@chula.ac.th [Electrochemistry and Optical Spectroscopy Research Unit, Department of Chemistry, Faculty of Science, Chulalongkorn University, Pathumwan, Bangkok 10330 (Thailand)

    2013-12-04

    Graphical abstract: -- Highlights: •A novel electrode based on electrospun graphene/polyaniline/polystyrene nanofibers has been developed. •The proposed system provides ultrahigh sensitivity, good selectivity and wide linearity for the determination of dopamine. •This system was successfully applied to determine dopamine in complex biological environment with excellent reproducibility. -- Abstract: A novel and highly sensitive electrochemical system based on electrospun graphene/polyaniline/polystyrene (G/PANI/PS) nanofiber-modified screen-printed carbon electrodes has been developed for dopamine (DA) determination. A dramatic increase (9 times) in the current signal for the redox reaction of a standard, ferri/ferrocyanide [Fe(CN){sub 6}]{sup 3−/4−} couple was found when compared to an unmodified electrode. This modified electrode also exhibited favorable electron transfer kinetics and excellent electrocatalytic activity toward the oxidation of DA. When used together with square wave voltammetry (SWV), DA can be selectively determined in the presence of the common interferents (i.e. ascorbic acid and uric acid). Under optimal conditions, a very low limit of detection (0.05 nM) and limit of quantification (0.30 nM) were achieved for DA. In addition, a wide dynamic range of 0.1 nM to 100 μM was found for this electrode system. Finally, the system can be successfully applied to determine DA in complex biological environment (e.g. human serum, urine) with excellent reproducibility.

  6. The association between heroin expenditure and dopamine transporter availability--a single-photon emission computed tomography study.

    Science.gov (United States)

    Lin, Shih-Hsien; Chen, Kao Chin; Lee, Sheng-Yu; Chiu, Nan Tsing; Lee, I Hui; Chen, Po See; Yeh, Tzung Lieh; Lu, Ru-Band; Chen, Chia-Chieh; Liao, Mei-Hsiu; Yang, Yen Kuang

    2015-03-30

    One of the consequences of heroin dependency is a huge expenditure on drugs. This underlying economic expense may be a grave burden for heroin users and may lead to criminal behavior, which is a huge cost to society. The neuropsychological mechanism related to heroin purchase remains unclear. Based on recent findings and the established dopamine hypothesis of addiction, we speculated that expenditure on heroin and central dopamine activity may be associated. A total of 21 heroin users were enrolled in this study. The annual expenditure on heroin was assessed, and the availability of the dopamine transporter (DAT) was assessed by single-photon emission computed tomography (SPECT) using [(99m)TC]TRODAT-1. Parametric and nonparametric correlation analyses indicated that annual expenditure on heroin was significantly and negatively correlated with the availability of striatal DAT. After adjustment for potential confounders, the predictive power of DAT availability was significant. Striatal dopamine function may be associated with opioid purchasing behavior among heroin users, and the cycle of spiraling dysfunction in the dopamine reward system could play a role in this association. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  7. Dopamine D1 receptor activation regulates the expression of the estrogen synthesis gene aromatase B in radial glial cell

    Directory of Open Access Journals (Sweden)

    Lei eXing

    2015-09-01

    Full Text Available Radial glial cells (RGCs are abundant stem-like non-neuronal progenitors that are important for adult neurogenesis and brain repair, yet little is known about their regulation by neurotransmitters. Here we provide evidence for neuronal-glial interactions via a novel role for dopamine to stimulate RGC function. Goldfish were chosen as the model organism due to the abundance of RGCs and regenerative abilities of the adult central nervous system. A close anatomical relationship was observed between tyrosine hydroxylase-positive catecholaminergic cell bodies and axons and dopamine-D1 receptor expressing RGCs along the ventricular surface of telencephalon, a site of active neurogenesis. A primary cell culture model was established and immunofluorescence analysis indicates that in vitro RGCs from female goldfish retain their major characteristics in vivo, including expression of glial fibrillary acidic protein and brain lipid binding protein. The estrogen synthesis enzyme aromatase B is exclusively found in RGCs, but this is lost as cells differentiate to neurons and other glial types in adult teleost brain. Pharmacological experiments using the cultured RGCs established that specific activation of dopamine D1 receptors up-regulates aromatase B mRNA through a cyclic adenosine monophosphate-dependent molecular mechanism. These data indicate that dopamine enhances the steroidogenic function of this neuronal progenitor cell.

  8. Selection Based on FOXA2 Expression Is Not Sufficient to Enrich for Dopamine Neurons From Human Pluripotent Stem Cells

    Science.gov (United States)

    Aguila, Julio Cesar; Blak, Alexandra; van Arensbergen, Joris; Sousa, Amaia; Vázquez, Nerea; Aduriz, Ariane; Gayosso, Mayela; Lopez Mato, Maria Paz; Lopez de Maturana, Rakel; Hedlund, Eva; Sonntag, Kai-Christian

    2014-01-01

    Human embryonic and induced pluripotent stem cells are potential cell sources for regenerative approaches in Parkinson disease. Inductive differentiation protocols can generate midbrain dopamine neurons but result in heterogeneous cell mixtures. Therefore, selection strategies are necessary to obtain uniform dopamine cell populations. Here, we developed a selection approach using lentivirus vectors to express green fluorescent protein under the promoter region of FOXA2, a transcription factor that is expressed in the floor plate domain that gives rise to dopamine neurons during embryogenesis. We first validated the specificity of the vectors in human cell lines against a promoterless construct. We then selected FOXA2-positive neural progenitors from several human pluripotent stem cell lines, which demonstrated a gene expression profile typical for the ventral domain of the midbrain and floor plate, but failed to enrich for dopamine neurons. To investigate whether this was due to the selection approach, we overexpressed FOXA2 in neural progenitors derived from human pluripotent stem cell lines. FOXA2 forced expression resulted in an increased expression of floor plate but not mature neuronal markers. Furthermore, selection of the FOXA2 overexpressing fraction also failed to enrich for dopamine neurons. Collectively, our results suggest that FOXA2 is not sufficient to induce a dopaminergic fate in this system. On the other hand, our study demonstrates that a combined approach of promoter activation and lentivirus vector technology can be used as a versatile tool for the selection of a defined cell population from a variety of human pluripotent stem cell lines. PMID:25024431

  9. Serotonin/dopamine interactions in a hyperactive mouse: reduced serotonin receptor 1B activity reverses effects of dopamine transporter knockout.

    Directory of Open Access Journals (Sweden)

    Frank Scott Hall

    Full Text Available Knockout (KO mice that lack the dopamine transporter (SL6A3; DAT display increased locomotion that can be attenuated, under some circumstances, by administration of drugs that normally produce psychostimulant-like effects, such as amphetamine and methylphenidate. These results have led to suggestions that DAT KO mice may model features of attention deficit hyperactivity disorder (ADHD and that these drugs may act upon serotonin (5-HT systems to produce these unusual locomotor decreasing effects. Evidence from patterns of brain expression and initial pharmacologic studies led us to use genetic and pharmacologic approaches to examine the influence of altered 5-HT1B receptor activity on hyperactivity in DAT KO mice. Heterozygous 5-HT1B KO and pharmacologic 5-HT1B antagonism both attenuated locomotor hyperactivity in DAT KO mice. Furthermore, DAT KO mice with reduced, but not eliminated, 5-HT1B receptor expression regained cocaine-stimulated locomotion, which was absent in DAT KO mice with normal levels of 5-HT1B receptor expression. Further experiments demonstrated that the degree of habituation to the testing apparatus determined whether cocaine had no effect on locomotion in DAT KO or reduced locomotion, helping to resolve differences among prior reports. These findings of complementation of the locomotor effects of DAT KO by reducing 5-HT1B receptor activity underscore roles for interactions between specific 5-HT receptors and dopamine (DA systems in basal and cocaine-stimulated locomotion and support evaluation of 5-HT1B antagonists as potential, non-stimulant ADHD therapeutics.

  10. Dopamine receptors in the Parkinsonian brain

    International Nuclear Information System (INIS)

    Rinne, U.K.; Loennberg, P.; Koskinen, V.

    1981-01-01

    Striatal dopamine receptors were studied in 44 patients with Parkinson disease by the radioligand-binding technique using 3 H-spiroperidol. The specific binding of 3 H-spiroperidol was either significantly increased or reduced in the caudate nucleus and putamen of parkinsonian patients without levodopa therapy. Scatchard analysis showed that there were corresponding changes in the receptor number, but no significant changes in the mean dissociation constant. The increased binding of 3 H-spiroperidol in the basal ganglia was also found in parkinsonian patients suffering from psychotic episodes and treated with neuroleptic drugs. Normal and low binding of 3 H-spiroperidol was found in patients treated with levodopa. Clinically, the patient with low binding were more disabled and had lost the beneficial response to levodopa. Thus in Parkinson disease in some patients a denervation supersensitivity seemed to develop and in some others a loss of postsynaptic dopamine receptor sites in the neostriatium. The latter alteration may contribute to the decreased response of parkinsonian patients to chronic levodopa therapy. (author)

  11. Sex differences in the brain's dopamine signature of cigarette smoking.

    Science.gov (United States)

    Cosgrove, Kelly P; Wang, Shuo; Kim, Su-Jin; McGovern, Erin; Nabulsi, Nabeel; Gao, Hong; Labaree, David; Tagare, Hemant D; Sullivan, Jenna M; Morris, Evan D

    2014-12-10

    Cigarette smoking is a major public health danger. Women and men smoke for different reasons and cessation treatments, such as the nicotine patch, are preferentially beneficial to men. The biological substrates of these sex differences are unknown. Earlier PET studies reported conflicting findings but were each hampered by experimental and/or analytical limitations. Our new image analysis technique, lp-ntPET (Normandin et al., 2012; Morris et al., 2013; Kim et al., 2014), has been optimized for capturing brief (lasting only minutes) and highly localized dopaminergic events in dynamic PET data. We coupled our analysis technique with high-resolution brain scanning and high-frequency motion correction to create the optimal experiment for capturing and characterizing the effects of smoking on the mesolimbic dopamine system in humans. Our main finding is that male smokers smoking in the PET scanner activate dopamine in the right ventral striatum during smoking but female smokers do not. This finding-men activating more ventrally than women-is consistent with the established notion that men smoke for the reinforcing drug effect of cigarettes whereas women smoke for other reasons, such as mood regulation and cue reactivity. lp-ntPET analysis produces a novel multidimensional endpoint: voxel-level temporal patterns of neurotransmitter release ("DA movies") in individual subjects. By examining these endpoints quantitatively, we demonstrate that the timing of dopaminergic responses to cigarette smoking differs between men and women. Men respond consistently and rapidly in the ventral striatum whereas women respond faster in a discrete subregion of the dorsal putamen. Copyright © 2014 the authors 0270-6474/14/3416851-05$15.00/0.

  12. Biologic Effects of Dopamine on Tumor Vasculature in Ovarian Carcinoma

    Directory of Open Access Journals (Sweden)

    Myrthala Moreno-Smith

    2013-05-01

    Full Text Available Chronic sympathetic nervous system activation results in increased angiogenesis and tumor growth in orthotopic mouse models of ovarian carcinoma. However, the mechanistic effects of such activation on the tumor vasculature are not well understood. Dopamine (DA, an inhibitory catecholamine, regulates the functions of normal and abnormal blood vessels. Here, we examined whether DA, an inhibitory catecholamine, could block the effects of chronic stress on tumor vasculature and tumor growth. Exogenous administration of DA not only decreased tumor microvessel density but also increased pericyte coverage of tumor vessels following daily restraint stress in mice. Daily restraint stress resulted in significantly increased tumor growth in the SKOV3ip1 and HeyA8 ovarian cancer models. DA treatment blocked stress-mediated increases in tumor growth and increased pericyte coverage of tumor endothelial cells. Whereas the antiangiogenic effect of DA is mediated by dopamine receptor 2 (DR2, our data indicate that DA, through DR1, stimulates vessel stabilization by increasing pericyte recruitment to tumor endothelial cells. DA significantly stimulated migration of mouse 10T1/2 pericyte-like cells in vitro and increased cyclic adenosine mono-phosphate (cAMP levels in these cells. Moreover, DA or the DR1 agonist SKF 82958 increased platinum concentration in SKOV3ip1 tumor xenografts following cisplatin administration. In conclusion, DA stabilizes tumor blood vessels through activation of pericyte cAMP-protein kinase A signaling pathway by DR1. These findings could have implications for blocking the stimulatory effects of chronic stress on tumor growth.

  13. Dysregulation of Striatal Dopamine Receptor Binding in Suicide.

    Science.gov (United States)

    Fitzgerald, Megan L; Kassir, Suham A; Underwood, Mark D; Bakalian, Mihran J; Mann, J John; Arango, Victoria

    2017-03-01

    Inconsistent evidence implicates disruptions of striatal dopaminergic indices in suicide and major depression. To determine whether there are alterations in the striatal dopamine system in suicide, we conducted a quantitative autoradiographic survey of dopamine transporter (DAT; [ 3 H]mazindol), D1 receptor ([ 3 H]SCH23390), and D2 receptor ([ 3 H]sulpiride) binding in the dorsal striatum postmortem from matched suicides and controls. Axis I and axis II psychiatric diagnosis, recent treatment history, and early life adversity (ELA) were determined by psychological autopsy. Mean DAT, D2, and D1 receptor binding did not differ in suicide. However, there was a positive correlation between D1 and D2 receptor binding in the dorsal striatum of control subjects (R 2 =0.31, p<0.05) that was not present in suicides (R 2 =0.00, p=0.97). In suicides and controls with reported ELA, there was no correlation between striatal DAT and D1 receptor binding (R 2 =0.07, p=0.33), although DAT and D1 receptor binding was positively correlated in subjects with no report of ELA (R 2 =0.32, p<0.05). After controlling for age, there were no significant ELA-related mean differences. Binding of D1 receptors and DAT throughout the striatum correlated negatively with age (D1 receptor: R 2 =0.12, p<0.05; DAT: R 2 =0.36, p<0.001). There appears to be an imbalance in dopaminergic receptor and transporter expression related to suicide that differs from that associated with ELA or age.

  14. Synthesis of 3-[18F]fluoromethyl-BTCP and evaluation as a potential PET radioligand for the dopamine transporter in baboons

    International Nuclear Information System (INIS)

    Ponchant, M.; Crouzel, C.; Varastet, M.; Hantraye, P.;

    1993-01-01

    In an attempt to visualize in vivo the dopamine transporter and evaluate its potential as an imaging tool for monitoring dopamine fiber degeneration by positron emission tomography, the 18 F-positron-emitting analogue of 3-fluoromethyl-1-[2-benzothienyl)-cyclohexyl]-piperidine, [ 18 F]BTCP, was synthesized and tested in a primate model of hemiparkinsonism. When comparing binding ratios between the intact and the dopamine-denervated striatum, there was a modest loss of binding in denervated striatum, suggesting that degeneration of dopaminergic fibers could be detected using 3-[ 18 F]fluoromethyl-BTCP. However due to a high non-specific binding in vivo, the interest of 3-[ 18 F]fluoromethyl-BTCP to image the dopamine reuptake system in vivo appears limited. (author)

  15. Fabrication of Chitosan-gold Nanocomposites Combined with Optical Fiber as SERS Substrates to Detect Dopamine Molecules

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Jaewook; Kang, Ikjoong [Gachon Univ., Seongnam (Korea, Republic of)

    2014-01-15

    This research was aimed to fabricate an optical fiber-based SERS substrate which can detect dopamine neurotransmitters. Chitosan nanoparticles (NPs) were firstly anchored on the surface of optical fiber, and then gold layer was subseque N{sub T}ly deposited on the anchored chitosan NPs via electroless plating method. Finally, chitosan-gold nanocomposites combined with optical fiber reacted with dopamine molecules of 100-1500 mg/ day which is a standard daily dose for Parkinson's disease patientss. The amplified Raman signal at 1348 cm{sup -1} obtained from optical fiber-based SERS substrate was plotted versus dopamine concentrations (1-10 mM), demonstrating an approximate linearity of Y = 303.03X + 2385.8 (R{sup 2} = 0.97) with narrow margin errors. The optical fiber-based Raman system can be potentially applicable to in-vitro (or in-vivo) detection of probe molecules.

  16. Pharmacological profile of the abeorphine 201-678, a potent orally active and long lasting dopamine agonist

    Energy Technology Data Exchange (ETDEWEB)

    Jaton, A.L.; Giger, R.K.A.; Vigouret, J.M.; Enz, A.; Frick, W.; Closse, A.; Markstein, R.

    1986-01-13

    The central dopaminergic effects of an abeorphine derivative 201-678 were compared to those of apomorphine and bromocriptine in different model systems. After oral administration, this compound induced contralateral turning in rats with 6-hydroxydopamine induced nigral lesions and exhibited strong anti-akinetic properties in rats with 6-hydroxydopamine induced hypothalamic lesions. It decreased dopamine metabolism in striatum and cortex, but did not modify noradrenaline and serotonin metabolism in the rat brain. 201-678 counteracted the in vivo increase of tyrosine hydroxylase activity induced by ..gamma..-butyrolactone. In vitro it stimulated DA-sensitive adenylate cyclase and inhibited acetylcholine release from rat striatal slices. This compound had high affinity for /sup 3/H-dopamine and /sup 3/H-clonidine binding sites. These results indicate that 201-678 is a potent, orally active dopamine agonist with a long duration of action. Furthermore it appears more selective than other dopaminergic drugs. 29 references, 5 figures, 3 tables.

  17. No evidence of association between structural polymorphism at the dopamine D3 receptor locus and alcoholism in the Japanese

    Energy Technology Data Exchange (ETDEWEB)

    Higuchi, Susumu; Muramatsu, Taro; Matsushita, Sachio [National Institute on Alcoholism, Kanagawa (Japan); Murayama, Masanobu [Akagi Kougen Hospital, Gunma (Japan)

    1996-07-26

    Dopaminergic systems mediate reward mechanisms and are involved in reinforcing self-administration of dependence-forming substances, including alcohol. Studies have reported that polymorphisms of the dopamine D2 receptor, whose structure and function are similar to those of the dopamine D3 receptor, increase the susceptibility to alcoholism. The observations led to the examination of the possible association between a structural polymorphism of the D3 receptor gene and alcoholism. Genotyping results, employing a PCR-RFLP method, showed no difference in allele and genotype frequencies of the D3 BalI polymorphism (Ser{sup 9}/Gly{sup 9}) between Japanese alcoholics and controls. Moreover, these frequencies were not altered in alcoholics with inactive aldehyde dehydrogenase-2 (ALDH2), a well-defined negative risk factor for alcoholism. These results strongly suggest that the dopamine D3 receptor is not associated with alcoholism. 19 refs., 1 fig., 1 tab.

  18. α2A- and α2C-Adrenoceptors as Potential Targets for Dopamine and Dopamine Receptor Ligands.

    Science.gov (United States)

    Sánchez-Soto, Marta; Casadó-Anguera, Verònica; Yano, Hideaki; Bender, Brian Joseph; Cai, Ning-Sheng; Moreno, Estefanía; Canela, Enric I; Cortés, Antoni; Meiler, Jens; Casadó, Vicent; Ferré, Sergi

    2018-03-18

    The poor norepinephrine innervation and high density of Gi/o-coupled α 2A - and α 2C -adrenoceptors in the striatum and the dense striatal dopamine innervation have prompted the possibility that dopamine could be an effective adrenoceptor ligand. Nevertheless, the reported adrenoceptor agonistic properties of dopamine are still inconclusive. In this study, we analyzed the binding of norepinephrine, dopamine, and several compounds reported as selective dopamine D 2 -like receptor ligands, such as the D 3 receptor agonist 7-OH-PIPAT and the D 4 receptor agonist RO-105824, to α 2 -adrenoceptors in cortical and striatal tissue, which express α 2A -adrenoceptors and both α 2A - and α 2C -adrenoceptors, respectively. The affinity of dopamine for α 2 -adrenoceptors was found to be similar to that for D 1 -like and D 2 -like receptors. Moreover, the exogenous dopamine receptor ligands also showed high affinity for α 2A - and α 2C -adrenoceptors. Their ability to activate Gi/o proteins through α 2A - and α 2C -adrenoceptors was also analyzed in transfected cells with bioluminescent resonance energy transfer techniques. The relative ligand potencies and efficacies were dependent on the Gi/o protein subtype. Furthermore, dopamine binding to α 2 -adrenoceptors was functional, inducing changes in dynamic mass redistribution, adenylyl cyclase activity, and ERK1/2 phosphorylation. Binding events were further studied with computer modeling of ligand docking. Docking of dopamine at α 2A - and α 2C -adrenoceptors was nearly identical to its binding to the crystallized D 3 receptor. Therefore, we provide conclusive evidence that α 2A - and α 2C -adrenoceptors are functional receptors for norepinephrine, dopamine, and other previously assumed selective D 2 -like receptor ligands, which calls for revisiting previous studies with those ligands.

  19. The Human Dopamine Transporter: Investigating the Role of the C Terminus in Surface Targeting

    DEFF Research Database (Denmark)

    Vægter, Christian Bjerggaard

    2005-01-01

    Dopaminergic neurotransmission is involved in the modulation of locomotor activity, emotional behavior, memory and cognition. Hence, imbalances in the dopaminergic system in humans have been hypothesized to contribute to the pathogenesis of a number of illnesses, including Parkinson's disease...... these mechanisms in further detail. All together the obtained results provide new insight into the regulation of the dopamine transporter and will direct future research strategies in this field....

  20. The Roles of Dopamine and Hypocretin in Reward: A Electroencephalographic Study.

    Directory of Open Access Journals (Sweden)

    Armand Mensen

    Full Text Available The proper functioning of the mesolimbic reward system is largely dependent on the neurotransmitter dopamine. Recent evidence suggests that the hypocretin system has significant projections to this reward system. We examined the distinct effects of reduced dopamine or reduced hypocretin levels on reward activity in patients with Parkinson's disease, dopamine deficient, as well as patients with narcolepsy-cataplexy, hypocretin depleted, and healthy controls. Participants performed a simple game-like task while high-density electroencephalography was recorded. Topography and timing of event-related potentials for both reward cue, and reward feedback was examined across the entire dataset. While response to reward cue was similar in all groups, two distinct time points were found to distinguish patients and controls for reward feedback. Around 160 ms both patient groups had reduced ERP amplitude compared to controls. Later at 250 ms, both patient groups also showed a clear event-related potential (ERP, which was absent in controls. The initial differences show that both patient groups show a similar, blunted response to reward delivery. The second potential corresponds to the classic feedback-related negativity (FRN potential which relies on dopamine activity and reflects reward prediction-error signaling. In particular the mismatch between predicted reward and reward subsequently received was significantly higher in PD compared to NC, independent of reward magnitude and valence. The intermediate FRN response in NC highlights the contribution of hypocretin in reward processing, yet also shows that this is not as detrimental to the reward system as in Parkinson's. Furthermore, the inability to generate accurate predictions in NC may explain why hypocretin deficiency mediates cataplexy triggered by both positive and negative emotions.

  1. The Roles of Dopamine and Hypocretin in Reward: A Electroencephalographic Study.

    Science.gov (United States)

    Mensen, Armand; Poryazova, Rositsa; Huegli, Gordana; Baumann, Christian R; Schwartz, Sophie; Khatami, Ramin

    2015-01-01

    The proper functioning of the mesolimbic reward system is largely dependent on the neurotransmitter dopamine. Recent evidence suggests that the hypocretin system has significant projections to this reward system. We examined the distinct effects of reduced dopamine or reduced hypocretin levels on reward activity in patients with Parkinson's disease, dopamine deficient, as well as patients with narcolepsy-cataplexy, hypocretin depleted, and healthy controls. Participants performed a simple game-like task while high-density electroencephalography was recorded. Topography and timing of event-related potentials for both reward cue, and reward feedback was examined across the entire dataset. While response to reward cue was similar in all groups, two distinct time points were found to distinguish patients and controls for reward feedback. Around 160 ms both patient groups had reduced ERP amplitude compared to controls. Later at 250 ms, both patient groups also showed a clear event-related potential (ERP), which was absent in controls. The initial differences show that both patient groups show a similar, blunted response to reward delivery. The second potential corresponds to the classic feedback-related negativity (FRN) potential which relies on dopamine activity and reflects reward prediction-error signaling. In particular the mismatch between predicted reward and reward subsequently received was significantly higher in PD compared to NC, independent of reward magnitude and valence. The intermediate FRN response in NC highlights the contribution of hypocretin in reward processing, yet also shows that this is not as detrimental to the reward system as in Parkinson's. Furthermore, the inability to generate accurate predictions in NC may explain why hypocretin deficiency mediates cataplexy triggered by both positive and negative emotions.

  2. Dopamine receptor D4 promoter hypermethylation increases the risk of drug addiction

    OpenAIRE

    Ji, Huihui; Xu, Xuting; Liu, Guili; Liu, Huifen; Wang, Qinwen; Shen, Wenwen; Li, Longhui; Xie, Xiaohu; Hu, Haochang; Xu, Lei; Zhou, Wenhua; Duan, Shiwei

    2017-01-01

    Heroin and methylamphetamine (METH) are two addictive drugs that cause serious problems for society. Dopamine receptor D4 (DRD4), a key receptor in the dopaminergic system, may facilitate the development of drug addiction. The aim of the present study was to investigate the association between the promoter methylation level of DRD4 gene and drug addiction. Bisulfite pyrosequencing technology was used to measure the methylation levels of DRD4 promoter in 60 drug addicts and 52 matched controls...

  3. Cocaine Self-Administration Produces Long-Lasting Alterations in Dopamine Transporter Responses to Cocaine

    Science.gov (United States)

    Siciliano, Cody A.; Fordahl, Steve C.

    2016-01-01

    Cocaine addiction is a debilitating neuropsychiatric disorder characterized by uncontrolled cocaine intake, which is thought to be driven, at least in part, by cocaine-induced deficits in dopamine system function. A decreased ability of cocaine to elevate dopamine levels has been repeatedly observed as a consequence of cocaine use in humans, and preclinical work has highlighted tolerance to cocaine's effects as a primary determinant in the development of aberrant cocaine taking behaviors. Here we determined that cocaine self-administration in rats produced tolerance to the dopamine transporter-inhibiting effects of cocaine in the nucleus accumbens core, which was normalized following a 14 or 60 d abstinence period; however, although these rats appeared to be similar to controls, a single self-administered infusion of cocaine at the end of abstinence, even after 60 d, fully reinstated tolerance to cocaine's effects. A single cocaine infusion in a naive rat had no effect on cocaine potency, demonstrating that cocaine self-administration leaves the dopamine transporter in a “primed” state, which allows for cocaine-induced plasticity to be reinstated by a subthreshold cocaine exposure. Further, reinstatement of cocaine tolerance was accompanied by decreased cocaine-induced locomotion and escalated cocaine intake despite extended abstinence from cocaine. These data demonstrate that cocaine leaves a long-lasting imprint on the dopamine system that is activated by re-exposure to cocaine. Further, these results provide a potential mechanism for severe cocaine binge episodes, which occur even after sustained abstinence from cocaine, and suggest that treatments aimed at transporter sites may be efficacious in promoting binge termination following relapse. SIGNIFICANCE STATEMENT Tolerance is a DSM-V criterion for substance abuse disorders. Abusers consistently show reduced subjective effects of cocaine concomitant with reduced effects of cocaine at its main site of action

  4. Dopamine induces soluble α-synuclein oligomers and nigrostriatal degeneration

    Science.gov (United States)

    Mor, Danielle E.; Tsika, Elpida; Mazzulli, Joseph R.; Gould, Neal S.; Kim, Hanna; Daniels, Malcolm J.; Doshi, Shachee; Gupta, Preetika; Grossman, Jennifer L.; Tan, Victor X.; Kalb, Robert G.; Caldwell, Kim A.; Caldwell, Guy A.; Wolfe, John H.; Ischiropoulos, Harry

    2018-01-01

    Parkinson’s disease is defined by the loss of dopaminergic neurons in the substantia nigra and formation of Lewy body inclusions containing aggregated α-synuclein. Efforts to explain dopamine neuron vulnerability are hindered by the lack of dopaminergic cell death in α-synuclein transgenic mice. To address this, we manipulated dopamine levels in addition to α-synuclein expression. Nigra-targeted expression of mutant tyrosine hydroxylase with enhanced catalytic activity increased dopamine without damaging neurons in non-transgenic mice. In contrast, raising dopamine in mice expressing human A53T mutant α-synuclein induced progressive nigrostriatal degeneration and reduced locomotion. Dopamine elevation in A53T mice increased levels of potentially toxic α-synuclein oligomers, resulting in conformationally and functionally modified species. Moreover, in genetically tractable C. elegans models expression of α-synuclein mutated at the site of interaction with dopamine prevented dopamine-induced toxicity. The data suggest a unique mechanism linking two cardinal features of Parkinson’s disease, dopaminergic cell death and α-synuclein aggregation. PMID:28920936

  5. Dopamine-imprinted monolithic column for capillary electrochromatography.

    Science.gov (United States)

    Aşır, Süleyman; Sarı, Duygu; Derazshamshir, Ali; Yılmaz, Fatma; Şarkaya, Koray; Denizli, Adil

    2017-11-01

    A dopamine-imprinted monolithic column was prepared and used in capillary electrochromatography as stationary phase for the first time. Dopamine was selectively separated from aqueous solution containing the competitor molecule norepinephrine, which is similar in size and shape to the template molecule. Morphology of the dopamine-imprinted column was observed by scanning electron microscopy. The influence of the organic solvent content of mobile phase, applied pressure and pH of the mobile phase on the recognition of dopamine by the imprinted monolithic column has been evaluated, and the imprinting effect in the dopamine-imprinted monolithic polymer was verified. Developed dopamine-imprinted monolithic column resulted in excellent separation of dopamine from structurally related competitor molecule, norepinephrine. Separation was achieved in a short period of 10 min, with the electrophoretic mobility of 5.81 × 10 -5  m 2 V -1 s -1 at pH 5.0 and 500 mbar pressure. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Noncovalent Interactions between Dopamine and Regular and Defective Graphene.

    Science.gov (United States)

    Fernández, Ana C Rossi; Castellani, Norberto J

    2017-08-05

    The role of noncovalent interactions in the adsorption of biological molecules on graphene is a subject of fundamental interest regarding the use of graphene as a material for sensing and drug delivery. The adsorption of dopamine on regular graphene and graphene with monovacancies (GV) is theoretically studied within the framework of density functional theory. Several adsorption modes are considered, and notably those in which the dopamine molecule is oriented parallel or quasi-parallel to the surface are the more stable. The adsorption of dopamine on graphene implies an attractive interaction of a dispersive nature that competes with Pauli repulsion between the occupied π orbitals of the dopamine ring and the π orbitals of graphene. If dopamine adsorbs at the monovacancy in the A-B stacking mode, a hydrogen bond is produced between one of the dopamine hydroxy groups and one carbon atom around the vacancy. The electronic charge redistribution due to adsorption is consistent with an electronic drift from the graphene or GV surface to the dopamine molecule. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Dopamine induces soluble α-synuclein oligomers and nigrostriatal degeneration.

    Science.gov (United States)

    Mor, Danielle E; Tsika, Elpida; Mazzulli, Joseph R; Gould, Neal S; Kim, Hanna; Daniels, Malcolm J; Doshi, Shachee; Gupta, Preetika; Grossman, Jennifer L; Tan, Victor X; Kalb, Robert G; Caldwell, Kim A; Caldwell, Guy A; Wolfe, John H; Ischiropoulos, Harry

    2017-11-01

    Parkinson's disease (PD) is defined by the loss of dopaminergic neurons in the substantia nigra and the formation of Lewy body inclusions containing aggregated α-synuclein. Efforts to explain dopamine neuron vulnerability are hindered by the lack of dopaminergic cell death in α-synuclein transgenic mice. To address this, we manipulated both dopamine levels and α-synuclein expression. Nigrally targeted expression of mutant tyrosine hydroxylase with enhanced catalytic activity increased dopamine levels without damaging neurons in non-transgenic mice. In contrast, raising dopamine levels in mice expressing human A53T mutant α-synuclein induced progressive nigrostriatal degeneration and reduced locomotion. Dopamine elevation in A53T mice increased levels of potentially toxic α-synuclein oligomers, resulting in conformationally and functionally modified species. Moreover, in genetically tractable Caenorhabditis elegans models, expression of α-synuclein mutated at the site of interaction with dopamine prevented dopamine-induced toxicity. These data suggest that a unique mechanism links two cardinal features of PD: dopaminergic cell death and α-synuclein aggregation.

  8. The binding sites for cocaine and dopamine in the dopamine transporter overlap

    DEFF Research Database (Denmark)

    Beuming, Thijs; Kniazeff, Julie; Bergmann, Marianne L

    2008-01-01

    Cocaine is a widely abused substance with psychostimulant effects that are attributed to inhibition of the dopamine transporter (DAT). We present molecular models for DAT binding of cocaine and cocaine analogs constructed from the high-resolution structure of the bacterial transporter homolog Leu......T. Our models suggest that the binding site for cocaine and cocaine analogs is deeply buried between transmembrane segments 1, 3, 6 and 8, and overlaps with the binding sites for the substrates dopamine and amphetamine, as well as for benztropine-like DAT inhibitors. We validated our models by detailed...... mutagenesis and by trapping the radiolabeled cocaine analog [3H]CFT in the transporter, either by cross-linking engineered cysteines or with an engineered Zn2+-binding site that was situated extracellularly to the predicted common binding pocket. Our data demonstrate the molecular basis for the competitive...

  9. Dopamine agonist withdrawal syndrome: implications for patient care.

    Science.gov (United States)

    Nirenberg, Melissa J

    2013-08-01

    Dopamine agonists are effective treatments for a variety of indications, including Parkinson's disease and restless legs syndrome, but may have serious side effects, such as orthostatic hypotension, hallucinations, and impulse control disorders (including pathological gambling, compulsive eating, compulsive shopping/buying, and hypersexuality). The most effective way to alleviate these side effects is to taper or discontinue dopamine agonist therapy. A subset of patients who taper a dopamine agonist, however, develop dopamine agonist withdrawal syndrome (DAWS), which has been defined as a severe, stereotyped cluster of physical and psychological symptoms that correlate with dopamine agonist withdrawal in a dose-dependent manner, cause clinically significant distress or social/occupational dysfunction, are refractory to levodopa and other dopaminergic medications, and cannot be accounted for by other clinical factors. The symptoms of DAWS include anxiety, panic attacks, dysphoria, depression, agitation, irritability, suicidal ideation, fatigue, orthostatic hypotension, nausea, vomiting, diaphoresis, generalized pain, and drug cravings. The severity and prognosis of DAWS is highly variable. While some patients have transient symptoms and make a full recovery, others have a protracted withdrawal syndrome lasting for months to years, and therefore may be unwilling or unable to discontinue DA therapy. Impulse control disorders appear to be a major risk factor for DAWS, and are present in virtually all affected patients. Thus, patients who are unable to discontinue dopamine agonist therapy may experience chronic impulse control disorders. At the current time, there are no known effective treatments for DAWS. For this reason, providers are urged to use dopamine agonists judiciously, warn patients about the risks of DAWS prior to the initiation of dopamine agonist therapy, and follow patients closely for withdrawal symptoms during dopamine agonist taper.

  10. Drug-driven AMPA receptor redistribution mimicked by selective dopamine neuron stimulation.

    Directory of Open Access Journals (Sweden)

    Matthew T C Brown

    2010-12-01

    Full Text Available Addictive drugs have in common that they cause surges in dopamine (DA concentration in the mesolimbic reward system and elicit synaptic plasticity in DA neurons of the ventral tegmental area (VTA. Cocaine for example drives insertion of GluA2-lacking AMPA receptors (AMPARs at glutamatergic synapes in DA neurons. However it remains elusive which molecular target of cocaine drives such AMPAR redistribution and whether other addictive drugs (morphine and nicotine cause similar changes through their effects on the mesolimbic DA system.We used in vitro electrophysiological techniques in wild-type and transgenic mice to observe the modulation of excitatory inputs onto DA neurons by addictive drugs. To observe AMPAR redistribution, post-embedding immunohistochemistry for GluA2 AMPAR subunit was combined with electron microscopy. We also used a double-floxed AAV virus expressing channelrhodopsin together with a DAT Cre mouse line to selectively express ChR2 in VTA DA neurons. We find that in mice where the effect of cocaine on the dopamine transporter (DAT is specifically blocked, AMPAR redistribution was absent following administration of the drug. Furthermore, addictive drugs known to increase dopamine levels cause a similar AMPAR redistribution. Finally, activating DA VTA neurons optogenetically is sufficient to drive insertion of GluA2-lacking AMPARs, mimicking the changes observed after a single injection of morphine, nicotine or cocaine.We propose the mesolimbic dopamine system as a point of convergence at which addictive drugs can alter neural circuits. We also show that direct activation of DA neurons is sufficient to drive AMPAR redistribution, which may be a mechanism associated with early steps of non-substance related addictions.

  11. Hypocretin 1/orexin A in the ventral tegmental area enhances dopamine responses to cocaine and promotes cocaine self-administration.

    Science.gov (United States)

    España, Rodrigo A; Melchior, James R; Roberts, David C S; Jones, Sara R

    2011-03-01

    Recent evidence indicates that the hypocretin/orexin system participates in the regulation of reinforcement and addiction processes. For example, manipulations that decrease hypocretin neurotransmission result in disruptions of neurochemical and behavioral responses to cocaine. To further assess the relationship between the hypocretin system and cocaine reinforcement, the current studies used microdialysis and in vivo voltammetry to examine the effects of hypocretin 1 on cocaine-induced enhancement of dopamine signaling in the nucleus accumbens core. Fixed ratio, discrete trials, and progressive ratio self-administration procedures were also used to assess whether hypocretin 1 promotes cocaine self-administration behavior. Infusions of hypocretin 1 into the ventral tegmental area increased the effects of cocaine on tonic and phasic dopamine signaling and increased the motivation to self-administer cocaine on the discrete trials and progressive ratio schedules. Together with previous observations demonstrating that a hypocretin 1 receptor antagonist disrupts dopamine signaling and reduces self-administration of cocaine, the current observations further indicate that the hypocretin system participates in reinforcement processes likely through modulation of the mesolimbic dopamine system.

  12. Problematic gambling on dopamine agonists: Not such a rarity.

    Science.gov (United States)

    Grosset, Katherine A; Macphee, Graeme; Pal, Guru; Stewart, David; Watt, Andrew; Davie, Jim; Grosset, D G

    2006-12-01

    Excessive gambling is recognized with dopamine agonist therapy, but the prevalence is unknown. We assessed the prevalence of excess gambling by specific prospective enquiry in Parkinson's disease patients attending six West Scotland movement disorder clinics. Of 388 patients taking anti-Parkinson medication, 17 (4.4%) developed pathological gambling, all of whom were prescribed dopamine agonists. Thus, 8% of patients taking dopamine agonists had pathological gambling. Pathological gambling is not uncommon, and patients should be made aware of this potential adverse effect. Copyright 2006 Movement Disorder Society.

  13. Evidence that Sleep Deprivation Downregulates Dopamine D2R in Ventral Striatum in the Human Brain

    OpenAIRE

    Volkow, Nora D.; Tomasi, Dardo; Wang, Gene-Jack; Telang, Frank; Fowler, Joanna S.; Logan, Jean; Benveniste, Helene; Kim, Ron; Thanos, Panayotis K.; Ferré, Sergi

    2012-01-01

    Dopamine D2 receptors are involved with wakefulness but their role in the decreased alertness associated with sleep deprivation is unclear. We had shown that sleep deprivation reduced dopamine D2/D3 receptor availability (measured with PET and [11C]raclopride in controls) in striatum, but could not determine if this reflected dopamine increases ([11C]raclopride competes with dopamine for D2/D3 receptor binding) or receptor downregulation. To clarify this, we compared the dopamine increases in...

  14. 25-Hydroxyvitamin D depletion does not exacerbate MPTP-induced dopamine neuron damage in mice.

    Directory of Open Access Journals (Sweden)

    E Danielle Dean

    Full Text Available Recent clinical evidence supports a link between 25-hydroxyvitamin D insufficiency (serum 25-hydroxyvitamin D [25(OHD] levels <30 ng/mL and Parkinson's disease. To investigate the effect of 25(OHD depletion on neuronal susceptibility to toxic insult, we induced a state of 25(OHD deficiency in mice and then challenged them with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP. We found there was no significant difference between control and 25(OHD-deficient animals in striatal dopamine levels or dopamine transporter and tyrosine hydroxylase expression after lesioning with MPTP. Additionally, we found no difference in tyrosine hydroxylase expression in the substantia nigra pars compacta. Our data suggest that reducing 25(OHD serum levels in mice has no effect on the vulnerability of nigral dopaminergic neurons in vivo in this model system of parkinsonism.

  15. Human dopamine D4 receptor gene: frequent occurrence of a null allele and observation of homozygosity.

    Science.gov (United States)

    Nöthen, M M; Cichon, S; Hemmer, S; Hebebrand, J; Remschmidt, H; Lehmkuhl, G; Poustka, F; Schmidt, M; Catalano, M; Fimmers, R

    1994-12-01

    We report a null mutation in the first exon of the human dopamine D4 receptor (DRD4) gene. The mutation is predicted to result in a truncated non-functional protein and is the first natural nonsense mutation found in a human dopamine receptor gene. It occurs with a frequency of about 2% in the general population. The distribution of the mutation was found to be similar in healthy controls and patients suffering from psychiatric diseases which included schizophrenia, bipolar affective disorder and Tourette's syndrome, indicating that heterozygosity for this mutation in the DRD4 gene is not causally related to major psychiatric diseases. We also identified an adult male who is homozygous for this mutation. He shows no symptoms of major psychiatric illness, but he displays somatic ailments including acousticous neurinoma, obesity and some disturbances of the autonomic nervous system. Some of these symptoms might be related to the absence of functional DRD4 protein.

  16. Role of Dopamine Signaling in Drug Addiction.

    Science.gov (United States)

    Chen, Wan; Nong, Zhihuan; Li, Yaoxuan; Huang, Jianping; Chen, Chunxia; Huang, Luying

    2017-01-01

    Addiction is a chronic, relapsing disease of the brain that includes drug-induced compulsive seeking behavior and consumption of drugs. Dopamine (DA) is considered to be critical in drug addiction due to reward mechanisms in the midbrain. In this article, we review the major animal models in addictive drug experiments in vivo and in vitro. We discuss the relevance of the structure and pharmacological function of DA receptors. To improve the understanding of the role of DA receptors in reward pathways, specific brain regions, including the Ventral tegmental area, Nucleus accumbens, Prefrontal cortex, and Habenula, are highlighted. These factors contribute to the development of novel therapeutic targets that act at DA receptors. In addiction, the development of neuroimaging method will increase our understanding of the mechanisms underlying drug addiction. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  17. Delusional parasitosis and the dopamine transporter. A new insight of etiology?

    Science.gov (United States)

    Huber, M; Kirchler, E; Karner, M; Pycha, R

    2007-01-01

    Delusional parasitosis (DP) is a psychotic condition in which a person has the unshakeable and mistaken belief (delusion) and/or aberrant perception (hallucination) of being infested with parasites. The disorder will be usually classified in a primary DP-group without a detectable cause (so-called pure forms), while secondary DP-groups are associated with general organic conditions, psychiatric illnesses and drugs (substance induced). Etiology and pathophysiology of DP remain however unknown. In the present paper we hypothesize for the first time a decreased striatal dopamine transporter (DAT)-functioning (corresponding with an increased extracellular dopamine-level) as etiologic condition for DP (primary and secondary groups). The DAT as key regulator of the dopamine-reuptake in the human brain is well known (regulation of the extracellular dopamine concentration). It is a presynaptic plasma membrane protein highly dense represented in the striatum. The hypothesis of a decreased DAT-functioning as etiologic condition by DP is revealed in case reports which show that DAT-inhibitors, such as cocaine, pemoline, methylphenidate and other amphetamine-derivatives can induce the clinical expression of DP. Several other associated causes of secondary DP-groups (medications, parkinson, chorea huntington, multiple system atrophy, diabetes, cerebrovascular diseases, alcoholism, traumatic brain injury, hyperuricemia, human immunodeficiency virus, iron deficiency, schizophrenia, depression) suggest that the clinical expression of DP may be related to a decreased striatal DAT-functioning (blocking, reduced ligand binding, reduced density, reduced activity). Our examined DP-cases (2-females) show means of magnetic resonance imaging a structurally damaged striatum. Furthermore, we presume that by the primary DP-group, the physiologically age-related decline of the DAT-density is pathologically elevated. Based on this hypothesis we show in the present paper the relation between DP

  18. Risk-assessment and risk-taking behavior predict potassium- and amphetamine-induced dopamine response in the dorsal striatum of rats

    Directory of Open Access Journals (Sweden)

    Sara ePalm

    2014-07-01

    Full Text Available Certain personality types and behavioral traits display high correlations to drug use and an increased level of dopamine in the reward system is a common denominator of all drugs of abuse. Dopamine response to drugs has been suggested to correlate with some of these personality types and to be a key factor influencing the predisposition to addiction. This study investigated if behavioral traits can be related to potassium- and amphetamine-induced dopamine response in the dorsal striatum, an area hypothesized to be involved in the shift from drug use to addiction. The open field and multivariate concentric square field™ tests were used to assess individual behavior in male Wistar rats. Chronoamperometric recordings were then made to study the potassium- and amphetamine-induced dopamine response in vivo. A classification based on risk-taking behavior in the open field was used for further comparisons. Risk-taking behavior was correlated between the behavioral tests and high risk takers displayed a more pronounced response to the dopamine uptake blocking effects of amphetamine. Behavioral parameters from both tests could also predict potassium- and amphetamine-induced dopamine responses showing a correlation between neurochemistry and behavior in risk-assessment and risk-taking parameters. In conclusion, the high risk-taking rats showed a more pronounced reduction of dopamine uptake in the dorsal striatum after amphetamine indicating that this area may contribute to the sensitivity of these animals to psychostimulants and proneness to addiction. Further, inherent dopamine activity was related to risk-assessment behavior, which may be of importance for decision-making and inhibitory control, key components in addiction.

  19. Differences in striatal dopamine transporter density between tremor dominant and non-tremor Parkinson's disease

    Energy Technology Data Exchange (ETDEWEB)

    Kaasinen, Valtteri; Kinos, Maija; Joutsa, Juho [University of Turku and Turku University Hospital, Division of Clinical Neurosciences, Turku (Finland); University of Turku and Turku University Hospital, Turku PET Centre, Turku (Finland); Seppaenen, Marko [University of Turku and Turku University Hospital, Turku PET Centre, Turku (Finland); University of Turku and Turku University Hospital, Department of Clinical Physiology and Nuclear Medicine, Turku (Finland); Noponen, Tommi [University of Turku and Turku University Hospital, Department of Clinical Physiology and Nuclear Medicine, Turku (Finland)

    2014-10-15

    Parkinson's disease (PD) can manifest with a tremor-dominant or a non-tremor (akinetic-rigid) phenotype. Although the tremor-dominant subtype may show a better prognosis, there is limited information on the phenotypic differences regarding the level of striatal dopamine transmission. The present study investigated striatal dopamine transporter (DAT) binding characteristics in a large sample of patients with and without tremor. [{sup 123}I]FP-CIT SPECT scans of 231 patients with a clinical diagnosis of PD and abnormal FP-CIT binding (157 with tremor, 74 without tremor) and 230 control patients with normal FP-CIT binding (148 with tremor, 82 without tremor) were analysed using an automated region-of-interest analysis of the scans (BRASS). Specific striatal binding ratios were compared between phenotypes and groups using age, sex, and symptom duration, predominant side of symptoms, dopaminergic medications and scanner as covariates. Patients with PD had 28.1 - 65.0 % lower binding in all striatal regions compared to controls (p < 0.001). The mean FP-CIT caudate nucleus uptake and the left caudate nucleus uptake were higher in PD patients with tremor than in PD patients without tremor (mean 9.0 % higher, left 10.5 % higher; p < 0.05), whereas there were no differences between tremor and non-tremor control patients. No significant effects of tremor on DAT binding were observed in the anterior or posterior putamen. The motor phenotype is associated with the extent of caudate dopamine terminal loss in PD, as dopamine function is relatively more preserved in tremor patients. Symptom type is related to caudate dopamine function only in association with Parkinsonian dopaminergic degeneration, not in intact dopamine systems in patients with non-PD tremor. (orig.)

  20. Dopamine Is Signaled by Mid-frequency Oscillations and Boosts Output Layers Visual Information in Visual Cortex.

    Science.gov (United States)

    Zaldivar, Daniel; Goense, Jozien; Lowe, Scott C; Logothetis, Nikos K; Panzeri, Stefano

    2018-01-22

    Neural oscillations are ubiquitously observed in cortical activity, and are widely believed to be crucial for mediating transmission of information across the cortex. Yet, the neural phenomena contributing to each oscillation band, and their effect on information coding and transmission, are largely unknown. Here, we investigated whether individual frequency bands specifically reflect changes in the concentrations of dopamine, an important neuromodulator, and how dopamine affects oscillatory information processing. We recorded the local field potential (LFP) at different depths of primary visual cortex (V1) in anesthetized monkeys (Macaca mulatta) during spontaneous activity and during visual stimulation with Hollywood movie clips while pharmacologically mimicking dopaminergic neuromodulation by systemic injection of L-DOPA (a metabolic precursor of dopamine). We found that dopaminergic neuromodulation had marked effects on both spontaneous and movie-evoked neural activity. During spontaneous activity, dopaminergic neuromodulation increased the power of the LFP specifically in the [19-38 Hz] band, suggesting that the power of endogenous visual cortex oscillations in this band can be used as a robust marker of dopaminergic neuromodulation. Moreover, dopamine increased visual information encoding over all frequencies during movie stimulation. The information increase due to dopamine was prominent in the supragranular layers of cortex that project to higher cortical areas and in the gamma [50-100 Hz] band that has been previously implicated in mediating feedforward information transfer. These results thus individuate new neural mechanisms by which dopamine may promote the readout of relevant sensory information by strengthening the transmission of information from primary to higher areas. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. AAV Vector-Mediated Gene Delivery to Substantia Nigra Dopamine Neurons: Implications for Gene Therapy and Disease Models

    Directory of Open Access Journals (Sweden)

    Katrina Albert

    2017-02-01

    Full Text Available Gene delivery using adeno-associated virus (AAV vectors is a widely used method to transduce neurons in the brain, especially due to its safety, efficacy, and long-lasting expression. In addition, by varying AAV serotype, promotor, and titer, it is possible to affect the cell specificity of expression or the expression levels of the protein of interest. Dopamine neurons in the substantia nigra projecting to the striatum, comprising the nigrostriatal pathway, are involved in movement control and degenerate in Parkinson′s disease. AAV-based gene targeting to the projection area of these neurons in the striatum has been studied extensively to induce the production of neurotrophic factors for disease-modifying therapies for Parkinson′s disease. Much less emphasis has been put on AAV-based gene therapy targeting dopamine neurons in substantia nigra. We will review the literature related to targeting striatum and/or substantia nigra dopamine neurons using AAVs in order to express neuroprotective and neurorestorative molecules, as well as produce animal disease models of Parkinson′s disease. We discuss difficulties in targeting substantia nigra dopamine neurons and their vulnerability to stress in general. Therefore, choosing a proper control for experimental work is not trivial. Since the axons along the nigrostriatal tract are the first to degenerate in Parkinson′s disease, the location to deliver the therapy must be carefully considered. We also review studies using AAV-a-synuclein (a-syn to target substantia nigra dopamine neurons to produce an α-syn overexpression disease model in rats. Though these studies are able to produce mild dopamine system degeneration in the striatum and substantia nigra and some behavioural effects, there are studies pointing to the toxicity of AAV-carrying green fluorescent protein (GFP, which is often used as a control. Therefore, we discuss the potential difficulties in overexpressing proteins in general in

  2. Translationally Controlled Tumor Protein Stimulates Dopamine Release from PC12 Cells via Ca2+-Independent Phospholipase A2 Pathways

    Directory of Open Access Journals (Sweden)

    Jihui Seo

    2016-10-01

    Full Text Available The translationally controlled tumor protein (TCTP, initially identified as a tumor- and growth-related protein, is also known as a histamine-releasing factor (HRF. TCTP is widely distributed in the neuronal systems, but its function is largely uncharacterized. Here, we report a novel function of TCTP in the neurotransmitter release from a neurosecretory, pheochromocytoma (PC12 cells. Treatment with recombinant TCTP (rTCTP enhanced both basal and depolarization (50 mM KCl-evoked [3H]dopamine release in concentration- and time-dependent manners. Interestingly, even though rTCTP induced the increase in intracellular calcium levels ([Ca2+]i, the rTCTP-driven effect on dopamine release was mediated by a Ca2+-independent pathway, as evidenced by the fact that Ca2+-modulating agents such as Ca2+ chelators and a voltage-gated L-type Ca2+-channel blocker did not produce any changes in rTCTP-evoked dopamine release. In a study to investigate the involvement of phospholipase A2 (PLA2 in rTCTP-induced dopamine release, the inhibitor for Ca2+-independent PLA2 (iPLA2 produced a significant inhibitory effect on rTCTP-induced dopamine release, whereas this release was not significantly inhibited by Ca2+-dependent cytosolic PLA2 (cPLA2 and secretory PLA2 (sPLA2 inhibitors. We found that rTCTP-induced dopamine release from neuronal PC12 cells was modulated by a Ca2+-independent mechanism that involved PLA2 in the process, suggesting the regulatory role of TCTP in the neuronal functions.

  3. Dopamine Increases CD14+CD16+Monocyte Transmigration across the Blood Brain Barrier: Implications for Substance Abuse and HIV Neuropathogenesis.

    Science.gov (United States)

    Calderon, Tina M; Williams, Dionna W; Lopez, Lillie; Eugenin, Eliseo A; Cheney, Laura; Gaskill, Peter J; Veenstra, Mike; Anastos, Kathryn; Morgello, Susan; Berman, Joan W

    2017-06-01

    In human immunodeficiency virus-1 (HIV) infected individuals, substance abuse may accelerate the development and/or increase the severity of HIV associated neurocognitive disorders (HAND). It is proposed that CD14 + CD16 + monocytes mediate HIV entry into the central nervous system (CNS) and that uninfected and infected CD14 + CD16 + monocyte transmigration across the blood brain barrier (BBB) contributes to the establishment and propagation of CNS HIV viral reservoirs and chronic neuroinflammation, important factors in the development of HAND. The effects of substance abuse on the frequency of CD14 + CD16 + monocytes in the peripheral circulation and on the entry of these cells into the CNS during HIV neuropathogenesis are not known. PBMC from HIV infected individuals were analyzed by flow cytometry and we demonstrate that the frequency of peripheral blood CD14 + CD16 + monocytes in HIV infected substance abusers is increased when compared to those without active substance use. Since drug use elevates extracellular dopamine concentrations in the CNS, we examined the effects of dopamine on CD14 + CD16 + monocyte transmigration across our in vitro model of the human BBB. The transmigration of this monocyte subpopulation is increased by dopamine and the dopamine receptor agonist, SKF 38393, implicating D1-like dopamine receptors in the increase in transmigration elicited by this neurotransmitter. Thus, elevated extracellular CNS dopamine may be a novel common mechanism by which active substance use increases uninfected and HIV infected CD14 + CD16 + monocyte transmigration across the BBB. The influx of these cells into the CNS may increase viral seeding and neuroinflammation, contributing to the development of HIV associated neurocognitive impairments.

  4. Possible impact of dopamine SPECT on decision-making for drug treatment in Parkinsonian syndrome

    International Nuclear Information System (INIS)

    Hesse, S.; Barthel, H.; Polster, D.; Sabri, O.; Oehlwein, C.; Schwarz, J.; Wagner, A.

    2006-01-01

    Single-photon emission computed tomography (SPECT) markers allow measuring the integrity of the brain dopaminergic system in vivo. We used dopamine transporter (DAT) SPECT with [ 123 I]FP-CIT and dopamine D 2 /D 3 receptor SPECT with [ 123 I]IBZM to evaluate whether there is a reduction of DAT and/or D 2 /D 3 receptor SPECT in treated and untreated patients with Parkinsonian syndrome (PS). We found that almost a quarter of our patients treated with anti-Parkinsonian medication prior to SPECT imaging did not show evidence of a presynaptic dopaminergic deficit while 37 % of untreated patients were diagnosed as having Parkinson's disease. 17 % of treated patients had additional loss of D 2 /D 3 receptor binding capacity in concordance with the clinical follow-up diagnoses of multiple system atrophy, progressive nuclear palsy, and vascular Parkinsonism. Apart from 38 % clinically uncertain cases, SPECT was in concordance with 75 % of initial clinical diagnoses. 25 % were reclassified as indicated by SPECT findings and confirmed by a 1.5-year clinical follow-up. We conclude that dopamine SPECT may support establishing or refuting the clinical diagnosis and, therefore, help to make the decision for or against dopaminomimetic treatment in cases with PS. (author)

  5. Developing a neuronal model for the pathophysiology of schizophrenia based on the nature of electrophysiological actions of dopamine in the prefrontal cortex.

    Science.gov (United States)

    Yang, C R; Seamans, J K; Gorelova, N

    1999-08-01

    This review covers some recent findings of the electrophysiological mechanisms through which mesocortical dopamine modulates prefrontal cortical neurons. Dopamine has been shown to modulate several ionic conductances located along the soma-dendritic axis of prefrontal cortical pyramidal neurons. These ionic currents include high-voltage-activated calcium currents and slowly inactivating Na+ and K+ currents. They contribute actively in processing functionally segregated inputs during synaptic integration. In addition, dopamine mainly depolarizes the fast-spiking subtype of local GABAergic interneurons that connect the pyramidal neurons. This latter action can indirectly control pyramidal cell excitability. These electrophysiological data indicate that the actions of dopamine are neither "excitatory" nor "inhibitory" in pyramidal prefrontal cortex neurons. Rather, the actions of dopamine are dependent on somadendritic loci, timing of the arrival of synaptic inputs, strength of synaptic inputs, as well as the membrane potential range at which the PFC neuron is operating at a given moment. Based on available electrophysiological findings, a neuronal model of the pathophysiology of schizophrenia is presented. This model proposes that episodic hypo- and hyperactivity of the PFC and the associated dysfunctional mesocortical dopamine system (and their interconnected brain regions) may coexist in the same schizophrenic patient in the course of the illness. We hypothesize that the dysfunctional mesocortical dopamine input to the PFC may lead to abnormal modulation of ionic channels distributed in the dendritic-somatic compartments of PFC pyramidal neurons that project to the ventral tegmental area and/or nucleus accumbens. In some schizophrenics, a reduction of mesocortical dopamine to below optimal levels and/or a loss of local GABAergic inputs may result in a dysfunctional integration of extrinsic associative inputs by Ca2+ channel activity in the distal dendrites of PFC

  6. Essential Oils from the Medicinal Herbs Upregulate Dopamine Transporter in Rat Pheochromocytoma Cells.

    Science.gov (United States)

    Choi, Min Sun; Choi, Bang-sub; Kim, Sang Heon; Pak, Sok Cheon; Jang, Chul Ho; Chin, Young-Won; Kim, Young-Mi; Kim, Dong-il; Jeon, Songhee; Koo, Byung-Soo

    2015-10-01

    The dopamine transporter (DAT) protein, a component of the dopamine system, undergoes adaptive neurobiological changes from drug abuse. Prevention of relapse and reduction of withdrawal symptoms are still the major limitations in the current pharmacological treatments of drug addiction. The present study aimed to investigate the effects of essential oils extracted from Elsholtzia ciliata, Shinchim, Angelicae gigantis Radix, and Eugenia caryophyllata, well-known traditional Korean medicines for addiction, on the modulation of dopamine system in amphetamine-treated cells and to explore the possible mechanism underlying its therapeutic effect. The potential cytotoxic effect of essential oils was evaluated in PC12 rat pheochromocytoma cells using cell viability assays. Quantification of DAT, p-CREB, p-MAPK, and p-Akt was done by immunoblotting. DAT was significantly reduced in cells treated with 50 μM of amphetamine in a time-dependent manner. No significant toxicity of essential oils from Elsholtzia ciliata and Shinchim was observed at doses of 10, 25, and 50 μg/mL. However, essential oils from A. gigantis Radix at a dose of 100 μg/mL and E. caryophyllata at doses of 50 and 100 μg/mL showed cytotoxicity. Treatment with GBR 12909, a highly selective DAT inhibitor, significantly increased DAT expression compared with that of amphetamine only by enhancing phosphorylation of mitogen-activated protein kinases (MAPK) and Akt. In addition, essential oils effectively induced hyperphosphorylation of cyclic-AMP response element-binding protein (CREB), MAPK, and Akt, which resulted in DAT upregulation. Our study implies that the essential oils may rehabilitate brain dopamine function through increased DAT availability in abstinent former drug users.

  7. Dopamine transporter density of the basal ganglia assessed with I-123 IPT SPECT in methamphetamine abusers

    International Nuclear Information System (INIS)

    Lee, Joo Ryung; Ahn, Byeong Cheol; Kewm, Do Hun

    2005-01-01

    Functional imaging of dopamine transporter (DAT) defines integrity of the dopaminergic system, and DAT is the target site of drugs of abuse such as cocaine and methamphetamine. Functional imaging the DAT may be a sensitive and selective indicator of neurotoxic change by the drug. The aim of the present study is to evaluate the clinical implications of qualitative/quantitative analyses of dopamine transporter imaging in methamphetamine abusers. Six detoxified methamphetamine abusers (abuser group) and 4 volunteers (control group) were enrolled in this study. Brain MRI was performed in all of abuser group. Abuser group underwent psychiatric and depression assessment using brief psychiatric rating scale (BPRS) and Hamilton depression rating scale (HAMD), respectively. All of the subjects underwent I-123 IPT SPECT (IPT SPECT). IPT SPECT image was analysed with visual qualitative method and quantitative method using basal ganglia dopamine transporter (DAT) specific/non-specific binding ratio (SBR). Comparison of DAT SBR between abuser and control groups was performed. We also performed correlation tests between psychiatric and depression assessment results and DAT SBR in abuser group. All of abuser group showed normal MRI finding, but had residual psychiatric and depressive symptoms, and psychiatric and depressive symptom scores were exactly correlated (r=1.0, ρ =0.005) each other. Five of them showed abnormal finding on qualitative visual I-123 IPT SPECT. Abuser group had lower basal ganglia DAT SBR than that of control (2.38 ± 0.20 vs 3.04 ± 0.27, ρ =0.000). Psychiatric and depressive symptoms were negatively well correlated with basal ganglia DAT SBR (r=-0.908, ρ =0.012, r=-0.924, ρ =0.009) This results suggest that dopamine transporter imaging using I-123 IPT SPECT may be used to evaluate dopaminergic system of the basal ganglia and the clinical status in methamphetamine abusers

  8. Dopamine transporter density of the basal ganglia assessed with I-123 IPT SPECT in methamphetamine abusers

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Joo Ryung; Ahn, Byeong Cheol [Kyungpook National University Medical School, Daegu (Korea, Republic of); Kewm, Do Hun [National Bugok Mental Hospital, Changryung (Korea, Republic of)] (and others)

    2005-10-15

    Functional imaging of dopamine transporter (DAT) defines integrity of the dopaminergic system, and DAT is the target site of drugs of abuse such as cocaine and methamphetamine. Functional imaging the DAT may be a sensitive and selective indicator of neurotoxic change by the drug. The aim of the present study is to evaluate the clinical implications of qualitative/quantitative analyses of dopamine transporter imaging in methamphetamine abusers. Six detoxified methamphetamine abusers (abuser group) and 4 volunteers (control group) were enrolled in this study. Brain MRI was performed in all of abuser group. Abuser group underwent psychiatric and depression assessment using brief psychiatric rating scale (BPRS) and Hamilton depression rating scale (HAMD), respectively. All of the subjects underwent I-123 IPT SPECT (IPT SPECT). IPT SPECT image was analysed with visual qualitative method and quantitative method using basal ganglia dopamine transporter (DAT) specific/non-specific binding ratio (SBR). Comparison of DAT SBR between abuser and control groups was performed. We also performed correlation tests between psychiatric and depression assessment results and DAT SBR in abuser group. All of abuser group showed normal MRI finding, but had residual psychiatric and depressive symptoms, and psychiatric and depressive symptom scores were exactly correlated (r=1.0, {rho} =0.005) each other. Five of them showed abnormal finding on qualitative visual I-123 IPT SPECT. Abuser group had lower basal ganglia DAT SBR than that of control (2.38 {+-} 0.20 vs 3.04 {+-} 0.27, {rho} =0.000). Psychiatric and depressive symptoms were negatively well correlated with basal ganglia DAT SBR (r=-0.908, {rho} =0.012, r=-0.924, {rho} =0.009) This results suggest that dopamine transporter imaging using I-123 IPT SPECT may be used to evaluate dopaminergic system of the basal ganglia and the clinical status in methamphetamine abusers.

  9. Olfactory deprivation increases dopamine D2 receptor density in the rat olfactory bulb

    International Nuclear Information System (INIS)

    Guthrie, K.M.; Pullara, J.M.; Marshall, J.F.; Leon, M.

    1991-01-01

    Unilateral olfactory deprivation during postnatal development results in significant anatomical and neurochemical changes in the deprived olfactory bulb. Perhaps the most dramatic neurochemical change is the loss of dopaminergic expression by neurons of the glomerular region. The authors describe here the effects of early olfactory deprivation on other elements of the bulb dopaminergic system, namely the dopamine receptors of the olfactory bulb. Rat pups had a single naris occluded on postnatal day 2 (PN2). On PN20 or PN60, animals were sacrificed and the bulbs were examined for catecholamine levels or D2 and D1 dopamine receptor binding. Receptor densities were quantified by in vitro autoradiography using the tritiated antagonists spiperone (D2) and SCH23390 (D1). Dopamine uptake sites were similarly examined using tritiated mazindol. No significant specific labeling of D1 or mazindol sites was observed in the olfactory bulbs of control or experimental animals at either age. Normal animals displayed prominent labeling of D2 sites in the glomerular and nerve layers. After 60 days of deprivation, deprived bulbs exhibited an average increase in D2 receptor density of 32%. As determined by Scatchard analysis, the mean values for Kd and Bmax were 0.134 nM and 293 fmol/mg protein in normal bulbs, and 0.136 nM and 403 fmol/mg protein in deprived bulbs. The results suggest that, as in the neostriatum, dopamine depletion in the olfactory bulb leads to an upregulation of D2 receptor sites. This change may represent an attempt by the system to adapt neurochemically to reduced dopaminergic activity and thereby maintain bulb function

  10. Olfactory deprivation increases dopamine D2 receptor density in the rat olfactory bulb

    Energy Technology Data Exchange (ETDEWEB)

    Guthrie, K.M.; Pullara, J.M.; Marshall, J.F.; Leon, M. (University of California, Irvine (USA))

    1991-05-01

    Unilateral olfactory deprivation during postnatal development results in significant anatomical and neurochemical changes in the deprived olfactory bulb. Perhaps the most dramatic neurochemical change is the loss of dopaminergic expression by neurons of the glomerular region. The authors describe here the effects of early olfactory deprivation on other elements of the bulb dopaminergic system, namely the dopamine receptors of the olfactory bulb. Rat pups had a single naris occluded on postnatal day 2 (PN2). On PN20 or PN60, animals were sacrificed and the bulbs were examined for catecholamine levels or D2 and D1 dopamine receptor binding. Receptor densities were quantified by in vitro autoradiography using the tritiated antagonists spiperone (D2) and SCH23390 (D1). Dopamine uptake sites were similarly examined using tritiated mazindol. No significant specific labeling of D1 or mazindol sites was observed in the olfactory bulbs of control or experimental animals at either age. Normal animals displayed prominent labeling of D2 sites in the glomerular and nerve layers. After 60 days of deprivation, deprived bulbs exhibited an average increase in D2 receptor density of 32%. As determined by Scatchard analysis, the mean values for Kd and Bmax were 0.134 nM and 293 fmol/mg protein in normal bulbs, and 0.136 nM and 403 fmol/mg protein in deprived bulbs. The results suggest that, as in the neostriatum, dopamine depletion in the olfactory bulb leads to an upregulation of D2 receptor sites. This change may represent an attempt by the system to adapt neurochemically to reduced dopaminergic activity and thereby maintain bulb function.

  11. An Investigation of the Stoichiometry of Na+ Cotransport with Dopamine in Rat and Human Dopamine Transporters Expressed in Human Embryonic Kidney Cells

    National Research Council Canada - National Science Library

    Schumacher, Paul

    2001-01-01

    The neuronal membrane transporter for dopamine (DAT) is a member of the Na+ and Cl dependent family of transporters and concentrates dopamine intracellularly up to 106 fold over extracellular levels...

  12. High content of dopamine, a strong antioxidant, in Cavendish banana.

    Science.gov (United States)

    Kanazawa, K; Sakakibara, H

    2000-03-01

    A strong water-soluble antioxidant was identified in the popular commercial banana Musa cavendishii. It is dopamine, one of the catecholamines. For suppressing the oxygen uptake of linoleic acid in an emulsion and scavenging a diphenylpicrylhydrazyl radical, dopamine had greater antioxidative potency than glutathione, food additives such as butylated hydroxyanisole and hydroxytoluene, flavone luteolin, flavonol quercetin, and catechin, and similar potency to the strongest antioxidants gallocatechin gallate and ascorbic acid. Banana contained dopamine at high levels in both the peel and pulp. Dopamine levels ranged from 80-560 mg per 100 g in peel and 2.5-10 mg in pulp, even in ripened bananas ready to eat. Banana is thus one of the antioxidative foods.

  13. Missense dopamine transporter mutations associate with adult parkinsonism and ADHD

    DEFF Research Database (Denmark)

    Hansen, Freja H; Skjørringe, Tina; Yasmeen, Saiqa

    2014-01-01

    Parkinsonism and attention deficit hyperactivity disorder (ADHD) are widespread brain disorders that involve disturbances of dopaminergic signaling. The sodium-coupled dopamine transporter (DAT) controls dopamine homeostasis, but its contribution to disease remains poorly understood. Here, we......-deoxy-glucose-PET/MRI (FDG-PET/MRI) scan, the patient suffered from progressive dopaminergic neurodegeneration. In heterologous cells, both DAT variants exhibited markedly reduced dopamine uptake capacity but preserved membrane targeting, consistent with impaired catalytic activity. Computational simulations and uptake...... experiments suggested that the disrupted function of the DAT-Asp421Asn mutant is the result of compromised sodium binding, in agreement with Asp421 coordinating sodium at the second sodium site. For DAT-Asp421Asn, substrate efflux experiments revealed a constitutive, anomalous efflux of dopamine...

  14. Selective response of dopamine in the presence of ascorbic acid ...

    African Journals Online (AJOL)

    Selective response of dopamine in the presence of ascorbic acid and uric acid at gold nanoparticles and multi-walled carbon nanotubes grafted with ethylene diamine tetraacetic acid modified electrode.

  15. Simultaneous 99mTc and 123I dual-isotope brain striatal phantom single photon emission computed tomography: validation of 99mTc-TRODAT-1 and 123I-IBZM simultaneous dopamine system brain imaging.

    Science.gov (United States)

    Kao, Pan-Fu; Wey, Shiaw-Pyng; Yang, An-Shoei

    2009-11-01

    [2[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3,2,1]-oct-2-yl]-methyl](2-mercaptoethyl)-amino]ethyl]amino]ethanethiolato(3-)-N2,N2',S2,S2]oxo-[1R-exo-exo)])-[99mTc]-technetium (99mTc-TRODAT-1) and 123I-iodobenzamide (123I-IBZM) are radiotracers for brain dopamine pre- and postsynaptic neuron imaging. The purpose of this study was to evaluate imaging parameters and crossed energy interference using simultaneous single photon emission computed tomography (SPECT) 99mTc and 123I data acquisition. A five-compartment brain striatal phantom was filled with 99mTc and/or 123I radioactive solutions with different striatal-to-background ratios, ranging from 3:1 to 9:1. SPECT data were acquired with energy window settings of 15% for the centered window at 140 keV for 99mTc and a 10% asymmetric window at 159 keV for 123I. The experiments were carried out using either individual (99mTc or 123I only) or both radionuclides. The striatal-to-background ratios and energy crossed interference between 99mTc and 123I were calculated. The phantom SPECT images demonstrated that the energy crossed interferences from 123I to 99mTc, and vice versa, were 22 +/- 12.4% and 0.4 +/- 1.0%, respectively. A net interference of 7.1 +/- 4.0% for the counts in the 15% centered 99mTc window can be expected from 123I and a net interference of 1.6 +/- 3.3% for the counts in the 10% asymmetric 123I window was derived from 99mTc. The correlation of striatal-to-background ratios between single isotope and simultaneous dual-isotope was excellent (R2 = 0.99). The imaging parameters used in this simultaneous dualisotope SPECT imaging could be used in future clinical practice for imaging patients with movement disorders by using 99mTc-TRODAT-1 and 123I-IBZM. The striatal-to-background ratios were not affected by the crossed interference between 99mTc and 123I.

  16. Simultaneous 99mTC and 123I Dual-Isotope Brain Striatal Phantom Single Photon Emission Computed Tomography: Validation of 99mTC-Trodat-1 and 123I-IBZM Simultaneous Dopamine System Brain Imaging

    Directory of Open Access Journals (Sweden)

    Pan-Fu Kao

    2009-11-01

    Full Text Available [2[[2-[[[3-(4-chlorophenyl-8-methyl-8-azabicyclo[3,2,1]-oct-2-yl]-methyl](2-mercaptoethylamino]ethyl]amino]ethanethiolato(3--N2,N2′,S2,S2]oxo-[1R-exo-exo]-[99mTc]-technetium (99mTc-TRODAT-1 and 123I-iodobenzamide (123I-IBZM are radiotracers for brain dopamine preand postsynaptic neuron imaging. The purpose of this study was to evaluate imaging parameters and crossed energy interference using simultaneous single photon emission computed tomography (SPECT 99mTc and 123I data acquisition. A five-compartment brain striatal phantom was filled with 99mTc and/or 123I radioactive solutions with different striatal-to-background ratios, ranging from 3:1 to 9:1. SPECT data were acquired with energy window settings of 15% for the centered window at 140 keV for 99mTc and a 10% asymmetric window at 159 keV for 123I. The experiments were carried out using either individual (99mTc or 123I only or both radionuclides. The striatal-to-background ratios and energy crossed interference between 99mTc and 123I were calculated. The phantom SPECT images demonstrated that the energy crossed interferences from 123I to 99mTc, and vice versa, were 22 ± 12.4% and 0.4 ± 1.0%, respectively. A net interference of 7.1 ± 4.0% for the counts in the 15% centered 99mTc window can be expected from 123I and a net interference of 1.6 ± 3.3% for the counts in the 10% asymmetric 123I window was derived from 99mTc. The correlation of striatal-to-background ratios between single isotope and simultaneous dual-isotope was excellent (R2 = 0.99. The imaging parameters used in this simultaneous dual-isotope SPECT imaging could be used in future clinical practice for imaging patients with movement disorders by using 99mTc-TRODAT-1 and 123I-IBZM. The striatal-to-background ratios were not affected by the crossed interference between 99mTc and 123I.

  17. SEP-225289 serotonin and dopamine transporter occupancy: a PET study.

    Science.gov (United States)

    DeLorenzo, Christine; Lichenstein, Sarah; Schaefer, Karen; Dunn, Judith; Marshall, Randall; Organisak, Lisa; Kharidia, Jahnavi; Robertson, Brigitte; Mann, J John; Parsey, Ramin V

    2011-07-01

    SEP-225289 is a novel compound that, based on in vitro potencies for transporter function, potentially inhibits reuptake at dopamine, norepinephrine, and serotonin transporters. An open-label PET study was conducted during the development of SEP-225289 to investigate its dopamine and serotonin transporter occupancy. Different single doses of SEP-225289 were administered to healthy volunteers in 3 cohorts: 8 mg (n = 7), 12 mg (n = 5), and 16 mg (n = 7). PET was performed before and approximately 24 h after oral administration of SEP-225289, to assess occupancy at trough levels. Dopamine and serotonin transporter occupancies were estimated from PET using (11)C-N-(3-iodoprop-2E-enyl)-2β-carbomethoxy-3β-(4-methylphenyl)nortropane ((11)C-PE2I) and (11)C-N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine ((11)C-DASB), respectively. Plasma concentration of SEP-225289 was assessed before ligand injection, and subjects were monitored for adverse events. Average dopamine and serotonin transporter occupancies increased with increasing doses of SEP-225289. Mean dopamine and serotonin transporter occupancies were 33% ± 11% and 2% ± 13%, respectively, for 8 mg; 44% ± 4% and 9% ± 10%, respectively, for 12 mg; and 49% ± 7% and 14% ± 15%, respectively, for 16 mg. On the basis of the relationship between occupancy and plasma concentration, dopamine transporter IC(50) (the plasma concentration of drug at 50% occupancy) was determined (4.5 ng/mL) and maximum dopamine transporter occupancy was extrapolated (85%); however, low serotonin transporter occupancy prevented similar serotonin transporter calculations. No serious adverse events were reported. At the doses evaluated, occupancy of the dopamine transporter was significantly higher than that of the serotonin transporter, despite similar in vitro potencies, confirming that, in addition to in vitro assays, PET occupancy studies can be instrumental to the drug development process by informing early decisions about

  18. In vivo neurochemical characterization of clothianidin induced striatal dopamine release.

    Science.gov (United States)

    Faro, L R F; Oliveira, I M; Durán, R; Alfonso, M

    2012-12-16

    Clothianidin (CLO) is a neonicotinoid insecticide with selective action on nicotinic acetylcholine receptors. The aim of this study was to determine the neurochemical basis for CLO-induced striatal dopamine release using the microdialysis technique in freely moving and conscious rats. Intrastriatal administration of CLO (3.5mM), produced an increase in both spontaneous (2462 ± 627% with respect to basal values) and KCl-evoked (4672 ± 706% with respect to basal values) dopamine release. This effect was attenuated in Ca(2+)-free medium, and was prevented in reserpine pre-treated animals or in presence of tetrodotoxin (TTX). To investigate the involvement of dopamine transporter (DAT), the effect of CLO was observed in presence of nomifensine. The coadministration of CLO and nomifensine produced an additive effect on striatal dopamine release. The results suggest that the effect of CLO on striatal dopamine release is predominantly mediated by an exocytotic mechanism, Ca(2+), vesicular and TTX-dependent and not by a mechanism mediated by dopamine transporter. Published by Elsevier Ireland Ltd.

  19. Photoaffinity ligand for dopamine D2 receptors: azidoclebopride

    International Nuclear Information System (INIS)

    Niznik, H.B.; Guan, J.H.; Neumeyer, J.L.; Seeman, P.

    1985-01-01

    In order to label D2 dopamine receptors selectively and covalently by means of a photosensitive compound, azidoclebopride was synthesized directly from clebopride. The dissociation constant (KD) of clebopride for the D2 dopamine receptor (canine brain striatum) was 1.5 nM, while that for azidoclebopride was 21 nM. The affinities of both clebopride and azidoclebopride were markedly reduced in the absence of sodium chloride. In the presence of ultraviolet light, azidoclebopride inactivated D2 dopamine receptors irreversibly, as indicated by the inability of the receptors to bind [ 3 H]spiperone. Maximal photoinactivation of about 60% of the D2 dopamine receptors occurred at 1 microM azidoclebopride; 30% of the receptors were inactivated at 80 nM azidoclebopride (pseudo-IC50). Dopamine agonists selectively protected the D2 receptors from being inactivated by azidoclebopride, the order of potency being (-)-N-n-propylnorapomorphine greater than apomorphine greater than (+/-)-6,7-dihydroxy-2-aminotetralin greater than (+)-N-n-propylnorapomorphine greater than dopamine greater than noradrenaline greater than serotonin. Similarly, dopaminergic antagonists prevented the photoinactivation of D2 receptors by azidoclebopride with the following order of potency: spiperone greater than (+)-butaclamol greater than haloperidol greater than clebopride greater than (-)-sulpiride greater than (-)-butaclamol

  20. Demonstration of specific dopamine receptors on human pituitary adenomas

    International Nuclear Information System (INIS)

    Koga, Masafumi; Nakao, Haruyoshi; Arao, Masayo; Sato, Bunzo; Noma, Keizo; Morimoto, Yasuhiko; Kishimoto, Susumu; Mori, Shintaro; Uozumi, Toru

    1987-01-01

    Dopamine receptors on human pituitary adenoma membranes were characterized using [ 3 H]spiperone as the radioligand. The specific [ 3 H]spiperone binding sites on prolactin (PRL)-secreting adenoma membranes were recognized as a dopamine receptor, based upon the data showing high affinity binding, saturability, specificity, temperature dependence, and reversibility. All of 14 PRL-secreting adenomas had high affinity dopamine receptors, with a dissociation constant (Kd) of 0.85±0.11 nmol/l (mean±SEM) and a maximal binding capacity (Bmax) of 428±48.6 fmol/mg protein. Among 14 growth hormone (GH)-secreting adenomas examined, 8 (57%) had dopamine receptors with a Kd of 1.90±0.47 nmol/l and a Bmax of 131±36.9 fmol/mg protein. Furthermore, 15 of 24 (58%) nonsecreting pituitary adenomas also had dopamine receptors with a Kd of 1.86±0.37 nmol/l and a Bmax of 162±26.0 fmol/mg protein. These results indicate that some GH-secreting adenomas as well as some nonsecreting pituitary adenomas contain dopamine receptors. But their affinity and number of binding sites are significantly lower (P<0.05) and fewer (P<0.001) respectively, than those in PRL-secreting adenomas. (author)

  1. Development of specific dopamine D-1 agonists and antagonists

    International Nuclear Information System (INIS)

    Sakolchai, S.

    1987-01-01

    To develop potentially selective dopamine D-1 agonists and to investigate on the structural requirement for D-1 activity, the derivatives of dibenzocycloheptadiene are synthesized and pharmacologically evaluated. The target compounds are 5-aminomethyl-10,11-dihydro-1,2-dihydroxy-5H-dibenzo[a,d]cycloheptene hydrobromide 10 and 9,10-dihydroxy-1,2,3,7,8,12b-hexahydrobenzo[1,2]cyclohepta[3,4,5d,e]isoquinoline hydrobromide 11. In a dopamine-sensitive rat retinal adenylate cyclase assay, a model for D-1 activity, compound 10 is essentially inert for both agonist and antagonist activity. In contrast, compound 11 is approximately equipotent to dopamine in activation of the D-1 receptor. Based on radioligand and binding data, IC 50 of compound 11 for displacement of 3 H-SCH 23390, a D-1 ligand, is about 7 fold less than that for displacement of 3 H-spiperone, a D-2 ligand. These data indicate that compound 11 is a potent selective dopamine D-1 agonist. This study provides a new structural class of dopamine D-1 acting agent: dihydroxy-benzocycloheptadiene analog which can serve as a lead compound for further drug development and as a probe for investigation on the nature of dopamine D-1 receptor

  2. Effects of cysteamine on dopamine-mediated behaviors: evidence for dopamine-somatostatin interactions in the striatum

    Energy Technology Data Exchange (ETDEWEB)

    Martin-Iverson, M.T.; Radke, J.M.; Vincent, S.R.

    1986-06-01

    The effects of prior treatment with cysteamine, a drug which appears to deplete selectively the neuropeptide somatostatin, on apomorphine-induced stereotypy and amphetamine-induced locomotor activity and conditioned place preferences were investigated. Twelve hours following systemic cysteamine injections apomorphine-induced stereotypy was attenuated and striatal somatostatin levels were reduced by half. Systemic cysteamine also decreased the motor stimulant effects of amphetamine, without influencing the rewarding properties as determined by the conditioned place preference procedure. Direct injections of cysteamine into the nucleus accumbens also decreased the locomotor response to amphetamine, and produced a local reduction in somatostatin levels in the accumbens. Cysteamine did not appear to alter monoamine turnover in the striatum after either systemic or intra-accumbens injections. These results suggest that somatostatin in the nucleus accumbens and caudate-putamen modulates the motor, but not the reinforcing properties of dopaminergic drugs, possibly via an action postsynaptic to dopamine-releasing terminals. Furthermore, it is evident from these results that cysteamine is an important tool with which to study the central actions of somatostatin.

  3. A pilot study of genetic variants in dopamine regulators with indoor tanning and melanoma

    Science.gov (United States)

    Flores, Kristina G.; Erdei, Esther; Luo, Li; White, Kirsten A. M.; Leng, Shuguang; Berwick, Marianne; Lazovich, DeAnn

    2014-01-01

    Many people frequently tan indoors despite being aware of the increased risk of melanoma. Ultraviolet radiation is hypothesized to modify biological reward pathways, for example, through the dopamine neurotransmitter system, to reinforce tanning behaviour. In this pilot study, we relied on questionnaire and DNA data from a recently completed case–control study to examine 67 single-nucleotide polymorphisms (SNPs) and related haplotypes in five dopamine receptor and drug metabolism genes in relation to indoor tanning among controls. We also examined the association between individual SNPS and likelihood of melanoma, adjusting for or stratifying on indoor tanning status. In candidate and haplotype gene analyses, variants only in the DRD2 dopamine receptor and ANKK1 signalling genes were positively associated with indoor tanning use among controls; only associations for ANKK1 remained statistically significant (P < 0.05) after adjustment. Several SNPs in ANKK1 and DRD2 associated with indoor tanning among controls were also found to be associated with increased risk of melanoma. Upon stratifying for indoor tanning status, one ANKK1 SNP was positively associated with melanoma among non-tanners, while three DRD2 SNPS were positively associated with melanoma among tanners or non-tanners, depending on the SNP. These alleles represent important genomic regions to further explore addictive tanning behaviour. PMID:23947671

  4. Characterization of an Invertebrate-Type Dopamine Receptor of the American Cockroach, Periplaneta americana

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    Britta Troppmann

    2014-01-01

    Full Text Available We have isolated a cDNA coding for a putative invertebrate-type dopamine receptor (Peadop2 from P. americana brain by using a PCR-based strategy. The mRNA is present in samples from brain and salivary glands. We analyzed the distribution of the PeaDOP2 receptor protein with specific affinity-purified polyclonal antibodies. On Western blots, PeaDOP2 was detected in protein samples from brain, subesophageal ganglion, thoracic ganglia, and salivary glands. In immunocytochemical experiments, we detected PeaDOP2 in neurons with their somata being located at the anterior edge of the medulla bilaterally innervating the optic lobes and projecting to the ventro-lateral protocerebrum. In order to determine the functional and pharmacological properties of the cloned receptor, we generated a cell line constitutively expressing PeaDOP2. Activation of PeaDOP2-expressing cells with dopamine induced an increase in intracellular cAMP. In contrast, a C-terminally truncated splice variant of this receptor did not exhibit any functional property by itself. The molecular and pharmacological characterization of the first dopamine receptor from P. americana provides the basis for forthcoming studies focusing on the significance of the dopaminergic system in cockroach behavior and physiology.

  5. Novel, Selective, and Developable Dopamine D3Antagonists with a Modified "Amino" Region.

    Science.gov (United States)

    Micheli, Fabrizio

    2017-08-22

    This Minireview describes a presentation made at the XXIV National Meeting in Medicinal Chemistry (NMMC) held in Perugia (Italy), September 11-14, 2016. It relates to the discovery of novel templates of the so-called "amino" region of dopamine D 3 receptor antagonists. Moving from the early scaffolds, which were modified in the amine portion, this review discusses the variations that led to the discovery of new systems published in 2016, which allowed the identification of compounds endowed with great selectivity over the dopamine D 2 receptor and the human ether-à-go-go-related gene (hERG) ion channel. The main efforts in characterizing these compounds were devoted not only to determining their potency and selectivity relative to closely associated targets (e.g., the dopamine D 2 receptor), but to ensure a large therapeutic window versus liability points such as hERG. In particular, we present examples of derivatives with selectivities greater than 2000-fold. Furthermore, much focus is devoted to the overall developability of the scaffolds, ensuring that appropriate physicochemical and pharmacokinetic parameters are present in all compounds progressing through the screening cascade. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Dopamine Induces Oscillatory Activities in Human Midbrain Neurons with Parkin Mutations.

    Science.gov (United States)

    Zhong, Ping; Hu, Zhixing; Jiang, Houbo; Yan, Zhen; Feng, Jian

    2017-05-02

    Locomotor symptoms in Parkinson's disease (PD) are accompanied by widespread oscillatory neuronal activities in basal ganglia. Here, we show that activation of dopamine D1-class receptors elicits a large rhythmic bursting of spontaneous excitatory postsynaptic currents (sEPSCs) in midbrain neurons differentiated from induced pluripotent stem cells (iPSCs) of PD patients with parkin mutations, but not normal subjects. Overexpression of wild-type parkin, but not its PD-causing mutant, abolishes the oscillatory activities in patient neurons. Dopamine induces a delayed enhancement in the amplitude of spontaneous, but not miniature, EPSCs, thus increasing quantal content. The results suggest that presynaptic regulation of glutamatergic transmission by dopamine D1-class receptors is significantly potentiated by parkin mutations. The aberrant dopaminergic regulation of presynaptic glutamatergic transmission in patient-specific iPSC-derived midbrain neurons provides a mechanistic clue to PD pathophysiology, and it demonstrates the usefulness of this model system in understanding how mutations of parkin cause movement symptoms in Parkinson's disease. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  7. An autonomous circadian clock in the inner mouse retina regulated by dopamine and GABA.

    Directory of Open Access Journals (Sweden)

    Guo-Xiang Ruan

    2008-10-01

    Full Text Available The influence of the mammalian retinal circadian clock on retinal physiology and function is widely recognized, yet the cellular elements and neural regulation of retinal circadian pacemaking remain unclear due to the challenge of long-term culture of adult mammalian retina and the lack of an ideal experimental measure of the retinal circadian clock. In the current study, we developed a protocol for long-term culture of intact mouse retinas, which allows retinal circadian rhythms to be monitored in real time as luminescence rhythms from a PERIOD2::LUCIFERASE (PER2::LUC clock gene reporter. With this in vitro assay, we studied the characteristics and location within the retina of circadian PER2::LUC rhythms, the influence of major retinal neurotransmitters, and the resetting of the retinal circadian clock by light. Retinal PER2::LUC rhythms were routinely measured from whole-mount retinal explants for 10 d and for up to 30 d. Imaging of vertical retinal slices demonstrated that the rhythmic luminescence signals were concentrated in the inner nuclear layer. Interruption of cell communication via the major neurotransmitter systems of photoreceptors and ganglion cells (melatonin and glutamate and the inner nuclear layer (dopamine, acetylcholine, GABA, glycine, and glutamate did not disrupt generation of retinal circadian PER2::LUC rhythms, nor did interruption of intercellular communication through sodium-dependent action potentials or connexin 36 (cx36-containing gap junctions, indicating that PER2::LUC rhythms generation in the inner nuclear layer is likely cell autonomous. However, dopamine, acting through D1 receptors, and GABA, acting through membrane hyperpolarization and casein kinase, set the phase and amplitude of retinal PER2::LUC rhythms, respectively. Light pulses reset the phase of the in vitro retinal oscillator and dopamine D1 receptor antagonists attenuated these phase shifts. Thus, dopamine and GABA act at the molecular level of PER

  8. Dopamine receptor and Gα(olf expression in DYT1 dystonia mouse models during postnatal development.

    Directory of Open Access Journals (Sweden)

    Lin Zhang

    Full Text Available DYT1 dystonia is a heritable, early-onset generalized movement disorder caused by a GAG deletion (ΔGAG in the DYT1 gene. Neuroimaging studies and studies using mouse models suggest that DYT1 dystonia is associated with dopamine imbalance. However, whether dopamine imbalance is key to DYT1 or other forms of dystonia continues to be debated.We used Dyt1 knock out (Dyt1 KO, Dyt1 ΔGAG knock-in (Dyt1 KI, and transgenic mice carrying one copy of the human DYT1 wild type allele (DYT1 hWT or human ΔGAG mutant allele (DYT1 hMT. D1R, D2R, and Gα(olf protein expression was analyzed by western blot in the frontal cortex, caudate-putamen and ventral midbrain in young adult (postnatal day 60; P60 male mice from all four lines; and in the frontal cortex and caudate putamen in juvenile (postnatal day 14; P14 male mice from the Dyt1 KI and KO lines. Dopamine receptor and Gα(olf protein expression were significantly decreased in multiple brain regions of Dyt1 KI and Dyt1 KO mice and not significantly altered in the DYT1 hMT or DYT1 hWT mice at P60. The only significant change at P14 was a decrease in D1R expression in the caudate-putamen of the Dyt1 KO mice.We found significant decreases in key proteins in the dopaminergic system in multiple brain regions of Dyt1 KO and Dyt1 KI mouse lines at P60. Deletion of one copy of the Dyt1 gene (KO mice produced the most pronounced effects. These data offer evidence that impaired dopamine receptor signaling may be an early and significant contributor to DYT1 dystonia pathophysiology.

  9. Ventral striatal dopamine synthesis capacity predicts financial extravagance in Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Andrew David Lawrence

    2013-02-01

    Full Text Available Impulse control disorders (ICDs, including disordered gambling, can occur in a significant number of patients with Parkinson’s disease (PD receiving dopaminergic therapy. The neurobiology underlying susceptibility to such problems is unclear, but risk likely results from an interaction between dopaminergic medication and a pre-existing trait vulnerability. Impulse control and addictive disorders form part of a broader psychopathological spectrum of disorders, which share a common underlying genetic vulnerability, referred to as externalizing. The broad externalizing risk factor is a continuously varying trait reflecting vulnerability to various impulse control problems, manifested at the overt level by disinhibitory symptoms and at the personality level by antecedent traits such as impulsivity and novelty/sensation seeking. Trait ‘disinhibition’ is thus a core endophenotype of ICDs, and a key target for neurobiological investigation. The ventral striatal dopamine system has been hypothesized to underlie individual variation in behavioural disinhibition. Here, we examined whether individual differences in ventral striatal dopamine synthesis capacity predicted individual variation in disinhibitory temperament traits in individuals with PD. Eighteen early-stage male PD patients underwent 6-[18F]Fluoro-L-DOPA (FDOPA positron emission tomography (PET scanning to measure striatal dopamine synthesis capacity, and completed a measure of disinhibited personality. Consistent with our predictions, we found that levels of ventral, but not dorsal, striatal dopamine synthesis capacity predicted disinhibited personality, particularly a propensity for financial extravagance. Our results are consistent with recent preclinical models of vulnerability to behavioural disinhibition and addiction proneness, and provide novel insights into the neurobiology of potential vulnerability to impulse control problems in PD and other disorders.

  10. Changes in dopamine transporter binding in nucleus accumbens following chronic self-administration cocaine: heroin combinations.

    Science.gov (United States)

    Pattison, Lindsey P; McIntosh, Scot; Sexton, Tammy; Childers, Steven R; Hemby, Scott E

    2014-10-01

    Concurrent use of cocaine and heroin (speedball) has been shown to exert synergistic effects on dopamine neurotransmission in the nucleus accumbens (NAc), as observed by significant increases in extracellular dopamine levels and compensatory elevations in the maximal reuptake rate of dopamine. The present studies were undertaken to determine whether chronic self-administration of cocaine, heroin or a combination of cocaine:heroin led to compensatory changes in the abundance and/or affinity of high- and low-affinity DAT binding sites. Saturation binding of the cocaine analog [(125) I] 3β-(4-iodophenyl)tropan-2β-carboxylic acid methyl ester ([(125) I]RTI-55) in rat NAc membranes resulted in binding curves that were best fit to two-site binding models, allowing calculation of dissociation constant (Kd ) and binding density (Bmax ) values corresponding to high- and low-affinity DAT binding sites. Scatchard analysis of the saturation binding curves clearly demonstrate the presence of high- and low- affinity binding sites in the NAc, with low-affinity sites comprising 85 to 94% of the binding sites. DAT binding analyses revealed that self-administration of cocaine and a cocaine:heroin combination increased the affinity of the low-affinity site for the cocaine congener RTI-55 compared to saline. These results indicate that the alterations observed following chronic speedball self-administration are likely due to the cocaine component alone; thus further studies are necessary to elaborate upon the synergistic effect of cocaine:heroin combinations on the dopamine system in the NAc. © 2014 Wiley Periodicals, Inc.

  11. [3H]mazindol binding associated with neuronal dopamine and norepinephrine uptake sites.

    Science.gov (United States)

    Javitch, J A; Blaustein, R O; Snyder, S H

    1984-07-01

    [3H]Mazindol labels neuronal dopamine uptake sites in corpus striatum membranes (KD = 18 nM) and neuronal norepinephrine uptake sites in cerebral cortex and submaxillary/sublingual gland membranes (KD = 4 nM). The potencies of various inhibitors of biogenic amine uptake in reducing [3H]mazindol binding in striatal membranes correlate with their potencies for inhibition of neuronal [3H]dopamine accumulation, whereas their potencies in reducing [3H]mazindol binding to cortical and salivary gland membranes correlate with their potencies for inhibition of neuronal [3H]norepinephrine accumulation. Similar to the dopamine and norepinephrine uptake systems, [3H]mazindol binding in all three tissues is dependent upon sodium (with potassium, lithium, rubidium, and Tris being ineffective substitutes) and chloride (with sulfate and phosphate being ineffective substitutes). In membranes of the cerebral cortex and salivary gland, half-maximal stimulation is observed at 50-80 mM NaCl, whereas in membranes of the corpus striatum half-maximal stimulation occurs at 240 mM NaCl. In striatal membranes NaCl increases the affinity of [3H]mazindol binding with no effect on the maximal number of sites. The enhancement of affinity is due to a selective slowing of the dissociation of the ligand from its binding site. The association of [3H]mazindol binding sites with neuronal dopamine uptake sites in the corpus striatum is further supported by the reduction of [3H]mazindol binding sites in striatal membranes following destruction of dopaminergic neurons by 6-hydroxydopamine. Similarly, the association of [3H]mazindol binding sites with neuronal norepinephrine uptake sites in cerebral cortex is supported by the reduction of [3H]mazindol binding to cortical membranes following destruction of noradrenergic neurons by N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine.

  12. SPECT imaging of D2 dopamine receptors and endogenous dopamine release in mice

    International Nuclear Information System (INIS)

    Jongen, Cynthia; Bruin, Kora de; Booij, Jan; Beekman, Freek

    2008-01-01

    The dopamine D 2 receptor (D2R) is important in the mediation of addiction. [ 123 I]iodobenzamide (IBZM), a SPECT ligand for the D2R, has been used for in vivo studies of D2R availability in humans, monkeys, and rats. Although mouse models are important in the study of addiction, [ 123 I]IBZM has not been used in mice SPECT studies. This study evaluates the use of [ 123 I]IBZM for measuring D2R availability in mice. Pharmacokinetics of [ 123 I]IBZM in mice were studied with pinhole SPECT imaging after intravenous (i.v.) injection of [ 123 I]IBZM (20, 40, and 70 MBq). In addition, the ability to measure the release of endogenous dopamine after amphetamine administration with [ 123 I]IBZM SPECT was investigated. Thirdly, i.v. administration, the standard route of administration, and intraperitoneal (i.p.) administration of [ 123 I]IBZM were compared. Specific binding of [ 123 I]IBZM within the mouse striatum could be clearly visualized with SPECT. Peak specific striatal binding ratios were reached around 90 min post-injection. After amphetamine administration, the specific binding ratios of [ 123 I]IBZM decreased significantly (-27.2%; n=6; p=0.046). Intravenous administration of [ 123 I]IBZM led to significantly higher specific binding than i.p. administration of the same dose. However, we found that i.v. administration of a dose of 70 MBq [ 123 I]IBZM might result in acute ethanol intoxication because ethanol is used as a preparative aid for the routine production of [ 123 I]IBZM. Imaging of D2R availability and endogenous dopamine release in mice is feasible using [ 123 I]IBZM single pinhole SPECT. Using commercially produced [ 123 I]IBZM, a dose of 40 MBq injected i.v. can be recommended. (orig.)

  13. Sport physiology, dopamine and nitric oxide - Some speculations and hypothesis generation.

    Science.gov (United States)

    Landers, J G; Esch, Tobias

    2015-12-01

    Elite Spanish professional soccer players surprisingly showed a preponderance of an allele coding for nitric oxide synthase (NOS) that resulted in lower nitric oxide (NO) compared with Spanish endurance and power athletes and sedentary men. The present paper attempts a speculative explanation. Soccer is an "externally-paced" (EP) sport and team work dependent, requiring "executive function skills". We accept that time interval estimation skill is, in part, also an executive skill. Dopamine (DA) is prominent among the neurotransmitters with a role in such skills. Polymorphisms affecting dopamine (especially DRD2/ANKK1-Taq1a which leads to lower density of dopamine D2 receptors in the striatum, leading to increased striatal dopamine synthesis) and COMT val 158 met (which prolongs the action of dopamine in the cortex) feature both in the time interval estimation and the executive skills literatures. Our paper may be a pioneering attempt to stimulate empirical efforts to show how genotypes among soccer players may be connected via neurotransmitters to certain cognitive abilities that predict sporting success, perhaps also in some other externally-paced team sports. Graphing DA levels against time interval estimation accuracy and also against certain executive skills reveals an inverted-U relationship. A pathway from DA, via endogenous morphine and mu3 receptors on endothelia, to the generation of NO in tiny quantities has been demonstrated. Exercise up-regulates DA and this pathway. With somewhat excessive exercise, negative feedback from NO down-regulates DA, hypothetically keeping it near the peak of the inverted-U. Other research, not yet done on higher animals or humans, shows NO "fine-tuning" movement. We speculate that Caucasian men, playing soccer recreationally, would exemplify the above pattern and their nitric oxide synthase (NOS) would reflect the norm of their community, whereas professional players of soccer and perhaps other EP sports, with DA boosted by

  14. Dopamine, prolactin and treatment of psychoses

    Directory of Open Access Journals (Sweden)

    Marić-Bojović Nađa P.

    2015-01-01

    Full Text Available Prolactin (pro-lactis, lat. is a hormone discovered around eight decades ago, with a numerous functions in human body including the effects on growth and development, influences on behavior, metabolism, reproduction, etc. More than 60 years after antipsychotic drugs were introduced, these medications have been keeping prolactin in the spotlight of the psychiatric research community as practically all D2-antagonists change prolactin levels. Hyperprolactinemia has been evaluated in several aspects, either related to patient's characteristics (genetic and functional individual features or to some drug-related phenomena (penetrability across the blood-brain barrier; D2 receptor binding affinity; capacity to antagonize serotonin receptors, but a critical review of the current literature indicates many unknowns in the field. The present paper will discuss the mechanism and dynamics of changes in prolactin levels throughout treatment with dopamine antagonists on the molecular and clinical level, and the risk of certain acute vs. late adverse effects. Moreover, different techniques that could be applied in common psychiatric practice aiming to control prolactin levels will be considered, with a special emphasis on the possibilities following synthesis and increasing availability of a third generation antipsychotics.

  15. Decreased lymphocyte dopamine transporter in romantic lovers.

    Science.gov (United States)

    Marazziti, Donatella; Baroni, Stefano; Giannaccini, Gino; Piccinni, Armando; Mucci, Federico; Catena-Dell'Osso, Mario; Rutigliano, Grazia; Massimetti, Gabriele; Dell'Osso, Liliana

    2017-06-01

    The role of dopamine (DA) in romantic love is suggested by different evidence and is supported by the findings of some brain imaging studies. The DA transporter (DAT) is a key structure in regulating the concentration of the neurotransmitter in the synaptic cleft. Given the presence of DAT in blood cells, the present study aimed to explore it in resting lymphocytes of 30 healthy subjects of both sexes in the early stage of romantic love (no longer than 6 months), as compared with 30 subjects involved in a long-lasting relationship. All subjects had no physical or psychiatric illness. The DAT was measured by means of the [3H]-WIN 35,428 binding and the [3H]-DA reuptake to resting lymphocytes membranes. Romantic love was assessed by a specific questionnaire developed by us. The results showed that the subjects in the early phase of romantic love had a global alteration of the lymphocyte DAT involving both a decreased number of proteins (Bmax) and a reduced functionality (Vmax). Taken together, these findings would indicate the presence of increased levels of DA in romantic love that, if paralleled by similar concentrations in the brain, would explain some peculiar features of this human feeling.

  16. Presynaptic Dopamine Synthesis Capacity in Schizophrenia and Striatal Blood Flow Change During Antipsychotic Treatment and Medication-Free Conditions.

    Science.gov (United States)

    Eisenberg, Daniel Paul; Yankowitz, Lisa; Ianni, Angela M; Rubinstein, Dani Y; Kohn, Philip D; Hegarty, Catherine E; Gregory, Michael D; Apud, José A; Berman, Karen F

    2017-10-01

    Standard-of-care biological treatment of schizophrenia remains dependent upon antipsychotic medications, which demonstrate D 2 receptor affinity and elicit variable, partial clinical responses via neural mechanisms that are not entirely understood. In the striatum, where D 2 receptors are abundant, antipsychotic medications may affect neural function in studies of animals, healthy volunteers, and patients, yet the relevance of this to pharmacotherapeutic actions remains unresolved. In this same brain region, some individuals with schizophrenia may demonstrate phenotypes consistent with exaggerated dopaminergic signaling, including alterations in dopamine synthesis capacity; however, the hypothesis that dopamine system characteristics underlie variance in medication-induced regional blood flow changes has not been directly tested. We therefore studied a cohort of 30 individuals with schizophrenia using longitudinal, multi-session [ 15 O]-water and [ 18 F]-FDOPA positron emission tomography to determine striatal blood flow during active atypical antipsychotic medication treatment and after at least 3 weeks of placebo treatment, along with presynaptic dopamine synthesis capacity (ie, DOPA decarboxylase activity). Regional striatal blood flow was significantly higher during active treatment than during the placebo condition. Furthermore, medication-related increases in ventral striatal blood flow were associated with more robust amelioration of excited factor symptoms during active medication and with higher dopamine synthesis capacity. These data indicate that atypical medications enact measureable physiological alterations in limbic striatal circuitry that vary as a function of dopaminergic tone and may have relevance to aspects of therapeutic responses.

  17. Synaptic vesicle glycoprotein 2C (SV2C) modulates dopamine release and is disrupted in Parkinson disease.

    Science.gov (United States)

    Dunn, Amy R; Stout, Kristen A; Ozawa, Minagi; Lohr, Kelly M; Hoffman, Carlie A; Bernstein, Alison I; Li, Yingjie; Wang, Minzheng; Sgobio, Carmelo; Sastry, Namratha; Cai, Huaibin; Caudle, W Michael; Miller, Gary W

    2017-03-14

    Members of the synaptic vesicle glycoprotein 2 (SV2) family of proteins are involved in synaptic function throughout the brain. The ubiquitously expressed SV2A has been widely implicated in epilepsy, although SV2C with its restricted basal ganglia distribution is poorly characterized. SV2C is emerging as a potentially relevant protein in Parkinson disease (PD), because it is a genetic modifier of sensitivity to l-DOPA and of nicotine neuroprotection in PD. Here we identify SV2C as a mediator of dopamine homeostasis and report that disrupted expression of SV2C within the basal ganglia is a pathological feature of PD. Genetic deletion of SV2C leads to reduced dopamine release in the dorsal striatum as measured by fast-scan cyclic voltammetry, reduced striatal dopamine content, disrupted α-synuclein expression, deficits in motor function, and alterations in neurochemical effects of nicotine. Furthermore, SV2C expression is dramatically altered in postmortem brain tissue from PD cases but not in Alzheimer disease, progressive supranuclear palsy, or multiple system atrophy. This disruption was paralleled in mice overexpressing mutated α-synuclein. These data establish SV2C as a mediator of dopamine neuron function and suggest that SV2C disruption is a unique feature of PD that likely contributes to dopaminergic dysfunction.

  18. D2 dopamine receptors enable Δ9-tetrahydrocannabinol induced memory impairment and reduction of hippocampal extracellular acetylcholine concentration

    Science.gov (United States)

    Nava, F; Carta, G; Battasi, A M; Gessa, G L

    2000-01-01

    The systemic administration of Δ9-tetrahydrocannabinol (2.5–7.5 mg kg−1) reduced hippocampal extracellular acetylcholine concentration and impaired working memory in rats.Both effects were antagonized not only by the CB1 cannabinoid receptor antagonist SR141716A (0.5 mg kg−1, i.p.) but also unexpectedly by the D2 dopamine receptor antagonist S(−)-sulpiride (5, 10 and 25 mg kg−1, i.p.). Conversely, Δ9-tetrahydrocannabinol-induced memory impairment and inhibition of hippocampal extracellular acetylcholine concentration were potentiated by the subcutaneous administration of the D2 dopamine receptor agonist (−)-quinpirole (25 and 500 μg kg−1). The inhibition of hippocampal extracellular acetylcholine concentration and working memory produced by the combination of (−)-quinpirole and Δ9-tetrahydrocannabinol was suppressed by either SR141716A or S(−)-sulpiride.Our findings suggest that impairment of working memory and inhibition of hippocampal extracellular acetylcholine concentration are mediated by the concomitant activation of D2 dopamine and CB1 cannabinoid receptors, and that D2 dopamine receptor antagonists may be useful in the treatment of the cognitive deficits induced by marijuana. PMID:10903956

  19. Neurochemostat: A Neural Interface SoC with Integrated Chemometrics for Closed-Loop Regulation of Brain Dopamine

    Science.gov (United States)

    Bozorgzadeh, Bardia; Schuweiler, Douglas R.; Bobak, Martin J.; Garris, Paul A.; Mohseni, Pedram

    2016-01-01

    This paper presents a 3.3 × 3.2mm2 system-on-chip (SoC) fabricated in AMS 0.35µm 2P/4M CMOS for closed-loop regulation of brain dopamine. The SoC uniquely integrates neurochemical sensing, on-the-fly chemometrics, and feedback-controlled electrical stimulation to realize a “neurochemostat” by maintaining brain levels of electrically evoked dopamine between two user-set thresholds. The SoC incorporates a 90µW, custom-designed, digital signal processing (DSP) unit for real-time processing of neurochemical data obtained by 400V/s fast-scan cyclic voltammetry (FSCV) with a carbon-fiber microelectrode (CFM). Specifically, the DSP unit executes a chemometrics algorithm based upon principal component regression (PCR) to resolve in real time electrically evoked brain dopamine levels from pH change and CFM background-current drift, two common interferents encountered using FSCV with a CFM in vivo. Further, the DSP unit directly links the chemically resolved dopamine levels to the activation of the electrical microstimulator in on-off-keying (OOK) fashion. Measured results from benchtop testing, flow injection analysis (FIA), and biological experiments with an anesthetized rat are presented. PMID:26390501

  20. Specification Of Midbrain Dopamine Neurons From Primate Pluripotent Stem Cells

    Science.gov (United States)

    Xi, Jiajie; Liu, Yan; Liu, Huisheng; Chen, Hong; Emborg, Marina E.; Zhang, Su-Chun

    2012-01-01

    By sequentially applying sonic hedgehog (C25II) and CHIR99021 (GSK3β inhibitor) to induce the midbrain floor plate progenitors and fibroblast growth factor 8 (FGF8) to promote dopaminergic differentiation in a chemically defined medium, we have established a robust system for generation of midbrain dopamine (DA) neurons from human and rhesus monkey embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). We found that CHIR99021 specifies diencephalon to hindbrain fates in a concentration-dependent manner and only a narrow concentration range of CHIR99021 at a particular window is necessary to induce the midbrain floor plate progenitors, expressing Corin, En1, FoxA2 and Lmx1a. FGF8 enhances the dopaminergic fate of the progenitors, thus generating DA neurons with midbrain characteristics, including expression of TH, Lmx1a/b, FoxA2, FoxP1, Nurr1 and En1 as well as typical electrophysiological properties. More than half of these DA neurons expressed A9 DA neuron markers Girk2 and ALDH1a1. The new strategy will allow generation of enriched populations of functional midbrain DA neurons from both human and monkey PSCs for disease modeling, drug testing, and potential cell therapy. PMID:22696177

  1. Reduced Striatal Dopamine Transporters in People with Internet Addiction Disorder

    Directory of Open Access Journals (Sweden)

    Haifeng Hou

    2012-01-01

    Full Text Available In recent years, internet addiction disorder (IAD has become more prevalent worldwide and the recognition of its devastating impact on the users and society has rapidly increased. However, the neurobiological mechanism of IAD has not bee fully expressed. The present study was designed to determine if the striatal dopamine transporter (DAT levels measured by T99mc-TRODAT-1 single photon emission computed tomography (SPECT brain scans were altered in individuals with IAD. SPECT brain scans were acquired on 5 male IAD subjects and 9 healthy age-matched controls. The volume (V and weight (W of bilateral corpus striatum as well as the T99mc-TRODAT-1 uptake ratio of corpus striatum/the whole brain (Ra were calculated using mathematical models. It was displayed that DAT expression level of striatum was significantly decreased and the V, W, and Ra were greatly reduced in the individuals with IAD compared to controls. Taken together, these results suggest that IAD may cause serious damages to the brain and the neuroimaging findings further illustrate IAD is associated with dysfunctions in the dopaminergic brain systems. Our findings also support the claim that IAD may share similar neurobiological abnormalities with other addictive disorders.

  2. Dopamine regulates angiogenesis in normal dermal wound tissues.

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    Saurav Shome

    Full Text Available Cutaneous wound healing is a normal physiological process and comprises different phases. Among these phases, angiogenesis or new blood vessel formation in wound tissue plays an important role. Skin is richly supplied by sympathetic nerves and evidences indicate the significant role of the sympathetic nervous system in cutaneous wound healing. Dopamine (DA is an important catecholamine neurotransmitter released by the sympathetic nerve endings and recent studies have demonstrated the potent anti-angiogenic action of DA, which is mediated through its D(2 DA receptors. We therefore postulate that this endogenous catecholamine neurotransmitter may have a role in the neovascularization of dermal wound tissues and subsequently in the process of wound healing. In the present study, the therapeutic efficacy of D(2 DA receptor antagonist has been investigated for faster wound healing in a murine model of full thickness dermal wound. Our results indicate that treatment with specific D(2 DA receptor antagonist significantly expedites the process of full thickness normal dermal wound healing in mice by inducing angiogenesis in wound tissues. The underlined mechanisms have been attributed to the up-regulation of homeobox transcription factor HoxD3 and its target α5β1 integrin, which play a pivotal role in wound angiogenesis. Since D(2 DA receptor antagonists are already in clinical use for other disorders, these results have significant translational value from the bench to the bedside for efficient wound management along with other conventional treatment modalities.

  3. Dopamine Modulates Serotonin Innervation in the Drosophila Brain

    Directory of Open Access Journals (Sweden)

    Janna Niens

    2017-10-01

    Full Text Available Parkinson’s disease (PD results from a progressive degeneration of the dopaminergic nigrostriatal system leading to a decline in movement control, with resting tremor, rigidity and postural instability. Several aspects of PD can be modeled in the fruit fly, Drosophila melanogaster, including α-synuclein-induced degeneration of dopaminergic neurons, or dopamine (DA loss by genetic elimination of neural DA synthesis. Defective behaviors in this latter model can be ameliorated by feeding the DA precursor L-DOPA, analogous to the treatment paradigm for PD. Secondary complication from L-DOPA treatment in PD patients are associated with ectopic synthesis of DA in serotonin (5-HT-releasing neurons, leading to DA/5-HT imbalance. Here we examined the neuro-anatomical adaptations resulting from imbalanced DA/5-HT signaling in Drosophila mutants lacking neural DA. We find that, similar to rodent models of PD, lack of DA leads to increased 5-HT levels and arborizations in specific brain regions. Conversely, increased DA levels by L-DOPA feeding leads to reduced connectivity of 5-HT neurons to their target neurons in the mushroom body (MB. The observed alterations of 5-HT neuron plasticity indicate that loss of DA signaling is not solely responsible for the behavioral disorders observed in Drosophila models of PD, but rather a combination of the latter with alterations of 5-HT circuitry.

  4. Pro-dopamine regulator, KB220Z, attenuates hoarding and shopping behavior in a female, diagnosed with SUD and ADHD.

    Science.gov (United States)

    McLaughlin, Thomas; Blum, Kenneth; Steinberg, Bruce; Modestino, Edward J; Fried, Lyle; Baron, David; Siwicki, David; Braverman, Eric R; Badgaiyan, Rajendra D

    2018-03-01

    Background Addictive-like behaviors (e.g., hoarding and shopping) may be the result of the cumulative effects of dopaminergic and other neurotransmitter genetic variants as well as elevated stress levels. We, therefore, propose that dopamine homeostasis may be the preferred goal in combating such challenging and unwanted behaviors, when simple dopaminergic activation through potent agonists may not provide any resolution. Case presentation C.J. is a 38-year-old, single, female, living with her mother. She has a history of substance use disorder as well as attention deficit hyperactivity disorder, inattentive type. She had been stable on buprenorphine/naloxone combination and amphetamine, dextroamphetamine mixed salts for many years when unexpectedly she lost her job for oversleeping and not calling into work. KB200z (a pro-dopamine compound) was added to her regimen for complaints of low drive and motivation. After taking this nutraceutical for 4 weeks, she noticed a marked improvement in her mental status and many behaviors. She noted that her shopping and hoarding addictions had appreciably decreased. Furthermore, her lifelong history of terrifying lucid dreams was eliminated. Finally, she felt more in control; her locus of control shifted from external to more internal. Discussion The hypothesis is that C.J.'s reported, behavioral, and psychological benefits resulted from the pro-dopamine-regulating effect of KB220Z across the brain reward