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Sample records for thalamic dopamine d2

  1. Striatal dopamine D2 receptor availability predicts the thalamic and medial prefrontal responses to reward in cocaine abusers three years later

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    Asensio, S.; Goldstein, R.; Asensio, S.; Romero, M.J.; Romero, F.J.; Wong, C.T.; Alia-Klein, N.; Tomasi, D.; Wang, G.-J.; Telang, F..; Volkow, N.D.; Goldstein, R.Z.

    2010-05-01

    Low levels of dopamine (DA) D2 receptor availability at a resting baseline have been previously reported in drug addicted individuals and have been associated with reduced ventral and dorsal prefrontal metabolism. The reduction in DA D2 receptor availability along with the reduced ventral frontal metabolism is thought to underlie compromised sensitivity to nondrug reward, a core characteristic of drug addiction. We therefore hypothesized that variability in DA D2 receptor availability at baseline will covary with dynamic responses to monetary reward in addicted individuals. Striatal DA D2 receptor availability was measured with [{sup 11}C]raclopride and positron emission tomography and response to monetary reward was measured (an average of three years later) with functional magnetic resonance imaging in seven cocaine-addicted individuals. Results show that low DA D2 receptor availability in the dorsal striatum was associated with decreased thalamic response to monetary reward; while low availability in ventral striatum was associated with increased medial prefrontal (Brodmann Area 6/8/32) response to monetary reward. These preliminary results, that need to be replicated in larger sample sizes and validated with healthy controls, suggest that resting striatal DA D2 receptor availability predicts variability in functional responses to a nondrug reinforcer (money) in prefrontal cortex, implicated in behavioral monitoring, and in thalamus, implicated in conditioned responses and expectation, in cocaine-addicted individuals.

  2. Striatal dopamine D2 receptor availability predicts the thalamic and medial prefrontal responses to reward in cocaine abusers three years later

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    Asensio, Samuel; Romero, Maria J.; Romero, Francisco J.; Wong, Christopher; Alia-Klein, Nelly; Tomasi, Dardo; Wang, Gene-Jack; Telang, Frank; Volkow, Nora D.; Goldstein, Rita Z.

    2009-01-01

    Low levels of dopamine (DA) D2 receptor availability at a resting baseline have been previously reported in drug addicted individuals and have been associated with reduced ventral and dorsal prefrontal metabolism. The reduction in DA D2 receptor availability along with the reduced ventral frontal metabolism is thought to underlie compromised sensitivity to non-drug reward, a core characteristic of drug addiction. We therefore hypothesized that variability in DA D2 receptor availability at baseline will covary with dynamic responses to monetary reward in addicted individuals. Striatal DA D2 receptor availability was measured with [11C]raclopride and positron emission tomography and response to monetary reward was measured (an average of 3 years later) with functional magnetic resonance imaging in seven cocaine addicted individuals. Results show that low DA D2 receptor availability in the dorsal striatum was associated with decreased thalamic response to monetary reward; while low availability in ventral striatum was associated with increased medial prefrontal (Brodmann Area 6/8/32) response to monetary reward. These preliminary results, that need to be replicated in larger sample sizes and validated with healthy controls, suggest that resting striatal DA D2 receptor availability predicts variability in functional responses to a non-drug reinforcer (money) in prefrontal cortex, implicated in behavioral monitoring, and in thalamus, implicated in conditioned responses and expectation, in cocaine addicted individuals. PMID:20034014

  3. 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

  4. Extrastriatal dopamine D2-receptor availability in social anxiety disorder.

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    Plavén-Sigray, Pontus; Hedman, Erik; Victorsson, Pauliina; Matheson, Granville J; Forsberg, Anton; Djurfeldt, Diana R; Rück, Christian; Halldin, Christer; Lindefors, Nils; Cervenka, Simon

    2017-05-01

    Alterations in the dopamine system are hypothesized to influence the expression of social anxiety disorder (SAD) symptoms. However, molecular imaging studies comparing dopamine function between patients and control subjects have yielded conflicting results. Importantly, while all previous investigations focused on the striatum, findings from activation and blood flow studies indicate that prefrontal and limbic brain regions have a central role in the pathophysiology. The objective of this study was to investigate extrastriatal dopamine D2-receptor (D2-R) availability in SAD. We examined 12 SAD patients and 16 healthy controls using positron emission tomography and the high-affinity D2-R radioligand [ 11 C]FLB457. Parametric images of D2-R binding potential were derived using the Logan graphical method with cerebellum as reference region. Two-tailed one-way independent ANCOVAs, with age as covariate, were used to examine differences in D2-R availability between groups using both region-based and voxel-wise analyses. The region-based analysis showed a medium effect size of higher D2-R levels in the orbitofrontal cortex (OFC) in patients, although this result did not remain significant after correction for multiple comparisons. The voxel-wise comparison revealed elevated D2-R availability in patients within OFC and right dorsolateral prefrontal cortex after correction for multiple comparisons. These preliminary results suggest that an aberrant extrastriatal dopamine system may be part of the disease mechanism in SAD. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  5. SPECT imaging of D2 dopamine receptors and endogenous dopamine release in mice

    NARCIS (Netherlands)

    Jongen, C.; De Bruin, K.; Beekman, F.J.; Booij, J.

    2008-01-01

    Purpose: The dopamine D2 receptor (D2R) is important in the mediation of addiction. [123I]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, [123I]IBZM

  6. SPECT imaging of D-2 dopamine receptors and endogenous dopamine release in mice

    NARCIS (Netherlands)

    Jongen, Cynthia; de Bruin, Kora; Beekman, Freek; Booij, Jan

    2008-01-01

    Purpose The dopamine D-2 receptor (D2R) is important in the mediation of addiction. [I-123]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, [I-123]IBZM

  7. Cocaine Inhibits Dopamine D2 Receptor Signaling via Sigma-1-D2 Receptor Heteromers

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    Navarro, Gemma; Moreno, Estefania; Bonaventura, Jordi; Brugarolas, Marc; Farré, Daniel; Aguinaga, David; Mallol, Josefa; Cortés, Antoni; Casadó, Vicent; Lluís, Carmen; Ferre, Sergi

    2013-01-01

    Under normal conditions the brain maintains a delicate balance between inputs of reward seeking controlled by neurons containing the D1-like family of dopamine receptors and inputs of aversion coming from neurons containing the D2-like family of dopamine receptors. Cocaine is able to subvert these balanced inputs by altering the cell signaling of these two pathways such that D1 reward seeking pathway dominates. Here, we provide an explanation at the cellular and biochemical level how cocaine may achieve this. Exploring the effect of cocaine on dopamine D2 receptors function, we present evidence of σ1 receptor molecular and functional interaction with dopamine D2 receptors. Using biophysical, biochemical, and cell biology approaches, we discovered that D2 receptors (the long isoform of the D2 receptor) can complex with σ1 receptors, a result that is specific to D2 receptors, as D3 and D4 receptors did not form heteromers. We demonstrate that the σ1-D2 receptor heteromers consist of higher order oligomers, are found in mouse striatum and that cocaine, by binding to σ1 -D2 receptor heteromers, inhibits downstream signaling in both cultured cells and in mouse striatum. In contrast, in striatum from σ1 knockout animals these complexes are not found and this inhibition is not seen. Taken together, these data illuminate the mechanism by which the initial exposure to cocaine can inhibit signaling via D2 receptor containing neurons, destabilizing the delicate signaling balance influencing drug seeking that emanates from the D1 and D2 receptor containing neurons in the brain. PMID:23637801

  8. Association of Dopamine D2 Receptor Gene with Creative Ideation

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    Yu, Qi; Zhang, Shun; Zhang, Jinghuan H.

    2017-01-01

    Although several studies suggest that dopamine D2 receptor (DRD2) gene may contribute to creativity, the relationship between DRD2 and creativity still needs to be further validated. To further test the relevance of DRD2 and creativity, this study explored the association between DRD2 and creative ideation in 483 unrelated healthy Chinese…

  9. Dopamine Synthesis Capacity is Associated with D2/3 Receptor Binding but Not Dopamine Release.

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    Berry, Anne S; Shah, Vyoma D; Furman, Daniella J; White III, Robert L; Baker, Suzanne L; O'Neil, James P; Janabi, Mustafa; D'Esposito, Mark; Jagust, William J

    2017-08-17

    Positron Emission Tomography (PET) imaging allows the estimation of multiple aspects of dopamine function including dopamine synthesis capacity, dopamine release, and D2/3 receptor binding. Though dopaminergic dysregulation characterizes a number of neuropsychiatric disorders including schizophrenia and addiction, there has been relatively little investigation into the nature of relationships across dopamine markers within healthy individuals. Here we used PET imaging in 40 healthy adults to compare, within individuals, the estimates of dopamine synthesis capacity (Ki) using 6-[18F]fluoro-l-m-tyrosine ([18F]FMT; a substrate for aromatic amino acid decarboxylase), baseline D2/3 receptor-binding potential using [11C]raclopride (a weak competitive D2/3 receptor antagonist), and dopamine release using [11C]raclopride paired with oral methylphenidate administration. Methylphenidate increases synaptic dopamine by blocking the dopamine transporter. We estimated dopamine release by contrasting baseline D2/3 receptor binding and D2/3 receptor binding following methylphenidate. Analysis of relationships among the three measurements within striatal regions of interest revealed a positive correlation between [18F]FMT Ki and the baseline (placebo) [11C]raclopride measure, such that participants with greater synthesis capacity showed higher D2/3 receptor-binding potential. In contrast, there was no relationship between [18F]FMT and methylphenidate-induced [11C]raclopride displacement. These findings shed light on the nature of regulation between pre- and postsynaptic dopamine function in healthy adults, which may serve as a template from which to identify and describe alteration with disease.Neuropsychopharmacology advance online publication, 4 October 2017; doi:10.1038/npp.2017.180.

  10. Amphetamine Self-Administration Attenuates Dopamine D2 Autoreceptor Function

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    Calipari, Erin S; Sun, Haiguo; Eldeeb, Khalil; Luessen, Deborah J; Feng, Xin; Howlett, Allyn C; Jones, Sara R; Chen, Rong

    2014-01-01

    Dopamine D2 autoreceptors located on the midbrain dopaminergic neurons modulate dopamine (DA) neuron firing, DA release, and DA synthesis through a negative-feedback mechanism. Dysfunctional D2 autoreceptors following repeated drug exposure could lead to aberrant DA activity in the ventral tegmental area (VTA) and projection areas such as nucleus accumbens (NAcc), promoting drug-seeking and -taking behavior. Therefore, it is important to understand molecular mechanisms underlying drug-induced changes in D2 autoreceptors. Here, we reported that 5 days of amphetamine (AMPH) self-administration reduced the ability of D2 autoreceptors to inhibit DA release in the NAcc as determined by voltammetry. Using the antibody-capture [35S]GTPγS scintillation proximity assay, we demonstrated for the first time that midbrain D2/D3 receptors were preferentially coupled to Gαi2, whereas striatal D2/D3 receptors were coupled equally to Gαi2 and Gαo for signaling. Importantly, AMPH abolished the interaction between Gαi2 and D2/D3 receptors in the midbrain while leaving striatal D2/D3 receptors unchanged. The disruption of the coupling between D2/D3 receptors and Gαi2 by AMPH is at least partially explained by the enhanced RGS2 (regulator of G-protein signaling 2) activity resulting from an increased RGS2 trafficking to the membrane. AMPH had no effects on the midbrain expression and trafficking of other RGS proteins such as RGS4 and RGS8. Our data suggest that midbrain D2/D3 receptors are more susceptible to AMPH-induced alterations. Reduced D2 autoreceptor function could lead to enhanced DA signaling and ultimately addiction-related behavior. RGS2 may be a potential non-dopaminergic target for pharmacological intervention of dysfunctional DA transmission and drug addiction. PMID:24513972

  11. Genetic variants of dopamine D2 receptor impact heterodimerization with dopamine D1 receptor.

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    Błasiak, Ewa; Łukasiewicz, Sylwia; Szafran-Pilch, Kinga; Dziedzicka-Wasylewska, Marta

    2017-04-01

    The human dopamine D2 receptor gene has three polymorphic variants that alter its amino acid sequence: alanine substitution by valine in position 96 (V96A), proline substitution by serine in position 310 (P310S) and serine substitution by cysteine in position 311 (S311C). Their functional role has never been the object of extensive studies, even though there is some evidence that their occurrence correlates with schizophrenia. The HEK293 cell line was transfected with dopamine D1 and D2 receptors (or genetic variants of the D2 receptor), coupled to fluorescent proteins which allowed us to measure the extent of dimerization of these receptors, using a highly advanced biophysical approach (FLIM-FRET). Additionally, Fluoro-4 AM was used to examine changes in the level of calcium release after ligand stimulation of cells expressing different combinations of dopamine receptors. Using FLIM-FRET experiments we have shown that in HEK 293 expressing dopamine receptors, polymorphic mutations in the D2 receptor play a role in dimmer formation with the dopamine D1 receptor. The association level of dopamine receptors is affected by ligand administration, with variable effects depending on polymorphic variant of the D2 dopamine receptor. We have found that the level of heteromer formation is reflected by calcium ion release after ligand stimulation and have observed variations of this effect dependent on the polymorphic variant and the ligand. The data presented in this paper support the hypothesis on the role of calcium signaling regulated by the D1-D2 heteromer which may be of relevance for schizophrenia etiology. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  12. Immunohistochemical detection of dopamine D2 receptors in neuroendocrine tumours.

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    Pawlikowski, Marek; Pisarek, Hanna; Winczyk, Katarzyna

    2011-01-01

    Recently, dopamine D2 receptors (RD2) have been found to be expressed in neuroendocrine tumours (NET), the tumours which arise from the diffuse neuroendocrine cells. Moreover, successful trials of the treatment of NET with cabergoline - D2 agonist, have been reported. These findings increase the interest of investigating RD2 expression in NET. The expression of RD2 was investigated immunohistochemically using the antibody which recognises both short (S) and long (L) isoforms of the receptor in 17 NET samples taken from 15 patients. In 17 NET samples, a positive reaction with the anti-RD2 antibody occurred in 11 cases. In six cases, the localisation of the immunostaining was cytoplasmic and in nine cases it was nuclear. Only in one case was the receptor cell membrane-located, and in two cases the immunoreaction was also localised in the blood vessels walls. The relation between RD2 expression and the grade of malignancy examined by means of Ki-67 antigen expression needs further study. However, preliminary observations indicate that the nuclear localisation of RD2 is linked to higher tumour malignancy. The next investigated question was the co-expression of somatostatin and dopamine receptors. This question seems important because of the perspectives of somatostatin-dopamine chimeras application in NET treatment. In the samples examined by us, RD2 were co-expressed in 5/10 cases with sstr1, in 3/10 with sstr2A, in 2/9 with sstr2B, in 3/10 with sstr3, and in 5/10 with sstr5. Dopamine D2 receptors are revealed by means of immunohistochemistry in the majority of NET. They exhibit cytoplasmic and/or nuclear localisations, the latter being possibly linked to a higher grade of malignancy, and are often co-expressed with somatostatin receptors (mostly with subtypes1 and 5).

  13. Dopamine reduces Parkinson's tremor through increased thalamic inhibition

    NARCIS (Netherlands)

    Dirkx, M.F.M.; Ouden, H.E.M. den; Aarts, E.; Timmer, M.H.M.; Bloem, B.R.; Toni, I.; Helmich, R.C.G.

    2016-01-01

    Objective: To identify cerebral mechanisms explaining the effects of dopamine on rest tremor in Parkinson's disease. Background: Resting tremor in Parkinson's disease is related to altered activity in the basal ganglia and in the cerebello-thalamo-cortical circuit. Dopaminergic medication reduces

  14. Role of dopamine D2 receptors in human reinforcement learning.

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    Eisenegger, Christoph; Naef, Michael; Linssen, Anke; Clark, Luke; Gandamaneni, Praveen K; Müller, Ulrich; Robbins, Trevor W

    2014-09-01

    Influential neurocomputational models emphasize dopamine (DA) as an electrophysiological and neurochemical correlate of reinforcement learning. However, evidence of a specific causal role of DA receptors in learning has been less forthcoming, especially in humans. Here we combine, in a between-subjects design, administration of a high dose of the selective DA D2/3-receptor antagonist sulpiride with genetic analysis of the DA D2 receptor in a behavioral study of reinforcement learning in a sample of 78 healthy male volunteers. In contrast to predictions of prevailing models emphasizing DA's pivotal role in learning via prediction errors, we found that sulpiride did not disrupt learning, but rather induced profound impairments in choice performance. The disruption was selective for stimuli indicating reward, whereas loss avoidance performance was unaffected. Effects were driven by volunteers with higher serum levels of the drug, and in those with genetically determined lower density of striatal DA D2 receptors. This is the clearest demonstration to date for a causal modulatory role of the DA D2 receptor in choice performance that might be distinct from learning. Our findings challenge current reward prediction error models of reinforcement learning, and suggest that classical animal models emphasizing a role of postsynaptic DA D2 receptors in motivational aspects of reinforcement learning may apply to humans as well.

  15. Reducing Ventral Tegmental Dopamine D2 Receptor Expression Selectively Boosts Incentive Motivation

    NARCIS (Netherlands)

    de Jong, Johannes W.; Roelofs, Theresia J M; Mol, Frédérique M U; Hillen, Anne E J; Meijboom, Katharina E.; Luijendijk, Mieneke C M; Van Der Eerden, Harrie A M; Garner, Keith M.; Vanderschuren, Louk J M J; Adan, Roger A H

    2015-01-01

    Altered mesolimbic dopamine signaling has been widely implicated in addictive behavior. For the most part, this work has focused on dopamine within the striatum, but there is emerging evidence for a role of the auto-inhibitory, somatodendritic dopamine D2 receptor (D2R) in the ventral tegmental area

  16. De novo expression of dopamine D2 receptors on microglia after stroke.

    NARCIS (Netherlands)

    Huck, J.H.; Freyer, D.; Bottcher, C.; Mladinov, M.; Muselmann-Genschow, C.; Thielke, M.; Gladow, N.; Bloomquist, D.; Mergenthaler, P.; Priller, J.

    2015-01-01

    Dopamine is the predominant catecholamine in the brain and functions as a neurotransmitter. Dopamine is also a potent immune modulator. In this study, we have characterized the expression of dopamine receptors on murine microglia. We found that cultured primary microglia express dopamine D1, D2, D3,

  17. Modeling of ligand binding to dopamine D2 receptor

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    Ostopovici-Halip Liliana

    2014-01-01

    Full Text Available The dopaminic receptors have been for long time the major targets for developing new small molecules with high affinity and selectivity to treat psychiatric disorders, neurodegeneration, drug abuse, and other therapeutic areas. In the absence of a 3D structure for the human D2 dopamine (HDD2 receptor, the efforts for discovery and design of new potential drugs rely on comparative models generation, docking and pharmacophore development studies. To get a better understanding of the HDD2 receptor binding site and the ligand-receptor interactions a homology model of HDD2 receptor based on the X-ray structure of β2-adrenergic receptor has been built and used to dock a set of partial agonists of HDD2 receptor. The main characteristics of the binding mode for the HDD2 partial agonists set are given by the ligand particular folding and a complex network of contacts represented by stacking interactions, salt bridge and hydrogen bond formation. The characterization of the partial agonist binding mode at HDD2 receptor provide the needed information to generate pharmacophore models which represent essential information in the future virtual screening studies in order to identify new potential HDD2 partial agonists.

  18. A peptide disrupting the D2R-DAT interaction protects against dopamine neurotoxicity.

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    Su, Ping; Liu, Fang

    2017-09-01

    Dopamine reuptake from extracellular space to cytosol leads to accumulation of dopamine, which triggers neurotoxicity in dopaminergic neurons. Previous studies have shown that both dopamine D2 receptor (D2R) and dopamine transporter (DAT) are involved in dopamine neurotoxicity. However, blockade of either D2R or DAT causes side effects due to antagonism of other physiological functions of these two proteins. We previously found that DAT can form a protein complex with D2R and its cell surface expression is facilitated via D2R-DAT interaction, which regulates dopamine reuptake and intracellular dopamine levels. Here we found that an interfering peptide (DAT-S1) disrupting the D2R-DAT interaction protects neurons against dopamine neurotoxicity, and this effect is mediated by inhibiting DAT cell surface expression and inhibiting both caspase-3 and PARP-1 cleavage. This study demonstrates the role of the D2R-DAT complex in dopamine neurotoxicity and investigated the potential mechanisms, which might help better understand the mechanisms of dopamine neurotoxicity. The peptide may provide some insights to improve treatments for dopamine neurotoxicity and related diseases, such as Parkinson's disease, as well as methamphetamine- and 3,4-methsylenedioxy methamphetamine-induced neurotoxicity. Copyright © 2017. Published by Elsevier Inc.

  19. Evaluation of potential agonist radioligands for imaging dopamine D2/3 receptors

    NARCIS (Netherlands)

    van Wieringen, J.P.

    2015-01-01

    Imaging dopamine receptors with PET and SPECT can shed light on the nature of neuropsychiatric disorders which are characterized by disturbances in dopamine D2/3 receptor functioning. Agonist radioligands are considered superior to antagonists because they are more sensitive to detect dopamine

  20. Cannabidiol is a partial agonist at dopamine D2High receptors, predicting its antipsychotic clinical dose.

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    Seeman, P

    2016-10-18

    Although all current antipsychotics act by interfering with the action of dopamine at dopamine D2 receptors, two recent reports showed that 800 to 1000 mg of cannabidiol per day alleviated the signs and symptoms of schizophrenia, although cannabidiol is not known to act on dopamine receptors. Because these recent clinical findings may indicate an important exception to the general rule that all antipsychotics interfere with dopamine at dopamine D2 receptors, the present study examined whether cannabidiol acted directly on D2 receptors, using tritiated domperidone to label rat brain striatal D2 receptors. It was found that cannabidiol inhibited the binding of radio-domperidone with dissociation constants of 11 nm at dopamine D2High receptors and 2800 nm at dopamine D2Low receptors, in the same biphasic manner as a dopamine partial agonist antipsychotic drug such as aripiprazole. The clinical doses of cannabidiol are sufficient to occupy the functional D2High sites. it is concluded that the dopamine partial agonist action of cannabidiol may account for its clinical antipsychotic effects.

  1. Varenicline increases striatal dopamine D(2/3) receptor binding in rats

    NARCIS (Netherlands)

    Crunelle, Cleo L.; Miller, Michelle L.; de Bruin, Kora; van den Brink, Wim; Booij, Jan

    2009-01-01

    Increasing dopamine D(2/3) receptor availability is postulated to be a treatment for drug addiction. Varenicline, an alpha4beta2-nicotinic partial agonist, is effective for nicotine dependence. We hypothesize that varenicline increases dopamine D(2/3) receptor availability. Twenty male drug-naïve

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

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    Baik, Ja-Hyun

    2013-11-01

    Dopamine (DA) regulates emotional and motivational behavior through the mesolimbic dopaminergic pathway. Changes in DA signaling in mesolimbic neurotransmission are widely believed to modify reward-related behaviors and are therefore closely associated with drug addiction. Recent evidence now suggests that as with drug addiction, obesity with compulsive eating behaviors involves reward circuitry of the brain, particularly the circuitry involving dopaminergic neural substrates. Increasing amounts of data from human imaging studies, together with genetic analysis, have demonstrated that obese people and drug addicts tend to show altered expression of DA D2 receptors in specific brain areas, and that similar brain areas are activated by food-related and drug-related cues. This review focuses on the functions of the DA system, with specific focus on the physiological interpretation and the role of DA D2 receptor signaling in food addiction.

  3. Cerebral decortication reverses the effect of amphetamine on striatal D2 dopamine binding site density.

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    Robertson, H A

    1986-12-23

    Unilateral ablation of the cerebral cortex produces a decrease of approximately 38% in striatal D2 dopamine binding site density. Chronic d-amphetamine treatment also produces a decrease of about 22% in D2 binding site density. Paradoxically, when rats were hemidecorticated and treated chronically with d-amphetamine, the density of striatal D2 dopamine binding sites on the decorticated side was increased (by about 50%) rather than decreased. Evidently d-amphetamine-induced down-regulation of D2 dopamine binding sites depends on an intact corticostriatal pathway.

  4. Deficits in dopamine D(2) receptors and presynaptic dopamine in heroin dependence: commonalities and differences with other types of addiction.

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    Martinez, Diana; Saccone, Phillip A; Liu, Fei; Slifstein, Mark; Orlowska, Daria; Grassetti, Alex; Cook, Stephanie; Broft, Allegra; Van Heertum, Ronald; Comer, Sandra D

    2012-02-01

    Positron emission tomography (PET) imaging studies have shown that addiction to a number of substances of abuse is associated with a decrease in dopamine D(2/3) receptor binding and decreased presynaptic dopamine release in the striatum. Some studies have also shown that these reductions are associated with the severity of addiction. For example, in cocaine dependence, low dopamine release is associated with the choice to self-administer cocaine. The goal of the present study was to investigate these parameters of striatal dopamine transmission in heroin dependence and their association with drug seeking behavior. Heroin-dependent and healthy control subjects were scanned with [(11)C]raclopride before and after stimulant administration (methylphenidate) to measure striatal D(2/3) receptor binding and presynaptic dopamine release. After the PET scans, the heroin-dependent subjects performed heroin self-administration sessions. Both striatal D(2/3) receptor binding and dopamine release were reduced in the heroin-dependent subjects compared with healthy control subjects. However, neither PET measure of dopamine transmission predicted the choice to self-administer heroin. These findings show that heroin addiction, like addiction to other drugs of abuse, is associated with low D(2/3) receptor binding and low presynaptic dopamine. However, neither of these outcome measures was associated with the choice to self-administer heroin. Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  5. Phasic dopamine release drives rapid activation of striatal D2-receptors

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    Marcott, Pamela F; Mamaligas, Aphroditi A; Ford, Christopher P

    2014-01-01

    Summary Striatal dopamine transmission underlies numerous goal-directed behaviors. Medium spiny neurons (MSNs) are a major target of dopamine in the striatum. However, as dopamine does not directly evoke a synaptic event in MSNs, the time course of dopamine signaling in these cells remains unclear. To examine how dopamine release activates D2-receptors on MSNs, G-protein activated inwardly rectifying potassium (GIRK2; Kir 3.2) channels were virally overexpressed in the striatum and the resulting outward currents were used as a sensor of D2-receptor activation. Electrical and optogenetic stimulation of dopamine terminals evoked robust D2-receptor inhibitory post-synaptic currents (IPSCs) in GIRK2-expressing MSNs that occurred in under a second. Evoked D2-IPSCs could be driven by repetitive stimulation and were not occluded by background dopamine tone. Together, the results indicate that D2-receptors on MSNs exhibit functional low affinity and suggest that striatal D2-receptors can encode both tonic and phasic dopamine signals. PMID:25242218

  6. Role of dopamine D2 receptors in plasticity of stress-induced addictive behaviours.

    Science.gov (United States)

    Sim, Hye-Ri; Choi, Tae-Yong; Lee, Hyo Jin; Kang, Eun Young; Yoon, Sehyoun; Han, Pyung-Lim; Choi, Se-Young; Baik, Ja-Hyun

    2013-01-01

    Dopaminergic systems are implicated in stress-related behaviour. Here we investigate behavioural responses to chronic stress in dopamine D2 receptor knockout mice and find that anxiety-like behaviours are increased compared with wild-type mice. Repeated stress exposure suppresses cocaine-induced behavioural sensitization, cocaine-seeking and relapse behaviours in dopamine D2 receptor knockout mice. Cocaine challenge after drug withdrawal in cocaine-experienced wild-type or dopamine D2 receptor knockout mice is associated with inhibition of long-term depression in the nucleus accumbens, and chronic stress during withdrawal prevents inhibition after cocaine challenge in cocaine-experienced dopamine D2 receptor knockout mice, but not in wild-type mice. Lentiviral-induced knockdown of dopamine D2 receptors in the nucleus accumbens of wild-type mice does not affect basal locomotor activity, but confers stress-induced inhibition of the expression of cocaine-induced behavioural sensitization. Stressed mice depleted of dopamine D2 receptors do not manifest long-term depression inhibition. Our results suggest that dopamine D2 receptors have roles in regulating synaptic modification triggered by stress and drug addiction.

  7. Detection of phasic dopamine by D1 and D2 striatal medium spiny neurons.

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    Yapo, Cedric; Nair, Anu G; Clement, Lorna; Castro, Liliana R; Hellgren Kotaleski, Jeanette; Vincent, Pierre

    2017-12-15

    Brief dopamine events are critical actors of reward-mediated learning in the striatum; the intracellular cAMP-protein kinase A (PKA) response of striatal medium spiny neurons to such events was studied dynamically using a combination of biosensor imaging in mouse brain slices and in silico simulations. Both D1 and D2 medium spiny neurons can sense brief dopamine transients in the sub-micromolar range. While dopamine transients profoundly change cAMP levels in both types of medium spiny neurons, the PKA-dependent phosphorylation level remains unaffected in D2 neurons. At the level of PKA-dependent phosphorylation, D2 unresponsiveness depends on protein phosphatase-1 (PP1) inhibition by DARPP-32. Simulations suggest that D2 medium spiny neurons could detect transient dips in dopamine level. The phasic release of dopamine in the striatum determines various aspects of reward and action selection, but the dynamics of the dopamine effect on intracellular signalling remains poorly understood. We used genetically encoded FRET biosensors in striatal brain slices to quantify the effect of transient dopamine on cAMP or PKA-dependent phosphorylation levels, and computational modelling to further explore the dynamics of this signalling pathway. Medium-sized spiny neurons (MSNs), which express either D 1 or D 2 dopamine receptors, responded to dopamine by an increase or a decrease in cAMP, respectively. Transient dopamine showed similar sub-micromolar efficacies on cAMP in both D1 and D2 MSNs, thus challenging the commonly accepted notion that dopamine efficacy is much higher on D 2 than on D 1 receptors. However, in D2 MSNs, the large decrease in cAMP level triggered by transient dopamine did not translate to a decrease in PKA-dependent phosphorylation level, owing to the efficient inhibition of protein phosphatase 1 by DARPP-32. Simulations further suggested that D2 MSNs can also operate in a 'tone-sensing' mode, allowing them to detect transient dips in basal dopamine

  8. Evidence That Sleep Deprivation Downregulates Dopamine D2R in Ventral Striatum in the Human Brain

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    Volkow N. D.; Fowler J.; Volkow, N.D.; Tomasi, D.; Wang, G.-J.; Fowler, J.S.; Logan, J.; Benveniste, H.; Kin, R.; Thanos, P.K.; Sergi F.

    2012-03-23

    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 [{sup 11}C]raclopride in controls) in striatum, but could not determine whether this reflected dopamine increases ([{sup 11}C]raclopride competes with dopamine for D2/D3 receptor binding) or receptor downregulation. To clarify this, we compared the dopamine increases induced by methylphenidate (a drug that increases dopamine by blocking dopamine transporters) during sleep deprivation versus rested sleep, with the assumption that methylphenidate's effects would be greater if, indeed, dopamine release was increased during sleep deprivation. We scanned 20 controls with [{sup 11}C]raclopride after rested sleep and after 1 night of sleep deprivation; both after placebo and after methylphenidate. We corroborated a decrease in D2/D3 receptor availability in the ventral striatum with sleep deprivation (compared with rested sleep) that was associated with reduced alertness and increased sleepiness. However, the dopamine increases induced by methylphenidate (measured as decreases in D2/D3 receptor availability compared with placebo) did not differ between rested sleep and sleep deprivation, and were associated with the increased alertness and reduced sleepiness when methylphenidate was administered after sleep deprivation. Similar findings were obtained by microdialysis in rodents subjected to 1 night of paradoxical sleep deprivation. These findings are consistent with a downregulation of D2/D3 receptors in ventral striatum with sleep deprivation that may contribute to the associated decreased wakefulness and also corroborate an enhancement of D2 receptor signaling in the arousing effects of methylphenidate in humans.

  9. 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.

  10. Potent haloperidol derivatives covalently binding to the dopamine D2 receptor.

    Science.gov (United States)

    Schwalbe, Tobias; Kaindl, Jonas; Hübner, Harald; Gmeiner, Peter

    2017-10-01

    The dopamine D 2 receptor (D 2 R) is a common drug target for the treatment of a variety of neurological disorders including schizophrenia. Structure based design of subtype selective D 2 R antagonists requires high resolution crystal structures of the receptor and pharmacological tools promoting a better understanding of the protein-ligand interactions. Recently, we reported the development of a chemically activated dopamine derivative (FAUC150) designed to covalently bind the L94C mutant of the dopamine D 2 receptor. Using FAUC150 as a template, we elaborated the design and synthesis of irreversible analogs of the potent antipsychotic drug haloperidol forming covalent D 2 R-ligand complexes. The disulfide- and Michael acceptor-functionalized compounds showed significant receptor affinity and an irreversible binding profile in radioligand depletion experiments. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Dopamine-induced apoptosis of lactotropes is mediated by the short isoform of D2 receptor.

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    Daniela Betiana Radl

    Full Text Available Dopamine, through D2 receptor (D2R, is the major regulator of lactotrope function in the anterior pituitary gland. Both D2R isoforms, long (D2L and short (D2S, are expressed in lactotropes. Although both isoforms can transduce dopamine signal, they differ in the mechanism that leads to cell response. The administration of D2R agonists, such as cabergoline, is the main pharmacological treatment for prolactinomas, but resistance to these drugs exists, which has been associated with alterations in D2R expression. We previously reported that dopamine and cabergoline induce apoptosis of lactotropes in primary culture in an estrogen-dependent manner. In this study we used an in vivo model to confirm the permissive action of estradiol in the apoptosis of anterior pituitary cells induced by D2R agonists. Administration of cabergoline to female rats induced apoptosis, measured by Annexin-V staining, in anterior pituitary gland from estradiol-treated rats but not from ovariectomized rats. To evaluate the participation of D2R isoforms in the apoptosis induced by dopamine we used lactotrope-derived PR1 cells stably transfected with expression vectors encoding D2L or D2S receptors. In the presence of estradiol, dopamine induced apoptosis, determined by ELISA and TUNEL assay, only in PR1-D2S cells. To study the role of p38 MAPK in apoptosis induced by D2R activation, anterior pituitary cells from primary culture or PR1-D2S were incubated with an inhibitor of the p38 MAPK pathway (SB203850. SB203580 blocked the apoptotic effect of D2R activation in lactotropes from primary cultures and PR1-D2S cells. Dopamine also induced p38 MAPK phosphorylation, determined by western blot, in PR1-D2S cells and estradiol enhanced this effect. These data suggest that, in the presence of estradiol, D2R agonists induce apoptosis of lactotropes by their interaction with D2S receptors and that p38 MAPK is involved in this process.

  12. Indirect modulation of dopamine D2 receptors as potential pharmacotherapy for schizophrenia: I. Adenosine agonists.

    Science.gov (United States)

    Dixon, D A; Fenix, L A; Kim, D M; Raffa, R B

    1999-04-01

    To review preclinical and clinical information related to pharmacologic modulation of dopamine D2 receptors as potential novel antipsychotic therapy. Specifically, to summarize the data that suggest a modulatory action of adenosine A2A receptors on dopamine D2 receptors and, therefore, a possible rational role of adenosine A2A agonists as novel antipsychotic agents. Primary and review articles were identified by MEDLINE search (from 1966 to May 1998) and through secondary sources. All of the articles identified from the data sources were evaluated and all information deemed relevant was included in this review. For all of the older and many of the newer antipsychotic agents, there is a strong correlation between clinical antipsychotic activity and affinity for dopamine D2 receptors. Unfortunately, dopamine D2 receptors are believed to also be involved in the adverse effect profile of these agents. The indirect modulation of dopamine D2 receptors, rather than direct block, might produce antipsychotic effects without the usual adverse reactions. Several lines of evidence from animal studies suggest that the use of selective A2A agonists might represent a novel approach to the treatment of psychoses. Dopamine receptor modulation might represent a novel antipsychotic approach or adjunct therapy. The data regarding adenosine agonists (particularly selective A2A receptor agonists) are inconclusive at the present time. Direct clinical demonstration of effectiveness is required.

  13. Dopamine D2 receptors preferentially regulate the development of light responses of the inner retina

    Science.gov (United States)

    Tian, Ning; Xu, Hong-ping; Wang, Ping

    2014-01-01

    Retinal light responsiveness measured via electroretinography undergoes developmental modulation and is thought to be critically regulated by both visual experience and dopamine. The primary goal of this study is to determine whether the dopamine D2 receptor regulates the visual experience-dependent functional development of the retina. Accordingly, we recorded electroretinograms from wild type mice and mice with a genetic deletion of the gene that encodes the dopamine D2 receptor raised under normal cyclic light conditions and constant darkness. Our results demonstrate that mutation of the dopamine D2 receptors preferentially increases the amplitude of the inner retinal light responses evoked by high intensity light measured as oscillatory potentials in adult mice. During postnatal development, all three major components of electroretinograms, the a-wave, b-wave and oscillatory potentials, increase with age. Comparatively, mutation of the dopamine D2 receptors preferentially reduces the age-dependent increase of b-waves evoked by low intensity light. Light deprivation from birth reduces the amplitude of b-waves and completely diminishes the increased amplitude of oscillatory potentials. Taken together, these results demonstrate that the dopamine D2 receptor plays an important role in the activity-dependent functional development of the mouse retina. PMID:25393815

  14. Functional coupling between heterologously expressed dopamine D(2) receptors and KCNQ channels

    DEFF Research Database (Denmark)

    Ljungstrom, Trine; Grunnet, Morten; Jensen, Bo Skaaning

    2003-01-01

    Activation of KCNQ potassium channels by stimulation of co-expressed dopamine D(2) receptors was studied electrophysiologically in Xenopus laevis oocytes and in mammalian cells. To address the specificity of the interaction between D(2)-like receptors and KCNQ channels, combinations of KCNQ1...

  15. Dopamine D2 receptor occupancy by olanzapine or risperidone in young patients with schizophrenia

    NARCIS (Netherlands)

    Lavalaye, J.; Linszen, D. H.; Booij, J.; Reneman, L.; Gersons, B. P.; van Royen, E. A.

    1999-01-01

    A crucial characteristic of antipsychotic medication is the occupancy of the dopamine (DA) D2 receptor. We assessed striatal DA D2 receptor occupancy by olanzapine and risperidone in 36 young patients [31 males, 5 females; mean age 21.1 years (16-28)] with first episode schizophrenia, using

  16. Dopamine D1-D2 receptor heteromer signaling pathway in the brain: emerging physiological relevance

    Directory of Open Access Journals (Sweden)

    Hasbi Ahmed

    2011-06-01

    Full Text Available Abstract Dopamine is an important catecholamine neurotransmitter modulating many physiological functions, and is linked to psychopathology of many diseases such as schizophrenia and drug addiction. Dopamine D1 and D2 receptors are the most abundant dopaminergic receptors in the striatum, and although a clear segregation between the pathways expressing these two receptors has been reported in certain subregions, the presence of D1-D2 receptor heteromers within a unique subset of neurons, forming a novel signaling transducing functional entity has been shown. Recently, significant progress has been made in elucidating the signaling pathways activated by the D1-D2 receptor heteromer and their potential physiological relevance.

  17. Imaging addiction: D2 receptors and dopamine signaling in the striatum as biomarkers for impulsivity

    Science.gov (United States)

    Trifilieff, Pierre; Martinez, Diana

    2014-01-01

    Dependence to drugs of abuse is closely associated with impulsivity, or the propensity to choose a lower, but immediate, reward over a delayed, but more valuable outcome. Here, we review clinical and preclinical studies showing that striatal dopamine signaling and D2 receptor levels – which have been shown to be decreased in addiction - directly impact impulsivity, which is itself predictive of drug self-administration. Based on these studies, we propose that the alterations in D2 receptor binding and dopamine release seen in imaging studies of addiction constitute neurobiological markers of impulsivity. Recent studies in animals also show that higher striatal dopamine signaling at the D2 receptor is associated with a greater willingness to expend effort to reach goals, and we propose that this same relationship applies to humans, particularly with respect to recovery from addiction. PMID:23851257

  18. Visualization of ligand-induced dopamine D2S and D2L receptor internalization by TIRF microscopy.

    Science.gov (United States)

    Tabor, Alina; Möller, Dorothee; Hübner, Harald; Kornhuber, Johannes; Gmeiner, Peter

    2017-09-07

    G protein-coupled receptors (GPCRs), including the dopamine receptors, represent a group of important pharmacological targets. Upon agonist binding, GPCRs frequently undergo internalization, a process that is known to attenuate functional responses upon prolonged exposure to agonists. In this study, internalization was visualized by means of total internal reflection fluorescence (TIRF) microscopy at a level of discrete single events near the plasma membrane with high spatial resolution. A novel method has been developed to determine the relative extent of internalized fluorescent receptor-ligand complexes by comparative fluorescence quantification in living CHO cells. The procedure entails treatment with the reducing agent sodium borohydride, which converts cyanine-based fluorescent ligands on the membrane surface to a long-lived reduced form. Because the highly polar reducing agent is not able to pass the cell membrane, the fluorescent receptor-ligand complexes located in internalized compartments remain fluorescent under TIRF illumination. We applied the method to investigate differences of the short (D2S) and the long (D2L) isoforms of dopamine D2 receptors in their ability to undergo agonist-induced internalization.

  19. Reduced striatal dopamine D2 receptors in people with Internet addiction.

    Science.gov (United States)

    Kim, Sang Hee; Baik, Sang-Hyun; Park, Chang Soo; Kim, Su Jin; Choi, Sung Won; Kim, Sang Eun

    2011-06-11

    An increasing amount of research has suggested that Internet addiction is associated with abnormalities in the dopaminergic brain system. We hypothesized that Internet addiction would be associated with reduced levels of dopaminergic receptor availability in the striatum compared with controls. To test this hypothesis, a radiolabeled ligand [C]raclopride and positron emission tomography was used to assess dopamine D2 receptor binding potential in men with and without Internet addiction. Consistent with our prediction, individuals with Internet addiction showed reduced levels of dopamine D2 receptor availability in subdivisions of the striatum including the bilateral dorsal caudate and right putamen. This finding contributes to the understanding of neurobiological mechanism of Internet addiction.

  20. Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil.

    Science.gov (United States)

    Seeman, Philip; Guan, Hong-Chang; Hirbec, Hélène

    2009-08-01

    Although it is commonly stated that phencyclidine is an antagonist at ionotropic glutamate receptors, there has been little measure of its potency on other receptors in brain tissue. Although we previously reported that phencyclidine stimulated cloned-dopamine D2Long and D2Short receptors, others reported that phencyclidine did not stimulate D2 receptors in homogenates of rat brain striatum. This study, therefore, examined whether phencyclidine and other hallucinogens and psychostimulants could stimulate the incorporation of [(35)S]GTP-gamma-S into D2 receptors in homogenates of rat brain striatum, using the same conditions as previously used to study the cloned D2 receptors. Using 10 microM dopamine to define 100% stimulation, phencyclidine elicited a maximum incorporation of 46% in rat striata, with a half-maximum concentration of 70 nM for phencyclidine, when compared with 80 nM for dopamine, 89 nM for salvinorin A (48 nM for D2Long), 105 nM for lysergic acid diethylamide (LSD), 120 nM for R-modafinil, 710 nM for dizocilpine, 1030 nM for ketamine, and >10,000 nM for S-modafinil. These compounds also inhibited the binding of the D2-selective ligand [(3)H]domperidone. The incorporation was inhibited by the presence of 200 microM guanylylimidodiphosphate and also by D2 blockade, using 10 microM S-sulpiride, but not by D1 blockade with 10 microM SCH23390. Hypertonic buffer containing 150 mM NaCl inhibited the stimulation by phencyclidine, which may explain negative results by others. It is concluded that phencyclidine and other psychostimulants and hallucinogens can stimulate dopamine D2 receptors at concentrations related to their behavioral actions.

  1. Emotional response in dopamine D2L receptor-deficient mice.

    Science.gov (United States)

    Hranilovic, Dubravka; Bucan, Maja; Wang, Yanyan

    2008-12-22

    The dopamine D2 receptor (D2R) system has been implicated in emotional processing which is often impaired in neuropsychiatric disorders. The long (D2L) and the short (D2S) isoforms of D2R are generated by alternative splicing of the same gene. To study differential roles of the two D2R isoforms, D2L-deficient mice (D2L-/-) expressing functional D2S were previously generated. In this study the contribution of D2L isoform to emotional response was investigated by examining behaviors that reflect emotionality (exploratory behavior, anxiety-like behavior and learned helplessness) in D2L-/- and (wild-type) WT mice. While the thigmotactic, locomotor and general components of anxiety in zero maze did not differ among the genotypes, D2L-/- mice displayed significantly lower level of exploration in a hole board and zero maze, and significantly higher increase in latency to escape from a foot-shock after the learned helplessness training, compared with WT mice. These results suggest that D2L may play a more prominent role than D2S in mediating emotional response, such as behavioral reactions to novelty and inescapable stress. Our findings contribute to a better understanding of the molecular and cellular mechanisms underlying emotional responses.

  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. Effect of C-Terminal S-Palmitoylation on D2 Dopamine Receptor Trafficking and Stability.

    Directory of Open Access Journals (Sweden)

    Brittany Ebersole

    Full Text Available We have used bioorthogonal click chemistry (BCC, a sensitive non-isotopic labeling method, to analyze the palmitoylation status of the D2 dopamine receptor (D2R, a G protein-coupled receptor (GPCR crucial for regulation of processes such as mood, reward, and motor control. By analyzing a series of D2R constructs containing mutations in cysteine residues, we found that palmitoylation of the D2R most likely occurs on the C-terminal cysteine residue (C443 of the polypeptide. D2Rs in which C443 was deleted showed significantly reduced palmitoylation levels, plasma membrane expression, and protein stability compared to wild-type D2Rs. Rather, the C443 deletion mutant appeared to accumulate in the Golgi, indicating that palmitoylation of the D2R is important for cell surface expression of the receptor. Using the full-length D2R as bait in a membrane yeast two-hybrid (MYTH screen, we identified the palmitoyl acyltransferase (PAT zDHHC4 as a D2R interacting protein. Co-immunoprecipitation analysis revealed that several other PATs, including zDHHC3 and zDHHC8, also interacted with the D2R and that each of the three PATs was capable of affecting the palmitoylation status of the D2R. Finally, biochemical analyses using D2R mutants and the palmitoylation blocker, 2-bromopalmitate indicate that palmitoylation of the receptor plays a role in stability of the D2R.

  4. Predicting dopamine D2 receptor occupancy in humans using a physiology-based approach

    NARCIS (Netherlands)

    Johnson, Martin; Kozielska, Magdalena; Pilla Reddy, Venkatesh; Vermeulen, An; Barton, Hugh A.; Grimwood, Sarah; de Greef, Rik; Groothuis, Genoveva; Danhof, Meindert; Proost, Johannes

    2011-01-01

    Objectives: A hybrid physiology-based pharmacokinetic and pharmacodynamic model (PBPKPD) was used to predict the time course of dopamine receptor occupancy (D2RO) in human striatum following the administration of antipsychotic (AP) drugs, using in vitro and in silico information. Methods: A hybrid

  5. Cannabinoid-1 receptor antagonist rimonabant (SR141716) increases striatal dopamine D2 receptor availability

    NARCIS (Netherlands)

    Crunelle, Cleo L.; van de Giessen, Elsmarieke; Schulz, Sybille; Vanderschuren, Louk J. M. J.; de Bruin, Kora; van den Brink, Wim; Booij, Jan

    2013-01-01

    The cannabinoid 1 receptor antagonist rimonabant (SR141716) alters rewarding properties and intake of food and drugs. Additionally, striatal dopamine D2 receptor (DRD2) availability has been implicated in reward function. This study shows that chronic treatment of rats with rimonabant (1.0 and

  6. 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.

  7. Striatal dopamine D2/3 receptor availability in treatment resistant depression.

    Directory of Open Access Journals (Sweden)

    Bart P de Kwaasteniet

    Full Text Available Several studies demonstrated improvement of depressive symptoms in treatment resistant depression (TRD after administering dopamine agonists which suggest abnormal dopaminergic neurotransmission in TRD. However, the role of dopaminergic signaling through measurement of striatal dopamine D(2/3 receptor (D2/3R binding has not been investigated in TRD subjects. We used [(123I]IBZM single photon emission computed tomography (SPECT to investigate striatal D2/3R binding in TRD. We included 6 severe TRD patients, 11 severe TRD patients on antipsychotics (TRD AP group and 15 matched healthy controls. Results showed no significant difference (p = 0.75 in striatal D2/3R availability was found between TRD patients and healthy controls. In the TRD AP group D2/3R availability was significantly decreased (reflecting occupancy of D2/3Rs by antipsychotics relative to TRD patients and healthy controls (p<0.001 but there were no differences in clinical symptoms between TRD AP and TRD patients. This preliminary study therefore does not provide evidence for large differences in D2/3 availability in severe TRD patients and suggests this TRD subgroup is not characterized by altered dopaminergic transmission. Atypical antipsychotics appear to have no clinical benefit in severe TRD patients who remain depressed, despite their strong occupancy of D2/3Rs.

  8. Dopamine D2-receptor blockade enhances decoding of prefrontal signals in humans.

    Science.gov (United States)

    Kahnt, Thorsten; Weber, Susanna C; Haker, Helene; Robbins, Trevor W; Tobler, Philippe N

    2015-03-04

    The prefrontal cortex houses representations critical for ongoing and future behavior expressed in the form of patterns of neural activity. Dopamine has long been suggested to play a key role in the integrity of such representations, with D2-receptor activation rendering them flexible but weak. However, it is currently unknown whether and how D2-receptor activation affects prefrontal representations in humans. In the current study, we use dopamine receptor-specific pharmacology and multivoxel pattern-based functional magnetic resonance imaging to test the hypothesis that blocking D2-receptor activation enhances prefrontal representations. Human subjects performed a simple reward prediction task after double-blind and placebo controlled administration of the D2-receptor antagonist amisulpride. Using a whole-brain searchlight decoding approach we show that D2-receptor blockade enhances decoding of reward signals in the medial orbitofrontal cortex. Examination of activity patterns suggests that amisulpride increases the separation of activity patterns related to reward versus no reward. Moreover, consistent with the cortical distribution of D2 receptors, post hoc analyses showed enhanced decoding of motor signals in motor cortex, but not of visual signals in visual cortex. These results suggest that D2-receptor blockade enhances content-specific representations in frontal cortex, presumably by a dopamine-mediated increase in pattern separation. These findings are in line with a dual-state model of prefrontal dopamine, and provide new insights into the potential mechanism of action of dopaminergic drugs. Copyright © 2015 the authors 0270-6474/15/354104-08$15.00/0.

  9. Activation of D2 dopamine receptor-expressing neurons in the nucleus accumbens increases motivation

    Science.gov (United States)

    Soares-Cunha, Carina; Coimbra, Barbara; David-Pereira, Ana; Borges, Sonia; Pinto, Luisa; Costa, Patricio; Sousa, Nuno; Rodrigues, Ana J.

    2016-01-01

    Striatal dopamine receptor D1-expressing neurons have been classically associated with positive reinforcement and reward, whereas D2 neurons are associated with negative reinforcement and aversion. Here we demonstrate that the pattern of activation of D1 and D2 neurons in the nucleus accumbens (NAc) predicts motivational drive, and that optogenetic activation of either neuronal population enhances motivation in mice. Using a different approach in rats, we further show that activating NAc D2 neurons increases cue-induced motivational drive in control animals and in a model that presents anhedonia and motivational deficits; conversely, optogenetic inhibition of D2 neurons decreases motivation. Our results suggest that the classic view of D1–D2 functional antagonism does not hold true for all dimensions of reward-related behaviours, and that D2 neurons may play a more prominent pro-motivation role than originally anticipated. PMID:27337658

  10. Striatal dopamine D2 receptor binding and dopamine release during cue-elicited craving in recently abstinent opiate-dependent males

    NARCIS (Netherlands)

    Zijlstra, Fleur; Booij, Jan; van den Brink, Wim; Franken, Ingmar H. A.

    2008-01-01

    Opiate addiction is a chronic disorder characterized by relapse behaviour, often preceded by craving and anhedonia. Chronic craving and anhedonia have been associated with low availability of dopamine D2 receptors (D2Rs) and cue-elicited craving has been linked with endogenous dopamine release. We

  11. Dopamine D1 and D2 receptor immunoreactivities in the arcuate-median eminence complex and their link to the tubero-infundibular dopamine neurons

    Directory of Open Access Journals (Sweden)

    W. Romero-Fernandez

    2014-07-01

    Full Text Available Dopamine D1 and D2 receptor immunohistochemistry and Golgi techniques were used to study the structure of the adult rat arcuate-median eminence complex, and determine the distribution of the dopamine D1 and D2 receptor immunoreactivities therein, particularly in relation to the tubero-infundibular dopamine neurons. Punctate dopamine D1 and D2 receptor immunoreactivities, likely located on nerve terminals, were enriched in the lateral palisade zone built up of nerve terminals, while the densities were low to modest in the medial palisade zone. A codistribution of dopamine D1 receptor or dopamine D2 receptor immunoreactive puncta with tyrosine hydroxylase immunoreactive nerve terminals was demonstrated in the external layer. Dopamine D1 receptor but not dopamine D2 receptor immnunoreactivites nerve cell bodies were found in the ventromedial part of the arcuate nucleus and in the lateral part of the internal layer of the median eminence forming a continuous cell mass presumably representing neuropeptide Y immunoreactive nerve cell bodies. The major arcuate dopamine/ tyrosine hydroxylase nerve cell group was found in the dorsomedial part. A large number of tyrosine hydroxylase immunoreactive nerve cell bodies in this region demonstrated punctate dopamine D1 receptor immunoreactivity but only a few presented dopamine D2 receptor immunoreactivity which were mainly found in a substantial number of tyrosine hydroxylase cell bodies of the ventral periventricular hypothalamic nucleus, also belonging to the tubero-infundibular dopamine neurons. Structural evidence for projections of the arcuate nerve cells into the median eminence was also obtained. Distal axons formed horizontal axons in the internal layer issuing a variable number of collaterals classified into single or multiple strands located in the external layer increasing our understanding of the dopamine nerve terminal networks in this region.  Dopamine D1 and D2 receptors may therefore directly

  12. Dopamine-D2-receptor scintigraphy with {sup 123}I-Iodobenzofuran in malignant melanoma; Dopamin-D2-Rezeptorszintigraphie mit {sup 123}I-Jodbenzofuran beim malignen Melanom

    Energy Technology Data Exchange (ETDEWEB)

    Steinert, H. [Dept. fuer Medizinische Radiologie, Klinik fuer Nuklearmedizin, Universitaetsspital Zurich (Switzerland); Huch-Boeni, R.A. [Inst. fuer Diagnostische Radiologie, Universitaetsspital Zurich (Switzerland); Boeni, R. [Dermatologische Klinik, Universitaetsspital Zurich (Switzerland); Westera, G. [Dept. fuer Medizinische Radiologie, Klinik fuer Nuklearmedizin, Universitaetsspital Zurich (Switzerland); Buck, A. [Dept. fuer Medizinische Radiologie, Klinik fuer Nuklearmedizin, Universitaetsspital Zurich (Switzerland)

    1995-08-01

    In a prospective study the value of {sup 123}I-iodobenzofuran (IBF), a highly specific and affine dopamine-D2 receptor ligand was evaluated for the detection of melanoma metastases. With IBF-D2 receptor scintigraphy only 2 of 17 melanoma metastases could be detected. The interpretation of the abdomen was impaired by the hepatobiliary and renal excretion of the radionuclide. The ratio striatum/frontal cortex of 2,75 {+-} 0,49 3 h p.i. demonstrated a high D2-receptor binding of the ligand. IBF-D2-receptor scintigraphy is not suitable as a method of staging melanoma. (orig.) [Deutsch] In einer prospektiven Studie wurde die Wertigkeit von {sup 123}I-Jodbenzofuran (IBF), einem hochspezifischen und hochaffinen Dopamin-D2-Rezeptorliganden zum Nachweis von Melanommetastasen untersucht. Mit der IBF-D2-Rezeptorszintigraphie liessen sich nur 2 von 17 Melanommetastasen nachweisen. Die Beurteilung des Abdomens war durch die hepatobiliaere Ausscheidung des Radionuklids stark eingeschraenkt. Der Quotient Striatum/Frontalhirn von 2,75 {+-} 0,49 3 h p.i. belegte die hohe D2-Rezeptorbindung des Liganden. Die IBF-D2-Rezeptorszintigraphie ist als Staginguntersuchung beim Melanom nicht geeignet. (orig.)

  13. Dopamine D2 Receptors Enhance Population Dynamics in Primate Prefrontal Working Memory Circuits.

    Science.gov (United States)

    Ott, Torben; Nieder, Andreas

    2017-09-01

    Working memory is associated with persistent activity in the prefrontal cortex (PFC). The neuromodulator dopamine, which is released by midbrain neurons projecting into the frontal lobe, influences PFC neurons and networks via the dopamine D1 (D1R) and the D2 receptor (D2R) families. Although behavioral, clinical and computational evidence suggest an involvement of D2Rs in working memory, a neuronal explanation is missing. We report an enhancement of persistent working memory responses of PFC neurons after iontophoretically stimulating D2Rs in monkeys memorizing the number of items in a display. D2R activation improved working memory representation at the population level and increased population dynamics during the transition from visual to mnemonic representations. Computational modeling suggests that D2Rs act by modulating interneuron-to-pyramidal signaling. By increasing the population's response dynamics, D2Rs might put PFC networks in a more flexible state and enhance the neurons' working memory coding, thereby controlling dynamic cognitive control. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  14. Receptor, Ligand and Transducer Contributions to Dopamine D2 Receptor Functional Selectivity.

    Directory of Open Access Journals (Sweden)

    Sean M Peterson

    Full Text Available Functional selectivity (or biased agonism is a property exhibited by some G protein-coupled receptor (GPCR ligands, which results in the modulation of a subset of a receptor's signaling capabilities and more precise control over complex biological processes. The dopamine D2 receptor (D2R exhibits pleiotropic responses to the biogenic amine dopamine (DA to mediate complex central nervous system functions through activation of G proteins and β-arrestins. D2R is a prominent therapeutic target for psychological and neurological disorders in which DA biology is dysregulated and targeting D2R with functionally selective drugs could provide a means by which pharmacotherapies could be developed. However, factors that determine GPCR functional selectivity in vivo may be multiple with receptors, ligands and transducers contributing to the process. We have recently described a mutagenesis approach to engineer biased D2R mutants in which G protein-dependent ([Gprot]D2R and β-arrestin-dependent signaling ([βarr]D2R were successfully separated (Peterson, et al. PNAS, 2015. Here, permutations of these mutants were used to identify critical determinants of the D2R signaling complex that impart signaling bias in response to the natural or synthetic ligands. Critical residues identified in generating [Gprot]D2R and [βarr]D2R conferred control of partial agonism at G protein and/or β-arrestin activity. Another set of mutations that result in G protein bias was identified that demonstrated that full agonists can impart unique activation patterns, and provided further credence to the concept of ligand texture. Finally, the contributions and interplay between different transducers indicated that G proteins are not aberrantly activated, and that receptor kinase and β-arrestin activities are inextricably linked. These data provide a thorough elucidation of the feasibility and malleability of D2R functional selectivity and point to means by which novel in vivo

  15. Neurovascular coupling to D2/D3 dopamine receptor occupancy using simultaneous PET/functional MRI

    DEFF Research Database (Denmark)

    Sander, Christin Y; Hooker, Jacob M; Catana, Ciprian

    2013-01-01

    This study employed simultaneous neuroimaging with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) to demonstrate the relationship between changes in receptor occupancy measured by PET and changes in brain activity inferred by fMRI. By administering the D2/D3...... responses and receptor occupancies. The distinct CBV magnitudes between putamen and caudate at matched occupancies approximately matched literature differences in basal dopamine levels, suggesting that the relative fMRI measurements reflect basal D2/D3 dopamine receptor occupancy. These results can provide...... a basis for models that relate dopaminergic occupancies to hemodynamic changes in the basal ganglia. Overall, these data demonstrate the utility of simultaneous PET/fMRI for investigations of neurovascular coupling that correlate neurochemistry with hemodynamic changes in vivo for any receptor system...

  16. Emotion Dysregulation and Amygdala Dopamine D2-type Receptor Availability in Methamphetamine Users

    Science.gov (United States)

    Okita, Kyoji; Ghahremani, Dara G.; Payer, Doris E.; Robertson, Chelsea L.; Dean, Andy C.; Mandelkern, Mark A.; London, Edythe D.

    2016-01-01

    Background Individuals who use methamphetamine chronically exhibit emotional and dopaminergic neurochemical deficits. Although the amygdala has an important role in emotion processing and receives dopaminergic innervation, little is known about how dopamine transmission in this region contributes to emotion regulation. This investigation aimed to evaluate emotion regulation in subjects who met DSM-IV criteria for methamphetamine dependence, and to test for a relationship between self-reports of difficulty in emotion regulation and D2-type dopamine receptor availability in the amygdala. Method Ninety-four methamphetamine-using and 102 healthy-control subjects completed the Difficulties in Emotion Regulation Scale (DERS); 33 of those who used methamphetamine completed the Addiction Severity Index (ASI). A subset of 27 methamphetamine-group and 20 control-group subjects completed positron emission tomography with [18F]fallypride to assay amygdala D2-type dopamine receptor availability, measured as binding potential (BPND). Results The methamphetamine group scored higher than the control group on the DERS total score (p dopamine receptors in the amygdala contribute to emotion regulation in both healthy and methamphetamine-using subjects. PMID:26880595

  17. QSAR modeling on dopamine D2 receptor binding affinity of 6-methoxy benzamides.

    Science.gov (United States)

    Samanta, Soma; Debnath, Bikash; Gayen, Shovanlal; Ghosh, Balaram; Basu, Anindya; Srikanth, Kolluru; Jha, Tarun

    2005-10-01

    QSAR modeling was performed on 58 (S) N-[(1-ethyl-2-pyrrolidinyl) methyl]-6-methoxy benzamides as dopamine (DA) D2 receptor antagonists to identify the structural requirements for DA D2 receptor binding affinity. The study pointed out that the presence of hydrophobic substituents at R3 position and electron-donating groups at R5 position increased the biological activity. Substitutions at phenyl ring favored the binding affinity of these benzamides. Ethyl group and iodine at R3 position were advantageous to the activity whereas nitro group at phenyl ring hindered the antagonistic activity.

  18. Dopamine D2 Receptors Regulate Collateral Inhibition between Striatal Medium Spiny Neurons

    Science.gov (United States)

    van der Goes, Marie-Sophie; Partridge, John G.; Vicini, Stefano

    2013-01-01

    The principle neurons of the striatum are GABAergic medium spiny neurons (MSNs), whose collateral synapses onto neighboring neurons play critical roles in striatal function. MSNs can be divided by dopamine receptor expression into D1-class and D2-class MSNs, and alterations in D2 MSNs are associated with various pathological states. Despite overwhelming evidence for D2 receptors (D2Rs) in maintaining proper striatal function, it remains unclear how MSN collaterals are specifically altered by D2R activation. Here, we report that chronic D2R stimulation regulates MSN collaterals in vitro by presynaptic and postsynaptic mechanisms. We used corticostriatal cultures from mice in which MSN subtypes were distinguished by fluorophore expression. Quinpirole, an agonist for D2/3 receptors, was used to chronically activate D2Rs. Quinpirole increased the rate and strength of collateral formation onto D2R-containing MSNs as measured by dual whole-cell patch-clamp recordings. Additionally, these neurons were more sensitive to low concentrations of GABA and exhibited an increase in gephyrin puncta density, suggesting increased postsynaptic GABAA receptors. Last, quinpirole treatment increased presynaptic GABA release sites, as shown by increased frequency of sIPSCs and mIPSCs, correlating with increased VGAT (vesicular GABA transporter) puncta. Combined with the observation that there were no detectable differences in sensitivity to specific GABAA receptor modulators, we provide evidence that D2R activation powerfully transforms MSN collaterals via coordinated presynaptic and postsynaptic alterations. As the D2 class of MSNs is highly implicated in Parkinson's disease and other neurological disorders, our findings may contribute to understanding and treating the changes that occur in these pathological states. PMID:23986243

  19. Lack of association between polymorphisms of dopamine receptors, type D2, and bipolar affective illness in a Polish population.

    Science.gov (United States)

    Leszczyńska-Rodziewicz, Anna; Hauser, Joanna; Dmitrzak-Weglarz, Monika; Skibińka, Maria; Czerski, Piotr; Zakrzewska, Agnieszka; Kosmowska, Magdalena; Rybakowski, Janusz K

    2005-06-01

    Biochemical abnormalities are thought to be important factors causing bipolar disorder. Several lines of evidence suggest dopamine may play a role in its etiology, e.g. depressive syndrome is frequently encountered in subjects affected by Parkinson's disease, where dopamine depletion is observed. Thus the genes of the dopaminergic system are good candidates for studies on bipolar disorder. In the present study, we investigated polymorphisms of dopamine receptors, type D2, including the dopamine receptors D2, D3 and D4. Polish bipolar patients (n=339) and control subjects (n=366) were analyzed for three dopamine receptor gene polymorphisms: dopamine receptor D2 (DRD2) 141 ins/del, dopamine receptor D3 (DRD3) Ser9Gly, and dopamine receptor D4 (DRD4) 521 C/T. Allele and genotype frequencies did not differ significantly among patients and controls. We did not obtain any significant association between the studied polymorphisms and bipolar disorder. The results suggests that the studied gene variants of type D2 dopamine receptors are not promising candidate genes for bipolar affective illness. We did not consider the family history of the examined subjects, and also the control group was not psychiatrically screened, which may contribute to the lack of significant results.

  20. Dopamine D2 receptor availability in opiate addicts at baseline and during naloxone precipitated withdrawal

    Energy Technology Data Exchange (ETDEWEB)

    Wang, G.J.; Volkow, N.D.; Logan, J. [Brookhaven National Lab., Upton, NY (United States)]|[SUNY, Stony Brook, NY (United States)]|[Psychiatry Services VAMC Northport, NY (United States)] [and others

    1996-05-01

    To determine if changes in dopamine activity contribute to the clinical presentation of opiate withdrawal we assessed dopamine (DA) D2 receptor availability in opiate-dependent subjects at baseline and during naloxone-precipitated withdrawal. DA D2 receptor availability was evaluated in eleven male heroine and methadone users using positron emission tomography (PET) and [11-C]raclopride and compared to eleven age matched male control subjects. Nine of the opiate-dependent subjects and two of the control were tested twice after placebo and naloxone (0.02 mg/kg) iv injection 7-10 min. prior to [11-C]raclopride. DA D2 receptor availability was measured using the ratio of the distribution volume in the region of interest (caudate, putamen and ventral striatum) to that in the cerebellum which is a function of B{sub max}/K{sub d}. DA D2 receptor availability in putamen was significantly lower in opiate-dependent subjects (3.44 {plus_minus} 0.4) than that in controls (3.97 {plus_minus} 0.45, p {ge} 0.009). Naloxone induced a short lasting withdrawal in all of the opiate-dependent subjects (79 {plus_minus} 17% of maximum withdrawal), but not in controls, with significant increase in pulse (p {le} 0.006), blood pressure (p {le} 0.0001), lacrimation (p {le} 0.01), muscle twitches (p {le} 0.01), annoyance (p {le} 0.005), anxiety (p {le} 0.0006), restlessness (p {le} 0.0005) and unhappiness (p {le} 0.001). DA D2 receptor availability in basal ganglia after naloxone administration was not different from that of baseline. These results document abnormalities in DA D2 receptors in opiate-dependent subjects. However, DA D2 availability did not change with naloxone-precipitated withdrawal.

  1. Autoradiographic localization of dopamine D2-like receptors in the rabbit pulmonary vascular tree.

    Science.gov (United States)

    Kobayashi, Y; Ricci, A; Rossodivita, I; Amenta, F

    1994-06-01

    In the present study, the pharmacological characteristics and the anatomical localization of dopamine D2-like receptor sites in the extraparenchymal and in the intraparenchymal portion of the rabbit pulmonary artery were investigated using combined radioligand binding and light microscope autoradiography with [3H]-spiroperidol (spiperone) as a ligand. The ligand was bound to sections of the pulmonary artery in a manner consistent with the labelling of dopamine D2-like receptors with an equilibrium dissociation constant (Kd) of about 2.4 +/- 0.07 nmol/l and a maximum density of binding sites of 65 +/- 4.5 fmol/mg tissue. In contrast, binding experiments made with sections of rabbit lung did not allow the evaluation of specific binding. Light microscope autoradiography showed the development of specific silver grains within the tunica adventitia of extraparenchymal branches of rabbit pulmonary artery and of large and, to a lesser extent, of medium-sized intraparenchymal branches of the pulmonary artery. No silver grains were found within small branches of the pulmonary artery or of the pulmonary vein. Development of adventitial silver grains was inhibited by compounds active at dopamine receptors. The greater sensitivity to displacement by domperidone, haloperidol, (-)-sulpiride and bromocriptine than to displacement by N-propyl-norapomorphine, quinpirole or clozapine suggests that the [3H]-spiroperidol binding sites observed in extraparenchymal, large and medium-sized branches of the pulmonary artery belong, probably, to the dopamine D2 receptor subtype. The possible pre-junctional localization of these sites is discussed.

  2. Dopamine D2 Receptor Occupancy as a Predictor of Catalepsy in Rats : A Pharmacokinetic-Pharmacodynamic Modeling Approach

    NARCIS (Netherlands)

    Johnson, Martin; Kozielska, Magdalena; Reddy, Venkatesh Pilla; Vermeulen, An; Barton, Hugh A.; Grimwood, Sarah; de Greef, Rik; Groothuis, Geny M. M.; Danhof, Meindert; Proost, Johannes H.

    2014-01-01

    Objectives Dopamine D-2 receptor occupancy (D2RO) is the major determinant of efficacy and safety in schizophrenia drug therapy. Excessive D2RO (>80%) is known to cause catalepsy (CAT) in rats and extrapyramidal side effects (EPS) in human. The objective of this study was to use pharmacokinetic and

  3. Modulation of dopamine D(2) receptor signaling by actin-binding protein (ABP-280).

    Science.gov (United States)

    Li, M; Bermak, J C; Wang, Z W; Zhou, Q Y

    2000-03-01

    Proteins that bind to G protein-coupled receptors have recently been identified as regulators of receptor anchoring and signaling. In this study, actin-binding protein 280 (ABP-280), a widely expressed cytoskeleton-associated protein that plays an important role in regulating cell morphology and motility, was found to associate with the third cytoplasmic loop of dopamine D(2) receptors. The specificity of this interaction was originally identified in a yeast two-hybrid screen and confirmed by protein binding. The functional significance of the D(2) receptor-ABP-280 association was evaluated in human melanoma cells lacking ABP-280. D(2) receptor agonists were less potent in inhibiting forskolin-stimulated cAMP production in these cells. Maximal inhibitory responses of D(2) receptor activation were also reduced. Further yeast two-hybrid experiments showed that ABP-280 association is critically dependent on the carboxyl domain of the D(2) receptor third cytoplasmic loop, where there is a potential serine phosphorylation site (S358). Serine 358 was replaced with aspartic acid to mimic the effects of receptor phosphorylation. This mutant (D(2)S358D) displayed compromised binding to ABP-280 and coupling to adenylate cyclase. PKC activation also generated D(2) receptor signaling attenuation, but only in ABP-containing cells, suggesting a PKC regulatory role in D(2)-ABP association. A mechanism for these results may be derived from a role of ABP-280 in the clustering of D(2) receptors, as determined by immunocytochemical analysis in ABP-deficient and replete cells. Our results suggest a new molecular mechanism of modulating D(2) receptor signaling by cytoskeletal protein interaction.

  4. Characterization of dopamine D1 and D2 receptor-expressing neurons in the mouse hippocampus.

    Science.gov (United States)

    Gangarossa, Giuseppe; Longueville, Sophie; De Bundel, Dimitri; Perroy, Julie; Hervé, Denis; Girault, Jean-Antoine; Valjent, Emmanuel

    2012-12-01

    The hippocampal formation is part of an anatomical system critically involved in learning and memory. Increasing evidence suggests that dopamine plays an important role in learning and memory as well as in several forms of synaptic plasticity. However, the precise identification of neuronal populations expressing D1 or D2 dopamine receptors within the hippocampus is still lacking. To clarify this issue, we used BAC transgenic mice expressing enhanced green fluorescent protein (EGFP) under the control of the promoter of dopamine D1 or D2 receptors. In Drd1a-EGFP mice, sparse GFP-expressing neurons were detected among glutamatergic projecting neurons of the granular layer of the dentate gyrus and GABAergic interneurons located in the hilus. A dense immunofluorescence was observed in the outer and medial part of the molecular layer of the dentate gyrus as well as in the inner part of the molecular layer of CA1 corresponding to the terminals of pyramidal neurons of the entorhinal cortex defining the perforant and the temporo-ammonic pathway respectively. Finally, scattered D1 receptor-expressing neurons were also identified as GABAergic interneurons in the CA3/CA1 fields of the hippocampus. In Drd2-EGFP transgenic mice, GFP was exclusively detected in the glutamatergic mossy cells located in the polymorphic layer of the dentate gyrus. This pattern was confirmed in Drd2-Cre mice crossed with NLS-LacZ-Tau(mGFP) :LoxP and RCE:LoxP reporter lines. Our results demonstrate that D1 and D2 receptor-expressing neurons are strictly segregated in the mouse hippocampus. By clarifying the identity of D1 and D2 receptor-expressing neurons in the hippocampus, this study establishes a basis for future investigations aiming at elucidating their roles in the hippocampal network. Copyright © 2012 Wiley Periodicals, Inc.

  5. Distinct target size of dopamine D-1 and D-2 receptors in rat striatum.

    Science.gov (United States)

    Nielsen, M; Klimek, V; Hyttel, J

    1984-07-16

    Frozen rat striatal tissue was exposed to 10 MeV electrons from a linear accelerator. Based on the theory of target size analysis, the molecular weights of dopamine D-1 receptors (labelled by 3H-piflutixol) and dopamine D-2 receptors (labelled by 3H-spiroperidol) were 79,500 daltons and 136,700 daltons, respectively. The size of the dopamine-stimulated adenylate cyclase was 202,000 daltons. The estimated molecular sizes were deduced by reference to proteins with known molecular weights which were irradiated in parallel. The results showed that the molecular entities for 3H-piflutixol binding and 3H-spiroperidol binding were not identical. The present results do not allow conclusions as to whether D-1 and D-2 receptors are two distinct proteins in the membrane, or whether the receptors are located on the same protein. In the latter case the binding of 3H-spiroperidol needs the presence of a second molecule.

  6. Effects of dopamine D2/D3 receptor antagonism on human planning and spatial working memory.

    Science.gov (United States)

    Naef, M; Müller, U; Linssen, A; Clark, L; Robbins, T W; Eisenegger, C

    2017-04-25

    Psychopharmacological studies in humans suggest important roles for dopamine (DA) D2 receptors in human executive functions, such as cognitive planning and spatial working memory (SWM). However, studies that investigate an impairment of such functions using the selective DA D2/3 receptor antagonist sulpiride have yielded inconsistent results, perhaps because relatively low doses were used. We believe we report for the first time, the effects of a higher (800 mg p.o.) single dose of sulpiride as well as of genetic variation in the DA receptor D2 gene (DA receptor D2 Taq1A polymorphism), on planning and working memory. With 78 healthy male volunteers, we apply a between-groups, placebo-controlled design. We measure outcomes in the difficult versions of the Cambridge Neuropsychological Test Automated Battery One-Touch Stockings of Cambridge and the self-ordered SWM task. Volunteers in the sulpiride group showed significant impairments in planning accuracy and, for the more difficult problems, in SWM. Sulpiride administration speeded response latencies in the planning task on the most difficult problems. Volunteers with at least one copy of the minor allele (A1+) of the DA receptor D2 Taq1A polymorphism showed better SWM capacity, regardless of whether they received sulpiride or placebo. There were no effects on blood pressure, heart rate or subjective sedation. In sum, a higher single dose of sulpiride impairs SWM and executive planning functions, in a manner independent of the DA receptor D2 Taq1A polymorphism.

  7. Presynaptic D2 dopamine receptors control long-term depression expression and memory processes in the temporal hippocampus.

    Science.gov (United States)

    Rocchetti, Jill; Isingrini, Elsa; Dal Bo, Gregory; Sagheby, Sara; Menegaux, Aurore; Tronche, François; Levesque, Daniel; Moquin, Luc; Gratton, Alain; Wong, Tak Pan; Rubinstein, Marcelo; Giros, Bruno

    2015-03-15

    Dysfunctional mesocorticolimbic dopamine signaling has been linked to alterations in motor and reward-based functions associated with psychiatric disorders. Converging evidence from patients with psychiatric disorders and use of antipsychotics suggests that imbalance of dopamine signaling deeply alters hippocampal functions. However, given the lack of full characterization of a functional mesohippocampal pathway, the precise role of dopamine transmission in memory deficits associated with these disorders and their dedicated therapies is unknown. In particular, the positive outcome of antipsychotic treatments, commonly antagonizing D2 dopamine receptors (D2Rs), on cognitive deficits and memory impairments remains questionable. Following pharmacologic and genetic manipulation of dopamine transmission, we performed anatomic, neurochemical, electrophysiologic, and behavioral investigations to uncover the role of D2Rs in hippocampal-dependent plasticity and learning. Naïve mice (n = 4-21) were used in the different procedures. Dopamine modulated both long-term potentiation and long-term depression in the temporal hippocampus as well as spatial and recognition learning and memory in mice through D2Rs. Although genetic deletion or pharmacologic blockade of D2Rs led to the loss of long-term potentiation expression, the specific genetic removal of presynaptic D2Rs impaired long-term depression and performances on spatial memory tasks. Presynaptic D2Rs in dopamine fibers of the temporal hippocampus tightly modulate long-term depression expression and play a major role in the regulation of hippocampal learning and memory. This direct role of mesohippocampal dopamine input as uncovered here adds a new dimension to dopamine involvement in the physiology underlying deficits associated with neuropsychiatric disorders. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  8. 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:

  9. Modification of dopamine D2 receptor activity by pergolide in Parkinson's disease : An in vivo study by PET

    NARCIS (Netherlands)

    Linazasoro, G; Obeso, JA; Gomez, JC; Martinez, M; Antonini, A; Leenders, KL

    1999-01-01

    It is well known that chronic administration of pergolide and other dopamine agonists may induce a downregulation of dopamine D2 receptors in the rat model of Parkinson's disease (PD). To our knowledge, this effect has not been demonstrated in vivo in patients with PD. At present, the status of

  10. 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,…

  11. Occupancy of pramipexole (Sifrol at cerebral dopamine D2/3 receptors in Parkinson's disease patients

    Directory of Open Access Journals (Sweden)

    Angela Deutschländer

    2016-01-01

    Full Text Available Whereas positron emission tomography (PET with the antagonist ligand [18F]fallypride reveals the composite of dopamine D2 and D3 receptors in brain, treatment of Parkinson's disease (PD patients with the D3-prefering agonist pramipexole should result in preferential occupancy in the nucleus accumbens, where the D3-subtype is most abundant. To test this prediction we obtained pairs of [18F]fallypride PET recordings in a group of nine PD patients, first in a condition of treatment as usual with pramipexole (ON-Sifrol; 3 × 0.7 mg p.d., and again at a later date, after withholding pramipexole 48–72 h (OFF-Sifrol; in that condition the serum pramipexole concentration had declined by 90% and prolactin levels had increased four-fold, in conjunction with a small but significant worsening of PD motor symptoms. Exploratory comparison with historical control material showed 14% higher dopamine D2/3 availability in the more-affected putamen of patients OFF medication. On-Sifrol there was significant (p ˂ 0.01 occupancy at [18F]fallypride binding sites in globus pallidus (8% thalamus (9% and substantia nigra (19%, as well as marginally significant occupancy in frontal and temporal cortex of patients. Contrary to expectation, comparison of ON- and OFF-Sifrol results did not reveal any discernible occupancy in nucleus accumbens, or elsewhere in the extended striatum; present methods should be sensitive to a 10% change in dopamine D2/3 receptor availability in striatum; the significant findings elsewhere in the basal ganglia and in cerebral cortex are consistent with a predominance of D3 receptors in those structures, especially in substantia nigra, and imply that therapeutic effects of pramipexole may be obtained at sites outside the extended striatum.

  12. Ligand-Induced Regulation and Localization of Cannabinoid CB1 and Dopamine D2L Receptor HeterodimersS⃞

    OpenAIRE

    Przybyla, Julie A.; Val J Watts

    2010-01-01

    The cannabinoid CB1 (CB1) and dopamine D2 (D2) receptors are coexpressed in the basal ganglia, an area of the brain involved in such processes as cognition, motor function, and emotional control. Several lines of evidence suggest that CB1 and D2 receptors may oligomerize, providing a unique pharmacology in vitro and in vivo. However, limited information exists on the regulation of CB1 and D2 receptor ...

  13. Role of D2 dopamine receptors of the ventral pallidum in inhibitory avoidance learning.

    Science.gov (United States)

    Lénárd, László; Ollmann, Tamás; László, Kristóf; Kovács, Anita; Gálosi, Rita; Kállai, Veronika; Attila, Tóth; Kertes, Erika; Zagoracz, Olga; Karádi, Zoltán; Péczely, László

    2017-03-15

    In our present experiments, the role of D2 dopamine (DA) receptors of the ventral pallidum (VP) was investigated in one trial step-through inhibitory avoidance paradigm. Animals were shocked 3 times in the conditioning trial, with 0.5mA current for 1s. Subsequently bilateral microinjection of the D2 DA receptor agonist quinpirole was administered into the VP in three doses (0.1μg, 1.0μg or 5.0μg in 0.4μl saline). We also applied the D2 DA receptor antagonist sulpiride (0.4μg in 0.4μl saline) alone or 15min prior to the agonist treatment to elucidate whether the agonist effect was specific for the D2 DA receptors. Control animals received saline. In a supplementary experiment, it was also investigated whether application of the same conditioning method leads to the formation of short-term memory in the experimental animals. In the experiment with the D2 DA receptor agonist, only the 0.1μg quinpirole increased significantly the step-through latency during the test trials: retention was significant compared to the controls even 2 weeks after conditioning. The D2 DA receptor antagonist sulpiride pretreatment proved that the effect was due to the agonist induced activation of the D2 DA receptors of the VP. The supplementary experiment demonstrated that short-term memory is formed after conditioning in the experimental animals, supporting that the agonist enhanced memory consolidation in the first two experiments. Our results show that the activation of the D2 DA receptors in the VP facilitates memory consolidation as well as memory-retention in inhibitory avoidance paradigm. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Adolescent Maturation of Dopamine D1 and D2 Receptor Function and Interactions in Rodents

    Science.gov (United States)

    Dwyer, Jennifer B.; Leslie, Frances M.

    2016-01-01

    Adolescence is a developmental period characterized by heightened vulnerability to illicit drug use and the onset of neuropsychiatric disorders. These clinical phenomena likely share common neurobiological substrates, as mesocorticolimbic dopamine systems actively mature during this period. Whereas prior studies have examined age-dependent changes in dopamine receptor binding, there have been fewer functional analyses. The aim of the present study was therefore to determine whether the functional consequences of D1 and D2-like activation are age-dependent. Adolescent and adult rats were given direct D1 and D2 agonists, alone and in combination. Locomotor and stereotypic behaviors were measured, and brains were collected for analysis of mRNA expression for the immediate early genes (IEGs), cfos and arc. Adolescents showed enhanced D2-like receptor control of locomotor and repetitive behaviors, which transitioned to dominant D1-like mechanisms in adulthood. When low doses of agonists were co-administered, adults showed supra-additive behavioral responses to D1/D2 combinations, whereas adolescents did not, which may suggest age differences in D1/D2 synergy. D1/D2-stimulated IEG expression was particularly prominent in the bed nucleus of the stria terminalis (BNST). Given the BNST’s function as an integrator of corticostriatal, hippocampal, and stress-related circuitry, and the importance of neural network dynamics in producing behavior, an exploratory functional network analysis of regional IEG expression was performed. This data-driven analysis demonstrated similar developmental trajectories as those described in humans and suggested that dopaminergic drugs alter forebrain coordinated gene expression age dependently. D1/D2 recruitment of stress nuclei into functional networks was associated with low behavioral output in adolescents. Network analysis presents a novel tool to assess pharmacological action, and highlights critical developmental changes in functional

  15. Abnormal modulation of reward versus punishment learning by a dopamine D2-receptor antagonist in pathological gamblers.

    Science.gov (United States)

    Janssen, Lieneke Katharina; Sescousse, Guillaume; Hashemi, Mahur Melina; Timmer, Monique Harmina Maria; ter Huurne, Niels Peter; Geurts, Dirk Everdina Maria; Cools, Roshan

    2015-09-01

    Pathological gambling has been associated with dopamine transmission abnormalities, in particular dopamine D2-receptor deficiency, and reversal learning deficits. Moreover, pervasive theoretical accounts suggest a key role for dopamine in reversal learning. However, there is no empirical evidence for a direct link between dopamine, reversal learning and pathological gambling. The aim of the present study is to triangulate dopamine, reversal learning, and pathological gambling. Here, we assess the hypothesis that pathological gambling is accompanied by dopamine-related problems with learning from reward and punishment by investigating effects of the dopamine D2-receptor antagonist sulpiride (400 mg) on reward- and punishment-based reversal learning in 18 pathological gamblers and 22 healthy controls, using a placebo-controlled, double-blind, counter-balanced design. In line with previous studies, blockade of D2 receptors with sulpiride impaired reward versus punishment reversal learning in controls. By contrast, sulpiride did not have any outcome-specific effects in gamblers. These data demonstrate that pathological gambling is associated with a dopamine-related anomaly in reversal learning from reward and punishment.

  16. Single and Binge Methamphetamine Administrations Have Different Effects on the Levels of Dopamine D2 Autoreceptor and Dopamine Transporter in Rat Striatum

    Directory of Open Access Journals (Sweden)

    Heli Chauhan

    2014-04-01

    Full Text Available Methamphetamine (METH is a central nervous system psychostimulant with a high potential for abuse. At high doses, METH causes a selective degeneration of dopaminergic terminals in the striatum. Dopamine D2 receptor antagonists and dopamine transporter (DAT inhibitors protect against neurotoxicity of the drug by decreasing intracellular dopamine content and, consequently, dopamine autoxidation and production of reactive oxygen species. In vitro, amphetamines regulate D2 receptor and DAT functions via regulation of their intracellular trafficking. No data exists on axonal transport of both proteins and there is limited data on their interactions in vivo. The aim of the present investigation was to examine synaptosomal levels of presynaptic D2 autoreceptor and DAT after two different regimens of METH and to determine whether METH affects the D2 autoreceptor-DAT interaction in the rat striatum. We found that, as compared to saline controls, administration of single high-dose METH decreased D2 autoreceptor immunoreactivity and increased DAT immunoreactivity in rat striatal synaptosomes whereas binge high-dose METH increased immunoreactivity of D2 autoreceptor and had no effect on DAT immunoreactivity. Single METH had no effect on D2 autoreceptor-DAT interaction whereas binge METH increased the interaction between the two proteins in the striatum. Our results suggest that METH can affect axonal transport of both the D2 autoreceptor and DAT in an interaction-dependent and -independent manner.

  17. Single and binge methamphetamine administrations have different effects on the levels of dopamine D2 autoreceptor and dopamine transporter in rat striatum.

    Science.gov (United States)

    Chauhan, Heli; Killinger, Bryan A; Miller, Cheryl V; Moszczynska, Anna

    2014-04-08

    Methamphetamine (METH) is a central nervous system psychostimulant with a high potential for abuse. At high doses, METH causes a selective degeneration of dopaminergic terminals in the striatum. Dopamine D2 receptor antagonists and dopamine transporter (DAT) inhibitors protect against neurotoxicity of the drug by decreasing intracellular dopamine content and, consequently, dopamine autoxidation and production of reactive oxygen species. In vitro, amphetamines regulate D2 receptor and DAT functions via regulation of their intracellular trafficking. No data exists on axonal transport of both proteins and there is limited data on their interactions in vivo. The aim of the present investigation was to examine synaptosomal levels of presynaptic D2 autoreceptor and DAT after two different regimens of METH and to determine whether METH affects the D2 autoreceptor-DAT interaction in the rat striatum. We found that, as compared to saline controls, administration of single high-dose METH decreased D2 autoreceptor immunoreactivity and increased DAT immunoreactivity in rat striatal synaptosomes whereas binge high-dose METH increased immunoreactivity of D2 autoreceptor and had no effect on DAT immunoreactivity. Single METH had no effect on D2 autoreceptor-DAT interaction whereas binge METH increased the interaction between the two proteins in the striatum. Our results suggest that METH can affect axonal transport of both the D2 autoreceptor and DAT in an interaction-dependent and -independent manner.

  18. High affinity dopamine D2 receptor radioligands. 1. Regional rat brain distribution of iodinated benzamides

    Energy Technology Data Exchange (ETDEWEB)

    Kessler, R.M.; Ansari, M.S.; de Paulis, T.; Schmidt, D.E.; Clanton, J.A.; Smith, H.E.; Manning, R.G.; Gillespie, D.; Ebert, M.H. (Vanderbilt University School of Medicine, Nashville, TN (USA))

    1991-08-01

    Five 125I-labeled substituted benzamides, which are close structural analogues of (S)-sulpiride, eticlopride, and isoremoxipride, were evaluated for their selective in vivo uptake into dopamine D2 receptor rich tissue of the rat brain. Iodopride (KD 0.88 nM), an iodine substituted benzamide structurally related to sulpiride, displayed a maximal striatum: cerebellar uptake ratio of 7.6. Demonstration of saturation of the receptor with (125I)iodopride in striatum required uptake in frontal cortex to be used, rather than cerebellar uptake, to define nonspecific binding. Two other ligands structurally related to eticlopride, iclopride (KD 0.23 nM) and itopride (KD 0.16 nM), displayed maximal striatal: cerebellar uptake ratios of 9.8 and 3.3, respectively. The most potent ligands, epidepride (KD 0.057 nM) and ioxipride (KD 0.070 nM) showed striatal:cerebellar uptake ratios of 234 and 65, respectively. The observed uptake ratios correlated poorly with the affinity constants for the dopamine D2 receptor alone, but were highly correlated (r = 0.92) with the product of the receptor dissociation constant (KD) and the apparent lipophilicity (kw), as determined by reverse-phase HPLC at pH 7.5. Total striatal uptake also appeared dependent on lipophilicity, with maximal uptake occurring for ligands having log kw 2.4-2.8.

  19. Tridimensional personalities and polymorphism of dopamine D2 receptor among heroin addicts.

    Science.gov (United States)

    Teh, Lay K; Izuddin, Abu F; M H, Fazleen H; Zakaria, Zainul A; Salleh, Mohd Zaki

    2012-04-01

    Drug addiction is a multifactorial disorder. Researchers have posited that an individual's inherited behavioral propensity or temperament contributes to the disorder by shaping a personality strongly linked with the risk of drug abuse. Further, they hypothesize that the polymorphism of dopamine D2 receptor increases the susceptibility to and severity of addiction. We, therefore, investigated possible associations between dopamine D2 receptor (DRD2) and personality traits among intravenous heroin addicts. We assessed 93 intravenous heroin addicts and controls using Diagnostic and Statistical Manual, Fourth Edition (DSM-IV) and the Tridimensional Personality Questionnaire (TPQ). We confirmed drug-dependence status using a questionnaire based on DSM-IV criteria. We extracted DNA from the subjects' whole blood and genotyped it for DRD2 allelic variants. Genotype analysis showed a significantly higher frequency for the TaqIA polymorphism among the addicts (69.9%) compared to control subjects (42.6%; Fisher's exact χ(2), p personality traits but lower scores for reward dependence (RD) when compared to control subjects. The environmental cues are different for the addicts, and the healthy university students we used as controls. We recommend that researchers employ a gene-environment interaction approach to study factors associated with addictive behaviors in future studies. Taq1A may be implicated for an increased vulnerability to addiction. Screening of this marker might be useful for identifying individuals at risk of addiction.

  20. Cabergoline, dopamine D2 receptor agonist, prevents neuronal cell death under oxidative stress via reducing excitotoxicity.

    Science.gov (United States)

    Odaka, Haruki; Numakawa, Tadahiro; Adachi, Naoki; Ooshima, Yoshiko; Nakajima, Shingo; Katanuma, Yusuke; Inoue, Takafumi; Kunugi, Hiroshi

    2014-01-01

    Several lines of evidence demonstrate that oxidative stress is involved in the pathogenesis of neurodegenerative diseases, including Parkinson's disease. Potent antioxidants may therefore be effective in the treatment of such diseases. Cabergoline, a dopamine D2 receptor agonist and antiparkinson drug, has been studied using several cell types including mesencephalic neurons, and is recognized as a potent radical scavenger. Here, we examined whether cabergoline exerts neuroprotective effects against oxidative stress through a receptor-mediated mechanism in cultured cortical neurons. We found that neuronal death induced by H₂O₂ exposure was inhibited by pretreatment with cabergoline, while this protective effect was eliminated in the presence of a dopamine D2 receptor inhibitor, spiperone. Activation of ERK1/2 by H₂O₂ was suppressed by cabergoline, and an ERK signaling pathway inhibitor, U0126, similarly protected cortical neurons from cell death. This suggested the ERK signaling pathway has a critical role in cabergoline-mediated neuroprotection. Furthermore, increased extracellular levels of glutamate induced by H₂O₂, which might contribute to ERK activation, were reduced by cabergoline, while inhibitors for NMDA receptor or L-type Ca²⁺ channel demonstrated a survival effect against H₂O₂. Interestingly, we found that cabergoline increased expression levels of glutamate transporters such as EAAC1. Taken together, these results suggest that cabergoline has a protective effect on cortical neurons via a receptor-mediated mechanism including repression of ERK1/2 activation and extracellular glutamate accumulation induced by H₂O₂.

  1. Interaction between LSD and dopamine D2/3 binding sites in pig brain.

    Science.gov (United States)

    Minuzzi, Luciano; Nomikos, George G; Wade, Mark R; Jensen, Svend B; Olsen, Aage K; Cumming, Paul

    2005-06-15

    The psychoactive properties of the hallucinogen LSD have frequently been attributed to high affinity interactions with serotonin 5HT2 receptors in brain. Possible effects of LSD on dopamine D2/3 receptor availability have not previously been investigated in living brain. Therefore, we used PET to map the binding potential (pB) of [11C]raclopride in brain of three pigs, first in a baseline condition, and again at 1 and 4 h after administration of LSD (2.5 microg/kg, i.v.). There was a progressive treatment effect in striatum, where the pB was significantly reduced by 19% at 4 h after LSD administration. Concomitant maps of cerebral blood flow did not reveal significant changes in perfusion during this interval. Subsequent in vitro studies showed that LSD displaced [3H]raclopride (2 nM) from pig brain cryostat sections with an IC50 of 275 nM according to a one-site model. Fitting of a two-site model to the data suggested the presence of a component of the displacement curves with a subnanomolar IC50, comprising 20% of the total [3H]raclopride binding. In microdialysis experiments, LSD at similar and higher doses did not evoke changes in the interstitial concentration of dopamine or its acidic metabolites in rat striatum. Together, these results are consistent with a direct interaction between LSD and a portion of dopamine D2/3 receptors in pig brain, possibly contributing to the psychopharmacology of LSD. (c) 2005 Wiley-Liss, Inc.

  2. EANM procedure guidelines for brain neurotransmission SPECT/PET using dopamine D2 receptor ligands, version 2

    DEFF Research Database (Denmark)

    Van Laere, Koen; Varrone, Andrea; Booij, Jan

    2010-01-01

    The guidelines summarize the current views of the European Association of Nuclear Medicine Neuroimaging Committee (ENC). The aims of the guidelines are to assist nuclear medicine practitioners in making recommendations, performing, interpreting and reporting the results of clinical dopamine D2...... receptor SPECT or PET studies, and to achieve a high quality standard of dopamine D2 receptor imaging, which will increase the impact of this technique in neurological practice.The present document is an update of the first guidelines for SPECT using D2 receptor ligands labelled with (123)I [1...

  3. Threshold of Dopamine D2/3 Receptor Occupancy for Hyperprolactinemia in Older Patients With Schizophrenia.

    Science.gov (United States)

    Iwata, Yusuke; Nakajima, Shinichiro; Caravaggio, Fernando; Suzuki, Takefumi; Uchida, Hiroyuki; Plitman, Eric; Chung, Jun Ku; Mar, Wanna; Gerretsen, Philip; Pollock, Bruce G; Mulsant, Benoit H; Rajji, Tarek K; Mamo, David C; Graff-Guerrero, Ariel

    2016-12-01

    Although hyperprolactinemia carries a long-term risk of morbidity, the threshold of dopamine D2/3 receptor (D2/3R) occupancy for hyperprolactinemia has not been investigated in older patients with schizophrenia. Data were taken from a positron emission tomography (PET) study conducted between August 2007 and August 2015. The present post hoc study included 42 clinically stable outpatients with schizophrenia (DSM-IV) (mean ± SD age = 60.2 ± 6.7 years) taking olanzapine or risperidone. Subjects underwent [¹¹C]-raclopride PET scans to measure D2/3R occupancy before and after reducing their dose of antipsychotic by up to 40%. Blood samples were collected before each PET scan to measure prolactin levels. The relationship between prolactin levels and D2/3R occupancy was examined using stepwise linear regression analyses. The D2/3R occupancy thresholds for hyperprolactinemia were explored using Fisher exact tests. Prolactin levels decreased following dose reduction (mean ± SD = 24.1 ± 30.2 ng/mL to 17.2 ± 15.1 ng/mL; P < .001). Prolactin levels were associated with female gender (β = .32, P = .006, vs male), antipsychotics (β = .23, P = .02, risperidone vs olanzapine), and D2/3R occupancy (β = .23, P = .04). Those with D2/3R occupancy of 66% or higher were more likely to have hyperprolactinemia than those with D2/3R occupancy lower than 66% (P = .03). Sensitivity, specificity, positive predictive value, and negative predictive value of this threshold were 0.44, 0.81, 0.78, and 0.48, respectively. We identified a D2/3R occupancy threshold for hyperprolactinemia of 66% in older patients with schizophrenia, which is lower than that reported in younger patients (73%) by other researchers. Our results suggest a higher sensitivity to antipsychotics in older patients. Prolactin levels could assist in the determination of appropriate antipsychotic dosing to minimize adverse effects. ClinicalTrials.gov identifier: NCT00716755.

  4. New Repeat Polymorphism in the AKT1 Gene Predicts Striatal Dopamine D2/D3 Receptor Availability and Stimulant-Induced Dopamine Release in the Healthy Human Brain.

    Science.gov (United States)

    Shumay, Elena; Wiers, Corinde E; Shokri-Kojori, Ehsan; Kim, Sung Won; Hodgkinson, Colin A; Sun, Hui; Tomasi, Dardo; Wong, Christopher T; Weinberger, Daniel R; Wang, Gene-Jack; Fowler, Joanna S; Volkow, Nora D

    2017-05-10

    The role of the protein kinase Akt1 in dopamine neurotransmission is well recognized and has been implicated in schizophrenia and psychosis. However, the extent to which variants in the AKT1 gene influence dopamine neurotransmission is not well understood. Here we investigated the effect of a newly characterized variant number tandem repeat (VNTR) polymorphism in AKT1 [major alleles: L- (eight repeats) and H- (nine repeats)] on striatal dopamine D2/D3 receptor (DRD2) availability and on dopamine release in healthy volunteers. We used PET and [11C]raclopride to assess baseline DRD2 availability in 91 participants. In 54 of these participants, we also measured intravenous methylphenidate-induced dopamine release to measure dopamine release. Dopamine release was quantified as the difference in specific binding of [11C]raclopride (nondisplaceable binding potential) between baseline values and values following methylphenidate injection. There was an effect of AKT1 genotype on DRD2 availability at baseline for the caudate (F(2,90) = 8.2, p = 0.001) and putamen (F(2,90) = 6.6, p = 0.002), but not the ventral striatum (p = 0.3). For the caudate and putamen, LL showed higher DRD2 availability than HH; HL were in between. There was also a significant effect of AKT1 genotype on dopamine increases in the ventral striatum (F(2,53) = 5.3, p = 0.009), with increases being stronger in HH > HL > LL. However, no dopamine increases were observed in the caudate (p = 0.1) or putamen (p = 0.8) following methylphenidate injection. Our results provide evidence that the AKT1 gene modulates both striatal DRD2 availability and dopamine release in the human brain, which could account for its association with schizophrenia and psychosis. The clinical relevance of the newly characterized AKT1 VNTR merits investigation.SIGNIFICANCE STATEMENT The AKT1 gene has been implicated in schizophrenia and psychosis. This association is likely to reflect modulation of dopamine signaling by Akt1 kinase

  5. A structure-activity analysis of biased agonism at the dopamine D2 receptor.

    Science.gov (United States)

    Shonberg, Jeremy; Herenbrink, Carmen Klein; López, Laura; Christopoulos, Arthur; Scammells, Peter J; Capuano, Ben; Lane, J Robert

    2013-11-27

    Biased agonism offers an opportunity for the medicinal chemist to discover pathway-selective ligands for GPCRs. A number of studies have suggested that biased agonism at the dopamine D2 receptor (D2R) may be advantageous for the treatment of neuropsychiatric disorders, including schizophrenia. As such, it is of great importance to gain insight into the SAR of biased agonism at this receptor. We have generated SAR based on a novel D2R partial agonist, tert-butyl (trans-4-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)carbamate (4). This ligand shares structural similarity to cariprazine (2), a drug awaiting FDA approval for the treatment of schizophrenia, yet displays a distinct bias toward two different signaling end points. We synthesized a number of derivatives of 4 with subtle structural modifications, including incorporation of cariprazine fragments. By combining pharmacological profiling with analytical methodology to identify and to quantify bias, we have demonstrated that efficacy and biased agonism can be finely tuned by minor structural modifications to the head group containing the tertiary amine, a tail group that extends away from this moiety, and the orientation and length of a spacer region between these two moieties.

  6. Gilles de la Tourette syndrome is associated with hypermethylation of the dopamine D2 receptor gene.

    Science.gov (United States)

    Müller-Vahl, Kirsten R; Loeber, Gesa; Kotsiari, Alexandra; Müller-Engling, Linda; Frieling, Helge

    2017-03-01

    Several lines of evidence support a "dopaminergic hypothesis" in the pathophysiology of Gilles de la Tourette syndrome (TS). The aim of this study was to investigate for the first time epigenetic changes in DNA methylation in different dopamine genes in adult patients with TS. We included 51 well characterized adult patients with TS (41 males, 10 females, mean age = 35 ± 12.6 years, range, 18-71 years) and compared results with data from a group of 51 sex- and age-matched healthy controls. Bisulfite sequencing was used to measure peripheral DNA methylation of the dopamine transporter (DAT), the dopamine D2 receptor (DRD2), and the catechol-O-methyltransferase (COMT) genes. Compared to healthy controls, patients with TS showed significantly elevated methylation level of the DRD2 gene that positively correlated with tic severity. In contrast, DAT methylation was lower in more severely affected patients. Our results provide evidence for a role of altered epigenetic regulation of dopaminergic genes in the pathophysiology of TS. While DRD2 hypermethylation seems to be directly related to the neurobiology of TS that may lead to dopaminergic dysfunction resulting in enhanced thalamo-cortical movement-stimulating activity, DAT hypomethylation might reflect a secondary mechanism in order to compensate for increased dopaminergic signal transduction due to DRD2 hypermethylation. In addition, it can be speculated that spontaneous fluctuations of tics may be caused by short-term alterations of methylation levels of dopaminergic genes resulting in dynamic changes of tonic/phasic dopaminergic signaling in the striatum and thalamo-cortical output pathways. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  7. Challenges in the development of dopamine D2- and D3-selective radiotracers for PET imaging studies.

    Science.gov (United States)

    Mach, Robert H; Luedtke, Robert R

    2017-08-31

    The dopamine D2-like receptors (ie, D2/3 receptors) have been the most extensively studied CNS receptor with Positron Emission Tomography (PET). The 3 different radiotracers that have been used in these studies are [ 11 C]raclopride, [ 18 F]fallypride, and [ 11 C]PHNO. Because these radiotracers have a high affinity for both dopamine D2 and D3 receptors, the density of dopamine receptors in the CNS is reported as the D2/3 binding potential, which reflects a measure of the density of both receptor subtypes. Although the development of D2- and D3-selective PET radiotracers has been an active area of research for many years, this by and large presents an unmet need in the area of translational PET imaging studies. This article discusses some of the challenges that have inhibited progress in this area of research and the current status of the development of subtype selective radiotracers for imaging D3 and D2 dopamine receptors with PET. Copyright © 2017 John Wiley & Sons, Ltd.

  8. Imaging of dopamine transporters and D2 receptors in patients with Parkinson's disease and multiple system atrophy

    DEFF Research Database (Denmark)

    Knudsen, G M; Karlsborg, M; Thomsen, G

    2004-01-01

    of the striatonigral type (MSA) and healthy subjects. METHODS: SPECT measurements of the dopamine transporter (DAT) were done with 123I-beta-CIT, while for determination of the dopamine D2-like receptors (D2), 123I-epidepride was used. Clinical evaluation and SPECT scans were carried out in 14 patients with IPD, eight...... asymmetry than MSA patients. Striatal D2 binding did not differ significantly between patients and healthy controls but the ratio between caudate DAT and D2 binding was significantly higher in patients with IPD than in those with MSA, even when disease severity was taken into account. CONCLUSION: Patients...... diagnostic information, since the ratio between DAT and D2 receptor binding is significantly higher in IPD than in MSA...

  9. Cabergoline, dopamine D2 receptor agonist, prevents neuronal cell death under oxidative stress via reducing excitotoxicity.

    Directory of Open Access Journals (Sweden)

    Haruki Odaka

    Full Text Available Several lines of evidence demonstrate that oxidative stress is involved in the pathogenesis of neurodegenerative diseases, including Parkinson's disease. Potent antioxidants may therefore be effective in the treatment of such diseases. Cabergoline, a dopamine D2 receptor agonist and antiparkinson drug, has been studied using several cell types including mesencephalic neurons, and is recognized as a potent radical scavenger. Here, we examined whether cabergoline exerts neuroprotective effects against oxidative stress through a receptor-mediated mechanism in cultured cortical neurons. We found that neuronal death induced by H₂O₂ exposure was inhibited by pretreatment with cabergoline, while this protective effect was eliminated in the presence of a dopamine D2 receptor inhibitor, spiperone. Activation of ERK1/2 by H₂O₂ was suppressed by cabergoline, and an ERK signaling pathway inhibitor, U0126, similarly protected cortical neurons from cell death. This suggested the ERK signaling pathway has a critical role in cabergoline-mediated neuroprotection. Furthermore, increased extracellular levels of glutamate induced by H₂O₂, which might contribute to ERK activation, were reduced by cabergoline, while inhibitors for NMDA receptor or L-type Ca²⁺ channel demonstrated a survival effect against H₂O₂. Interestingly, we found that cabergoline increased expression levels of glutamate transporters such as EAAC1. Taken together, these results suggest that cabergoline has a protective effect on cortical neurons via a receptor-mediated mechanism including repression of ERK1/2 activation and extracellular glutamate accumulation induced by H₂O₂.

  10. Love to win or hate to lose? Asymmetry of dopamine D2 receptor binding predicts sensitivity to reward vs. punishment

    Science.gov (United States)

    Tomer, Rachel; Slagter, Heleen A; Christian, Bradley T; Fox, Andrew S; King, Carlye R; Murali, Dhanabalan; Gluck, Mark A; Davidson, Richard J

    2014-01-01

    Humans show consistent differences in the extent to which their behavior reflects a bias towards appetitive approach-related behavior or avoidance of aversive stimuli (Elliot, 2008). We examined the hypothesis that in healthy subjects this motivational bias (assessed by self-report and by a probabilistic learning task that allows direct comparison of the relative sensitivity to reward and punishment) reflects lateralization of dopamine signaling. Using [F-18]fallypride to measure D2/D3 binding , we found that self-reported motivational bias was predicted by the asymmetry of frontal D2 binding. Similarly, striatal and frontal asymmetries in D2 dopamine receptor binding, rather than absolute binding levels, predicted individual differences in learning from reward vs. punishment. These results suggest that normal variation in asymmetry of dopamine signaling may, in part, underlie human personality and cognition. PMID:24345165

  11. The dopamine D2 receptor gene in lamprey, its expression in the striatum and cellular effects of D2 receptor activation.

    Directory of Open Access Journals (Sweden)

    Brita Robertson

    Full Text Available All basal ganglia subnuclei have recently been identified in lampreys, the phylogenetically oldest group of vertebrates. Furthermore, the interconnectivity of these nuclei is similar to mammals and tyrosine hydroxylase-positive (dopaminergic fibers have been detected within the input layer, the striatum. Striatal processing is critically dependent on the interplay with the dopamine system, and we explore here whether D2 receptors are expressed in the lamprey striatum and their potential role. We have identified a cDNA encoding the dopamine D2 receptor from the lamprey brain and the deduced protein sequence showed close phylogenetic relationship with other vertebrate D2 receptors, and an almost 100% identity within the transmembrane domains containing the amino acids essential for dopamine binding. There was a strong and distinct expression of D2 receptor mRNA in a subpopulation of striatal neurons, and in the same region tyrosine hydroxylase-immunoreactive synaptic terminals were identified at the ultrastructural level. The synaptic incidence of tyrosine hydroxylase-immunoreactive boutons was highest in a region ventrolateral to the compact layer of striatal neurons, a region where most striatal dendrites arborise. Application of a D2 receptor agonist modulates striatal neurons by causing a reduced spike discharge and a diminished post-inhibitory rebound. We conclude that the D2 receptor gene had already evolved in the earliest group of vertebrates, cyclostomes, when they diverged from the main vertebrate line of evolution (560 mya, and that it is expressed in striatum where it exerts similar cellular effects to that in other vertebrates. These results together with our previous published data (Stephenson-Jones et al. 2011, 2012 further emphasize the high degree of conservation of the basal ganglia, also with regard to the indirect loop, and its role as a basic mechanism for action selection in all vertebrates.

  12. The Dopamine D2 Receptor Gene in Lamprey, Its Expression in the Striatum and Cellular Effects of D2 Receptor Activation

    Science.gov (United States)

    Robertson, Brita; Huerta-Ocampo, Icnelia; Ericsson, Jesper; Stephenson-Jones, Marcus; Pérez-Fernández, Juan; Bolam, J. Paul; Diaz-Heijtz, Rochellys; Grillner, Sten

    2012-01-01

    All basal ganglia subnuclei have recently been identified in lampreys, the phylogenetically oldest group of vertebrates. Furthermore, the interconnectivity of these nuclei is similar to mammals and tyrosine hydroxylase-positive (dopaminergic) fibers have been detected within the input layer, the striatum. Striatal processing is critically dependent on the interplay with the dopamine system, and we explore here whether D2 receptors are expressed in the lamprey striatum and their potential role. We have identified a cDNA encoding the dopamine D2 receptor from the lamprey brain and the deduced protein sequence showed close phylogenetic relationship with other vertebrate D2 receptors, and an almost 100% identity within the transmembrane domains containing the amino acids essential for dopamine binding. There was a strong and distinct expression of D2 receptor mRNA in a subpopulation of striatal neurons, and in the same region tyrosine hydroxylase-immunoreactive synaptic terminals were identified at the ultrastructural level. The synaptic incidence of tyrosine hydroxylase-immunoreactive boutons was highest in a region ventrolateral to the compact layer of striatal neurons, a region where most striatal dendrites arborise. Application of a D2 receptor agonist modulates striatal neurons by causing a reduced spike discharge and a diminished post-inhibitory rebound. We conclude that the D2 receptor gene had already evolved in the earliest group of vertebrates, cyclostomes, when they diverged from the main vertebrate line of evolution (560 mya), and that it is expressed in striatum where it exerts similar cellular effects to that in other vertebrates. These results together with our previous published data (Stephenson-Jones et al. 2011, 2012) further emphasize the high degree of conservation of the basal ganglia, also with regard to the indirect loop, and its role as a basic mechanism for action selection in all vertebrates. PMID:22563388

  13. Role of Kv1 potassium channels in regulating dopamine release and presynaptic D2 receptor function.

    Directory of Open Access Journals (Sweden)

    Philippe Martel

    Full Text Available Dopamine (DA release in the CNS is critical for motor control and motivated behaviors. Dysfunction of its regulation is thought to be implicated in drug abuse and in diseases such as schizophrenia and Parkinson's. Although various potassium channels located in the somatodendritic compartment of DA neurons such as G-protein-gated inward rectifying potassium channels (GIRK have been shown to regulate cell firing and DA release, little is presently known about the role of potassium channels localized in the axon terminals of these neurons. Here we used fast-scan cyclic voltammetry to study electrically-evoked DA release in rat dorsal striatal brain slices. We find that although G-protein-gated inward rectifying (GIRK and ATP-gated (K(ATP potassium channels play only a minor role, voltage-gated potassium channels of the Kv1 family play a major role in regulating DA release. The use of Kv subtype-selective blockers confirmed a role for Kv1.2, 1.3 and 1.6, but not Kv1.1, 3.1, 3.2, 3.4 and 4.2. Interestingly, Kv1 blockers also reduced the ability of quinpirole, a D2 receptor agonist, to inhibit evoked DA overflow, thus suggesting that Kv1 channels also regulate presynaptic D2 receptor function. Our work identifies Kv1 potassium channels as key regulators of DA release in the striatum.

  14. Reduced insulin sensitivity is related to less endogenous dopamine at D2/3 receptors in the ventral striatum of healthy nonobese humans.

    Science.gov (United States)

    Caravaggio, Fernando; Borlido, Carol; Hahn, Margaret; Feng, Zhe; Fervaha, Gagan; Gerretsen, Philip; Nakajima, Shinichiro; Plitman, Eric; Chung, Jun Ku; Iwata, Yusuke; Wilson, Alan; Remington, Gary; Graff-Guerrero, Ariel

    2015-02-25

    Food addiction is a debated topic in neuroscience. Evidence suggests diabetes is related to reduced basal dopamine levels in the nucleus accumbens, similar to persons with drug addiction. It is unknown whether insulin sensitivity is related to endogenous dopamine levels in the ventral striatum of humans. We examined this using the agonist dopamine D2/3 receptor radiotracer [(11)C]-(+)-PHNO and an acute dopamine depletion challenge. In a separate sample of healthy persons, we examined whether dopamine depletion could alter insulin sensitivity. Insulin sensitivity was estimated for each subject from fasting plasma glucose and insulin using the Homeostasis Model Assessment II. Eleven healthy nonobese and nondiabetic persons (3 female) provided a baseline [(11)C]-(+)-PHNO scan, 9 of which provided a scan under dopamine depletion, allowing estimates of endogenous dopamine at dopamine D2/3 receptor. Dopamine depletion was achieved via alpha-methyl-para-tyrosine (64mg/kg, P.O.). In 25 healthy persons (9 female), fasting plasma and glucose was acquired before and after dopamine depletion. Endogenous dopamine at ventral striatum dopamine D2/3 receptor was positively correlated with insulin sensitivity (r(7)=.84, P=.005) and negatively correlated with insulin levels (r(7)=-.85, P=.004). Glucose levels were not correlated with endogenous dopamine at ventral striatum dopamine D2/3 receptor (r(7)=-.49, P=.18). Consistently, acute dopamine depletion in healthy persons significantly decreased insulin sensitivity (t(24)=2.82, P=.01), increased insulin levels (t(24)=-2.62, P=.01), and did not change glucose levels (t(24)=-0.93, P=.36). In healthy individuals, diminished insulin sensitivity is related to less endogenous dopamine at dopamine D2/3 receptor in the ventral striatum. Moreover, acute dopamine depletion reduces insulin sensitivity. These findings may have important implications for neuropsychiatric populations with metabolic abnormalities. © The Author 2015. Published by

  15. Novel aza-analogous ergoline derived scaffolds as potent serotonin 5-HT6 and dopamine D2 receptor ligands

    DEFF Research Database (Denmark)

    Krogsgaard-Larsen, Niels; Jensen, Anders A.; Schrøder, T.J.

    2014-01-01

    By introducing distal substituents on a tetracyclic scaffold resembling the ergoline structure, two series of analogues were achieved exhibiting subnanomolar receptor binding affinities for the dopamine D2 and serotonin 5-HT6 receptor subtype, respectively. While the 5-HT6 ligands were antagonists......, the D2 ligands displayed intrinsic activities ranging from full agonism to partial agonism with low intrinsic activity. These structures could potentially be interesting for treatment of neurological diseases such as schizophrenia, Parkinson’s disease, and cognitive deficits....

  16. Estimating endogenous dopamine levels at D2 and D3 receptors in humans using the agonist radiotracer [(11)C]-(+)-PHNO.

    Science.gov (United States)

    Caravaggio, Fernando; Nakajima, Shinichiro; Borlido, Carol; Remington, Gary; Gerretsen, Philip; Wilson, Alan; Houle, Sylvain; Menon, Mahesh; Mamo, David; Graff-Guerrero, Ariel

    2014-11-01

    Using positron emission tomography (PET) and an acute dopamine depletion challenge it is possible to estimate endogenous dopamine levels occupying dopamine D2/3 receptors (D2/3R) in humans in vivo. Our group has developed [(11)C]-(+)-PHNO, the first agonist radiotracer with preferential in vivo affinity for D3R. Thus, the use of [(11)C]-(+)-PHNO offers the novel possibility of (i) estimating in vivo endogenous dopamine levels at D2/3R using an agonist radiotracer, and (ii) estimating endogenous dopamine levels at D3R in extrastriatal regions such as the substantia nigra, hypothalamus, and ventral pallidum. Ten healthy participants underwent a [(11)C]-(+)-PHNO PET scan under baseline conditions and another under acute endogenous dopamine depletion achieved via oral administration of alpha-methyl-para-tyrosine (64 mg/kg). [(11)C]-(+)-PHNO binding was sensitive to acute dopamine depletion, allowing in vivo estimates of endogenous dopamine in D2R-rich regions (caudate and putamen), mixed D2/3R-rich regions (ventral striatum and globus pallidus), and extrastriatal D3R-rich regions (hypothalamus and ventral pallidum). Dopamine depletion decreased self-reported vigor, which was correlated with the reduction in dopamine levels in the globus pallidus. [(11)C]-(+)-PHNO is a suitable radiotracer for use in estimating endogenous dopamine levels at D2R and D3R in neuropsychiatric populations.

  17. Estimating Endogenous Dopamine Levels at D2 and D3 Receptors in Humans using the Agonist Radiotracer [11C]-(+)-PHNO

    Science.gov (United States)

    Caravaggio, Fernando; Nakajima, Shinichiro; Borlido, Carol; Remington, Gary; Gerretsen, Philip; Wilson, Alan; Houle, Sylvain; Menon, Mahesh; Mamo, David; Graff-Guerrero, Ariel

    2014-01-01

    Using positron emission tomography (PET) and an acute dopamine depletion challenge it is possible to estimate endogenous dopamine levels occupying dopamine D2/3 receptors (D2/3R) in humans in vivo. Our group has developed [11C]-(+)-PHNO, the first agonist radiotracer with preferential in vivo affinity for D3R. Thus, the use of [11C]-(+)-PHNO offers the novel possibility of (i) estimating in vivo endogenous dopamine levels at D2/3R using an agonist radiotracer, and (ii) estimating endogenous dopamine levels at D3R in extrastriatal regions such as the substantia nigra, hypothalamus, and ventral pallidum. Ten healthy participants underwent a [11C]-(+)-PHNO PET scan under baseline conditions and another under acute endogenous dopamine depletion achieved via oral administration of alpha-methyl-para-tyrosine (64 mg/kg). [11C]-(+)-PHNO binding was sensitive to acute dopamine depletion, allowing in vivo estimates of endogenous dopamine in D2R-rich regions (caudate and putamen), mixed D2/3R-rich regions (ventral striatum and globus pallidus), and extrastriatal D3R-rich regions (hypothalamus and ventral pallidum). Dopamine depletion decreased self-reported vigor, which was correlated with the reduction in dopamine levels in the globus pallidus. [11C]-(+)-PHNO is a suitable radiotracer for use in estimating endogenous dopamine levels at D2R and D3R in neuropsychiatric populations. PMID:24874713

  18. Lisuride, a dopamine D2 receptor agonist, and anticraving drug expectancy as modifiers of relapse in alcohol dependence.

    Science.gov (United States)

    Schmidt, Lutz G; Kuhn, Silke; Smolka, Michael; Schmidt, Kai; Rommelspacher, Hans

    2002-02-01

    Due to a central role of dopamine in mediating ethanol intake and dependence, the authors tested lisuride, a dopamine D2 receptor agonist, for relapse prevention in alcoholics. Psychological and neuroendocrine determinants of outcome were also assessed within the study. This double-blind, placebo-controlled randomized study comprised 120 alcoholics who were subjected to an intend-to-treat analysis (ITT). After hospital detoxification, patients received an outpatient rehabilitation program and either the study medication or placebo for 6 months and follow-up for another 6 months without medication. Pharmacological and psychological effects on relapse and times to first drink were assessed using survival analysis and multivariate analysis of variance (ANOVA). Neuroendocrine assessments were made using growth hormone (GH) response to stimulation with dopamine D2 receptor agonist apomorphine. In contrast to our hypothesis, the pharmacological effects of lisuride shortened (effect size: 0.51) and the expectation of receiving the drug (while being on medication) prolonged the latency of relapse (effect size: 0.47) in weaned alcoholics. Lisuride was associated with side effects like dizziness and hypotension. Dopaminergic responsivity to apomorphine stimulation was reduced under lisuride. This study supports the view that alcoholics may relapse due to decreased dopamine function, resulting from intake of dopamine D2 receptor agonists. In particular, our data do not support the use of lisuride for relapse prevention in alcoholics. The favorable impact of anticraving drug expectancy on outcome was unrelated to this effect.

  19. A dopamine D2 receptor gene polymorphism and physical activity in two family studies.

    Science.gov (United States)

    Simonen, Riitta L; Rankinen, Tuomo; Pérusse, Louis; Leon, Arthur S; Skinner, James S; Wilmore, Jack H; Rao, D C; Bouchard, Claude

    2003-04-01

    A role for dopamine neurotransmission in the regulation of motor activity and reinforcement of behavior is supported by considerable evidence. We studied the association between a marker in the dopamine D2 receptor gene (DRD2) and physical activity level in two cohorts. A first cohort consisted of 721 participants from 161 families of the Quebec Family Study (QFS). Physical activity phenotypes were obtained from a three-day diary and a questionnaire probing physical activity during the past year. The second cohort was the HERITAGE Family Study (HERITAGE), which included 275 Black and 497 White participants from 228 families, among whom past year leisure time and occupational physical activity were probed. A fragment length polymorphism in exon 6 of the DRD2 gene was detected by the polymerase chain reaction (PCR) and NcoI digestion. Frequencies for the T and C alleles were 28% and 72% in the QFS. In the QFS, TT homozygote women had 25% and 34% lower age and BMI-adjusted physical activity level during the past year, compared to CC homozygotes and CT heterozygotes (F=4.42, P=.016). The DRD2 genotype was not associated with the QFS phenotypes obtained from the three-day diary. In the HERITAGE, the frequency of the T allele was 30% among Whites and 63% among Blacks. Similarly, the TT homozygote White women had 29-38% lower sports index (F=4.09, P=.023) and 27-33% lower work index (F=6.23, P=.004) than the CC homozygotes and CT heterozygotes. The results suggest that DNA sequence variation in the DRD2 gene is associated with physical activity levels among White women.

  20. Therapeutic window of dopamine D2/3 receptor occupancy to treat psychosis in Alzheimer's disease.

    Science.gov (United States)

    Reeves, Suzanne; McLachlan, Emma; Bertrand, Julie; Antonio, Fabrizia D; Brownings, Stuart; Nair, Akshay; Greaves, Suki; Smith, Alan; Taylor, David; Dunn, Joel; Marsden, Paul; Kessler, Robert; Howard, Robert

    2017-04-01

    See Caravaggio and Graff-Guerrero (doi:10.1093/awx023) for a scientific commentary on this article.Antipsychotic drugs, originally developed to treat schizophrenia, are used to treat psychosis, agitation and aggression in Alzheimer's disease. In the absence of dopamine D2/3 receptor occupancy data to inform antipsychotic prescribing for psychosis in Alzheimer's disease, the mechanisms underpinning antipsychotic efficacy and side effects are poorly understood. This study used a population approach to investigate the relationship between amisulpride blood concentration and central D2/3 occupancy in older people with Alzheimer's disease by combining: (i) pharmacokinetic data (280 venous samples) from a phase I single (50 mg) dose study in healthy older people (n = 20, 65-79 years); (ii) pharmacokinetic, 18F-fallypride D2/3 receptor imaging and clinical outcome data on patients with Alzheimer's disease who were prescribed amisulpride (25-75 mg daily) to treat psychosis as part of an open study (n = 28; 69-92 years; 41 blood samples, five pretreatment scans, 19 post-treatment scans); and (iii) 18F-fallypride imaging of an antipsychotic free Alzheimer's disease control group (n = 10, 78-92 years), to provide additional pretreatment data. Non-linear mixed effects modelling was used to describe pharmacokinetic-occupancy curves in caudate, putamen and thalamus. Model outputs were used to estimate threshold steady state blood concentration and occupancy required to elicit a clinically relevant response (>25% reduction in scores on delusions, hallucinations and agitation domains of the Neuropsychiatric Inventory) and extrapyramidal side effects (Simpson Angus Scale scores > 3). Average steady state blood levels were low (71 ± 30 ng/ml), and associated with high D2/3 occupancies (65 ± 8%, caudate; 67 ± 11%, thalamus; 52 ± 11%, putamen). Antipsychotic clinical response occurred at a threshold concentration of 20 ng/ml and D2/3 occupancies of 43% (caudate), 25% (putamen), 43

  1. Structure of the Human Dopamine D3 Receptor in Complex with a D2/D3 Selective Antagonist

    Energy Technology Data Exchange (ETDEWEB)

    Chien, Ellen Y.T.; Liu, Wei; Zhao, Qiang; Katritch, Vsevolod; Han, Gye Won; Hanson, Michael A.; Shi, Lei; Newman, Amy Hauck; Javitch, Jonathan A.; Cherezov, Vadim; Stevens, Raymond C. (Cornell); (Scripps); (NIDA); (Columbia); (UCSD); (Receptos)

    2010-11-30

    Dopamine modulates movement, cognition, and emotion through activation of dopamine G protein-coupled receptors in the brain. The crystal structure of the human dopamine D3 receptor (D3R) in complex with the small molecule D2R/D3R-specific antagonist eticlopride reveals important features of the ligand binding pocket and extracellular loops. On the intracellular side of the receptor, a locked conformation of the ionic lock and two distinctly different conformations of intracellular loop 2 are observed. Docking of R-22, a D3R-selective antagonist, reveals an extracellular extension of the eticlopride binding site that comprises a second binding pocket for the aryl amide of R-22, which differs between the highly homologous D2R and D3R. This difference provides direction to the design of D3R-selective agents for treating drug abuse and other neuropsychiatric indications.

  2. Dopamine D(2) receptor quantification in extrastriatal brain regions using [(123)I]epidepride with bolus/infusion

    DEFF Research Database (Denmark)

    Pinborg, L H; Videbaek, C; Knudsen, G M

    2000-01-01

    The iodinated benzamide epidepride, which shows a picomolar affinity binding to dopamine D(2) receptors, has been designed for in vivo studies using SPECT. The aim of the present study was to apply a steady-state condition by the bolus/infusion approach with [(123)I]epidepride for the quantificat...

  3. Dazzled by the dominions of dopamine: clinical roles of D3, D2, and D1 receptors.

    Science.gov (United States)

    Stahl, Stephen M

    2017-08-01

    Unravelling the mystery of dopamine neurotransmission, especially at its 3 most clinically relevant receptors, D3, D2, and D1, helps explain the pathophysiology of numerous psychiatric and neurologic symptoms in various CNS disorders that are theoretically caused by dysregulation of this neurotransmitter.

  4. Cav1.3 channels control D2-autoreceptor responses via NCS-1 in substantia nigra dopamine neurons

    Science.gov (United States)

    Dragicevic, Elena; Poetschke, Christina; Duda, Johanna; Schlaudraff, Falk; Lammel, Stephan; Schiemann, Julia; Fauler, Michael; Hetzel, Andrea; Watanabe, Masahiko; Lujan, Rafael; Malenka, Robert C.; Striessnig, Joerg

    2014-01-01

    Dopamine midbrain neurons within the substantia nigra are particularly prone to degeneration in Parkinson’s disease. Their selective loss causes the major motor symptoms of Parkinson’s disease, but the causes for the high vulnerability of SN DA neurons, compared to neighbouring, more resistant ventral tegmental area dopamine neurons, are still unclear. Consequently, there is still no cure available for Parkinson’s disease. Current therapies compensate the progressive loss of dopamine by administering its precursor l-DOPA and/or dopamine D2-receptor agonists. D2-autoreceptors and Cav1.3-containing L-type Ca2+ channels both contribute to Parkinson’s disease pathology. L-type Ca2+ channel blockers protect SN DA neurons from degeneration in Parkinson’s disease and its mouse models, and they are in clinical trials for neuroprotective Parkinson’s disease therapy. However, their physiological functions in SN DA neurons remain unclear. D2-autoreceptors tune firing rates and dopamine release of SN DA neurons in a negative feedback loop through activation of G-protein coupled potassium channels (GIRK2, or KCNJ6). Mature SN DA neurons display prominent, non-desensitizing somatodendritic D2-autoreceptor responses that show pronounced desensitization in PARK-gene Parkinson’s disease mouse models. We analysed surviving human SN DA neurons from patients with Parkinson’s disease and from controls, and detected elevated messenger RNA levels of D2-autoreceptors and GIRK2 in Parkinson’s disease. By electrophysiological analysis of postnatal juvenile and adult mouse SN DA neurons in in vitro brain-slices, we observed that D2-autoreceptor desensitization is reduced with postnatal maturation. Furthermore, a transient high-dopamine state in vivo, caused by one injection of either l-DOPA or cocaine, induced adult-like, non-desensitizing D2-autoreceptor responses, selectively in juvenile SN DA neurons, but not ventral tegmental area dopamine neurons. With pharmacological

  5. Low Dopamine D2 Receptor Increases Vulnerability to Obesity Via Reduced Physical Activity, Not Increased Appetitive Motivation.

    Science.gov (United States)

    Beeler, Jeff A; Faust, Rudolf P; Turkson, Susie; Ye, Honggang; Zhuang, Xiaoxi

    2016-06-01

    The dopamine D2 receptor (D2R) has received much attention in obesity studies. Data indicate that D2R is reduced in obesity and that the TaqA1 D2R variant may be more prevalent among obese persons. It is often suggested that reduced D2R generates a reward deficiency and altered appetitive motivation that induces compulsive eating and contributes to obesity. Although dopamine is known to regulate physical activity, it is often neglected in these studies, leaving open the question of whether reduced D2R contributes to obesity through alterations in energy expenditure and activity. We generated a D2R knockdown (KD) mouse line and assessed both energy expenditure and appetitive motivation under conditions of diet-induced obesity. The KD mice did not gain more weight or show increased appetitive motivation compared with wild-type mice in a standard environment; however, in an enriched environment with voluntary exercise opportunities, KD mice exhibited dramatically lower activity and became more obese than wild-type mice, obtaining no protective benefit from exercise opportunities. These data suggest the primary contribution of altered D2R signaling to obesity lies in altered energy expenditure rather than the induction of compulsive overeating. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  6. Hallucinogenic 5-HT2AR agonists LSD and DOI enhance dopamine D2R protomer recognition and signaling of D2-5-HT2A heteroreceptor complexes.

    Science.gov (United States)

    Borroto-Escuela, Dasiel O; Romero-Fernandez, Wilber; Narvaez, Manuel; Oflijan, Julia; Agnati, Luigi F; Fuxe, Kjell

    2014-01-03

    Dopamine D2LR-serotonin 5-HT2AR heteromers were demonstrated in HEK293 cells after cotransfection of the two receptors and shown to have bidirectional receptor-receptor interactions. In the current study the existence of D2L-5-HT2A heteroreceptor complexes was demonstrated also in discrete regions of the ventral and dorsal striatum with in situ proximity ligation assays (PLA). The hallucinogenic 5-HT2AR agonists LSD and DOI but not the standard 5-HT2AR agonist TCB2 and 5-HT significantly increased the density of D2like antagonist (3)H-raclopride binding sites and significantly reduced the pKiH values of the high affinity D2R agonist binding sites in (3)H-raclopride/DA competition experiments. Similar results were obtained in HEK293 cells and in ventral striatum. The effects of the hallucinogenic 5-HT2AR agonists on D2R density and affinity were blocked by the 5-HT2A antagonist ketanserin. In a forskolin-induced CRE-luciferase reporter gene assay using cotransfected but not D2R singly transfected HEK293 cells DOI and LSD but not TCB2 significantly enhanced the D2LR agonist quinpirole induced inhibition of CRE-luciferase activity. Haloperidol blocked the effects of both quinpirole alone and the enhancing actions of DOI and LSD while ketanserin only blocked the enhancing actions of DOI and LSD. The mechanism for the allosteric enhancement of the D2R protomer recognition and signalling observed is likely mediated by a biased agonist action of the hallucinogenic 5-HT2AR agonists at the orthosteric site of the 5-HT2AR protomer. This mechanism may contribute to the psychotic actions of LSD and DOI and the D2-5-HT2A heteroreceptor complex may thus be a target for the psychotic actions of hallunicogenic 5-HT2A agonists. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. Altered ratio of D1 and D2 dopamine receptors in mouse striatum is associated with behavioral sensitization to cocaine.

    Directory of Open Access Journals (Sweden)

    Dawn Thompson

    Full Text Available BACKGROUND: Drugs of abuse elevate brain dopamine levels, and, in vivo, chronic drug use is accompanied by a selective decrease in dopamine D2 receptor (D2R availability in the brain. Such a decrease consequently alters the ratio of D1R:D2R signaling towards the D1R. Despite a plethora of behavioral studies dedicated to the understanding of the role of dopamine in addiction, a molecular mechanism responsible for the downregulation of the D2R, in vivo, in response to chronic drug use has yet to be identified. METHODS AND FINDINGS: ETHICS STATEMENT: All animal work was approved by the Gallo Center IACUC committee and was performed in our AAALAC approved facility. In this study, we used wild type (WT and G protein coupled receptor associated sorting protein-1 (GASP-1 knock out (KO mice to assess molecular changes that accompany cocaine sensitization. Here, we show that downregulation of D2Rs or upregulation of D1Rs is associated with a sensitized locomotor response to an acute injection of cocaine. Furthermore, we demonstrate that disruption of GASP-1, that targets D2Rs for degradation after endocytosis, prevents cocaine-induced downregulation of D2Rs. As a consequence, mice with a GASP-1 disruption show a reduction in the sensitized locomotor response to cocaine. CONCLUSIONS: Together, our data suggests that changes in the ratio of the D1:D2R could contribute to cocaine-induced behavioral plasticity and demonstrates a role of GASP-1 in regulating both the levels of the D2R and cocaine sensitization.

  8. [Anti-cholinesterase activity of dopamine D2 receptor antagonist: its clinical significance].

    Science.gov (United States)

    Mizumoto, A; Itoh, Z

    1989-08-01

    Anti-cholinesterase activity of dopamine D2 receptor antagonist, domperidone was studied by means of chronically implanted force transducers in the gastrointestinal (GI) tract in five conscious dogs. Cisapride was used as a drug to stimulate endogenous release of acetylcholine. In the digestive state, cisapride (0.25 mg/kg) stimulated 18.6 +/- 5.6% increase in the motor index of the gastric antrum alone, however, combined administration with domperidone (1.0 mg/kg-hr) significantly enhanced the motor index in the gastric antrum and duodenum. In the gastric antrum, the increase was 68.1 +/- 7.2%. During the interdigestive state, cisapride did not always induce the interdigestive migrating contractions (IMC)-like contractions in the GI tract, but the background infusion of domperidone significantly increased the incidence of the occurrence of IMC-like contractions by cisapride. In in vitro study, weak but significant anti-cholinesterase activity was found in domperidone, the activity being about 1/1,000 of that of neostigmine. In dog experiment, similar enhancement of motor stimulating activity of cisapride was observed when neostigmine was given at 1.0 micrograms/kg-hr. In conclusion, domperidone has anti-cholinesterase activity and acts to enhance motor stimulating activity of cisapride through inhibition of cholinesterase activity in the upper digestive tract.

  9. Dissecting the functions of conserved prolines within transmembrane helices of the D2 dopamine receptor.

    Science.gov (United States)

    Van Arnam, Ethan B; Lester, Henry A; Dougherty, Dennis A

    2011-10-21

    G protein-coupled receptors (GPCRs) contain a number of conserved proline residues in their transmembrane helices, and it is generally assumed these play important functional and/or structural roles. Here we use unnatural amino acid mutagenesis, employing α-hydroxy acids and proline analogues, to examine the functional roles of five proline residues in the transmembrane helices of the D2 dopamine receptor. The well-known tendency of proline to disrupt helical structure is important at all sites, while we find no evidence for a functional role for backbone amide cis-trans isomerization, another feature associated with proline. At most proline sites, the loss of the backbone NH is sufficient to explain the role of the proline. However, at one site, P210(5.50), a substituent on the backbone N appears to be essential for proper function. Interestingly, the pattern in functional consequences that we see is mirrored in the pattern of structural distortions seen in recent GPCR crystal structures.

  10. Atypical antipsychotic properties of blonanserin, a novel dopamine D2 and 5-HT2A antagonist.

    Science.gov (United States)

    Ohno, Yukihiro; Okano, Motoki; Imaki, Junta; Tatara, Ayaka; Okumura, Takahiro; Shimizu, Saki

    2010-08-01

    Blonanserin is a novel antipsychotic agent that preferentially interacts with dopamine D(2) and 5-HT(2A) receptors. To assess the atypical properties of blonanserin, we evaluated its propensity to induce extrapyramidal side effects (EPS) and to enhance forebrain Fos expression in mice. The actions of AD-6048, a primary metabolite of blonanserin, in modulating haloperidol-induced EPS were also examined. Blonanserin (0.3-10mg/kg, p.o.) did not significantly alter the pole-descending behavior of mice in the pole test or increase the catalepsy time, while haloperidol (0.3-3mg/kg, p.o.) caused pronounced bradykinesia and catalepsy. Blonanserin and haloperidol at the above doses significantly enhanced Fos expression in the shell (AcS) region of the nucleus accumbens and dorsolateral striatum (dlST). The extent of blonanserin-induced Fos expression in the AcS was comparable to that induced by haloperidol. However, the striatal Fos expression by blonanserin was less prominent as compared to haloperidol. Furthermore, combined treatment of AD-6048 (0.1-3mg/kg, s.c.) with haloperidol (0.5mg/kg, i.p.) significantly attenuated haloperidol-induced bradykinesia and catalepsy. The present results show that blonanserin behaves as an atypical antipsychotic both in inducing EPS and enhancing forebrain Fos expression. In addition, AD-6048 seems to contribute at least partly to the atypical properties of blonanserin. Copyright 2010 Elsevier Inc. All rights reserved.

  11. Striatal dopamine D2/3 receptor regulation by stress inoculation in squirrel monkeys

    Directory of Open Access Journals (Sweden)

    Alex G. Lee

    2016-06-01

    Full Text Available Intermittent mildly stressful situations provide opportunities to learn, practice, and improve coping in a process called stress inoculation. Stress inoculation also enhances cognitive control and response inhibition of impulsive motivated behavior. Cognitive control and motivation have been linked to striatal dopamine D2 and/or D3 receptors (DRD2/3 in rodents, monkeys, and humans. Here, we study squirrel monkeys randomized early in life to stress inoculation with or without maternal companionship and a no-stress control treatment condition. Striatal DRD2/3 availability in adulthood was measured in vivo by [11C]raclopride binding using positron emission tomography (PET. DRD2/3 availability was greater in caudate and putamen compared to ventral striatum as reported in PET studies of humans and other non-human primates. DRD2/3 availability in ventral striatum was also consistently greater in stress inoculated squirrel monkeys compared to no-stress controls. Squirrel monkeys exposed to stress inoculation in the presence of their mother did not differ from squirrel monkeys exposed to stress inoculation without maternal companionship. Similar effects in different social contexts extend the generality of our findings and together suggest that stress inoculation increases striatal DRD2/3 availability as a correlate of cognitive control in squirrel monkeys.

  12. Comparative MD Simulations Indicate a Dual Role for Arg1323.50 in Dopamine-Dependent D2R Activation.

    Directory of Open Access Journals (Sweden)

    Ralf C Kling

    Full Text Available Residue Arg3.50 belongs to the highly conserved DRY-motif of class A GPCRs, which is located at the bottom of TM3. On the one hand, Arg3.50 has been reported to help stabilize the inactive state of GPCRs, but on the other hand has also been shown to be crucial for stabilizing active receptor conformations and mediating receptor-G protein coupling. The combined results of these studies suggest that the exact function of Arg3.50 is likely to be receptor-dependent and must be characterized independently for every GPCR. Consequently, we now present comparative molecular-dynamics simulations that use our recently described inactive-state and Gα-bound active-state homology models of the dopamine D2 receptor (D2R, which are either bound to dopamine or ligand-free, performed to identify the function of Arg1323.50 in D2R. Our results are consistent with a dynamic model of D2R activation in which Arg1323.50 adopts a dual role, both by stabilizing the inactive-state receptor conformation and enhancing dopamine-dependent D2R-G protein coupling.

  13. Bidirectional allosteric interactions between cannabinoid receptor 1 (CB1) and dopamine receptor 2 long (D2L) heterotetramers.

    Science.gov (United States)

    Bagher, Amina M; Laprairie, Robert B; Toguri, J Thomas; Kelly, Melanie E M; Denovan-Wright, Eileen M

    2017-10-15

    Type 1 cannabinoid (CB1) and dopamine 2 long form (D2L) receptors can physically interact to form heteromers that display unique pharmacology in vitro compared to homomeric complexes. Co-expression of CB1 and D2L and co-application of CB1 and D2 agonists increases cAMP levels while administration of either agonist alone decreases cAMP levels. To understand the observed co-agonist response, our first goal of the current study was to define the stoichiometry of CB1/D2L/Gα protein complexes. Using bioluminescence resonance energy transfer 2 (BRET(2)), we confirmed that, CB1 homodimers, D2L homodimers, and CB1/D2L heteromers are formed. By using sequential resonance energy transfer 2 (SRET(2)) combined with bimolecular fluorescence complementation (BiFC), we were able to demonstrate that CB1/D2L form heterotetramers consisting of CB1 and D2L homodimers. We demonstrated that CB1/D2L heterotetramers are coupled to at least two Gα proteins. The second aim of the study was to investigate allosteric effects of a D2L agonist (quinpirole) on CB1 receptor function and to investigate the effects of a CB1 agonist [arachidonyl-2-chloroethylamide (ACEA)] on D2L receptor function within CB1/D2L heterotetramers. Treating cells co-expressing CB1 and D2L with both ACEA and quinpirole switched CB1 and D2L receptor coupling and signaling from Gαi to Gαs proteins, enhanced β-arrestin1 recruitment and receptor co-internalization. The concept of bidirectional allosteric interaction within CB1/D2 heterotetramers has important implications for understanding the activity of receptor complexes in native tissues and under pathological conditions. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Recruitment of beta-arrestin2 to the dopamine D2 receptor: insights into anti-psychotic and anti-parkinsonian drug receptor signaling

    DEFF Research Database (Denmark)

    Klewe, Ib V; Nielsen, Søren M; Tarpø, Louise

    2008-01-01

    Drugs acting at dopamine D2-like receptors play a pivotal role in the treatment of both schizophrenia and Parkinson's disease. Recent studies have demonstrated a role for G-protein independent D2 receptor signaling pathways acting through beta-arrestin. In this study we describe the establishment...... of a Bioluminescence Resonance Energy Transfer (BRET) assay for measuring dopamine induced recruitment of human beta-arrestin2 to the human dopamine D2 receptor. Dopamine, as well as the dopamine receptor agonists pramipexole and quinpirole, acted as full agonists in the assay as reflected by their ability to elicit...... marked concentration dependent increases in the BRET signal signifying beta-arrestin2 recruitment to the D2 receptor. As expected from their effect on G-protein coupling and cAMP levels mediated through the D2 receptor RNPA, pergolide, apomorphine, ropinirole, bromocriptine, 3PPP, terguride, aripiprazole...

  15. Exploring personality traits related to dopamine D2/3 receptor availability in striatal subregions of humans.

    Science.gov (United States)

    Caravaggio, Fernando; Fervaha, Gagan; Chung, Jun Ku; Gerretsen, Philip; Nakajima, Shinichiro; Plitman, Eric; Iwata, Yusuke; Wilson, Alan; Graff-Guerrero, Ariel

    2016-04-01

    While several studies have examined how particular personality traits are related to dopamine D2/3 receptor (D2/3R) availability in the striatum of humans, few studies have reported how multiple traits measured in the same persons are differentially related to D2/3R availability in different striatal sub-regions. We examined how personality traits measured with the Karolinska Scales of Personality are related to striatal D2/3R availability measured with [(11)C]-raclopride in 30 healthy humans. Based on previous the literature, five personality traits were hypothesized to be most likely related to D2/3R availability: impulsiveness, monotony avoidance, detachment, social desirability, and socialization. We found self-reported impulsiveness was negatively correlated with D2/3R availability in the ventral striatum and globus pallidus. After controlling for age and gender, monotony avoidance was also negatively correlated with D2/3R availability in the ventral striatum and globus pallidus. Socialization was positively correlated with D2/3R availability in the ventral striatum and putamen. After controlling for age and gender, the relationship between socialization and D2/3R availability in these regions survived correction for multiple comparisons (p-threshold=.003). Thus, within the same persons, different personality traits are differentially related to in vivo D2/3R availability in different striatal sub-regions. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

  16. Exploring peronality traits related to dopamine D2/3 receptor availability in striatal subregions of humans

    Science.gov (United States)

    Caravaggio, Fernando; Fervaha, Gagan; Chung, Jun Ku; Gerretsen, Philip; Nakajima, Shinichiro; Plitman, Eric; Iwata, Yusuke; Wilson, Alan; Graff-Guerrero, Ariel

    2016-01-01

    While several studies have examined how particular personality traits are related to dopamine D2/3 receptor (D2/3R) availability in the striatum of humans, few studies have reported how multiple traits measured in the same persons are differentially related to D2/3R availability in different striatal sub-regions. We examined how personality traits measured with the Karolinska Scales of Personality are related to striatal D2/3R availability measured with [11C]-raclopride in 30 healthy humans. Based on previous literature, five personality traits were hypothesized to be most likely related to D2/3R availability: impulsiveness, monotony avoidance, detachment, social desirability, and socialization. We found self-reported impulsiveness was negatively correlated with D2/3R availability in the ventral striatum and globus pallidus. After controlling for age and gender, monotony avoidance was also negatively correlated with D2/3R availability in the ventral striatum and globus pallidus. Socialization was positively correlated with D2/3R availability in the ventral striatum and putamen. After controlling for age and gender, the relationship between socialization and D2/3R availability in these regions survived correction for multiple comparisons (p-threshold=.003). Thus, within the same persons, different personality traits are differentially related to in vivo D2/3R availability in different striatal sub-regions. PMID:26944295

  17. Localisation of Dopamine D1-Like and D2-Like Receptors in the Pulmonary Vasculature

    National Research Council Canada - National Science Library

    Kobayashi, Yuta; Amenta, Francesco; Ricci, Alberto; Hattori, Keisuke

    1995-01-01

    The pharmacological profile and the anatomical localisation of dopamine receptor subtypes were investigated in the rabbit pulmonary vascular bed using combined radioligand binding and light microscope...

  18. Dopamine D2-receptor affinity of antipsychotics in relation to subjective well-being in patients with a psychotic disorder.

    Science.gov (United States)

    de Wit, Iris E; van Dijk, Floor A; Meijer, Carin J; van Tricht, Mirjam J; de Haan, Lieuwe

    2017-09-01

    Dopamine D2-receptor blockade by antipsychotic medication reduces psychotic symptoms, but may reduce subjective well-being. The current study aims to further explore the relation between dopamine D2-receptor affinity and subjective well-being within a large sample of patients with psychotic disorders. Patients participated in a longitudinal naturalistic cohort study: the Genetic Risk and Outcome of Psychosis (GROUP) study. Three groups of antipsychotic medication were created on the basis of their affinity for the D2-receptor: (i) loose or partial agonistic binding, (ii) moderate binding, and (iii) tight binding. Subjective well-being was assessed using the Subjective Well-being under Neuroleptics scale (SWN) at baseline and the 3-year follow-up. In addition, we compared changes in SWN scores when switching to a more 'loose or partial agonistic' binding agent or to a 'tighter' binding agent between baseline and the 3-year follow-up. The final group included 388 patients at baseline and 290 at the 3-year follow-up. No significant differences in the SWN scores were found between the three affinity groups at baseline and the 3-year follow-up. In addition, analyses yielded no significant changes in SWN scores after switching to a more 'loose or partial agonistic' or more 'tight' binding antipsychotic agent. We did not find further support for the hypothesis that subjective well-being is associated with antipsychotics affinity for dopamine D2-receptors. This might imply that the effect of antipsychotic D2-receptors binding on subjective well-being is not large enough to be detected in this cross-sectional study. Other factors besides dopamine antagonism are probably more relevant for subjective well-being.

  19. Effect of dopamine, dopamine D-1 and D-2 receptor modulation on ACTH and cortisol levels in normal men and women

    DEFF Research Database (Denmark)

    Boesgaard, S; Hagen, C; Andersen, A N

    1990-01-01

    women received dopamine (4.0 micrograms.kg-1.min-1) or glucose for 18 h. During the infusions cortisol and ACTH levels were similar on the two study days. Administration of metoclopramide (10 mg) after 17 h induced a significant increase in cortisol levels during dopamine infusion (p less than 0......The regulation of the hypothalamic-pituitary-adrenal axis by dopamine is not fully understood. Therefore, we have studied the effect of dopamine, metoclopramide, a D-2 receptor antagonist, and fenoldopam, a specific D-1 receptor agonist, on ACTH and cortisol levels in normal subjects. Normal women...... received 5-h infusions of either glucose (N = 6) or dopamine at rates of 0.04 (N = 6), 0.4 (N = 6) and 4.0 micrograms.kg-1.min-1 (N = 8). After 3 h, 10 mg metoclopramide was given iv. No intergroup differences regarding ACTH and cortisol levels were observed (p greater than 0.05). In a second study six...

  20. Agonist binding fraction of dopamine D2/3 receptors in rat brain: a quantitative autoradiographic study.

    Science.gov (United States)

    Minuzzi, Luciano; Cumming, Paul

    2010-01-01

    There has arisen considerable interest in the study of dopamine D(2/3) agonist binding sites by positron emission tomography (PET), based on the claim that agonist sites represent a functional subset of the total number of sites labeled by more conventional antagonist ligands. To test the basis of this claim, we used quantitative autoradiography to measure the abundance of binding sites of a dopamine D(2/3) agonist ([(3)H]NPA) and an antagonist ([(3)H]raclopride) in cryosections of rat brain. Saturation binding studies revealed that the B(max) for [(3)H]NPA was nearly identical to that of [(3)H]raclopride in dorsal brain regions, but was 25% less in the ventral striatum and 56% less in the olfactory tubercle. We also tested the displacement of the two ligands by the hallucinogen LSD, which is known to have dopamine agonist properties. Whereas displacement of [(3)H]raclopride by increasing LSD concentrations was monophasic, displacement of [(3)H]NPA was biphasic, suggesting an action of LSD via a subset of dopamine D(2/3) agonist binding sites. Addition of the stable GTP analogue Gpp(NH)p to the medium abolished 90% of the [(3)H]NPA binding, and increased [(3)H]raclopride binding by 10%, with a shift to the right in the LSD competition curve, suggesting retention of endogenous dopamine in washed cryostat sections. Thus [(3)H]NPA and [(3)H]raclopride binding sites have nearly identical abundances in rat dorsal striatum, but are distinct in the ventral striatum, and with respect to their displacement by LSD. Copyright 2010 Elsevier Ltd. All rights reserved.

  1. Dopamine D2 receptor radiotracers [{sup 11}C](+)-PHNO and [{sup 3}H]raclopride are indistinguishably inhibited by D2 agonists and antagonists ex vivo

    Energy Technology Data Exchange (ETDEWEB)

    McCormick, Patrick N. [Institute of Medical Science, University of Toronto, Toronto, Ontario, M5S 1A8 (Canada)], E-mail: patrick.mccormick@camhpet.ca; Kapur, Shitij [Department of Psychiatry, University of Toronto, Toronto, Ontario, M5S 1A8 (Canada); PET Center, Center for Addiction and Mental Health, Toronto, Ontario, M5T 1R8 (Canada); Seeman, Philip [Department of Psychiatry, University of Toronto, Toronto, Ontario, M5S 1A8 (Canada); Department of Pharmacology, University of Toronto, Toronto, Ontario, M5S 1A8 (Canada); Wilson, Alan A. [Department of Psychiatry, University of Toronto, Toronto, Ontario, M5S 1A8 (Canada); PET Center, Center for Addiction and Mental Health, Toronto, Ontario, M5T 1R8 (Canada)

    2008-01-15

    Introduction: In vitro, the dopamine D2 receptor exists in two states, with high and low affinity for agonists. The high-affinity state is the physiologically active state thought to be involved in dopaminergic illnesses such as schizophrenia. The positron emission tomography radiotracer [{sup 11}C](+)-PHNO ([{sup 11}C](+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4] oxazin-9-o l), being a D2 agonist, should selectively label the high-affinity state at tracer dose and therefore be more susceptible to competition by agonist as compared to the antagonist [{sup 3}H]raclopride, which binds to both affinity states. Methods: We tested this prediction using ex vivo dual-radiotracer experiments in conscious rats. D2 antagonists (haloperidol or clozapine), a partial agonist (aripiprazole), a full agonist [(-)-NPA] or the dopamine-releasing drug amphetamine (AMPH) were administered to rats prior to an intravenous coinjection of [{sup 11}C](+)-PHNO and [{sup 3}H]raclopride. Rats were sacrificed 60 min after radiotracer injection. Striatum, cerebellum and plasma samples were counted for {sup 11}C and {sup 3}H. The specific binding ratio {l_brace}SBR, i.e., [%ID/g (striatum)-%ID/g (cerebellum)]/(%ID/g (cerebellum){r_brace} was used as the outcome measure. Results: In response to D2 antagonists, partial agonist or full agonist, [{sup 11}C](+)-PHNO and [{sup 3}H]raclopride SBRs responded indistinguishably in terms of both ED{sub 50} and Hill slope (e.g., (-)-NPA ED{sub 50} values are 0.027 and 0.023 mg/kg for [{sup 11}C](+)-PHNO and [{sup 3}H]raclopride, respectively). In response to AMPH challenge, [{sup 11}C](+)-PHNO and [{sup 3}H]raclopride SBRs were inhibited to the same degree. Conclusions: We have shown that the SBRs of [{sup 11}C](+)-PHNO- and [{sup 3}H]raclopride do not differ in their response to agonist challenge. These results do not support predictions of the in vivo binding behavior of a D2 agonist radiotracer and cast some doubt on the in vivo

  2. Spatial Reversal Learning in Chronically Sensitized Rats and in Undrugged Sensitized Rats with Dopamine D2-Like Receptor Agonist Quinpirole

    OpenAIRE

    Hana eHatalova; Dominika eRadostová; Adéla ePištíková; Karel eVales; Ales eStuchlik

    2014-01-01

    Dopamine plays a role in generating flexible adaptive responses in changing environments. Chronic administration of D2-like agonist quinpirole (QNP) induces behavioral sensitization and stereotypical behaviors reminiscent of obsessive–compulsive disorder (OCD). Some of these symptoms persist even after QNP discontinuation. In QNP-sensitization, perseverative behavior has often been implicated. To test the effect of QNP-sensitization on reversal learning and its association with perseveration ...

  3. Biological Insights of the Dopaminergic Stabilizer ACR16 at the Binding Pocket of Dopamine D2 Receptor.

    Science.gov (United States)

    Ekhteiari Salmas, Ramin; Seeman, Philip; Aksoydan, Busecan; Stein, Matthias; Yurtsever, Mine; Durdagi, Serdar

    2017-04-19

    The dopamine D2 receptor (D2R) plays an important part in the human central nervous system and it is considered to be a focal target of antipsychotic agents. It is structurally modeled in active and inactive states, in which homodimerization reaction of the D2R monomers is also applied. The ASP2314 (also known as ACR16) ligand, a D2R stabilizer, is used in tests to evaluate how dimerization and conformational changes may alter the ligand binding space and to provide information on alterations in inhibitory mechanisms upon activation. The administration of the D2R agonist ligand ACR16 [ 3 H](+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol ((+)PHNO) revealed K i values of 32 nM for the D2 high R and 52 μM for the D2 low R. The calculated binding affinities of ACR16 with post processing molecular dynamics (MD) simulations analyses using MM/PBSA for the monomeric and homodimeric forms of the D2 high R were -9.46 and -8.39 kcal/mol, respectively. The data suggests that the dimerization of the D2R leads negative cooperativity for ACR16 binding. The dimerization reaction of the D2 high R is energetically favorable by -22.95 kcal/mol. The dimerization reaction structurally and thermodynamically stabilizes the D2 high R conformation, which may be due to the intermolecular forces formed between the TM4 of each monomer, and the result strongly demonstrates dimerization essential for activation of the D2R.

  4. Love to win or hate to Lose? Asymmetry of dopamine D2 receptor binding predicts sensitivity to reward versus punishment.

    Science.gov (United States)

    Tomer, Rachel; Slagter, Heleen A; Christian, Bradley T; Fox, Andrew S; King, Carlye R; Murali, Dhanabalan; Gluck, Mark A; Davidson, Richard J

    2014-05-01

    Humans show consistent differences in the extent to which their behavior reflects a bias toward appetitive approach-related behavior or avoidance of aversive stimuli [Elliot, A. J. Approach and avoidance motivation. In A. J. Elliot (Ed.), Handbook of approach and avoidance motivation (pp. 3-14). New York: Psychology Press, 2008]. We examined the hypothesis that in healthy participants this motivational bias (assessed by self-report and by a probabilistic learning task that allows direct comparison of the relative sensitivity to reward and punishment) reflects lateralization of dopamine signaling. Using [F-18]fallypride to measure D2/D3 binding, we found that self-reported motivational bias was predicted by the asymmetry of frontal D2 binding. Similarly, striatal and frontal asymmetries in D2 dopamine receptor binding, rather than absolute binding levels, predicted individual differences in learning from reward versus punishment. These results suggest that normal variation in asymmetry of dopamine signaling may, in part, underlie human personality and cognition.

  5. Leptin Increases Striatal Dopamine D2 Receptor Binding in Leptin-Deficient Obese (ob/ob) Mice

    Energy Technology Data Exchange (ETDEWEB)

    Pfaffly, J.; Michaelides, M.; Wang, G-J.; Pessin, J.E.; Volkow, N.D.; Thanos, P.K.

    2010-06-01

    Peripheral and central leptin administration have been shown to mediate central dopamine (DA) signaling. Leptin-receptor deficient rodents show decreased DA D2 receptor (D2R) binding in striatum and unique DA profiles compared to controls. Leptin-deficient mice show increased DA activity in reward-related brain regions. The objective of this study was to examine whether basal D2R-binding differences contribute to the phenotypic behaviors of leptin-deficient ob/ob mice, and whether D2R binding is altered in response to peripheral leptin treatment in these mice. Leptin decreased body weight, food intake, and plasma insulin concentration in ob/ob mice but not in wild-type mice. Basal striatal D2R binding (measured with autoradiography [{sup 3}H] spiperone) did not differ between ob/ob and wild-type mice but the response to leptin did. In wild-type mice, leptin decreased striatal D2R binding, whereas, in ob/ob mice, leptin increased D2R binding. Our findings provide further evidence that leptin modulates D2R expression in striatum and that these effects are genotype/phenotype dependent.

  6. Dopamine D2/3 occupancy of ziprasidone across a day: a within-subject PET study

    Science.gov (United States)

    Suzuki, Takefumi; Graff-Guerrero, Ariel; Uchida, Hiroyuki; Remington, Gary; Caravaggio, Fernando; Borlido, Carol; Pollock, Bruce; Mulsant, Benoit; DeLuca, Vincenzo; Ismail, Zahinoor; Mamo, David

    2013-01-01

    Rationale Ziprasidone is an atypical antipsychotic recommended to be administered twice daily. Objectives The purpose of this study was to investigate whether occupancy of the dopamine D2/3 receptors by ziprasidone is maintained across a day employing a within subject design. Methods Positron Emission Tomography (PET) scans with [11C]-raclopride were performed in 12 patients with schizophrenia while treated with ziprasidone 60mg twice daily. Each patient completed [11C]-raclopride PET scans at 5, 13 and 23 hours after the last dose of ziprasidone. Dopamine D2/3 receptor occupancy was estimated with reference to binding potential data of 44 age- and sex-matched control subjects in the caudate, putamen and ventral striatum. Results Eleven scans were available at each time point, and the mean occupancies at 5-, 13- and 23-hour scans were 66%, 39% and 2% in the putamen; 62%, 35% and −6% in the caudate; and 68%, 47% and 11% in the ventral striatum, respectively. The time-course of receptor occupancy across the regions indicated an occupancy half-life of 8.3 hours. The serum level of ziprasidone associated with 50% D2/3 receptors occupancy was estimated to be 204nmol/L (84ng/ml). Prolactin levels were highest at 5-hour post-dose and none showed hyperprolactinemia at 23-hour scans. Conclusions The absence of ziprasidone striatal D2/3 receptor binding 23-hour after taking 60 mg under steady state conditions is consistent with its peripheral half-life. The results support our earlier report that ziprasidone 60 mg administered twice daily appears to be the minimal dose expected to achieve therapeutic central dopamine D2 receptor occupancy (i.e. 60%). PMID:23417515

  7. Functional Homomers and Heteromers of Dopamine D2L and D3 Receptors Co-exist at the Cell Surface

    Science.gov (United States)

    Pou, Chantevy; Mannoury la Cour, Clotilde; Stoddart, Leigh A.; Millan, Mark J.; Milligan, Graeme

    2012-01-01

    Human dopamine D2long and D3 receptors were modified by N-terminal addition of SNAP or CLIP forms of O6-alkylguanine-DNA-alkyltransferase plus a peptide epitope tag. Cells able to express each of these four constructs only upon addition of an antibiotic were established and used to confirm regulated and inducible control of expression, the specificity of SNAP and CLIP tag covalent labeling reagents, and based on homogenous time-resolved fluorescence resonance energy transfer, the presence of cell surface D2long and D3 receptor homomers. Following constitutive expression of reciprocal constructs, potentially capable of forming and reporting the presence of cell surface D2long-D3 heteromers, individual clones were assessed for levels of expression of the constitutively expressed protomer. This was unaffected by induction of the partner protomer and the level of expression of the partner required to generate detectable cell surface D2long–D3 heteromers was defined. Such homomers and heteromers were found to co-exist and using a reconstitution of function approach both homomers and heteromers of D2long and D3 receptors were shown to be functional, potentially via trans-activation of associated G protein. These studies demonstrate the ability of dopamine D2long and D3 receptors to form both homomers and heteromers, and show that in cells expressing each subtype a complex mixture of homomers and heteromers co-exists at steady state. These data are of potential importance both to disorders in which D2long and D3 receptors are implicated, like schizophrenia and Parkinson disease, and also to drugs exerting their actions via these sites. PMID:22291025

  8. Pre- and Postsynaptic Role of Dopamine D2 Receptor DD2R in Drosophila Olfactory Associative Learning

    Directory of Open Access Journals (Sweden)

    Cheng Qi

    2014-11-01

    Full Text Available Dopaminergic neurons in Drosophila play critical roles in diverse brain functions such as motor control, arousal, learning, and memory. Using genetic and behavioral approaches, it has been firmly established that proper dopamine signaling is required for olfactory classical conditioning (e.g., aversive and appetitive learning. Dopamine mediates its functions through interaction with its receptors. There are two different types of dopamine receptors in Drosophila: D1-like (dDA1, DAMB and D2-like receptors (DD2R. Currently, no study has attempted to characterize the role of DD2R in Drosophila learning and memory. Using a DD2R-RNAi transgenic line, we have examined the role of DD2R, expressed in dopamine neurons (i.e., the presynaptic DD2R autoreceptor, in larval olfactory learning. The function of postsynaptic DD2R expressed in mushroom body (MB was also studied as MB is the center for Drosophila learning, with a function analogous to that of the mammalian hippocampus. Our results showed that suppression of presynaptic DD2R autoreceptors impairs both appetitive and aversive learning. Similarly, postsynaptic DD2R in MB neurons appears to be involved in both appetitive and aversive learning. The data confirm, for the first time, that DD2R plays an important role in Drosophila olfactory learning.

  9. Dopamine D2 Receptors Modulate Pyramidal Neurons in Mouse Medial Prefrontal Cortex through a Stimulatory G-Protein Pathway.

    Science.gov (United States)

    Robinson, Sarah E; Sohal, Vikaas S

    2017-10-18

    Dopaminergic modulation of prefrontal cortex (PFC) is thought to play key roles in many cognitive functions and to be disrupted in pathological conditions, such as schizophrenia. We have previously described a phenomenon whereby dopamine D2 receptor (D2R) activation elicits afterdepolarizations (ADPs) in subcortically projecting (SC) pyramidal neurons within L5 of the PFC. These D2R-induced ADPs only occur following synaptic input, which activates NMDARs, even when the delay between the synaptic input and ADPs is relatively long (e.g., several hundred milliseconds). Here, we use a combination of electrophysiological, optogenetic, pharmacological, transgenic, and chemogenetic approaches to elucidate cellular mechanisms underlying this phenomenon in male and female mice. We find that knocking out D2Rs eliminates the ADP in a cell-autonomous fashion, confirming that this ADP depends on D2Rs. Hyperpolarizing current injection, but not AMPA receptor blockade, prevents synaptic stimulation from facilitating D2R-induced ADPs, suggesting that this phenomenon depends on the recruitment of voltage-dependent currents (e.g., NMDAR-mediated Ca 2+ influx) by synaptic input. Finally, the D2R-induced ADP is blocked by inhibitors of cAMP/PKA signaling, insensitive to pertussis toxin or β-arrestin knock-out, and mimicked by G s -DREADD stimulation, suggesting that D2R activation elicits the ADP by stimulating cAMP/PKA signaling. These results show that this unusual physiological phenomenon, in which D2Rs enhance cellular excitability in a manner that depends on synaptic input, is mediated at the cellular level through the recruitment of signaling pathways associated with G s , rather than the G i/o -associated mechanisms that have classically been ascribed to D2Rs. SIGNIFICANCE STATEMENT Dopamine D2 receptors (D2Rs) in the prefrontal cortex (PFC) are thought to play important roles in behaviors, including working memory and cognitive flexibility. Variation in D2Rs has also been

  10. Alterations of Dopamine D2 Receptors and Related Receptor-Interacting Proteins in Schizophrenia: The Pivotal Position of Dopamine Supersensitivity Psychosis in Treatment-Resistant Schizophrenia

    Directory of Open Access Journals (Sweden)

    Yasunori Oda

    2015-12-01

    Full Text Available Although the dopamine D2 receptor (DRD2 has been a main target of antipsychotic pharmacotherapy for the treatment of schizophrenia, the standard treatment does not offer sufficient relief of symptoms to 20%–30% of patients suffering from this disorder. Moreover, over 80% of patients experience relapsed psychotic episodes within five years following treatment initiation. These data strongly suggest that the continuous blockade of DRD2 by antipsychotic(s could eventually fail to control the psychosis in some point during long-term treatment, even if such treatment has successfully provided symptomatic improvement for the first-episode psychosis, or stability for the subsequent chronic stage. Dopamine supersensitivity psychosis (DSP is historically known as a by-product of antipsychotic treatment in the manner of tardive dyskinesia or transient rebound psychosis. Numerous data in psychopharmacological studies suggest that the up-regulation of DRD2, caused by antipsychotic(s, is likely the mechanism underlying the development of the dopamine supersensitivity state. However, regardless of evolving notions of dopamine signaling, particularly dopamine release, signal transduction, and receptor recycling, most of this research has been conducted and discussed from the standpoint of disease etiology or action mechanism of the antipsychotic, not of DSP. Hence, the mechanism of the DRD2 up-regulation or mechanism evoking clinical DSP, both of which are caused by pharmacotherapy, remains unknown. Once patients experience a DSP episode, they become increasingly difficult to treat. Light was recently shed on a new aspect of DSP as a treatment-resistant factor. Clarification of the detailed mechanism of DSP is therefore crucial, and a preventive treatment strategy for DSP or treatment-resistant schizophrenia is urgently needed.

  11. Expression and function of CB1 receptor in the rat striatum: localization and effects on D1 and D2 dopamine receptor-mediated motor behaviors.

    Science.gov (United States)

    Martín, Ana Belén; Fernandez-Espejo, Emilio; Ferrer, Belén; Gorriti, Miguel Angel; Bilbao, Ainhoa; Navarro, Miguel; Rodriguez de Fonseca, Fernando; Moratalla, Rosario

    2008-06-01

    Cannabinoid CB1 receptors are densely expressed on striatal projection neurons expressing dopamine D1 or D2 receptors. However, the specific neuronal distribution of CB1 receptors within the striatum is not known. Previous research has established that the endocannabinoid system controls facilitation of behavior by dopamine D2 receptors, but it is not clear if endocannabinoids also modulate D1 receptor-mediated motor behavior. In the present study, we show that cannabinoid CB1 receptor mRNA is present in striatonigral neurons expressing substance P and dopamine D1 receptors, as well as in striatopallidal neurons expressing enkephalin and dopamine D2 receptors. We explored the functional relevance of the interaction between dopamine D1 and D2 receptors and cannabinoid CB1 receptors with behavioral pharmacology experiments. Potentiation of endogenous cannabinoid signaling by the uptake blocker AM404 blocked dopamine D1 receptor-mediated grooming and D2 receptor-mediated oral stereotypies. In addition, contralateral turning induced by unilateral intrastriatal infusion of D1 receptor agonists is counteracted by AM404 and potentiated by the cannabinoid antagonist SR141716A. These results indicate that the endocannabinoid system negatively modulates D1 receptor-mediated behaviors in addition to its previously described effect on dopamine D2 receptor-mediated behaviors. The effect of AM404 on grooming behavior was absent in dopamine D1 receptor knockout mice, demonstrating its dependence on D1 receptors. This study indicates that the endocannabinoid system is a relevant negative modulator of both dopamine D1 and D2 receptor-mediated behaviors, a finding that may contribute to our understanding of basal ganglia motor disorders.

  12. G-Protein Sensitivity of Ligand Binding to Human Dopamine D2 and D3 Receptors Expressed in Escherichia coli : Clues for a Constrained D3 Receptor Structure

    NARCIS (Netherlands)

    Vanhauwe, Jurgen F.M.; Josson, Katty; Luyten, Walter H.M.L.; Driessen, Arnold J.; Leysen, Josée E.

    2000-01-01

    Human dopamine D2 and D3 receptors were expressed in Chinese hamster ovary (CHO) and Escherichia coli cells to compare their ligand binding properties in the presence or absence of G-proteins and to analyze their ability to interact with Gi/o-proteins. Binding affinities of agonists (dopamine,

  13. Association between the dopamine D2 receptor TaqI A2 allele and low activity COMT allele with obsessive-compulsive disorder in males

    NARCIS (Netherlands)

    Denys, Damiaan; van Nieuwerburgh, Filip; Deforce, Dieter; Westenberg, Herman

    2006-01-01

    BACKGROUND: Mounting evidence suggests the involvement of the dopamine system in the pathophysiology of obsessive-compulsive disorder. METHOD: The relationship of the dopamine D(2) receptor (DRD2) TaqI A, and catechol-O-methyl-transferase (COMT) NlaIII High/Low activity polymorphism to

  14. Motivational salience and genetic variability of dopamine D2 receptor expression interact in the modulation of interference processing

    Directory of Open Access Journals (Sweden)

    Anni eRichter

    2013-06-01

    Full Text Available Dopamine has been implicated in the fine-tuning of complex cognitive and motor function and also in the anticipation of future rewards. This dual function of dopamine suggests that dopamine might be involved in the generation of active motivated behavior. The DRD2 TaqIA polymorphism of the dopamine D2 receptor gene (rs1800497 has previously been suggested to affect striatal function with carriers of the less common A1 allele exhibiting reduced striatal D2 receptor density and increased risk for addiction. Here we aimed to investigate the influences of DRD2 TaqIA genotype on the modulation of interference processing by reward and punishment. 46 young, healthy volunteers participated in a behavioral experiment, and 32 underwent functional magnetic resonance imaging (fMRI. Participants performed a flanker task with a motivation manipulation (monetary reward, monetary loss, neither, or both. Reaction times (RTs were shorter in motivated flanker trials, irrespective of congruency. In the fMRI experiment motivation was associated with reduced prefrontal activation during incongruent versus congruent flanker trials, possibly reflecting increased processing efficiency. DRD2 TaqIA genotype did not affect overall RTs, but interacted with motivation on the congruency-related RT differences, with A1 carriers showing smaller interference effects to reward alone and A2 homozygotes exhibiting a specific interference reduction during combined reward and punishment trials. In fMRI, anterior cingulate activity showed a similar pattern of genotype-related modulation. Additionally, A1 carriers showed increased anterior insula activation relative to A2 homozygotes. Our results point to a role for genetic variations of the dopaminergic system in individual differences of cognition-motivation interaction.

  15. Role of basolateral amygdala dopamine D2 receptors in impulsive choice in acute cocaine-treated rats.

    Science.gov (United States)

    Li, Yijing; Zuo, Yanfang; Yu, Peng; Ping, Xingjie; Cui, Cailian

    2015-01-01

    Psychostimulant substances have been found to either increase or inhibit impulsive choice (preference to choose small immediate reward over large delayed reward) in laboratory animals. Although central dopamine transmission has been demonstrated to be involved in impulsivity and drug addiction, little is known regarding dopaminergic neurotransmission in addictive drug-induced alteration of impulse control. In this study, we used a delay discounting model to measure impulsive choice in rats and found that acute cocaine dose-dependently decreased impulsive choice in rats. Intraperitoneal injection (i.p.) of D1 receptor antagonist SCH23390 (0.02 mg/kg) could increase the impulsive choice but had no effect on the inhibition of impulsive choice induced by acute cocaine exposure. D2 receptor antagonist eticlopride (0.06 mg/kg) had no effect on the choice behavior itself, but it reversed acute cocaine-induced impulse inhibition. Moreover, bilateral microinjection of eticlopride (1 μg/side) into the basolateral amygdala (BLA) but not the nucleus accumbens (NAc) core reversed the inhibitory effect of acute cocaine on impulsive choice. These data suggest important but dissociable roles of dopamine D1 and D2 receptors in impulse control. The preference of delayed rewards depends on D1 receptors, whereas acute cocaine inhibited impulsive choice by activating D2 receptors in the BLA. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. Evaluation of Antipsychotic Dose Reduction in Late-Life Schizophrenia: A Prospective Dopamine D2/3 Receptor Occupancy Study.

    Science.gov (United States)

    Graff-Guerrero, Ariel; Rajji, Tarek K; Mulsant, Benoit H; Nakajima, Shinichiro; Caravaggio, Fernando; Suzuki, Takefumi; Uchida, Hiroyuki; Gerretsen, Philip; Mar, Wanna; Pollock, Bruce G; Mamo, David C

    2015-09-01

    Patients with late-life schizophrenia (LLS) are highly susceptible to antipsychotic adverse effects. Treatment guidelines endorse lower antipsychotic doses. However, the optimal dose of antipsychotics and associated dopamine D2/3 receptor (D2/3R) occupancies remain largely unexplored in patients with LLS. To evaluate effects of antipsychotic dose reduction on striatal dopamine D2/3R occupancies, clinical variables, and blood pharmacokinetic measures in patients with LLS. An open-label, single-arm prospective study with a 3- to 6-month follow-up period (January 10, 2007, to October 21, 2013) was conducted at an academic tertiary care center with practice for ambulatory care. Participants included 35 outpatients with clinically stable LLS (patients aged ≥ 50 years receiving olanzapine or risperidone monotherapy at the same dose for 6 to 12 months). Follow-up was completed on October 21, 2013, and analysis was conducted from October 22, 2014, to February 2, 2015. Carbon 11-labeled raclopride positron emission tomography, clinical measures, and blood pharmacokinetic measures performed before and after gradual dose reduction by up to 40% from the baseline dose and at least 3 months after dose reduction. Striatal dopamine D2/3R occupancies with antipsychotics, clinical measures (Positive and Negative Syndrome Scale, Brief Psychiatric Rating Scale, Targeted Inventory on Problems in Schizophrenia, Simpson-Angus Scale, Barnes Rating Scale for Drug-Induced Akathisia, Udvalg for Kliniske Undersøgelser Side Effect Rating Scale), and blood pharmacokinetic measures (prolactin and antipsychotic blood levels). Dopamine D2/3R occupancy of the entire sample decreased by a mean (SD) of 6.2% (8.2%) following dose reduction (from 70% [12%] to 64% [12%]; P < .001). The lowest D2/3R occupancy associated with clinical stability was 50%. Extrapyramidal symptoms (EPSs) were more likely to occur with D2/3R occupancies higher than 60%: 90.5% (19 of 21) of the participants with

  17. Dopamine Receptor D2 Polymorphism Moderates the Effect of Parental Education on Adolescents' School Performance

    Science.gov (United States)

    Keltikangas-Jarvinen, Liisa; Pullmann, Helle; Pulkki-Raback, Laura; Alatupa, Saija; Lipsanen, Jari; Airla, Nina; Lehtimaki, Terho

    2008-01-01

    High parental socioeconomic status is known to have a positive effect on students' academic achievement. We examined whether variation in the dopamine receptor gene (DRD2 polymorphism, rs 1800497) modifies the association between parental educational level and school performance in adolescence. The participants were a randomly selected subsample…

  18. Neurochemical correlates of accumbal dopamine D2 and amygdaloid 5-HT 1B receptor densities on observational learning of aggression.

    Science.gov (United States)

    Suzuki, Hideo; Lucas, Louis R

    2015-06-01

    Social learning theory postulates that individuals learn to engage in aggressive behavior through observing an aggressive social model. Prior studies have shown that repeatedly observing aggression, also called "chronic passive exposure to aggression," changes accumbal dopamine D2 receptor (D2R) and amygdaloid 5-HT1B receptor (5-HT1BR) densities in observers. But, the association between these outcomes remains unknown. Thus, in our study, we used a rat paradigm to comprehensively examine the linkage between aggression, D2R density in the nucleus accumbens core (AcbC) and shell (AcbSh), and 5-HT1BR density in the medial (MeA), basomedial (BMA), and basolateral (BLA) amygdala following chronic passive exposure to aggression. Male Sprague-Dawley rats (N = 72) were passively exposed to either aggression or nonaggression acutely (1 day) or chronically (23 days). When observer rats were exposed to aggression chronically, they showed increased aggressive behavior and reduced D2R density in bilateral AcbSh. On the other hand, exposure to aggression, regardless of exposure length, increased the 5-HT1BR density in bilateral BLA. Finally, low D2R in the AcbSh significantly interacted with high 5-HT1BR density in the BLA to predict high levels of aggression in observer rats. Our results advance our understanding of the neurobiological mechanisms in the observational learning of aggression, highlighting that dopamine-serotonin interaction, or AcbSh-BLA interaction, may contribute to a risk factor for aggression in observers who chronically witness aggressive interactions.

  19. Neurochemical Correlates of Accumbal Dopamine D2 and Amygdaloid 5-HT1B Receptor Densities on Observational Learning of Aggression

    Science.gov (United States)

    Suzuki, Hideo; Lucas, Louis R.

    2015-01-01

    Social learning theory postulates that individuals learn to engage in aggressive behavior through observing an aggressive social model. Prior studies have shown that repeatedly observing aggression, also called “chronic passive exposure to aggression,” changes accumbal dopamine D2 receptor (D2R) and amygdaloid 5-HT1B receptor (5-HT1BR) densities in observers. But, the association between these outcomes remains unknown. Thus, our study used a rat paradigm to comprehensively examine the linkage between aggression, D2R density in the nucleus accumbens core (AcbC) and shell (AcbSh), and 5-HT1BR density in the medial (MeA), basomedial (BMA), and basolateral (BLA) amygdala following chronic passive exposure to aggression. Male Sprague-Dawley rats (N = 72) were passively exposed to either aggression or non-aggression acutely (1 day) or chronically (23 days). When observer rats were exposed to aggression chronically, they showed increased aggressive behavior and reduced D2R density in the bilateral AcbSh. On the other hand, exposure to aggression, regardless of exposure length, increased 5-HT1BR density in the bilateral BLA. Finally, low D2R in the AcbSh significantly interacted with high 5-HT1BR density in the BLA in predicting high levels of aggression in observer rats. Our results advance our understanding of the neurobiological mechanisms for observational learning of aggression, highlighting that dopamine-serotonin interaction, or AcbSh-BLA interaction, may contribute to a risk factor for aggression in observers who chronically witness aggressive interactions. PMID:25650085

  20. Modulation of Postnatal Neurogenesis by Perinatal Asphyxia: Effect of D1 and D2 Dopamine Receptor Agonists.

    Science.gov (United States)

    Tapia-Bustos, A; Perez-Lobos, R; Vío, V; Lespay-Rebolledo, C; Palacios, E; Chiti-Morales, A; Bustamante, D; Herrera-Marschitz, M; Morales, P

    2017-01-01

    Perinatal asphyxia (PA) is associated to delayed cell death, affecting neurocircuitries of basal ganglia and hippocampus, and long-term neuropsychiatric disabilities. Several compensatory mechanisms have been suggested to take place, including cell proliferation and neurogenesis. There is evidence that PA can increase postnatal neurogenesis in hippocampus and subventricular zone (SVZ), modulated by dopamine, by still unclear mechanisms. We have studied here the effect of selective dopamine receptor agonists on cell death, cell proliferation and neurogenesis in organotypic cultures from control and asphyxia-exposed rats. Hippocampus and SVZ sampled at 1-3 postnatal days were cultured for 20-21 days. At day in vitro (DIV) 19, cultures were treated either with SKF38393 (10 and 100 µM, a D1 agonist), quinpirole (10 µM, a D2 agonist) or sulpiride (10 μM, a D2 antagonist) + quinpirole (10 μM) and BrdU (10 μM, a mitosis marker) for 24 h. At DIV 20-21, cultures were processed for immunocytochemistry for microtubule-associated protein-2 (MAP-2, a neuronal marker), and BrdU, evaluated by confocal microscopy. Some cultures were analysed for cell viability at DIV 20-21 (LIVE/DEAD kit). PA increased cell death, cell proliferation and neurogenesis in hippocampus and SVZ cultures. The increase in cell death, but not in cell proliferation, was inhibited by both SKF38393 and quinpirole treatment. Neurogenesis was increased by quinpirole, but only in hippocampus, in cultures from both asphyxia-exposed and control-animals, effect that was antagonised by sulpiride, leading to the conclusion that dopamine modulates neurogenesis in hippocampus, mainly via D2 receptors.

  1. Caffeine increases striatal dopamine D2/D3 receptor availability in the human brain

    OpenAIRE

    Volkow, N.D.; Wang, G-J; Logan, J; Alexoff, D; Fowler, J.S.; Thanos, P K; Wong, C.; Casado, V.; Ferre, S.; Tomasi, D

    2015-01-01

    Caffeine, the most widely consumed psychoactive substance in the world, is used to promote wakefulness and enhance alertness. Like other wake-promoting drugs (stimulants and modafinil), caffeine enhances dopamine (DA) signaling in the brain, which it does predominantly by antagonizing adenosine A2A receptors (A2AR). However, it is unclear if caffeine, at the doses consumed by humans, increases DA release or whether it modulates the functions of postsynaptic DA receptors through its interactio...

  2. Cognition and Dopamine D2 Receptor Availability in the Striatum in Older Patients with Schizophrenia.

    Science.gov (United States)

    Rajji, Tarek K; Mulsant, Benoit H; Nakajima, Shinichiro; Caravaggio, Fernando; Suzuki, Takefumi; Uchida, Hiroyuki; Gerretsen, Philip; Mar, Wanna; Pollock, Bruce G; Mamo, David C; Graff-Guerrero, Ariel

    2017-01-01

    To assess the impact of reducing the dose of antipsychotics on cognition and dopaminergic D2 receptor availability in the whole striatum, and identify their relationship in patients with schizophrenia aged 50 years or older. Open-label prospective PET [11C]-raclopride study. A tertiary care center outpatient setting. Thirty-seven clinically stable participants with schizophrenia or schizoaffective disorder, aged 50 years or greater, and having been treated with olanzapine or risperidone monotherapy at the same dose for at least 6 months. Gradual reduction in their olanzapine or risperidone daily dose of up to 40%. Clinical and cognitive assessments, and [11C]-raclopride PET to determine D2 receptor availability at baseline and after the dose reduction. Main outcome measures were overall cognition and D2 receptor availability in whole striatum. Reducing the antipsychotic dose resulted in an increase in D2 receptor availability in the whole striatum and an association between D2 receptor availability and overall cognition despite lack of change in the latter. There was also an association between change in D2 receptor availability and change in overall cognition. Our findings suggest that optimizing D2 receptor availability by reducing antipsychotic dose allows this system to contribute more significantly to cognitive function in patients with schizophrenia. This uncovered association could be harnessed by cognitive-enhancing interventions. Copyright © 2017 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

  3. Striatal Dopamine D2/D3 Receptor Availability Is Associated with Executive Function in Healthy Controls but Not Methamphetamine Users.

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    Michael E Ballard

    Full Text Available Dopamine D2/D3 receptor availability in the striatum has been linked with executive function in healthy individuals, and is below control levels among drug addicts, possibly contributing to diminished executive function in the latter group. This study tested for an association of striatal D2/D3 receptor availability with a measure of executive function among research participants who met DSM-IV criteria for methamphetamine dependence.Methamphetamine users and non-user controls (n = 18 per group completed the Wisconsin Card Sorting Test and positron emission tomography with [18F]fallypride.The methamphetamine users displayed significantly lower striatal D2/D3 receptor availability on average than controls after controlling for age and education (p = 0.008, but they did not register greater proportions of either perseverative or non-perseverative errors when controlling for education (both ps ≥ 0.622. The proportion of non-perseverative, but not perseverative, errors was negatively correlated with striatal D2/D3 receptor availability among controls (r = -0.588, p = 0.010, but not methamphetamine users (r = 0.281, p = 0.258, and the group-wise interaction was significant (p = 0.030.These results suggest that cognitive flexibility, as measured by perseverative errors on the Wisconsin Card Sorting Test, is not determined by signaling through striatal D2/D3 receptors in healthy controls, and that in stimulant abusers, who have lower D2/D3 receptor availability, compensation can effectively maintain other executive functions, which are associated with D2/D3 receptor signaling in controls.

  4. Striatal dopamine D2/3 receptor-mediated neurotransmission in major depression: Implications for anhedonia, anxiety and treatment response.

    Science.gov (United States)

    Peciña, Marta; Sikora, Magdalena; Avery, Erich T; Heffernan, Joseph; Peciña, Susana; Mickey, Brian J; Zubieta, Jon-Kar

    2017-10-01

    Dopamine (DA) neurotransmission within the brain's reward circuit has been implicated in the pathophysiology of depression and in both, cognitive and pharmacological mechanisms of treatment response. Still, a direct relationship between measures of DA neurotransmission and reward-related deficits in patients with depression has not been demonstrated. To gain insight into the symptom-specific alterations in the DA system in patients with depression, we used positron emission tomography (PET) and the D 2/3 receptor-selective radiotracer [ 11 C]raclopride in twenty-three non-smoking un-medicated Major Depressive Disorder (MDD) patients and sixteen healthy controls (HC). We investigated the relationship between D 2/3 receptor availability and baseline measures of depression severity, anxiety, anhedonia, and cognitive and pharmacological mechanisms of treatment response. We found that, compared to controls, patients with depression showed greater D 2/3 receptor availability in several striatal regions, including the bilateral ventral pallidum/nucleus accumbens (vPAL/NAc), and the right ventral caudate and putamen. In the depressed sample, D 2/3 receptor availability in the caudal portion of the ventral striatum (NAc/vPAL) correlated with higher anxiety symptoms, whereas D 2/3 receptor availability in the rostral area of the ventral striatum correlated negatively with the severity of motivational anhedonia. Finally, MDD non-remitters showed greater baseline anxiety, greater D 2/3 availability in the NAc/vPAL, and greater placebo-induced DA release in the bilateral NAc. Our results demonstrate abnormally high D 2/3 receptor availability in the ventral striatum of patients with MDD, which seem to be associated with comorbid anxiety symptoms and lack of response to antidepressants. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.

  5. Involvement of dopamine D1/D5 and D2 receptors in context-dependent extinction learning and memory reinstatement

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    Marion Agnes Emma Andre

    2016-01-01

    Full Text Available Dopamine contributes to the regulation of higher order information processing and executive control. It is important for memory consolidation processes, and for the adaptation of learned responses based on experience. In line with this, under aversive learning conditions, application of dopamine receptor antagonists prior to extinction result in enhanced memory reinstatement. Here, we investigated the contribution of the dopaminergic system to extinction and memory reinstatement (renewal of an appetitive spatial learning task in rodents. Rats were trained for 3 days in a T-maze (context ‘A’ to associate a goal arm with a food reward, despite low reward probability (acquisition phase. On day 4, extinction learning (unrewarded occurred, that was reinforced by a context change (‘B’. On day 5, re-exposure to the (unrewarded ‘A’-context took place (renewal of context ‘A’, followed by extinction of context ‘A’. In control animals, significant extinction occurred on day 4, that was followed by an initial memory reinstatement (renewal on day 5, that was, in turn, succeeded by extinction of renewal. Intracerebral treatment with a D1/D5-receptor antagonist prior to the extinction trials, elicited a potent enhancement of extinction in context ‘B’. By contrast, a D1/D5-agonist impaired renewal in context ’A’. Extinction in the ‘A’ context on day 5 was unaffected by the D1/D5-ligands. Treatment with a D2-receptor antagonist prior to extinction had no overall effect on extinction in context ‘B or renewal in context ‘A’, although extinction of the renewal effect was impaired on day 5, compared to controls.Taken together, these data suggest that dopamine acting on the D1/D5-receptor modulates both acquisition and consolidation of context-dependent extinction. By contrast, the D2-receptor may contribute to context-independent aspects of this kind of extinction learning.

  6. Effects of Acute and Chronic Treatments with Dopamine D2 and D3 Receptor Ligands on Cocaine versus Food Choice in Rats

    DEFF Research Database (Denmark)

    Thomsen, Morgane; Barrett, Andrew C; Butler, Paul

    2017-01-01

    effects of dopamine D2- and D3-preferring ligands on choice between intravenous cocaine and palatable food in rats. Under baseline conditions, cocaine maintained dose-dependent increases in cocaine choice and reciprocal decreases in food choice. Acutely, the D2 agonist R-(-)-norpropylapomorphine (NPA...

  7. Development of a population pharmacokinetic model to predict brain distribution and dopamine D2 receptor occupancy of raclopride in nonanesthetized rat

    NARCIS (Netherlands)

    Wong, Y.C.; Ilz, aut ikkova T.I.; Wijk, van R.C.; Hartman, R.J.; Lange, de E.C.M.

    2018-01-01

    BACKGROUND: Raclopride is a selective antagonist of the dopamine D2 receptor. It is one of the most frequently used in vivo D2 tracers (at low doses) for assessing drug-induced receptor occupancy (RO) in animals and humans. It is also commonly used as a pharmacological blocker (at high doses) to

  8. Nucleus Accumbens Dopamine D2-Receptor Expressing Neurons Control Behavioral Flexibility in a Place Discrimination Task in the IntelliCage

    Science.gov (United States)

    Macpherson, Tom; Morita, Makiko; Wang, Yanyan; Sasaoka, Toshikuni; Sawa, Akira; Hikida, Takatoshi

    2016-01-01

    Considerable evidence has demonstrated a critical role for the nucleus accumbens (NAc) in the acquisition and flexibility of behavioral strategies. These processes are guided by the activity of two discrete neuron types, dopamine D1- or D2-receptor expressing medium spiny neurons (D1-/D2-MSNs). Here we used the IntelliCage, an automated…

  9. Ventral striatum binding of a dopamine D2/3 receptor agonist but not antagonist predicts normal body mass index.

    Science.gov (United States)

    Caravaggio, Fernando; Raitsin, Sofia; Gerretsen, Philip; Nakajima, Shinichiro; Wilson, Alan; Graff-Guerrero, Ariel

    2015-01-15

    Positron emission tomography research has shown that dopamine D2/3 receptor (D2/3R) availability is negatively correlated with body mass index (BMI) in obese but not in healthy subjects. However, previous positron emission tomography studies have not looked specifically at the ventral striatum (VS), which plays an important role in motivation and feeding. Furthermore, these studies have only used antagonist radiotracers. Normal-weight rats given free access to high-fat diets demonstrate behavioral sensitization to D2/3R agonists but not to antagonists. Sensitization is associated with increased D2/3R affinity, which affects binding of agonists but not antagonists. We examined the association between BMI within the nonobese range (18.6-27.8) and D2/3R availability in the VS with the use of the agonist radiotracer [(11)C]-(+)-PHNO (n = 26) and the antagonist [(11)C]-raclopride (n = 35) in healthy humans. In the VS, we found a positive correlation between BMI and [(11)C]-(+)-PHNO binding but no relationship with [(11)C]-raclopride binding. Secondary analyses revealed no relationship between BMI and binding in the dorsal striatum with either radiotracer. We propose that in nonobese individuals, higher BMI may be associated with increased D2R affinity in the VS. This increased affinity may potentiate the incentive salience of food cues and counteract the effects of satiety cues, thereby increasing feeding. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  10. Addiction-related alterations in D1 and D2 dopamine receptor behavioral responses following chronic cocaine self-administration.

    Science.gov (United States)

    Edwards, Scott; Whisler, Kimberly N; Fuller, Dwain C; Orsulak, Paul J; Self, David W

    2007-02-01

    The cocaine-addicted phenotype can be modeled in rats based on individual differences in preferred levels of cocaine intake and a propensity for relapse in withdrawal. These cocaine-taking and -seeking behaviors are strongly but differentially regulated by postsynaptic D1 and D2 receptors in the mesolimbic dopamine system. Thus, we determined whether addiction-related differences in cocaine self-administration would be related to differential sensitivity in functional D1 and D2 receptor responses. Using a population of 40 outbred Sprague-Dawley rats trained to self-administer cocaine for 3 weeks, we found that animals with higher preferred levels of cocaine intake exhibited a vertical and rightward shift in the self-administration dose-response function, and were more resistant to extinction from cocaine self-administration, similar to phenotypic changes reported in other models of cocaine addiction. After 3 weeks of withdrawal from cocaine self-administration, high intake rats were subsensitive to the ability of the D1 agonist SKF 81297 to inhibit cocaine-seeking behavior elicited by cocaine priming, but supersensitive to cocaine seeking triggered by the D2 agonist quinpirole, when compared to low intake rats. Additionally, high intake rats developed profound increases in locomotor responses to D2 receptor challenge from early to late withdrawal times, whereas low intake rats developed increased responsiveness to D1 receptor challenge. In a second experiment, responses to the mixed D1/D2 agonist apomorphine and the NMDA glutamate receptor antagonist MK-801 failed to differ between low and high intake rats. These findings suggest that cocaine addiction is related specifically to differential alterations in functional D1 and D2 receptors and their ability to modulate cocaine-seeking behavior.

  11. Polymorphic variants in the dopamine receptor D2 in women with endometriosis-related infertility.

    Science.gov (United States)

    Szczepańska, Malgorzata; Mostowska, Adrianna; Wirstlein, Przemyslaw; Skrzypczak, Jana; Misztal, Matthew; Jagodziński, Paweł P

    2015-08-01

    Data suggests that dopamine receptor DRD2 gene variants may contribute to hyperprolactinemia and that they may be risk factors for endometriosis-related infertility. The purpose of the present study was to determine whether nucleotide variants of the DRD2 gene may be associated with infertility related to endometriosis. Five DRD2 SNPs, rs1800497, rs6277, rs2283265, rs4245146 and rs4648317, which are located in different blocks of linkage disequilibrium, were studied in 151 cases and 381 controls. No significant differences between DRD2 rs1800497, rs6277, rs2283265, rs4245146 and rs4648317 genotype, allele nor haplotype frequencies were observed in women with endometriosis-related infertility compared with the control group. The present results did not confirm DRD2 gene variants to be genetic risk factors for endometriosis-related infertility.

  12. The mRNA Expression Status of Dopamine Receptor D2, Dopamine Receptor D3 and DARPP-32 in T Lymphocytes of Patients with Early Psychosis

    Directory of Open Access Journals (Sweden)

    Yin Cui

    2015-11-01

    Full Text Available Peripheral blood lymphocytes are an attractive tool because there is accumulating evidence indicating that lymphocytes may be utilized as a biomarker in the field of psychiatric study as they could reveal the condition of cells distributed in the brain. Here, we measured the mRNA expression status of dopamine receptor D2 (DRD2, DRD3, and dopamine and cyclic adenosine 3′,5′-monophosphate regulated phosphoprotein-32 (DARPP-32 in T lymphocytes of patients with early psychosis by quantitative real-time polymerase chain reaction (q-PCR and explored the relationships between their mRNA levels and the psychopathological status of patients. The present study demonstrated that the mRNA expression levels of DRD3 in T lymphocytes were significantly different among controls, and in patients with psychotic disorder not otherwise specified (NOS and schizophrenia/schizophreniform disorder. However, no significant differences in mRNA expression levels of DRD2 and DARPP-32 were found among the three groups. We found a significant positive correlation between the DRD2 mRNA level and the score of the excited factor of the Positive and Negative Syndrome Scale (PANSS in patients with schizophrenia/schizophreniform disorder. These findings suggest that DRD3 mRNA levels may serve as a potential diagnostic biomarker differentiating patients with early psychosis from controls.

  13. D1 and D2 specific dopamine antagonist modulate the caudate nucleus neuronal responses to chronic methylphenidate exposure.

    Science.gov (United States)

    Venkataraman, Sidish; Claussen, Catherine; Dafny, Nachum

    2017-02-01

    The psychostimulant, methylphenidate (MPD), is the first line treatment as a pharmacotherapy to treat behavioral disorders such as attention deficit hyperactivity disorder (ADHD). MPD is commonly misused in non-ADHD (normal) youth and young adults both as a recreational drug and for cognitive enhancing effects to improve their grades. MPD is known to act on the reward circuit; including the caudate nucleus (CN). The CN is comprised of medium spiny neurons containing largely dopamine (DA) D1 and D2 receptors. It has been widely shown that the DA system plays an important role in the response to MPD exposure. We investigated the role of both D1 and D2 DA receptors in the CN response to chronic MPD administration using specific D1 and D2 DA antagonist. Four groups of young adult, male SD rats were used: a saline (control) and three MPD dose groups (0.6, 2.5, and 10.0 mg/kg). The experiment lasted 11 consecutive days. Each MPD dose group was randomly divided into two subgroups to receive either a 0.4 mg/kg SCH-23390 selective D1 DA antagonist or a 0.3 mg/kg raclopride selective D2 DA antagonist prior to their final (repetitive) MPD rechallenge administration. It was observed that selective D1 DA antagonist (SCH-23390) given 30 min prior to the last MPD exposure at ED11 partially reduced or prevented the effect induced by MPD exposure in CN neuronal firing rates across all MPD doses. Selective D2 DA antagonist (raclopride) resulted in less obvious trends; some CN neuronal firing rates exhibited a slight increase in all MPD doses.

  14. Associations between dopamine D2 receptor gene polymorphisms and schizophrenia risk: a PRISMA compliant meta-analysis

    Directory of Open Access Journals (Sweden)

    He HR

    2016-12-01

    Full Text Available Hairong He,1 Huanhuan Wu,1,2 Lihong Yang,1 Fan Gao,1 Yajuan Fan,3 Junqin Feng,3 Xiancang Ma1,3 1Clinical Research Center, The First Affiliated Hospital of Xi’an Jiaotong University, 2College of Pharmacy, Xi’an Medical University, 3Department of Psychiatry, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China Objective: To determine the relationships between dopamine D2 receptor gene polymorphisms and the risk of schizophrenia using meta-analysis.Method: The PubMed, Embase, and China National Knowledge Infrastructure databases were searched to identify relevant literature published up to February 2016. The allele contrast model was used. STATA software was used for statistical analysis, with odds ratios (ORs and 95% confidence intervals (CIs calculated to evaluate the associations between dopamine D2 receptor gene polymorphisms and the risk of schizophrenia. Meta-regression and publication bias, trim-and-fill, subgroup, sensitivity, cumulative, and fail-safe number analyses were also performed.Results: This meta-analysis included 81 studies. The rs1801028 and rs1799732 were associated with schizophrenia risk among Asians (P=0.04, OR =1.25, 95% CI =1.01–1.55; P<0.01, OR =0.76, 95% CI =0.63–0.92, respectively, while the rs6277 was associated with schizophrenia risk in Caucasians (P<0.01, OR=0.72, 95% CI =0.66–0.79. The rs1800497 was also associated with schizophrenia risk in population-based controls (P<0.01, OR =0.84, 95% CI =0.72–0.97. The rs6275, rs1079597, and rs1800498 were not associated with schizophrenia risk. In addition, meta-regression indicated that the controls may be sources of heterogeneity for the rs1801028 single-nucleotide polymorphism (SNP, while ethnicity may be sources of heterogeneity for the rs6277 SNP. Publication bias was significant for the rs1801028 SNP, and this result changed after the publication bias was adjusted using the trim-and-fill method

  15. Distinct motor impairments of dopamine D1 and D2 receptor knockout mice revealed by three types of motor behavior

    Directory of Open Access Journals (Sweden)

    Toru eNakamura

    2014-07-01

    Full Text Available Both D1R and D2R knock out (KO mice of the major dopamine receptors show significant motor impairments. However, there are some discrepant reports, which may be due to the differences in genetic background and experimental procedures. In addition, only few studies directly compared the motor performance of D1R and D2R KO mice. In this paper, we examined the behavioral difference among N10 congenic D1R and D2R KO, and wild type (WT mice. First, we examined spontaneous motor activity in the home cage environment for consecutive five days. Second, we examined motor performance using the rota-rod task, a standard motor task in rodents. Third, we examined motor ability with the Step-Wheel task in which mice were trained to run in a motor-driven turning wheel adjusting their steps on foothold pegs to drink water. The results showed clear differences among the mice of three genotypes in three different types of behavior. In monitoring spontaneous motor activities, D1R and D2R KO mice showed higher and lower 24 h activities, respectively, than WT mice. In the rota-rod tasks, at a low speed, D1R KO mice showed poor performance but later improved, whereas D2R KO mice showed a good performance at early days without further improvement. When first subjected to a high speed task, the D2R KO mice showed poorer rota-rod performance at a low speed than the D1R KO mice. In the Step-Wheel task, across daily sessions, D2R KO mice increased the duration that mice run sufficiently close to the spout to drink water, and decreased time to touch the floor due to missing the peg steps and number of times the wheel was stopped, which performance was much better than that of D1R KO mice. These incongruent results between the two tasks for D1R and D2R KO mice may be due to the differences in the motivation for the rota-rod and Step-Wheel tasks, aversion- and reward-driven, respectively. The Step-Wheel system may become a useful tool for assessing the motor ability of WT

  16. Membrane omega-3 fatty acids modulate the oligomerisation kinetics of adenosine A2A and dopamine D2 receptors

    Science.gov (United States)

    Guixà-González, Ramon; Javanainen, Matti; Gómez-Soler, Maricel; Cordobilla, Begoña; Domingo, Joan Carles; Sanz, Ferran; Pastor, Manuel; Ciruela, Francisco; Martinez-Seara, Hector; Selent, Jana

    2016-01-01

    Membrane levels of docosahexaenoic acid (DHA), an essential omega-3 polyunsaturated fatty acid (ω-3 PUFA), are decreased in common neuropsychiatric disorders. DHA modulates key cell membrane properties like fluidity, thereby affecting the behaviour of transmembrane proteins like G protein-coupled receptors (GPCRs). These receptors, which have special relevance for major neuropsychiatric disorders have recently been shown to form dimers or higher order oligomers, and evidence suggests that DHA levels affect GPCR function by modulating oligomerisation. In this study, we assessed the effect of membrane DHA content on the formation of a class of protein complexes with particular relevance for brain disease: adenosine A2A and dopamine D2 receptor oligomers. Using extensive multiscale computer modelling, we find a marked propensity of DHA for interaction with both A2A and D2 receptors, which leads to an increased rate of receptor oligomerisation. Bioluminescence resonance energy transfer (BRET) experiments performed on living cells suggest that this DHA effect on the oligomerisation of A2A and D2 receptors is purely kinetic. This work reveals for the first time that membrane ω-3 PUFAs play a key role in GPCR oligomerisation kinetics, which may have important implications for neuropsychiatric conditions like schizophrenia or Parkinson’s disease.

  17. Synthesis, Molecular Properties Estimations, and Dual Dopamine D2 and D3 Receptor Activities of Benzothiazole-Based Ligands

    Directory of Open Access Journals (Sweden)

    Moritz Schübler

    2017-09-01

    Full Text Available Neurleptic drugs, e.g., aripiprazole, targeting the dopamine D2S and D3 receptors (D2SR and D3R in the central nervous system are widely used in the treatment of several psychotic and neurodegenerative diseases. Therefore, a new series of benzothiazole-based ligands (3-20 was synthesized by applying the bioisosteric approach derived from the selective D3Rs ligand BP-897 (1 and its structurally related benz[d]imidazole derivative (2. Herein, introduction of the benzothiazole moiety was well tolerated by D2SR and D3R binding sites leading to antagonist affinities in the low nanomolar concentration range at both receptor subtypes. However, all novel compounds showed lower antagonist affinity to D3R when compared to that of 1. Further exploration of different substitution patterns at the benzothiazole heterocycle and the basic 4-phenylpiperazine resulted in the discovery of high dually acting D2SR and D3R ligands. Moreover, the methoxy substitution at 2-position of 4-phenylpiperazine resulted in significantly (22-fold increased D2SR binding affinity as compared to the parent ligand 1, and improved physicochemical and drug-likeness properties of ligands 3-11. However, the latter structural modifications failed to improve the drug-able properties in ligands having un-substituted 4-phenylpiperazine analogs (12-20. Accordingly, compound 9 showed in addition to high dual affinity at the D2SR and D3R [Ki (hD2SR = 2.8 ± 0.8 nM; Ki (hD3R = 3.0 ± 1.6 nM], promising clogS, clogP, LE (hD2SR, hD3R, LipE (hD2SR, hD3R, and drug-likeness score values of −4.7, 4.2, (0.4, 0.4, (4.4, 4.3, and 0.7, respectively. Also, the deaminated analog 10 [Ki (hD2SR = 3.2 ± 0.4 nM; Ki (hD3R = 8.5 ± 2.2 nM] revealed clogS, clogP, LE (hD2SR, hD3R, LipE (hD2SR, hD3R and drug-likeness score values of −4.7, 4.2, (0.4, 0.4, (3.9, 3.5, and 0.4, respectively. The results observed for the newly developed benzothiazole-based ligands 3-20 provide clues for the diversity in structure

  18. Synthesis, molecular properties estimations, and dual dopamine D2 and D3 receptor activities of Benzthiazole-based ligands.

    Science.gov (United States)

    Schübler, Moritz; Sadek, Bassem; Kottke, Tim; Weizel, Lilia; Stark, Holger

    2017-09-01

    Neurleptic drugs, e.g. aripiprazole, targeting the dopamine D2s and D3 receptors (D2sR and D3R) in the central nervous system are widely used in the treatment of several psychotic and neurodegenerative diseases. Therefore, a new series of benz[d]thiazole-based ligands (1-18) was synthesized by applying the bioisosteric approach derived from the selective D3Rs ligand BP-897 and its structurally related benz[d]imidazole derivatives. Herein, introduction of the benz[d]thiazole moiety was well tolerated by D2sR and D3R binding sites leading to antagonist affinities in the low nanomolar concentration range at both receptor subtypes. Further exploration of different substitution patterns at the benz[d]thiazole heterocycle and the basic 4-phenylpiperazine resulted in the discovery of high dually acting D2sR and D3R ligands. Moreover, the methoxy substitution at 2-position of 4-phenylpiperazine resulted in significantly (22-fold) increased D2sR binding affinity as compared to the parent ligand BP-897, and improved physicochemical and drug-likeness properties of ligands 1-9. However, the latter structural modifications failed to improve the drug-able properties in ligands having un-substituted 4-phenylpiperazine analogues (10-18). Accordingly, compound 7 showed in addition to high dual affinity at the D2sR and D3R (Ki (hD2SR) = 2.8 ± 0.8 nM; Ki (hD3R) = 3.0 ± 1.6 nM), promising clogS, clogP, LE (hD2sR, hD3R), LipE (hD2sR, hD3R), and drug-likeness score values of -4.7, 4.2, (0.4, 0.4), (4.4, 4.3), and 0.7, respectively. Also, the deaminated analogue 8 (Ki (hD2SR) = 3.2 ± 0.4 nM; Ki (hD3R) = 8.5 ± 2.2 nM) revealed clogS, clogP, LE (hD2sR, hD3R), LipE (hD2sR, hD3R) and drug-likeness score values of -4.7, 4.2, (0.4, 0.4), (3.9, 3.5), and 0.4, respectively. The results observed for the newly developed benz[d]thiazole-based ligands 1-18 provide clues for the diversity in structure activity relationships (SARs) at the D2sR and D3R subtypes.

  19. Predicting treatment response in schizophrenia: The role of striatal and frontal dopamine D2/D3 receptor binding potential

    DEFF Research Database (Denmark)

    Nørbak, Henrik; Wulff, Sanne; Nielsen, Mette Ødegaard

    included 25 patients. The ligand [123I]epidepride was used for quantification of extrastriatal dopamine D2/D3 receptors. Patients were randomised to twelve weeks of treatment with either risperidone or zuclopenthixol. Results: In the IBZMcohort the mean PANSS total score was 79 at baseline and 65 at follow...... group (Rho=-0,417 P=0,060). In the EPIcohort the mean PANSS total score was 70 at baseline and 48 at follow up. In the frontal cortex we found a positive correlation (Rho=0.56 P=0.003) between BP and change in positive symptom score for the whole group as well as in the subgroup treated with risperidone...

  20. D2 and D4 dopamine receptor gene polymorphisms and personality traits in a young Korean population.

    Science.gov (United States)

    Lee, Heon-Jeong; Lee, Hong-Seock; Kim, Yong-Ku; Kim, Leen; Lee, Min Soo; Jung, In-Kwa; Suh, Kwang-Yoon; Kim, Sangduk

    2003-08-15

    The correlation between the D4 dopamine receptor gene (DRD4) and the D2 dopamine receptor gene (DRD2) polymorphisms was investigated with personality traits. For this study, homogeneous population consisting of 243 young alcohol- and drug-naive Koreans who were blood-unrelated with a mean age (+/-SD) of 13.87 (+/-0.30) years old was analyzed for the DRD4 and the DRD2 polymorphisms with their personality trait by Temperament and character inventory (TCI). The association between Novelty seeking (NS) score and DRD4 long alleles was only observed among the female subjects (t = 2.11, P = 0.037), but not in the male counter part. Female subjects who carried the DRD2 less frequent alleles (TaqI A1, TaqI B1, and Intron6 1) showed higher RD4 scores (dependence vs. independence) of Reward dependence (RD) than those without these alleles (P personality traits. These results, thus, confirmed the previous findings in which the long repeats of the DRD4-exon III polymorphism are related to NS personality trait, and also suggested that the DRD2 less frequent alleles were also associated with the reward-dependent trait. Copyright 2003 Wiley-Liss, Inc.

  1. Examining the Effects of Sodium Ions on the Binding of Antagonists to Dopamine D2 and D3 Receptors.

    Science.gov (United States)

    Newton, Claire L; Wood, Martyn D; Strange, Philip G

    2016-01-01

    Many G protein-coupled receptors have been shown to be sensitive to the presence of sodium ions (Na+). Using radioligand competition binding assays, we have examined and compared the effects of sodium ions on the binding affinities of a number of structurally diverse ligands at human dopamine D2 and dopamine D3 receptor subtypes, which are important therapeutic targets for the treatment of psychotic disorders. At both receptors, the binding affinities of the antagonists/inverse agonists SB-277011-A, L,741,626, GR 103691 and U 99194 were higher in the presence of sodium ions compared to those measured in the presence of the organic cation, N-methyl-D-glucamine, used to control for ionic strength. Conversely, the affinities of spiperone and (+)-butaclamol were unaffected by the presence of sodium ions. Interestingly, the binding of the antagonist/inverse agonist clozapine was affected by changes in ionic strength of the buffer used rather than the presence of specific cations. Similar sensitivities to sodium ions were seen at both receptors, suggesting parallel effects of sodium ion interactions on receptor conformation. However, no clear correlation between ligand characteristics, such as subtype selectivity, and sodium ion sensitivity were observed. Therefore, the properties which determine this sensitivity remain unclear. However these findings do highlight the importance of careful consideration of assay buffer composition for in vitro assays and when comparing data from different studies, and may indicate a further level of control for ligand binding in vivo.

  2. Ciliary neurotrophic factor mediates dopamine D2 receptor-induced CNS neurogenesis in adult mice.

    Science.gov (United States)

    Yang, Peng; Arnold, Sheila A; Habas, Agata; Hetman, Michal; Hagg, Theo

    2008-02-27

    Neurogenesis continues in the adult forebrain subventricular zone (SVZ) and the dentate gyrus of the hippocampal formation. Degeneration of dopaminergic projections in Parkinson's disease and animals reduces, whereas ciliary neurotrophic factor (CNTF) promotes, neurogenesis. We tested whether the dopaminergic system promotes neurogenesis through CNTF. Astrocytes of the SVZ and dentate gyrus expressed CNTF and were close to dopaminergic terminals. Dopaminergic denervation in adult mice reduced CNTF mRNA by approximately 60%, whereas systemic treatment with the D2 agonist quinpirole increased CNTF mRNA in the SVZ and hippocampal formation, and in cultured astrocytes by 1.5-5 fold. The effect of quinpirole in vitro was blocked by the D2 antagonist eticlopride and did not cause astroglial proliferation or hypertrophy. Systemic quinpirole injections increased proliferation in wild-type mice by approximately 25-75% but not in CNTF-/- littermates or in the SVZ of mice infused with CNTF antibodies. Quinpirole increased the number of neuroblasts in wild-type but not in CNTF-/- littermates. Neurogenesis was reduced by approximately 20% in CNTF-/- mice, confirming the endogenous role of CNTF. Nigrostriatal denervation did not affect SVZ proliferation in CNTF-/- mice, suggesting that the dopaminergic innervation normally regulates neurogenesis through CNTF. Quinpirole acted on postsynaptic receptors as it reversed the reduced proliferation seen after dopaminergic denervation in wild-type mice. Thus, CNTF mediates dopaminergic innervation- and D2 receptor-induced neurogenesis in the adult forebrain. Because CNTF is predominantly expressed in the nervous system, this mechanism and the ability to pharmacologically modulate it have implications for Parkinson's disease and cell-replacement therapies for other disorders.

  3. Electroacupuncture-Induced Neuroprotection against Cerebral Ischemia in Rats: Role of the Dopamine D2 Receptor

    Directory of Open Access Journals (Sweden)

    Ming-Shu Xu

    2013-01-01

    Full Text Available Background. Cerebral ischemia is known to produce brain damage and related behavioural deficits, including memory deficits and motor disorders. Evidence shows that EA significantly promotes recovery of neurological function and thus improves quality of life. Objective. Evidence exists for the involvement of catecholamines in human neuroplasticity. A better understanding of dopaminergic (DAergic modulation in this process will be important. Methods. A total of 72 adult male Sprague-Dawley (SD rats were divided into 6 groups: normal, model, EA, spiperone group, EA + spiperone group, and pergolide. The middle cerebral artery occlusion (MCAO model was used in all 6 groups except the normal group. A behavioural assessment was conducted at 1, 3, 5, and 7 days after MCAO. The percent of brain infarct area was also determined 7 days after MCAO. Tyrosine hydroxylase (TH and growth-associated protein 43 (GAP-43 fluorescence double labeling was performed in the striatum. Results. In this study, we found that EA at Fengchi (GB20 acupoints resulted in marked improvements based on a behavioural assessment. Both TTC staining and GAP-43 immunofluorescence labeling results showed that EA treatment reduced ischemia injury and promoted neuroplasticity compared with the model group. The D2R-selective agonist, pergolide, showed similar results, but these results were reversed by the D2R-selective antagonist, spiperone. We also found that there were more colocalization and expression of GAP-43 and TH in the EA and pergolide groups than those in the other groups. Conclusion. These results suggest that the neuroplasticity induced by EA was mediated by D2 autoreceptors in DAergic neurons.

  4. Dopamine D2 receptor status assessed by IBZM SPECT - A sensitive indicator for cerebral hypoxia

    Energy Technology Data Exchange (ETDEWEB)

    Tatsch, K.; Schwarz, J.; Welz, A. [Univ. of Munich (Germany)] [and others

    1995-05-01

    The striatum is highly sensitive to tissue hypoxia. Thus, it may be suggested that cerebral hypoxia could affect the integrity of the striatal receptor system. Purpose of the current SPECT investigations with IBZM was to evaluate whether hypoxic conditions cause detectable changes in the D2 receptor status. 25 controls and 30 pts with history of cerebral hypoxia (resuscitation after cardiac arrest: n=19, CABG surgery under cardiopulmonary bypass: n=11) were investigated with SPECT 2h p.i. of 185 MBq I-123 IBZM. For semiquant, evaluation transverse slices corrected for attenuation were used to calculate striatal to frontal cortex (S/FC) ratios. In 13/19 pts with cerebral hypoxia due to cardiac arrest IBZM binding was severely reduced after successful resuscitation. 7 died, 5 were in a vegetative state, 1 remained severely disabled. In 6/19 S/FC ratios were normal/mildly reduced, 2 of them had a good outcome, 4 were moderatley disabled. In pts with CABG IBZM binding was preoperatively normal. After hypoxia due to cardiac surgery striatal S/FC ratios decreased slightly, persisting on this level even 6 months after surgery. Neuropsychological/psychiatric testing showed only minor or transient changes in this group of patients. The striatal D2 receptor status seems to be a sensitive indicator for cerebral hypoxia. After hypoxia due to cardiac arrest IBZM results well correlate (in contrast to morphological or SEP findings) with the clinical outcome and thus may serve as early predictor of the individual prognosis. The moderate decline in IBZM binding following CABG surgery suggests mild cerebral hypoxia despite of protective hypothermia. Sensitively indicating cerebral hypoxia changes in the D2 receptor status assessed by IBZM SPECT may serve as a valuable diagnostic tool for testing neuroprotective drugs or modified surgical techniques.

  5. Terguride, a dopamine D(2) partial agonist, as a discriminative stimulus in rats.

    Science.gov (United States)

    Yamaguchi, M.; Kimura-Iwasaki, K.; Akai, T.; Nakada, Y.; Nakagawa, H.

    1991-06-01

    Drug discrimination training with terguride, a 9, 10-transdihydrogenated derivative of lisuride, was carried out using a two-lever food-reinforced procedure (FR 10) in rats, to investigate its influence on central dopaminergic (DA) and serotonergic (5-HT) functions. The terguride (0.05mg/kg, i.p.) discrimination was established within 64 +/- 5 training sessions (mean +/- S.E.) and was stably maintained thereafter. Higher doses of terguride could not be used for discriminative training due to response disruption. In generalization tests with terguride, drug-appropriate responding increased dose-dependently and reached levels of 45 and 99% at 0.01 and 0.05mg/kg i.p. The D(2) agonist lisuride at low doses and the DA autoreceptor agonist (-)-3-PPP substituted for terguride. The DA agonist apomorphine and the 5-HT agonist 5-MeO-DMT produced dose-dependent but incomplete substitution. The D(1) agonist SKF38393, the DA antagonist haloperidol, the D(2) antagonist sulpiride, the D(1) antagonist SCH23390, the 5-HT(1A) agonist 8-OH-DPAT, the 5-HT(1B) agonist m-CPP and the 5-HT(2) agonist DOI were not generalized. In antagonism tests, sulpride completely blocked the terguride-appropriate response, but SCH23390 and the 5-HT antagonist methysergide did not. These results indicate that discriminative stimulus properties of terguride in rats are mediated primarily by activation of receptors with characteristics similar to those of presynaptic D(2) autoreceptors.

  6. Dopamine D2-receptor imaging with [sup 123]I-iodobenzamide SPECT in migraine patients abusing ergotamine: does ergotamine cross the blood brain barrier

    Energy Technology Data Exchange (ETDEWEB)

    Verhoeff, N.P.; Visser, W.H.; Ferrari, M.D.; Saxena, P.R.; Royen, E.A. van (Erasmus Univ., Rotterdam (Netherlands))

    1993-10-01

    Two migraine patients were studied by in vivo SPECT using the dopamine D2-receptor specific radioligand [sup 123]I-3-iodo-6-methoxybenzamide ([sup 123]I-IBZM) during ergotamine abuse and after withdrawal. Results were compared with 15 healthy controls. Striatum/cerebellum and striatum/occipital cortex ratios of count rate density were calculated as a semiquantitative measurement for striatal dopamine D2-receptor binding potential. No differences were found in striatal uptake of [sup 123]I-IBZM between healthy controls and the patients when on or off ergotamine. Preliminary evidence suggests that ergotamine may not occupy striatal dopamine D2-receptors to a large extent and thus may not cross the blood brain barrier in large quantities. 23 refs., 3 figs.

  7. [123I]epidepride binding to cerebellar dopamine D2/D3 receptors is displaceable: implications for the use of cerebellum as a reference region

    DEFF Research Database (Denmark)

    Pinborg, Lars H; Videbaek, Charlotte; Ziebell, Morten

    2007-01-01

    The low density of cerebellar dopamine D(2)/D(3) receptors provides the basis for using the cerebellum as a representation of free- and non-specifically bound radioligand in positron emission tomography (PET) and single photon emission computed tomography (SPECT) studies. With the development...... of ultra high-affinity dopamine D(2)/D(3) ligands like [(123)I]epidepride, [(18)F]fallypride, and [(11)C]FLB-457, quantification of extrastriatal low density receptor populations including the cerebellum is possible with important implications for calculation of binding parameters. [(123)I...... [(123)I]epidepride binding to dopamine D(2)/D(3) receptors in the cerebellum. Using the cerebellum as a representation of free and non-specifically bound radioligand and neglecting the specifically bound component may lead to results that erroneously imply that antipsychotic drugs bind to extrastriatal...

  8. Dopamine and the management of attentional resources: genetic markers of striatal D2 dopamine predict individual differences in the attentional blink.

    Science.gov (United States)

    Colzato, Lorenza S; Slagter, Heleen A; de Rover, Mischa; Hommel, Bernhard

    2011-11-01

    The attentional blink (AB)--a deficit in reporting the second of two target stimuli presented in close succession in a rapid sequence of distracters--has been related to processing limitations in working memory. Given that dopamine (DA) plays a crucial role working memory, the present study tested whether individual differences in the size of the AB can be predicted by differences in genetic predisposition related to the efficiency of dopaminergic pathways. Polymorphisms related to mesocortical and nigrostriatal dopaminergic pathways were considered, as well as polymorphisms related to norepinephrine (NE), a transmitter system that has also been suspected to play a role in the AB. In a sample of 157 healthy adults, we studied the dependency of the individual magnitude of the AB and the C957T polymorphism at the DRD2 gene (associated with striatal DA/D2 receptors), the DARPP32 polymorphism (associated with striatal DA/D1), the COMT Val(158)Met polymorphism (associated with frontal DA), DBH444 g/a and DBH5'-ins/del polymorphisms (polymorphisms strongly correlated with DA beta hydroxylase, the enzyme catalyzing the DA-NE conversion) and NET T-182C (a polymorphism related to the NE transporter). DRD2 C957T T/T homozygotes showed a significantly smaller AB, whereas polymorphisms associated with frontal DA and NE were unrelated to performance. This outcome pattern suggests a crucial role of the nigrostriatal dopaminergic pathway and of nigrostriatal D2 receptors, in particular, in the management of attentional resources.

  9. Abundant immunohistochemical expression of dopamine D2 receptor and p53 protein in meningiomas: follow-up, relation to gender, age, tumor grade, and recurrence

    Directory of Open Access Journals (Sweden)

    G. Trott

    2015-05-01

    Full Text Available Meningiomas are common, usually benign tumors, with a high postoperative recurrence rate. However, the genesis and development of these tumors remain controversial. We aimed to investigate the presence and implications of a mutated p53 protein and dopamine D2 receptor in a representative series of meningiomas and to correlate these findings with age, gender, tumor grade, and recurrence. Tumor tissue samples of 157 patients diagnosed with meningioma (37 males and 120 females, mean age 53.6±14.3 years who underwent surgical resection between 2003 and 2012 at our institution were immunohistochemically evaluated for the presence of p53 protein and dopamine D2 receptor and were followed-up to analyze tumor recurrence or regrowth. Tumors were classified as grades I (n=141, 89.8%, II (n=13, 8.3%, or grade III (n=3, 1.9%. Dopamine D2 receptor and p53 protein expression were positive in 93.6% and 49.7% of the cases, respectively. Neither of the markers showed significant expression differences among different tumor grades or recurrence or regrowth statuses. Our findings highlight the potential role of p53 protein in meningioma development and/or progression. The high positivity of dopamine D2 receptor observed in this study warrants further investigation of the therapeutic potential of dopamine agonists in the evolution of meningiomas.

  10. Specific binding of photoaffinity-labeling peptidomimetics of Pro-Leu-Gly-NH2 to the dopamine D2L receptor: evidence for the allosteric modulation of the dopamine receptor.

    Science.gov (United States)

    Mann, Amandeep; Verma, Vaneeta; Basu, Dipannita; Skoblenick, Kevin J; Beyaert, Michael G R; Fisher, Abigail; Thomas, Nancy; Johnson, Rodney L; Mishra, Ram K

    2010-09-01

    The present study was undertaken to investigate the mechanistic role of l-prolyl-l-leucyl-glycinamide (PLG) in modulating agonist binding to the dopamine D(2L) receptor. Competition and displacement assays indicate that the photoaffinity-labeling peptidomimetics of PLG, 3(R)-[(4(S)-(4-azido-2-hydroxy-benzoyl) amino-2(S)-pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide hydrochloride (1a) and 3(R)-[(4(S)-(4-azido-2-hydroxy-5-iodo-benzoyl)amino-2(S)-pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide hydrochloride (1b) bind at the same site as PLG. Autoradiography was used to establish the covalent binding of [(125)I]-1b to an approximately 51kDa protein in bovine striatal membranes. Western blot analysis with a dopamine D(2L)-specific antibody, in combination with autoradiography, following a two-dimensional gel separation, suggested this approximately 51kDa protein to be the dopamine D(2L) receptor. Further evidence for binding of 1b to dopamine D(2L) was provided by samples immunoprecipitated with the D(2L) antibody. These samples were analyzed by western blotting in parallel with autoradiography of [(125)I]-1b labeled protein. Both methods revealed bands at approximately 51kDa. Furthermore, PLG is shown to compete with 1b for binding to the dopamine D(2L) receptor as determined by autoradiography, as well as competition experiments with PLG and 1a. Collectively, these findings suggest the successful development of a photoaffinity-labeling agent, compound 1b, that has been used to elucidate the interaction of PLG specifically with the dopamine D(2L) receptor. Copyright (c) 2010 Elsevier B.V. All rights reserved.

  11. Dopamine D2 receptors mediate the increase in reinstatement of the conditioned rewarding effects of cocaine induced by acute social defeat.

    Science.gov (United States)

    Reguilón, Marina Daiana; Montagud-Romero, Sandra; Ferrer-Pérez, Carmen; Roger-Sánchez, Concepción; Aguilar, María Asunción; Miñarro, José; Rodríguez-Arias, Marta

    2017-03-15

    Social stress modifies the activity of brain areas involved in the rewarding effects of psychostimulants, inducing neuroadaptations in the dopaminergic mesolimbic system and modifying the sensitivity of dopamine receptors. In the present study we evaluated the effect of the dopamine D1- and D2-like receptor antagonists (SCH23390 and raclopride, respectively) on the short-time effects of acute social defeat (ASD). Male OF1 mice were socially defeated before each conditioning session of the conditioned place preference (CPP) induced by 1mg/kg or 25mg/kg of cocaine plus the corresponding dopamine antagonist. A final experiment was designed to evaluate the effect of the dopamine antagonists on the CPP induced by 3mg/kg of cocaine with or without a stress experience. Mice exposed to ASD showed an increase in reinstatement of the conditioned reinforcing effects of cocaine that was blocked by all of the dopamine receptor antagonists. Blockade of dopamine D2-like receptors with raclopride specifically prevented the effects of stress without affecting the rewarding properties of cocaine. However, SCH23390 inhibited cocaine-induced preference in the control groups and even induced aversion in defeated mice conditioned with the lower dose of cocaine. Moreover, the lowest dose of SCH23390 blocked the rewarding effects of 3mg/kg of cocaine-induced CPP. Our results confirm that the dopamine D2 receptor is involved in the short-term effects of ASD on the rewarding effects of cocaine. The dopamine D1 receptor is clearly involved in the rewarding effects of cocaine, but its role in the effects of ASD remains to be demonstrated. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Differential expression of a(2a), A(1)-adenosine and D(2)-dopamine receptor genes in rat peripheral arterial chemoreceptors during postnatal development.

    Science.gov (United States)

    Gauda, E B; Northington, F J; Linden, J; Rosin, D L

    2000-07-28

    The sensitivity of peripheral arterial chemoreceptors in the carotid body to hypoxia increases with postnatal maturation. Carotid sinus nerve activity is augmented by adenosine binding to A(2a)-adenosine receptors and attenuated by dopamine binding to D(2)-dopamine receptors. In this study, we used in situ hybridization histochemistry to determine the change in the levels of mRNA expression for A(2a) and A(1)-adenosine receptors and D(2)-dopamine receptors in the rat carotid body. We also investigated the cellular distribution and possible colocalization of these receptor mRNAs and tyrosine hydroxylase (TH) mRNAs during the first 2 weeks of postnatal development. By using immunohistocytochemistry, we detected A(2a)-adenosine receptor protein in the carotid body and petrosal ganglion. We found that A(2a)-adenosine receptor mRNA and protein are expressed in the carotid body in animals at 0, 3, 6 and 14 postnatal days. The level of A(2a)-adenosine receptor mRNA expression significantly decreased by 14 postnatal days (P<0.02 vs. day 0) while D(2)-dopamine receptor mRNA levels significantly increased by day 3 and remained greater than D(2)-dopamine receptor mRNA levels at day 0 (P<0.001 all ages vs. day 0). TH mRNA was colocalized in cells in the carotid body with A(2a) adenosine receptor and D(2)-dopamine receptor mRNAs. A(1)-adenosine receptor mRNA was not expressed in the carotid body at any of the ages examined. In the petrosal ganglion, A(1)-adenosine receptor mRNA was abundantly expressed in numerous cells, A(2a)-adenosine receptor mRNA was expressed in a moderate number of cells while D(2)-dopamine receptor mRNA was seen in a few cells in the rostral petrosal ganglion. In conclusion, using in situ hybridization histochemistry, we have shown that mRNA for both the excitatory, A(2a)-adenosine receptor, and the inhibitory, D(2)-dopamine receptor, is developmentally regulated in presumably type I cells in the carotid body which may contribute to the maturation of

  13. Neurochemical evidence supporting dopamine D1-D2 receptor heteromers in the striatum of the long-tailed macaque: changes following dopaminergic manipulation.

    Science.gov (United States)

    Rico, Alberto J; Dopeso-Reyes, Iria G; Martínez-Pinilla, Eva; Sucunza, Diego; Pignataro, Diego; Roda, Elvira; Marín-Ramos, David; Labandeira-García, José L; George, Susan R; Franco, Rafael; Lanciego, José L

    2017-05-01

    Although it has long been widely accepted that dopamine receptor types D1 and D2 form GPCR heteromers in the striatum, the presence of D1-D2 receptor heteromers has been recently challenged. In an attempt to properly characterize D1-D2 receptor heteromers, here we have used the in situ proximity ligation assay (PLA) in striatal sections comprising the caudate nucleus, the putamen and the core and shell territories of the nucleus accumbens. Experiments were carried out in control macaques as well as in MPTP-treated animals (with and without dyskinesia). Obtained data support the presence of D1-D2 receptor heteromers within all the striatal subdivisions, with the highest abundance in the accumbens shell. Dopamine depletion by MPTP resulted in an increase of D1-D2 density in caudate and putamen which was normalized by levodopa treatment. Two different sizes of heteromers were consistently found, thus suggesting that besides individual heteromers, D1-D2 receptor heteromers are sometimes organized in macromolecular complexes made of a number of D1-D2 heteromers. Furthermore, the PLA technique was combined with different neuronal markers to properly characterize the identities of striatal neurons expressing D1-D2 heteromers. We have found that striatal projection neurons giving rise to either the direct or the indirect basal ganglia pathways expressed D1-D2 heteromers. Interestingly, macromolecular complexes of D1-D2 heteromers were only found within cholinergic interneurons. In summary, here we provide overwhelming proof that D1 and D2 receptors form heteromeric complexes in the macaque striatum, thus representing a very appealing target for a number of brain diseases involving dopamine dysfunction.

  14. The importance of the adenosine A(2A) receptor-dopamine D(2) receptor interaction in drug addiction.

    Science.gov (United States)

    Filip, M; Zaniewska, M; Frankowska, M; Wydra, K; Fuxe, K

    2012-01-01

    Drug addiction is a serious brain disorder with somatic, psychological, psychiatric, socio-economic and legal implications in the developed world. Illegal (e.g., psychostimulants, opioids, cannabinoids) and legal (alcohol, nicotine) drugs of abuse create a complex behavioral pattern composed of drug intake, withdrawal, seeking and relapse. One of the hallmarks of drugs that are abused by humans is that they have different mechanisms of action to increase dopamine (DA) neurotransmission within the mesolimbic circuitry of the brain and indirectly activate DA receptors. Among the DA receptors, D(2) receptors are linked to drug abuse and addiction because their function has been proven to be correlated with drug reinforcement and relapses. The recognition that D(2) receptors exist not only as homomers but also can form heteromers, such as with the adenosine (A)(2A) receptor, that are pharmacologically and functionally distinct from their constituent receptors, has significantly expanded the range of potential drug targets and provided new avenues for drug design in the search for novel drug addiction therapies. The aim of this review is to bring current focus on A(2A) receptors, their physiology and pharmacology in the central nervous system, and to discuss the therapeutic relevance of these receptors to drug addiction. We concentrate on the contribution of A(2A) receptors to the effects of different classes of drugs of abuse examined in preclinical behavioral experiments carried out with pharmacological and genetic tools. The consequences of chronic drug treatment on A(2A) receptor-assigned functions in preclinical studies are also presented. Finally, the neurochemical mechanism of the interaction between A(2A) receptors and drugs of abuse in the context of the heteromeric A(2A)-D(2) receptor complex is discussed. Taken together, a significant amount of experimental analyses provide evidence that targeting A(2A) receptors may offer innovative translational strategies

  15. CHRONIC Δ9-THC IN RHESUS MONKEYS: EFFECTS ON COGNITIVE PERFORMANCE AND DOPAMINE D2/D3 RECEPTOR AVAILABILITY.

    Science.gov (United States)

    John, William S; Martin, Thomas J; Solingapuram Sai, Kiran K; Nader, Susan H; Gage, H D; Mintz, Akiva; Nader, Michael A

    2017-12-04

    Cannabis-related impairments to cognitive function may represent novel therapeutic targets for cannabis-use disorder, although the nature, persistence, and reversibility of those deficits remain unclear. Adult male rhesus monkeys (N=6) responded in the mornings on tasks designed to assess different cognitive domains using CANTAB touchscreens followed by responding maintained under a fixed-ratio (FR) 10 schedule of food presentation in different operant chambers. First, the acute effects of Δ9-tetrahydrocannabinol (THC; 0.01-0.56 mg/kg, i.v.) on cognitive performance, FR responding and body temperature were determined. Next, THC (1.0-2.0 mg/kg, s.c.) was administered daily after FR10 sessions for 12 weeks during which the residual effects of THC (i.e., 22 hrs after administration) on cognition were examined and the acute effects of THC were redetermined. In a subgroup of monkeys, dopamine D2/D3 receptor availability was assessed after 4 weeks of chronic THC exposure and compared to drug-naive controls using positron emission tomography and [11C]-raclopride (N=4/group). Acute THC pretreatments dose-dependently decreased FR responding and body temperature, while impairment to cognitive performance was task specific. During chronic treatment, THC produced persistent residual impairment only to working memory; tolerance differentially developed to acute cognitive impairments. There was recovery from residual cognitive impairments to working memory within 2 weeks of abstinence. Compared to controls, D2/D3 receptor availability was not altered during chronic THC treatment. In conclusion, THC-induced disruptions in cognition were task-specific, as was tolerance development, and not related to changes in D2/D3 receptor availability. Intervention strategies for cannabis-use disorder that enhance working memory performance may facilitate positive treatment outcomes. The American Society for Pharmacology and Experimental Therapeutics.

  16. Dopamine D1-D2 receptor heteromer in dual phenotype GABA/glutamate-coexpressing striatal medium spiny neurons: regulation of BDNF, GAD67 and VGLUT1/2.

    Directory of Open Access Journals (Sweden)

    Melissa L Perreault

    Full Text Available In basal ganglia a significant subset of GABAergic medium spiny neurons (MSNs coexpress D1 and D2 receptors (D1R and D2R along with the neuropeptides dynorphin (DYN and enkephalin (ENK. These coexpressing neurons have been recently shown to have a region-specific distribution throughout the mesolimbic and basal ganglia circuits. While the functional relevance of these MSNs remains relatively unexplored, they have been shown to exhibit the unique property of expressing the dopamine D1-D2 receptor heteromer, a novel receptor complex with distinct pharmacology and cell signaling properties. Here we showed that MSNs coexpressing the D1R and D2R also exhibited a dual GABA/glutamate phenotype. Activation of the D1R-D2R heteromer in these neurons resulted in the simultaneous, but differential regulation of proteins involved in GABA and glutamate production or vesicular uptake in the nucleus accumbens (NAc, ventral tegmental area (VTA, caudate putamen and substantia nigra (SN. Additionally, activation of the D1R-D2R heteromer in NAc shell, but not NAc core, differentially altered protein expression in VTA and SN, regions rich in dopamine cell bodies. The identification of a MSN with dual inhibitory and excitatory intrinsic functions provides new insights into the neuroanatomy of the basal ganglia and demonstrates a novel source of glutamate in this circuit. Furthermore, the demonstration of a dopamine receptor complex with the potential to differentially regulate the expression of proteins directly involved in GABAergic inhibitory or glutamatergic excitatory activation in VTA and SN may potentially provide new insights into the regulation of dopamine neuron activity. This could have broad implications in understanding how dysregulation of neurotransmission within basal ganglia contributes to dopamine neuronal dysfunction.

  17. The dopamine D1-D2 receptor heteromer exerts tonic inhibitory effect on the expression of amphetamine-induced locomotor sensitization

    Science.gov (United States)

    Shen, Maurice Y.F.; Perreault, Melissa L.; Fan, Theresa; George, Susan R.

    2014-01-01

    A role for the dopamine D1-D2 receptor heteromer in the regulation of reward and addiction-related processes has been previously implicated. In the present study, we examined the effects of D1-D2 heteromer stimulation by the agonist SKF 83959 and its disruption by a selective TAT-D1 peptide on amphetamine-induced locomotor sensitization, a behavioural model widely used to study the neuroadaptations associated with psychostimulant addiction. D1-D2 heteromer activation by SKF 83959 did not alter the acute locomotor effects of amphetamine but significantly inhibited amphetamine-induced locomotor responding across the 5 day treatment regimen. In addition, a single injection of SKF 83959 was sufficient to abolish the expression of locomotor sensitization induced by a priming injection of amphetamine after a 72-hour withdrawal. Conversely, inhibition of D1-D2 heteromer activity by the TAT-D1 peptide enhanced subchronic amphetamine-induced locomotion and the expression of amphetamine locomotor sensitization. Treatment solely with the TAT-D1 disrupting peptide during the initial 5 day treatment phase was sufficient to induce a sensitized locomotor phenotype in response to the priming injection of amphetamine. Together these findings demonstrate that the dopamine D1-D2 receptor heteromer exerts tonic inhibitory control on neurobiological processes involved in sensitization to amphetamine, indicating that the dopamine D1-D2 receptor heteromer may be a novel molecular substrate in addiction processes involving psychostimulants. PMID:25444866

  18. MDMA-evoked changes in the binding of dopamine D(2) receptor ligands in striatum of rats with unilateral serotonin depletion

    DEFF Research Database (Denmark)

    Ostergaard, Søren Dinesen; Alstrup, Aage Kristian Olsen; Gramsbergen, Jan Bert

    2010-01-01

    We earlier reported an anomalous 50% decrease in [(11)C]N-methylspiperone ([(11)C]NMSP) binding to dopamine D(2)-like receptors in living pig striatum after challenge with 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy"), suggesting either (1) a species peculiarity in the vulnerability of buty...

  19. Molecular modeling of the dopamine D-2 and serotonin 5-HT1A receptor binding modes of the enantiomers of 5-OMe-BPAT

    NARCIS (Netherlands)

    Homan, EJ; Wikstrom, HV; Grol, CJ

    Molecular modeling studies were undertaken in order to elucidate the possible dopamine D-2 and serotonin 5-HT1A receptor binding modes of the enantiomers of 5-methoxy-2-[N-(2-benzamidoethyl)-N-n-pylamino]tetralin (5-OMe-BPAT, 1). For this purpose, a combination of indirect molecular modeling and

  20. In vivo measurement of haloperidol affinity to dopamine D2/D3 receptors by [123I]IBZM and single photon emission computed tomography

    DEFF Research Database (Denmark)

    Videbaek, C; Toska, K; Friberg, L

    2001-01-01

    This study examines the feasibility of a steady-state bolus-integration method with the dopamine D2/D3 receptor single photon emission computer tomography (SPECT) tracer, [123I]IBZM, for determination of in vivo affinity of haloperidol. The nonspecific binding of [123I]IBZM was examined in the rat...

  1. Sex-specific effects of naturally occurring variants in the dopamine receptor D2 locus on insulin secretion and Type 2 diabetes susceptibility

    DEFF Research Database (Denmark)

    Guigas, B; de Leeuw van Weenen, J E; van Leeuwen, N

    2014-01-01

    AIMS: Modulation of dopamine receptor D2 (DRD2) activity affects insulin secretion in both rodents and isolated pancreatic β-cells. We hypothesized that single nucleotide polymorphisms in the DRD2/ANKK1 locus may affect susceptibility to Type 2 diabetes in humans. METHODS: Four potentially...

  2. The Area Method and the Table-Look-Up Method for 123I Epidepride SPECT Studies of Dopamine D2 Receptors

    DEFF Research Database (Denmark)

    Videbæk, Charlotte; Pindborg, Lars; Haldin, C

    1998-01-01

    Videbæk, C., Pinborg, L.H., Lassen, A., Halldin, C., Swahn, C-G., Yndgaard, S., Paulson, O.B. and Lassen, N.A. The Area Method and the Table-Look-Up Method for 123I Epidepride SPECT Studies of Dopamine D2 Receptors Abstract in Neuroimage 5(4), A21 Neurobiology Research Unit, Rigshospitalet, DENMARK...

  3. [¹¹C]-(+)-PHNO PET imaging of dopamine D(2/3) receptors in Parkinson's disease with impulse control disorders.

    Science.gov (United States)

    Payer, Doris E; Guttman, Mark; Kish, Stephen J; Tong, Junchao; Strafella, Antonio; Zack, Martin; Adams, John R; Rusjan, Pablo; Houle, Sylvain; Furukawa, Yoshiaki; Wilson, Alan A; Boileau, Isabelle

    2015-02-01

    Dopamine agonist medications with high affinity for the D3 dopamine receptor are commonly used to treat Parkinson's disease, and have been associated with pathological behaviors categorized under the umbrella of impulse control disorders (ICD). The aim of this study was to investigate whether ICD in Parkinson's patients are associated with greater D3 dopamine receptor availability. We used positron emission tomography (PET) radioligand imaging with the D3 dopamine receptor preferring agonist [¹¹C]-(+)-propyl-hexahydro-naphtho-oxazin (PHNO) in Parkinson's patients with (n = 11) and without (n = 21) ICD, and age-, sex-, and education-matched healthy control subjects (n = 18). Contrary to hypotheses, [¹¹C]-(+)-PHNO binding in D3 -rich brain areas was not elevated in Parkinson's patients with ICD compared with those without; instead, [¹¹C]-(+)-PHNO binding in ventral striatum was 20% lower (P = 0.011), correlating with two measures of ICD severity (r = -0.8 and -0.9), which may reflect higher dopamine tone in ventral striatum. In dorsal striatum, where [¹¹C]-(+)-PHNO binding is associated with D2 receptor levels, [¹¹C]-(+)-PHNO binding was elevated across patients compared with controls. We conclude that although D3 dopamine receptors have been linked to the occurrence of ICD in Parkinson's patients. Our findings do not support the hypothesis that D3 receptor levels are elevated in Parkinson's patients with ICD. We also did not find ICD-related abnormalities in D2 receptor levels. Our findings argue against the possibility that differences in D2/3 receptor levels can account for the development of ICD in PD; however, we cannot rule out that differences in dopamine levels (particularly in ventral striatum) may be involved. © 2015 International Parkinson and Movement Disorder Society.

  4. Possible role of dopamine D1-like and D2-like receptors in behavioural activation and evaluation of response efficacy in the forced swimming test.

    Science.gov (United States)

    D'Aquila, Paolo S; Galistu, Adriana

    2012-03-01

    Based on the different effects of the dopamine D1-like and D2-like receptor antagonists SCH 23390 and raclopride on the measures of licking microstructure in rats ingesting a sucrose solution, we suggested that the behavioural activation of reward-associated responses depends on dopamine D1-like receptor stimulation, and its level is updated, or "reboosted", on the basis of a dopamine D2-like receptor-mediated evaluation process. The aim of this study was to test this hypothesis on the forced swimming test response. The effects of the dopamine D1-like and D2-like receptor antagonists SCH 23390 (0.01-0.04 mg/kg) and raclopride (0.025-0.25 mg/kg) administered before a 15-min exposure to forced swimming, and the response to a second session performed 24 h later, were examined. SCH 23390 dose-dependently reduced climbing scores in the first session and increased them in the second session, but the within-session decline of this measure was similar to that observed in the control group in both sessions. Raclopride-treated subjects showed a slightly reduced level of climbing scores at the beginning of the first session, but persisted in emitting this costly behavioural response up to the end of the session, while no effects were observed in the second session. These results, along with our results examining licking for sucrose, are consistent with the hypothesis that behavioural activation and response effort allocation are directly mediated by dopamine D1-like receptor stimulation, but the level of this activation is updated, or "reboosted", on the basis of a dopamine D2-like receptor-mediated mechanism of response efficacy evaluation. Copyright © 2011 Elsevier Ltd. All rights reserved.

  5. Dopamine D2 Receptor Is Involved in Alleviation of Type II Collagen-Induced Arthritis in Mice

    Directory of Open Access Journals (Sweden)

    Jian-Hua Lu

    2015-01-01

    Full Text Available Human and murine lymphocytes express dopamine (DA D2-like receptors including DRD2, DRD3, and DRD4. However, their roles in rheumatoid arthritis (RA are less clear. Here we showed that lymphocyte DRD2 activation alleviates both imbalance of T-helper (Th17/T-regulatory (Treg cells and inflamed symptoms in a mouse arthritis model of RA. Collagen-induced arthritis (CIA was prepared by intradermal injection of chicken collagen type II (CII in tail base of DBA/1 mice or Drd2−/− C57BL/6 mice. D2-like receptor agonist quinpirole downregulated expression of proinflammatory Th17-related cytokines interleukin- (IL- 17 and IL-22 but further upregulated expression of anti-inflammatory Treg-related cytokines transforming growth factor- (TGF- β and IL-10 in lymphocytes in vitro and in ankle joints in vivo in CIA mice. Quinpirole intraperitoneal administration reduced both clinical arthritis score and serum anti-CII IgG level in CIA mice. However, Drd2−/− CIA mice manifested more severe limb inflammation and higher serum anti-CII IgG level and further upregulated IL-17 and IL-22 expression and downregulated TGF-β and IL-10 expression than wild-type CIA mice. In contrast, Drd1−/− CIA mice did not alter limb inflammation or anti-CII IgG level compared with wild-type CIA mice. These results suggest that DRD2 activation is involved in alleviation of CIA symptoms by amelioration of Th17/Treg imbalance.

  6. Upregulation of Cannabinoid Type 1 Receptors in Dopamine D2 Receptor Knockout Mice Is Reversed by Chronic Forced Ethanol Consumption

    Energy Technology Data Exchange (ETDEWEB)

    Thanos, P.K.; Wang, G.; Thanos, P.K.; Gopez, V.; Delis, F.; Michaelides, M.; Grand, D.K.; Wang, G.-J.; Kunos, G.; Volkow, N.D.

    2011-01-01

    The anatomical proximity of the cannabinoid type 1 (CNR1/CB1R) and the dopamine D2 receptors (DRD2), their ability to form CB1R-DRD2 heteromers, their opposing roles in locomotion, and their involvement in ethanol's reinforcing and addictive properties prompted us to study the levels and distribution of CB1R after chronic ethanol intake, in the presence and absence of DRD2. We monitored the drinking patterns and locomotor activity of Drd2+/+ and Drd2-/- mice consuming either water or a 20% (v/v) ethanol solution (forced ethanol intake) for 6 months and used the selective CB1 receptor antagonist [{sup 3}H]SR141716A to quantify CB1R levels in different brain regions with in vitro receptor autoradiography. We found that the lack of DRD2 leads to a marked upregulation (approximately 2-fold increase) of CB1R in the cerebral cortex, the caudate-putamen, and the nucleus accumbens, which was reversed by chronic ethanol intake. The results suggest that DRD2-mediated dopaminergic neurotransmission and chronic ethanol intake exert an inhibitory effect on cannabinoid receptor expression in cortical and striatal regions implicated in the reinforcing and addictive properties of ethanol.

  7. Spatial reversal learning in chronically sensitized rats and in undrugged sensitized rats with dopamine d2-like receptor agonist quinpirole.

    Science.gov (United States)

    Hatalova, Hana; Radostova, Dominika; Pistikova, Adela; Vales, Karel; Stuchlik, Ales

    2014-01-01

    Dopamine plays a role in generating flexible adaptive responses in changing environments. Chronic administration of D2-like agonist quinpirole (QNP) induces behavioral sensitization and stereotypical behaviors reminiscent of obsessive-compulsive disorder (OCD). Some of these symptoms persist even after QNP discontinuation. In QNP-sensitization, perseverative behavior has often been implicated. To test the effect of QNP-sensitization on reversal learning and its association with perseveration we selected an aversively motivated hippocampus-dependent task, active place avoidance on a Carousel. Performance was measured as the number of entrances into a to-be-avoided sector (errors). We tested separately QNP-sensitized rats in QNP-drugged and QNP-undrugged state in acquisition and reversal tasks on the Carousel. In acquisition learning there were no significant differences between groups and their respective controls. In reversal, QNP-sensitized drugged rats showed a robust but transient increase in number of errors compared to controls. QNP-sensitized rats in an undrugged state were not overtly different from the control animals but displayed an altered learning manifested by more errors at the beginning compensated by quicker learning in the second session compared to control animals. Importantly, performance was not associated with perseveration in neither QNP-sensitized drugged nor QNP-sensitized undrugged animals. The present results show that chronic QNP treatment induces robust reversal learning deficit only when the substance is continuously administered, and suggest that QNP animal model of OCD is also feasible model of cognitive alterations in this disorder.

  8. Spatial reversal learning in chronically sensitized rats and in undrugged sensitized rats with dopamine D2-like receptor agonist quinpirole

    Directory of Open Access Journals (Sweden)

    Hana eHatalova

    2014-04-01

    Full Text Available Dopamine plays a role in generating flexible adaptive responses in changing environments. Chronic administration of D2-like agonist quinpirole (QNP induces behavioral sensitization and stereotypical behaviors reminiscent of obsessive-compulsive disorder (OCD. Some of these symptoms persist even after QNP discontinuation. In QNP- sensitization, perseverative behavior has often been implicated. To test the effect of QNP- sensitization on reversal learning and its association with perseveration we selected an aversively motivated hippocampus-dependent task, active place avoidance on a Carousel. Performance was measured as the number of entrances into a to-be-avoided sector (errors. We tested separately QNP sensitized rats in QNP-drugged and QNP-undrugged state in acquisition and reversal tasks on the Carousel. In acquisition learning there were no significant differences between groups and their respective controls. In reversal, QNP-sensitized drugged rats showed a robust but transient increase in number of errors compared to controls. QNP-sensitized rats in an undrugged state were not overtly different from the control animals but displayed an altered learning manifested by more errors at the beginning compensated by quicker learning in the second session compared to control animals. Importantly performance was not associated with perseveration in neither QNP-sensitized drugged nor QNP-sensitized undrugged animals. The present results show that chronic QNP treatment induces robust reversal learning deficit only when the substance is continuously administered, and suggest that QNP animal model of OCD is also feasible model of cognitive alterations in this disorder.

  9. In the Blink of an Eye: Relating Positive-Feedback Sensitivity to Striatal Dopamine D2-Like Receptors through Blink Rate

    Science.gov (United States)

    Groman, Stephanie M.; James, Alex S.; Seu, Emanuele; Tran, Steven; Clark, Taylor A.; Harpster, Sandra N.; Crawford, Maverick; Burtner, Joanna Lee; Feiler, Karen; Roth, Robert H.; Elsworth, John D.; London, Edythe D.

    2014-01-01

    For >30 years, positron emission tomography (PET) has proven to be a powerful approach for measuring aspects of dopaminergic transmission in the living human brain; this technique has revealed important relationships between dopamine D2-like receptors and dimensions of normal behavior, such as human impulsivity, and psychopathology, particularly behavioral addictions. Nevertheless, PET is an indirect estimate that lacks cellular and functional resolution and, in some cases, is not entirely pharmacologically specific. To identify the relationships between PET estimates of D2-like receptor availability and direct in vitro measures of receptor number, affinity, and function, we conducted neuroimaging and behavioral and molecular pharmacological assessments in a group of adult male vervet monkeys. Data gathered from these studies indicate that variation in D2-like receptor PET measurements is related to reversal-learning performance and sensitivity to positive feedback and is associated with in vitro estimates of the density of functional dopamine D2-like receptors. Furthermore, we report that a simple behavioral measure, eyeblink rate, reveals novel and crucial links between neuroimaging assessments and in vitro measures of dopamine D2 receptors. PMID:25339755

  10. Extrastriatal dopamine D-2/3 receptors and cortical grey matter volumes in antipsychotic-naive schizophrenia patients before and after initial antipsychotic treatment

    DEFF Research Database (Denmark)

    Nørbak-Emig, Henrik; Pinborg, Lars H.; Raghava, Jayachandra M.

    2017-01-01

    OBJECTIVES: Long-term dopamine D2/3 receptor blockade, common to all antipsychotics, may underlie progressive brain volume changes observed in patients with chronic schizophrenia. In the present study, we examined associations between cortical volume changes and extrastriatal dopamine D2/3 recept...... binding potentials (BPND) in first-episode schizophrenia patents at baseline and after antipsychotic treatment. METHODS: Twenty-two initially antipsychotic-naïve patients underwent magnetic resonance imaging (MRI), [(123)I]epidepride single-photon emission computerised tomography (SPECT......), and psychopathology assessments before and after 3 months of treatment with either risperidone (N = 13) or zuclopenthixol (N = 9). Twenty healthy controls matched on age, gender and parental socioeconomic status underwent baseline MRI and SPECT. RESULTS: Neither extrastriatal D2/3 receptor BPND at baseline, nor...

  11. Revision of the Classical Dopamine D2 Agonist Pharmacophore Based on an Integrated Medicinal Chemistry, Homology Modelling and Computational Docking Approach

    DEFF Research Database (Denmark)

    Krogsgaard-Larsen, N; Harpsøe, Kasper; Kehler, J

    2014-01-01

    The scientific advances during the 1970ies and 1980ies within the field of dopaminergic neurotransmission enabled the development of a pharmacophore that became the template for design and synthesis of dopamine D2 agonists during the following four decades. A major drawback, however......, is that this model fails to accommodate certain classes of restrained dopamine D2 agonists including ergoline structures. To accommodate these, a revision of the original model was required. The present study has addressed this by an extension of the original model without compromising its obvious qualities...... in the binding mode for certain compounds, including a series of ergoline analogues, which was reported recently. The ambiguity was confirmed by docking to a homology model of the D2 receptor as well as by pharmacological characterization of individual enantiomers of one of the analogues. The present research...

  12. A peptide targeting an interaction interface disrupts the dopamine D1-D2 receptor heteromer to block signaling and function in vitro and in vivo: effective selective antagonism

    Science.gov (United States)

    Hasbi, Ahmed; Perreault, Melissa L.; Shen, Maurice Y. F.; Zhang, Lucia; To, Ryan; Fan, Theresa; Nguyen, Tuan; Ji, Xiaodong; O'Dowd, Brian F.; George, Susan R.

    2014-01-01

    Although the dopamine D1-D2 receptor heteromer has emerging physiological relevance and a postulated role in different neuropsychiatric disorders, such as drug addiction, depression, and schizophrenia, there is a need for pharmacological tools that selectively target such receptor complexes in order to analyze their biological and pathophysiological functions. Since no selective antagonists for the D1-D2 heteromer are available, serial deletions and point mutations were used to precisely identify the amino acids involved in an interaction interface between the receptors, residing within the carboxyl tail of the D1 receptor that interacted with the D2 receptor to form the D1-D2 receptor heteromer. It was determined that D1 receptor carboxyl tail residues 404Glu and 405Glu were critical in mediating the interaction with the D2 receptor. Isolated mutation of these residues in the D1 receptor resulted in the loss of agonist activation of the calcium signaling pathway mediated through the D1-D2 receptor heteromer. The physical interaction between the D1 and D2 receptor could be disrupted, as shown by coimmunoprecipitation and BRET analysis, by a small peptide generated from the D1 receptor sequence that contained these amino acids, leading to a switch in G-protein affinities and loss of calcium signaling, resulting in the inhibition of D1-D2 heteromer function. The use of the D1-D2 heteromer-disrupting peptide in vivo revealed a pathophysiological role for the D1-D2 heteromer in the modulation of behavioral despair. This peptide may represent a novel pharmacological tool with potential therapeutic benefits in depression treatment.—Hasbi, A., Perreault, M. L., Shen, M. Y. F., Zhang, L., To, R., Fan, T., Nguyen, T., Ji, X., O'Dowd, B. F., George, S. R. A peptide targeting an interaction interface disrupts the dopamine D1-D2 receptor heteromer to block signaling and function in vitro and in vivo: effective selective antagonism. PMID:25063849

  13. D2-dopamine receptor-mediated inhibition of intracellular Ca2+ mobilization and release of acetylcholine from guinea-pig neostriatal slices.

    OpenAIRE

    Fujiwara, H.; Kato, N; Shuntoh, H; Tanaka, C

    1987-01-01

    The effect of dopamine receptor activation on electrically- or high K+ (30 mM)-evoked neurotransmitter release and rise in intracellular Ca2+ concentration was investigated using slices of guinea-pig neostriatum. A specific D2-dopamine receptor agonist, LY-171555 (a laevorotatory enantiomer of LY-141865: N-propyl tricyclic pyrazole) at 10(-6) M inhibited electrical stimulation- and high K+-evoked release of [3H]-acetylcholine ([3H]-ACh) to 47.7 +/- 6.0% and 54.1 +/- 5.0% of control, respectiv...

  14. The impact of common dopamine D2 receptor gene polymorphisms on D2/3 receptor availability: C957T as a key determinant in putamen and ventral striatum.

    Science.gov (United States)

    Smith, C T; Dang, L C; Buckholtz, J W; Tetreault, A M; Cowan, R L; Kessler, R M; Zald, D H

    2017-04-11

    Dopamine function is broadly implicated in multiple neuropsychiatric conditions believed to have a genetic basis. Although a few positron emission tomography (PET) studies have investigated the impact of single-nucleotide polymorphisms (SNPs) in the dopamine D2 receptor gene (DRD2) on D2/3 receptor availability (binding potential, BP ND ), these studies have often been limited by small sample size. Furthermore, the most commonly studied SNP in D2/3 BP ND (Taq1A) is not located in the DRD2 gene itself, suggesting that its linkage with other DRD2 SNPs may explain previous PET findings. Here, in the largest PET genetic study to date (n=84), we tested for effects of the C957T and -141C Ins/Del SNPs (located within DRD2) as well as Taq1A on BP ND of the high-affinity D2 receptor tracer 18 F-Fallypride. In a whole-brain voxelwise analysis, we found a positive linear effect of C957T T allele status on striatal BP ND bilaterally. The multilocus genetic scores containing C957T and one or both of the other SNPs produced qualitatively similar striatal results to C957T alone. The number of C957T T alleles predicted BP ND in anatomically defined putamen and ventral striatum (but not caudate) regions of interest, suggesting some regional specificity of effects in the striatum. By contrast, no significant effects arose in cortical regions. Taken together, our data support the critical role of C957T in striatal D2/3 receptor availability. This work has implications for a number of psychiatric conditions in which dopamine signaling and variation in C957T status have been implicated, including schizophrenia and substance use disorders.

  15. Identification of the Beer Component Hordenine as Food-Derived Dopamine D2 Receptor Agonist by Virtual Screening a 3D Compound Database

    Science.gov (United States)

    Sommer, Thomas; Hübner, Harald; El Kerdawy, Ahmed; Gmeiner, Peter; Pischetsrieder, Monika; Clark, Timothy

    2017-03-01

    The dopamine D2 receptor (D2R) is involved in food reward and compulsive food intake. The present study developed a virtual screening (VS) method to identify food components, which may modulate D2R signalling. In contrast to their common applications in drug discovery, VS methods are rarely applied for the discovery of bioactive food compounds. Here, databases were created that exclusively contain substances occurring in food and natural sources (about 13,000 different compounds in total) as the basis for combined pharmacophore searching, hit-list clustering and molecular docking into D2R homology models. From 17 compounds finally tested in radioligand assays to determine their binding affinities, seven were classified as hits (hit rate = 41%). Functional properties of the five most active compounds were further examined in β-arrestin recruitment and cAMP inhibition experiments. D2R-promoted G-protein activation was observed for hordenine, a constituent of barley and beer, with approximately identical ligand efficacy as dopamine (76%) and a Ki value of 13 μM. Moreover, hordenine antagonised D2-mediated β-arrestin recruitment indicating functional selectivity. Application of our databases provides new perspectives for the discovery of bioactive food constituents using VS methods. Based on its presence in beer, we suggest that hordenine significantly contributes to mood-elevating effects of beer.

  16. D2 Dopamine receptor Taq1A polymorphism, body weight, and dietary intake in type 2 diabetes

    Science.gov (United States)

    Barnard, Neal D.; Noble, Ernest P.; Ritchie, Terry; Cohen, Joshua; Jenkins, David J.A.; Turner-McGrievy, Gabrielle; Gloede, Lise; Ferdowsian, Hope

    2008-01-01

    OBJECTIVE Certain D2 dopamine receptor Taq 1A genotypes (A1A1, A1A2) have been associated with obesity and substance abuse. We hypothesized that their presence would be associated with reduced efficacy of dietary interventions in individuals with type 2 diabetes. RESEARCH METHODS & PROCEDURES In the course of a randomized clinical trial in an outpatient research center in which 93 adults with type 2 diabetes were assigned to a low-fat vegan diet or a diet following 2003 American Diabetes Association guidelines for 74 weeks, Taq 1A genotype was determined. Nutrient intake, body weight, and hemoglobin A1c (A1c) were measured over 74 weeks. RESULTS The A1 allele was highly prevalent, occurring in 47% of white participants (n = 49), which was significantly higher than the 29% prevalence previously reported in nondiabetic whites (P=0.01). The A1 allele was found in 55% of black participants (n = 44). Black participants with A1+ genotypes had significantly greater mean body weight (11.2 kg heavier, P=0.05), and greater intake of fat (P=0.002), saturated fat (P=0.01) and cholesterol (P=0.02), compared with A2A2 (A1-) individuals; dietary changes during the study did not favor one genotype group. Among whites, baseline anthropometric and nutrient differences between gene groups were small. However, among whites in the vegan group, A1+ individuals reduced fat intake (P=0.04) and A1c (P=0.01) significantly less than did A1- individuals. CONCLUSIONS The A1 allele appears to be highly prevalent among individuals with type 2 diabetes. Potential influences on diet, weight, and glycemic control merit further exploration. PMID:18834717

  17. Acute Depletion of D2 Receptors from the Rat Substantia Nigra Alters Dopamine Kinetics in the Dorsal Striatum and Drug Responsivity.

    Science.gov (United States)

    Budygin, Evgeny A; Oleson, Erik B; Lee, Yun Beom; Blume, Lawrence C; Bruno, Michael J; Howlett, Allyn C; Thompson, Alexis C; Bass, Caroline E

    2016-01-01

    Recent studies have used conditional knockout mice to selectively delete the D2 autoreceptor; however, these approaches result in global deletion of D2 autoreceptors early in development. The present study takes a different approach using RNA interference (RNAi) to knockdown the expression of the D2 receptors (D2R) in the substantia nigra (SN), including dopaminergic neurons, which project primarily to the dorsal striatum (dStr) in adult rats. This approach restricts the knockdown primarily to nigrostriatal pathways, leaving mesolimbic D2 autoreceptors intact. Analyses of dopamine (DA) kinetics in the dStr reveal a decrease in DA transporter (DAT) function in the knockdown rats, an effect not observed in D2 autoreceptor knockout mouse models. SN D2 knockdown rats exhibit a behavioral phenotype characterized by persistent enhancement of locomotor activity in a familiar open field, reduced locomotor responsiveness to high doses of cocaine and the ability to overcome haloperidol-induced immobility on the bar test. Together these results demonstrate that presynaptic D2R can be depleted from specific neuronal populations and implicates nigrostriatal D2R in different behavioral responses to psychotropic drugs.

  18. Time-dependent effects of repeated THC treatment on dopamine D2/3 receptor-mediated signalling in midbrain and striatum.

    Science.gov (United States)

    Tournier, Benjamin B; Tsartsalis, Stergios; Dimiziani, Andrea; Millet, Philippe; Ginovart, Nathalie

    2016-09-15

    This study examined the time-course of alterations in levels and functional sensitivities of dopamine D2/3 receptors (D2/3R) during the course and up to 6 weeks following cessation of chronic treatment with Delta(9)-Tetrahydrocannabinol (THC) in rats. THC treatment led to an increase in D2/3R levels in striatum, as assessed using [(3)H]-(+)-PHNO, that was readily observable after one week of treatment, remained stably elevated during the subsequent 2 weeks of treatment, but fully reversed within 2 weeks of THC discontinuation. THC-induced D2/3R alterations were more pronounced and longer lasting in the dopamine cell body regions of the midbrain, wherein [(3)H]-(+)-PHNO binding was still elevated at 2 weeks but back to control values at 6 weeks after THC cessation. Parallel analyses of the psychomotor effects of pre- and post-synaptic doses of quinpirole also showed a pattern of D2/3R functional supersensitivity indicative of more rapid subsidence in striatum than in midbrain following drug cessation. These results indicate that chronic THC is associated with a biochemical and functional sensitization of D2/3R signaling, that these responses show a region-specific temporal pattern and are fully reversible following drug discontinuation. These results suggest that an increased post-synaptic D2/3R function and a decreased DA presynaptic signaling, mediated by increased D2/3R autoinhibition, may predominate during distinct phases of withdrawal and may contribute both to the mechanisms leading to relapse and to cannabinoid withdrawal symptoms. The different rates of normalization of D2/3R function in striatum and midbrain may be critical information for the development of new pharmacotherapies for cannabis dependence. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. Disruption of dopamine D1/D2 receptor complex is involved in the function of haloperidol in cardiac H9c2 cells.

    Science.gov (United States)

    Lencesova, L; Szadvari, I; Babula, P; Kubickova, J; Chovancova, B; Lopusna, K; Rezuchova, I; Novakova, Z; Krizanova, O; Novakova, M

    2017-12-15

    Haloperidol is an antipsychotic agent and acts as dopamine D2 receptor (D2R) antagonist, as a prototypical ligand of sigma1 receptors (Sig1R) and it increases expression of type 1 IP 3 receptors (IP 3 R1). However, precise mechanism of haloperidol action on cardiomyocytes through dopaminergic signaling was not described yet. This study investigated a role of dopamine receptors in haloperidol-induced increase in IP 3 R1 and Sig1R, and compared physiological effect of melperone and haloperidol on basic heart parameters in rats. We used differentiated NG-108 cells and H9c2 cells. Gene expression, Western blot and immunofluorescence were used to evaluate haloperidol-induced differences; proximity ligation assay (PLA) and immunoprecipitation to determine interactions of D1/D2 receptors. To evaluate cardiac parameters, Wistar albino male rats were used. We have shown that antagonism of D2R with either haloperidol or melperone results in upregulation of both, IP 3 R1 and Sig1R, which is associated with increased D2R, but reduced D1R expression. Immunofluorescence, immunoprecipitation and PLA support formation of heteromeric D1/D2 complexes in H9c2 cells. Treatment with haloperidol (but not melperone) caused decrease in systolic and diastolic blood pressure and significant increase in heart rate. Because D1R/D2R complexes can engage Gq-like signaling in other experimental systems, these results are consistent with the possibility that disruption of D1R/D2R complex in H9c2 cells might cause a decrease in IP 3 R1 activity, which in turn may account for the increase expression of IP 3 R and Sig1R. D2R is probably not responsible for changes in cardiac parameters, since melperone did not have any effect. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  20. Association of Novelty Seeking Scores and Striatal Dopamine D2/D3 Receptor Availability of Healthy Volunteers: Single Photon Emission Computed Tomography With 123I-iodobenzamide

    Directory of Open Access Journals (Sweden)

    Hsiang Yu Huang

    2010-10-01

    Full Text Available It has been speculated that novelty seeking (NS behavior is related to the dopaminergic system. Fifty-two subjects completed the Tridimensional Personality Questionnaire and underwent single photon emission computed tomography with 123I-iodobenzamide. A marginally positive correlation was noted between NS and striatal dopamine D2/D3 receptor availability (r = 0.25, p =0.07. A positive association was noted between the NS scores and left striatal D2/D3 receptor availability (r= 0.29, p =0.04. The results suggest that a relationship might exist between NS score and dopaminergic activity.

  1. Frontal fasciculi and psychotic symptoms in antipsychotic-naive patients with schizophrenia before and after 6 weeks of selective dopamine D2/3 receptor blockade

    DEFF Research Database (Denmark)

    Ebdrup, Bjørn H; Raghava, Jayachandra M; Nielsen, Mette Ødegaard

    2016-01-01

    BACKGROUND: Psychotic symptoms are core clinical features of schizophrenia. We tested recent hypotheses proposing that psychotic, or positive, symptoms stem from irregularities in long-range white matter tracts projecting into the frontal cortex, and we predicted that selective dopamine D2/3 rece......, and psychotic symptoms appeared specifically associated with frontal fasciculi integrity. Six weeks of amisulpride treatment normalized white matter. Potential remyelinating effects of dopamine D2/3 receptor antagonism warrant further clarification.......BACKGROUND: Psychotic symptoms are core clinical features of schizophrenia. We tested recent hypotheses proposing that psychotic, or positive, symptoms stem from irregularities in long-range white matter tracts projecting into the frontal cortex, and we predicted that selective dopamine D2...... corticospinal tract (CT). Fractional anisotropy in the right ATR correlated with positive symptoms (z = 2.64, p= 0.008). The ROI analyses showed significant associations between positive symptoms and FA of the frontal fasciculi, specifically the right arcuate fasciculus (z = 2.83, p= 0.005) and right superior...

  2. The role of striatal dopamine D2 receptors in the occurrence of extrapyramidal side effects: iodine-123-iodobenzamide single photon emission computed tomography study.

    Science.gov (United States)

    Corripio, Iluminada; Ferreira, Alcides; Portella, Maria J; Pérez, Víctor; Escartí, María J; Del Valle Camacho, Maria; Sauras, Rosa B; Alonso, Anna; Grasa, Eva Ma; Carrió, Ignasi; Catafau, Ana M; Alvarez, Enric

    2012-01-30

    Levels above 75% of striatal dopamine 2 receptor occupancy (D2RO) have been associated with extrapyramidal symptoms (EPS). The aim of the present study is to investigate the relationship between D2RO and EPS in a sample of psychotic patients in current treatment with both typical and atypical antipsychotics. Brain iodine-123-iodobenzamide single photon emission computed tomography ((123)I-IBZM SPECT) was performed in 81 patients taking stable doses of haloperidol, risperidone, olanzapine, quetiapine, clozapine or ziprasidone. First, the degree of D2RO and Positive and Negative Syndrome Scale (PANSS) scores was compared between the group of patients who presented EPS and the group free of EPS. Afterwards, these variables were compared among the different antipsychotic medications. The group with EPS presented means of D2RO significantly higher than the group free of EPS. Significant differences in D2RO were found in clozapine, quetiapine and ziprasidone groups compared with the haloperidol group. No differences were observed between either olanzapine or risperidone and haloperidol. No quetiapine- or clozapine-treated patients developed EPS. Haloperidol and risperidone demonstrated a relationship between striatal D2RO and EPS. The findings suggest that higher D2RO is related to appearance of EPS. Occupancy in the group with EPS was in agreement with previous studies that suggested a high degree of D2RO is necessary for the occurrence of EPS. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  3. Role of dopamine D2-like receptors within the ventral tegmental area and nucleus accumbens in antinociception induced by lateral hypothalamus stimulation.

    Science.gov (United States)

    Moradi, Marzieh; Yazdanian, Mohamadreza; Haghparast, Abbas

    2015-10-01

    Several lines of evidence have shown that stimulation of the lateral hypothalamus (LH) can induce antinociception. It has been indicated that hypothalamic orexinergic neurons send projections throughout the dopamine mesolimbic pathway. Functional interaction between the LH and the main area of the mesolimbic pathway such as the ventral tegmental area (VTA) and the nucleus accumbens (NAc) implicates in pain modulation. Thus, in this study, we investigated the role of D2-like dopamine receptors within the VTA and NAc in the LH stimulation-induced antinociception. Male Wistar rats weighing 230-280 g were unilaterally implanted with two separate cannulae into the LH and VTA or NAc. Animals received intra-VTA (0.25, 1 and 4 μg/0.3 μl DMSO) and intra-accumbal (0.125, 0.25, 1 and 4 μg/0.5 μl DMSO) infusions of sulpiride as a selective D2-like receptor antagonist, prior to intra-LH carbachol (125 nM/rat) administration. In the tail-flick test, the antinociceptive effects were measured using a tail-flick algesiometer and represented as maximal possible effect (%MPE) within 5, 15, 30, 45 and 60 min after injections. Our results showed that intra-VTA and intra-accumbal sulpiride dose-dependently attenuated the LH stimulation-induced antinociception. However, the blockade of D2-like receptors within the NAc was more significant than that of the VTA. These findings show that D2-like dopamine receptors in these regions play an important role in the LH-mediated modulation of nociceptive information in the acute model of pain in the rats. It seems that this pain modulating system is more relevant to D2-like receptors in the nucleus accumbens. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Analysis of the Glutamate Agonist LY404,039 Binding to Nonstatic Dopamine Receptor D2 Dimer Structures and Consensus Docking.

    Science.gov (United States)

    Salmas, Ramin Ekhteiari; Seeman, Philip; Aksoydan, Busecan; Erol, Ismail; Kantarcioglu, Isik; Stein, Matthias; Yurtsever, Mine; Durdagi, Serdar

    2017-06-21

    Dopamine receptor D2 (D2R) plays an important role in the human central nervous system and is a focal target of antipsychotic agents. The D2 High R and D2 Low R dimeric models previously developed by our group are used to investigate the prediction of binding affinity of the LY404,039 ligand and its binding mechanism within the catalytic domain. The computational data obtained using molecular dynamics simulations fit well with the experimental results. The calculated binding affinities of LY404,039 using MM/PBSA for the D2 High R and D2 Low R targets were -12.04 and -9.11 kcal/mol, respectively. The experimental results suggest that LY404,039 binds to D2 High R and D2 Low R with binding affinities (K i ) of 8.2 and 1640 nM, respectively. The high binding affinity of LY404,039 in terms of binding to [ 3 H]domperidone was inhibited by the presence of a guanine nucleotide, indicating an agonist action of the drug at D2 High R. The interaction analysis demonstrated that while Asp114 was among the most critical amino acids for D2 High R binding, residues Ser193 and Ser197 were significantly more important within the binding cavity of D2 Low R. Molecular modeling analyses are extended to ensemble docking as well as structure-based pharmacophore model (E-pharmacophore) development using the bioactive conformation of LY404,039 at the binding pocket as a template and screening of small-molecule databases with derived pharmacophore models.

  5. Involvement of Dopamine D1/D5 and D2 Receptors in Context-Dependent Extinction Learning and Memory Reinstatement

    OpenAIRE

    Marion Agnes Emma Andre; Denise eManahan-Vaughan

    2016-01-01

    Dopamine contributes to the regulation of higher order information processing and executive control. It is important for memory consolidation processes, and for the adaptation of learned responses based on experience. In line with this, under aversive learning conditions, application of dopamine receptor antagonists prior to extinction result in enhanced memory reinstatement. Here, we investigated the contribution of the dopaminergic system to extinction and memory reinstatement (renewal) of ...

  6. Functional characterisation of eel dopamine D2 receptors and involvement in the direct inhibition of pituitary gonadotrophins

    DEFF Research Database (Denmark)

    Jolly, C.; Rousseau, K.; Prézeau, L.

    2016-01-01

    pharmacologically related to the D2 family. In the European eel, two distinct D2 receptor (D2‐R) paralogous genes have been identified (D2A‐R and D2B‐R) and both were shown to be expressed in the pituitary. We investigated the potential role of each paralogue in the control of gonadotroph function in this species....... Eel recombinant D2A‐R or D2B‐R were expressed in HEK 293 cells, with a universal Gα subunit, and receptor activation was followed by inositol phosphate production. Recombinant D2‐Rs exhibited a comparable affinity for DA, although they had differential affinities for mammalian D2‐R agonists...... and antagonists, supporting subtle structure/activity differences. Furthermore, using eel pituitary cell primary cultures, the expression by gonadotroph cells of both native eel D2‐R paralogues was examined by in situ hybridisation of D2A‐R or D2B‐R transcripts, coupled with immunofluorescence of luteinising...

  7. Dopamine D2/3 Receptor Availability in the Striatum of Antipsychotic-Free Older Patients with Schizophrenia - A [11C]-raclopride PET Study

    Science.gov (United States)

    Nakajima, Shinichiro; Caravaggio, Fernando; Mamo, David C.; Mulsant, Benoit H.; Chung, Jun Ku; Plitman, Eric; Iwata, Yusuke; Gerretsen, Philip; Uchida, Hiroyuki; Suzuki, Takefumi; Mar, Wanna; Wilson, Alan A.; Houle, Sylvain; Graff-Guerrero, Ariel

    2015-01-01

    Background No study has examined dopamine D2/3 receptor (D2/3R) availability in antipsychotic-free older patients with schizophrenia. Methods We included patients with schizophrenia 50 years or older who were antipsychotic-free for at least 3 months. We compared non-displaceable binding potential (BPND) of [11C]-raclopride in the caudate, putamen, ventral striatum, and globus pallidus between patients and age- and sex-matched healthy controls. Results Ten patients participated (antipsychotic-naïve=4). No differences in BPND were found between patients and controls in any ROIs (F(1, 72)=.42, p=.52). Conclusion The preliminary results suggest no differences in D2/3R availability between antipsychotic-free older patients with schizophrenia and controls. PMID:25757713

  8. Dopamine D1/D2 receptors do not mediate the expression of conditioned place preference induced by the aftereffect of wheel running.

    Science.gov (United States)

    Trost, Alexandra; Hauber, Wolfgang

    2014-11-19

    Rats lever-press for access to running wheels suggesting that wheel running by itself is reinforcing. Furthermore, pairings of an episode of wheel running and subsequent confinement in a specific environment can establish a conditioned place preference (CPP). This finding implies that the reinforcing effects of wheel running outlast the actual occurrence of physical activity, a phenomenon referred to as aftereffect of wheel running. Aftereffect-induced CPP involves Pavlovian conditioning, i.e. repeated pairings of the aftereffect of wheel running with a specific environment creates a learned association between aftereffect and environment and, in turn, a preference for that environment. Given the involvement of dopamine systems in mediating effects of Pavlovian stimuli on appetitive behavior, a role of dopamine in mediating aftereffect-induced CPP seems plausible. Here we assessed whether the mixed D1/D2 receptor antagonist flupenthixol (0.25 mg/kg, i.p.) can block the expression of an aftereffect-induced CPP. In line with earlier studies, our results demonstrate that rats displayed a conditioned preference for environments paired with the aftereffect of wheel running and further show that the magnitude of CPP was not related to the wheel running rate. Furthermore, we found that flupenthixol (0.25 mg/kg, i.p.) reduced locomotor activity but did not attenuate the expression of an aftereffect-induced CPP. The expression of a CPP produced by the aftereffect of wheel running seems not to depend on dopamine D1/D2 receptor activation.

  9. Effects of the dopamine D2 allosteric modulator, PAOPA, on the expression of GRK2, arrestin-3, ERK1/2, and on receptor internalization.

    Directory of Open Access Journals (Sweden)

    Dipannita Basu

    Full Text Available The activity of G protein-coupled receptors (GPCRs is intricately regulated by a range of intracellular proteins, including G protein-coupled kinases (GRKs and arrestins. Understanding the effects of ligands on these signaling pathways could provide insights into disease pathophysiologies and treatment. The dopamine D2 receptor is a GPCR strongly implicated in the pathophysiology of a range of neurological and neuropsychiatric disorders, particularly schizophrenia. Previous studies from our lab have shown the preclinical efficacy of a novel allosteric drug, 3(R-[(2(S-pyrrolidinylcarbonylamino]-2-oxo-1-pyrrolidineacetamide (PAOPA, in attenuating schizophrenia-like behavioural abnormalities in rodent models of the disease. As an allosteric modulator, PAOPA binds to a site on the D2 receptor, which is distinct from the endogenous ligand-binding site, in order to modulate the binding of the D2 receptor ligand, dopamine. The exact signaling pathways affected by this allosteric modulator are currently unknown. The objectives of this study were to decipher the in vivo effects, in rats, of chronic PAOPA administration on D2 receptor regulatory and downstream molecules, including GRK2, arrestin-3 and extracellular receptor kinase (ERK 1/2. Additionally, an in vitro cellular model was also used to study PAOPA's effects on D2 receptor internalization. Results from western immunoblots showed that chronic PAOPA treatment increased the striatal expression of GRK2 by 41%, arrestin-3 by 34%, phospho-ERK1 by 51% and phospho-ERK2 by 36%. Results also showed that the addition of PAOPA to agonist treatment in cells increased D2 receptor internalization by 33%. This study provides the foundational evidence of putative signaling pathways, and changes in receptor localization, affected by treatment with PAOPA. It improves our understanding on the diverse mechanisms of action of allosteric modulators, while advancing PAOPA's development into a novel drug for the

  10. The relationship between the daily dose, the plasma concentration of blonanserin, and its plasma anti-dopamine D2 and anti-serotonin 5-HT2A activity.

    Science.gov (United States)

    Suzuki, Hidenobu; Gen, Keishi

    2010-01-01

    Blonanserin (BNS) possesses anti-serotonin 5-HT(2A) activity in addition to anti-dopamine D(2) activity, which is characteristic of second-generation antipsychotics, little information is available on its pharmacologic profile in vivo. We investigated the BNS daily dose, plasma concentration, plasma anti-D(2) activity, and plasma anti-5-HT(2A) activity in schizophrenia in a total of 14 subjects. Blood samples were taken 14 days after the BNS dose was fixed, and the plasma concentration was measured by means of high-performance liquid chromatographic (HPLC) method. In addition, the plasma anti-D(2) activity and anti-5-HT(2A) activity were measured by means of radioreceptor assays in which [(3)H]-spiperone and [(3)H]-ketanserin were used. The results revealed a statistically significant correlation between the daily dose and the plasma concentration (p = 0.04). Statistically significant correlations were also observed between the plasma concentration and the anti-D(2) activity and between the plasma concentration and the anti-5-HT(2A) activity (p = 0.003 and 0.04). It is therefore believed that both the anti-D(2) activity in plasma and the anti-5-HT(2A) activity in plasma are regulated almost solely by the unchanged principal. Moreover, the mean plasma serotonin/dopamine (S/D) ratio was 0.9 and BNS exhibited both anti-D(2) activity and also anti-5-HT(2A) activity in vivo, as well, so it was clear that the in vitro pharmacological profile was retained in vivo.

  11. Repeat variation in the human PER2 gene as a new genetic marker associated with cocaine addiction and brain dopamine D2 receptor availability.

    Science.gov (United States)

    Shumay, E; Fowler, J S; Wang, G-J; Logan, J; Alia-Klein, N; Goldstein, R Z; Maloney, T; Wong, C; Volkow, N D

    2012-03-06

    Low dopamine D2 receptor (D2R) levels in the striatum are consistently reported in cocaine abusers; inter-individual variations in the degree of the decrease suggest a modulating effect of genetic makeup on vulnerability to addiction. The PER2 (Period 2) gene belongs to the clock genes family of circadian regulators; circadian oscillations of PER2 expression in the striatum was modulated by dopamine through D2Rs. Aberrant periodicity of PER2 contributes to the incidence and severity of various brain disorders, including drug addiction. Here we report a newly identified variable number tandem repeat (VNTR) polymorphism in the human PER2 gene (VNTR in the third intron). We found significant differences in the VNTR alleles prevalence across ethnic groups so that the major allele (4 repeats (4R)) is over-represented in non-African population (4R homozygosity is 88%), but not in African Americans (homozygosity 51%). We also detected a biased PER2 genotype distribution among healthy controls and cocaine-addicted individuals. In African Americans, the proportion of 4R/three repeat (3R) carriers in healthy controls is much lower than that in cocaine abusers (23% vs 39%, P=0.004), whereas among non-Africans most 3R/4R heterozygotes are healthy controls (10.5% vs 2.5%, P=0.04). Analysis of striatal D2R availability measured with positron emission tomography and [(11)C]raclopride revealed higher levels of D2R in carriers of 4R/4R genotype (P<0.01). Taken together, these results provide preliminary evidence for the role of the PER2 gene in regulating striatal D2R availability in the human brain and in vulnerability for cocaine addiction.

  12. Dopamine and the management of attentional resources: genetic markers of striatal D2 dopamine predict individual differences in the attentional blink

    NARCIS (Netherlands)

    Colzato, L.S.; Slagter, H.A.; de Rover, M.; Hommel, B.

    2011-01-01

    The attentional blink (AB)—a deficit in reporting the second of two target stimuli presented in close succession in a rapid sequence of distracters—has been related to processing limitations in working memory. Given that dopamine (DA) plays a crucial role working memory, the present study tested

  13. Dopamine and the Management of Attentional Resources: Genetic Markers of Striatal D2 Dopamine Predict Individual Differences in the Attentional Blink

    Science.gov (United States)

    Colzato, Lorenza S.; Slagter, Heleen A.; de Rover, Mischa; Hommel, Bernhard

    2011-01-01

    The attentional blink (AB)--a deficit in reporting the second of two target stimuli presented in close succession in a rapid sequence of distracters--has been related to processing limitations in working memory. Given that dopamine (DA) plays a crucial role working memory, the present study tested whether individual differences in the size of the…

  14. Development of a population pharmacokinetic model to predict brain distribution and dopamine D2 receptor occupancy of raclopride in non-anesthetized rat.

    Science.gov (United States)

    Wong, Yin Cheong; Ilkova, Trayana; van Wijk, Rob C; Hartman, Robin; de Lange, Elizabeth C M

    2018-01-01

    Raclopride is a selective antagonist of the dopamine D2 receptor. It is one of the most frequently used in vivo D2 tracers (at low doses) for assessing drug-induced receptor occupancy (RO) in animals and humans. It is also commonly used as a pharmacological blocker (at high doses) to occupy the available D2 receptors and antagonize the action of dopamine or drugs on D2 in preclinical studies. The aims of this study were to comprehensively evaluate its pharmacokinetic (PK) profiles in different brain compartments and to establish a PK-RO model that could predict the brain distribution and RO of raclopride in the freely moving rat using a LC-MS based approach. Rats (n=24) received a 10-min IV infusion of non-radiolabeled raclopride (1.61μmol/kg, i.e. 0.56mg/kg). Plasma and the brain tissues of striatum (with high density of D2 receptors) and cerebellum (with negligible amount of D2 receptors) were collected. Additional microdialysis experiments were performed in some rats (n=7) to measure the free drug concentration in the extracellular fluid of the striatum and cerebellum. Raclopride concentrations in all samples were analyzed by LC-MS. A population PK-RO model was constructed in NONMEM to describe the concentration-time profiles in the unbound plasma, brain extracellular fluid and brain tissue compartments and to estimate the RO based on raclopride-D2 receptor binding kinetics. In plasma raclopride showed a rapid distribution phase followed by a slower elimination phase. The striatum tissue concentrations were consistently higher than that of cerebellum tissue throughout the whole experimental period (10-h) due to higher non-specific tissue binding and D2 receptor binding in the striatum. Model-based simulations accurately predicted the literature data on rat plasma PK, brain tissue PK and D2 RO at different time points after intravenous or subcutaneous administration of raclopride at tracer dose (RO 30%). For the first time a predictive model that could describe

  15. D2-like dopamine receptor mediates dopaminergic or gamma-aminobutyric acidergic inhibition of melanotropin-releasing hormone release from the pars intermedia in frogs (Rana nigromaculata).

    Science.gov (United States)

    Tonosaki, Y; Nishiyama, K; Honda, T; Ozaki, N; Sugiura, Y

    1995-12-01

    Frogs can adapt to their background by making their skin color lighter or darker as necessary, and this adaptation is regulated by MSH. We investigated the mechanism inhibiting MSH release from the pars intermedia (PI) of the pituitary gland in frogs (Rana nigromaculata) by ultrastructural immunohistochemistry and bioassay using the melanophore index. The PI contained fibers immunoreactive for tyrosine hydroxylase, gamma-aminobutyric acid (GABA), and neuropeptide Y, which made synaptic contacts with MSH cells. The synapses had an asymmetric profile with small round and large-cored synaptic vesicles. The skin of frogs adapted to a white background became darker after administration of 6-hydroxydopamine or autografting of the PI into the anterior chamber of the eye. The skin of autografted frogs became lighter after the administration of dopamine or GABA into the anterior chamber. Lightening of skin color with dopamine was inhibited by a D2 receptor antagonist (sulpiride), and the effect of GABA was blocked by both sulpiride and a GABAA receptor antagonist (bicuculline). These results indicate that MSH release from the PI in frogs may be inhibited by dopaminergic nerves via the D2-like receptor and by GABAergic nerves via the D2-like and GABAA receptors.

  16. Polysialic acid is required for dopamine D2 receptor-mediated plasticity involving inhibitory circuits of the rat medial prefrontal cortex.

    Directory of Open Access Journals (Sweden)

    Esther Castillo-Gómez

    Full Text Available Decreased expression of dopamine D2 receptors (D2R, dysfunction of inhibitory neurotransmission and impairments in the structure and connectivity of neurons in the medial prefrontal cortex (mPFC are involved in the pathogenesis of schizophrenia and major depression, but the relationship between these changes remains unclear. The polysialylated form of the neural cell adhesion molecule (PSA-NCAM, a plasticity-related molecule, may serve as a link. This molecule is expressed in cortical interneurons and dopamine, via D2R, modulates its expression in parallel to that of proteins related to synapses and inhibitory neurotransmission, suggesting that D2R-targeted antipsychotics/antidepressants may act by affecting the plasticity of mPFC inhibitory circuits. To understand the role of PSA-NCAM in this plasticity, rats were chronically treated with a D2R agonist (PPHT after cortical PSA depletion. PPHT-induced increases in GAD67 and synaptophysin (SYN neuropil expression were blocked when PSA was previously removed, indicating a role for PSA-NCAM in this plasticity. The number of PSA-NCAM expressing interneuron somata also increased after PPHT treatment, but the percentages of these cells belonging to different interneuronal subpopulations did not change. Cortical pyramidal neurons did not express PSA-NCAM, but puncta co-expressing this molecule and parvalbumin could be found surrounding their somata. PPHT treatment increased the number of PSA-NCAM and parvalbumin expressing perisomatic puncta, but decreased the percentage of parvalbumin puncta that co-expressed SYN. PSA depletion did not block these effects on the perisomatic region, but increased further the number of parvalbumin expressing puncta and increased the percentage of puncta co-expressing SYN and parvalbumin, suggesting that the polysialylation of NCAM may regulate perisomatic inhibition of mPFC principal neurons. Summarizing, the present results indicate that dopamine acting on D2R

  17. Selective Vulnerability of Striatal D2 versus D1 Dopamine Receptor-Expressing Medium Spiny Neurons in HIV-1 Tat Transgenic Male Mice.

    Science.gov (United States)

    Schier, Christina J; Marks, William D; Paris, Jason J; Barbour, Aaron J; McLane, Virginia D; Maragos, William F; McQuiston, A Rory; Knapp, Pamela E; Hauser, Kurt F

    2017-06-07

    Despite marked regional differences in HIV susceptibility within the CNS, there has been surprisingly little exploration into the differential vulnerability among neuron types and the circuits they underlie. The dorsal striatum is especially susceptible, harboring high viral loads and displaying marked neuropathology, with motor impairment a frequent manifestation of chronic infection. However, little is known about the response of individual striatal neuron types to HIV or how this disrupts function. Therefore, we investigated the morphological and electrophysiological effects of HIV-1 trans -activator of transcription (Tat) in dopamine subtype 1 (D1) and dopamine subtype 2 (D2) receptor-expressing striatal medium spiny neurons (MSNs) by breeding transgenic Tat-expressing mice to Drd1a -tdTomato- or Drd2 -eGFP-reporter mice. An additional goal was to examine neuronal vulnerability early during the degenerative process to gain insight into key events underlying the neuropathogenesis. In D2 MSNs, exposure to HIV-1 Tat reduced dendritic spine density significantly, increased dendritic damage (characterized by swellings/varicosities), and dysregulated neuronal excitability (decreased firing at 200-300 pA and increased firing rates at 450 pA), whereas insignificant morphologic and electrophysiological consequences were observed in Tat-exposed D1 MSNs. These changes were concomitant with an increased anxiety-like behavioral profile (lower latencies to enter a dark chamber in a light-dark transition task, a greater frequency of light-dark transitions, and reduced rearing time in an open field), whereas locomotor behavior was unaffected by 2 weeks of Tat induction. Our findings suggest that D2 MSNs and a specific subset of neural circuits within the dorsal striatum are preferentially vulnerable to HIV-1. SIGNIFICANCE STATEMENT Despite combination antiretroviral therapy (cART), neurocognitive disorders afflict 30-50% of HIV-infected individuals and synaptodendritic injury

  18. Effects of social reorganization on dopamine D2/D3 receptor availability and cocaine self-administration in male cynomolgus monkeys.

    Science.gov (United States)

    Czoty, P W; Gould, R W; Gage, H D; Nader, M A

    2017-09-01

    Studies have demonstrated that brain dopamine D2/D3 receptors (D2/D3R) and the reinforcing effects of cocaine can be influenced by a monkey's position in the social dominance hierarchy. In this study, we manipulated the social ranks of monkeys by reorganizing social groups and assessed effects on D2/D3R availability and cocaine self-administration. Male cynomolgus monkeys (N = 12) had been trained to self-administer cocaine under a concurrent cocaine-food reinforcement schedule. Previously, PET measures of D2/D3R availability in the caudate nucleus and putamen had been obtained with [ 18 F]fluoroclebopride during cocaine abstinence, while monkeys lived in stable social groups of four monkeys/pen. For this study, monkeys were reorganized into groups that consisted of (1) four previously dominant, (2) four previously subordinate, and (3) a mix of previously dominant and subordinate monkeys. After 3 months, D2/D3R availability was redetermined and cocaine self-administration was reexamined. D2/D3R availability significantly increased after reorganization in monkeys who were formerly subordinate, with the greatest increases observed in those that became dominant. No consistent changes in D2/D3R availability were observed in formerly dominant monkeys. Cocaine self-administration did not vary according to rank after reorganization of social groups. However, when compared to their previous cocaine self-administration data, the potency of cocaine as a reinforcer decreased in 9 of 11 monkeys. These results indicate that changing the social conditions can alter D2/D3R availability in subordinate monkeys in a manner suggestive of environmental enrichment. In most monkeys, social reorganization shifted the cocaine dose-response curve to the right, also consistent with environmental enrichment.

  19. Effects of Dopamine D2/D3 Blockade on Human Sensory and Sensorimotor Gating in Initially Antipsychotic-Naive, First-Episode Schizophrenia Patients

    DEFF Research Database (Denmark)

    Düring, Signe; Glenthøj, Birte Y; Andersen, Gitte Saltoft

    2014-01-01

    It has been suggested that psychophysiological measures of sensory and sensorimotor gating, P50 gating and prepulse inhibition of the startle reflex (PPI), underlie core features of schizophrenia and are linked to dopaminergic pathways in the striatum and prefrontal cortex. In the present study......, habituation, and sensitization. Treatment with amisulpride showed no effects on these measures, either at 2 or 6 weeks of follow-up. This is the first study investigating the effects of monotherapy with a relatively selective dopamine D2/D3 receptor antagonist (amisulpride) on sensory and sensorimotor gating...... be involved in symptomatology of patients with schizophrenia, but not in their sensorimotor gating deficits....

  20. Exploring the relationship between social attachment and dopamine D2/3 receptor availability in the brains of healthy humans using [11C]-(+)-PHNO

    Science.gov (United States)

    Caravaggio, Fernando; Chung, Jun Ku; Gerretsen, Philip; Fervaha, Gagan; Nakajima, Shinichiro; Plitman, Eric; Iwata, Yusuke; Wilson, Alan; Graff-Guerrero, Ariel

    2017-01-01

    Differences in striatal dopamine (DA) function may be related to differences in the degree of social attachment to others. Using positron emission tomography (PET), socially detached persons demonstrate reduced DA D2/3 receptor (D2/3R) availability in the striatum. However, previous PET studies have only used antagonist radiotracers for D2/3R and have not specifically examined regions of interest (ROIs) such as the ventral striatum (VS). In 32 healthy persons, we investigated the relationship between self-reported attachment and DA D2/3R availability in striatal and extrastriatal ROIs as measured using the agonist radiotracer [11C]-(+)-PHNO. Surprisingly, more social attachment—as measured by the attachment subscale of the temperament and character inventory—was related to less [11C]-(+)-PHNO binding in the VS (r(30) =−.43, p = .01). This relationship held in a subsample who also completed the detachment subscale of the Karolinska Scales of Personality (r(10) = .62, p = .03). However, no relationships were observed with BPND in the dorsal striatum or D3R-specific ROIs. One potential explanation for these findings is that persons who are more socially detached have less endogenous DA occupying D2/3R in the VS. This interpretation warrants investigation by future research. These findings may help us better understand the neurochemical basis of attachment. PMID:26873034

  1. Exploring the relationship between social attachment and dopamine D2/3receptor availability in the brains of healthy humans using [11C]-(+)-PHNO.

    Science.gov (United States)

    Caravaggio, Fernando; Chung, Jun Ku; Gerretsen, Philip; Fervaha, Gagan; Nakajima, Shinichiro; Plitman, Eric; Iwata, Yusuke; Wilson, Alan; Graff-Guerrero, Ariel

    2017-04-01

    Differences in striatal dopamine (DA) function may be related to differences in the degree of social attachment to others. Using positron emission tomography (PET), socially detached persons demonstrate reduced DA D 2/3 receptor (D 2/3 R) availability in the striatum. However, previous PET studies have only used antagonist radiotracers for D 2/3 R and have not specifically examined regions of interest (ROIs) such as the ventral striatum (VS). In 32 healthy persons, we investigated the relationship between self-reported attachment and DA D 2/3 R availability in striatal and extrastriatal ROIs as measured using the agonist radiotracer [ 11 C]-(+)-PHNO. Surprisingly, more social attachment-as measured by the attachment subscale of the temperament and character inventory-was related to less [ 11 C]-(+)-PHNO binding in the VS (r(30) = -.43, p = .01). This relationship held in a subsample who also completed the detachment subscale of the Karolinska Scales of Personality (r(10) = .62, p = .03). However, no relationships were observed with BP ND in the dorsal striatum or D 3 R-specific ROIs. One potential explanation for these findings is that persons who are more socially detached have less endogenous DA occupying D 2/3 R in the VS. This interpretation warrants investigation by future research. These findings may help us better understand the neurochemical basis of attachment.

  2. The Conserved Arginine Cluster in the Insert of the Third Cytoplasmic Loop of the Long Form of the D2 Dopamine Receptor (D2L-R Acts as an Intracellular Retention Signal

    Directory of Open Access Journals (Sweden)

    Valentina Kubale

    2016-07-01

    Full Text Available This study examined whether the conserved arginine cluster present within the 29-amino acid insert of the long form of the D2 dopamine receptor (D2L-R confers its predominant intracellular localization. We hypothesized that the conserved arginine cluster (RRR located within the insert could act as an RXR-type endoplasmic reticulum (ER retention signal. Arginine residues (R within the cluster at positions 267, 268, and 269 were charge-reserved to glutamic acids (E, either individually or in clusters, thus generating single, double, and triple D2L-R mutants. Through analyses of cellular localization by confocal microscopy and enzyme-linked immunosorbent assay (ELISA, radioligand binding assay, bioluminescence resonance energy transfer (BRET2 β-arrestin 2 (βarr2 recruitment assay, and cAMP signaling, it was revealed that charge reversal of the R residues at all three positions within the motif impaired their colocalization with ER marker calnexin and led to significantly improved cell surface expression. Additionally, these data demonstrate that an R to glutamic acid (E substitution at position 2 within the RXR motif is not functionally permissible. Furthermore, all generated D2L-R mutants preserved their functional integrity regarding ligand binding, agonist-induced βarr2 recruitment and Gαi-mediated signaling. In summary, our results show that the conserved arginine cluster within the 29-amino acid insert of third cytoplasmic loop (IC3 of the D2L-R appears to be the ER retention signal.

  3. D2-dopamine receptor-mediated inhibition of intracellular Ca2+ mobilization and release of acetylcholine from guinea-pig neostriatal slices.

    Science.gov (United States)

    Fujiwara, H; Kato, N; Shuntoh, H; Tanaka, C

    1987-06-01

    The effect of dopamine receptor activation on electrically- or high K+ (30 mM)-evoked neurotransmitter release and rise in intracellular Ca2+ concentration was investigated using slices of guinea-pig neostriatum. A specific D2-dopamine receptor agonist, LY-171555 (a laevorotatory enantiomer of LY-141865: N-propyl tricyclic pyrazole) at 10(-6) M inhibited electrical stimulation- and high K+-evoked release of [3H]-acetylcholine ([3H]-ACh) to 47.7 +/- 6.0% and 54.1 +/- 5.0% of control, respectively. The maximal inhibition by LY-171555 at 10(-5) M was 54.8 +/- 5.1% reduction of the control. The half-maximal effective concentration (EC50) of LY-171555 for the inhibition of [3H]-ACh release was 2.3 X 10(-7) M. A specific D2-dopamine receptor antagonist, (-)-sulpiride (10(-7) M) reversed the inhibition of [3H]-ACh release induced by LY-171555. A specific D1-dopamine receptor agonist, SK&F 38393 (2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-benzazepine) (10(-5) M) had no effect on the release of [3H]-ACh. LY-171555 (10(-6) M) also inhibited the high K+-evoked endogenous glutamate release, by 47% of control. This inhibitory effect was reversed by (-)-sulpiride (10(-7) M). We used a fluorescent, highly selective Ca2+ indicator, 'quin 2' to measure intracellular free Ca2+ concentrations ([Ca2+]i). Electrical stimulation of slices preloaded with quin 2 led to an elevation of relative fluorescence intensity and this response was reduced by the removal of Ca2+ from the bathing medium. These results indicate that the enhanced elevation in fluorescence intensity in the quin 2-loaded slices reflects the increase of intracellular free Ca2+ concentration, [Ca2+]i. The mixed D1- and D2-receptor agonist, apomorphine and LY-171555 inhibited the increase of [Ca2+]i induced by electrical stimulation or high K+ medium, in a concentration-dependent manner, while SK&F 38393 did not affect the increase of [Ca2+]i. The maximal inhibitory effect of LY-171555 at 3 X 10(-5) M was 35 +/- 3

  4. Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values.

    Science.gov (United States)

    Meltzer, H Y; Matsubara, S; Lee, J C

    1989-10-01

    The pKi values of 13 reference typical and 7 reference atypical antipsychotic drugs (APDs) for rat striatal dopamine D-1 and D-2 receptor binding sites and cortical serotonin (5-HT2) receptor binding sites were determined. The atypical antipsychotics had significantly lower pKi values for the D-2 but not 5-HT2 binding sites. There was a trend for a lower pKi value for the D-1 binding site for the atypical APD. The 5-HT2 and D-1 pKi values were correlated for the typical APD whereas the 5-HT2 and D-2 pKi values were correlated for the atypical APD. A stepwise discriminant function analysis to determine the independent contribution of each pKi value for a given binding site to the classification as a typical or atypical APD entered the D-2 pKi value first, followed by the 5-HT2 pKi value. The D-1 pKi value was not entered. A discriminant function analysis correctly classified 19 of 20 of these compounds plus 14 of 17 additional test compounds as typical or atypical APD for an overall correct classification rate of 89.2%. The major contributors to the discriminant function were the D-2 and 5-HT2 pKi values. A cluster analysis based only on the 5-HT2/D2 ratio grouped 15 of 17 atypical + one typical APD in one cluster and 19 of 20 typical + two atypical APDs in a second cluster, for an overall correct classification rate of 91.9%. When the stepwise discriminant function was repeated for all 37 compounds, only the D-2 and 5-HT2 pKi values were entered into the discriminant function.(ABSTRACT TRUNCATED AT 250 WORDS)

  5. The N-terminal region of the dopamine D2 receptor, a rhodopsin-like GPCR, regulates correct integration into the plasma membrane and endocytic routes

    Science.gov (United States)

    Cho, DI; Min, C; Jung, KS; Cheong, SY; Zheng, M; Cheong, SJ; Oak, MH; Cheong, JH; Lee, BK; Kim, KM

    2012-01-01

    BACKGROUND AND PURPOSE Functional roles of the N-terminal region of rhodopsin-like GPCR family remain unclear. Using dopamine D2 and D3 receptors as a model system, we probed the roles of the N-terminal region in the signalling, intracellular trafficking of receptor proteins, and explored the critical factors that determine the functionality of the N-terminal region. EXPERIMENTAL APPROACH The N-terminal region of the D2 receptor was gradually shortened or switched with that of the D3 receptor or a non-specific sequence (FLAG), or potential N-terminal glycosylation sites were mutated. Effects of these manipulations on surface expression, internalization, post-endocytic behaviours and signalling were determined. KEY RESULTS Shortening the N-terminal region of the D2 receptor enhanced receptor internalization and impaired surface expression and signalling; ligand binding, desensitization and down-regulation were not affected but their association with a particular microdomain, caveolae, was disrupted. Replacement of critical residues within the N-terminal region with the FLAG epitope failed to restore surface expression but partially restored the altered internalization and signalling. When the N-terminal regions were switched between D2 and D3 receptors, cell surface expression pattern of each receptor was switched. Mutations of potential N-terminal glycosylation sites inhibited surface expression but enhanced internalization of D2 receptors. CONCLUSIONS AND IMPLICATIONS Shortening of N-terminus or mutation of glycosylation sites located within the N-terminus enhanced receptor internalization but impaired the surface expression of D2 receptors. The N-terminal region of the D2 receptor, in a sequence-specific manner, controls the receptor's conformation and integration into the plasma membrane, which determine its subcellular localization, intracellular trafficking and signalling properties. PMID:22117524

  6. Intact discrimination reversal learning but slowed responding to reward-predictive cues after dopamine D1 and D2 receptor blockade in the nucleus accumbens of rats.

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    Calaminus, Carsten; Hauber, Wolfgang

    2007-04-01

    The prediction error hypothesis of dopamine action states that dopamine signals are necessary for the brain to update the predictive significance of cues. Yet, little is known whether D1 or D2 receptor-mediated signals in the nucleus accumbens core (AcbC) are required to learn a reversal of the predictive significance of cues. Here we examined the effects of a selective D1 or D2 receptor blockade in the AcbC on learning a reversal of previously acquired cue-reward magnitude contingencies. Rats were trained on a reaction time (RT) task demanding conditioned lever release with discriminative visual cues signalling in advance the upcoming reward magnitude (one or five food pellets). After acquisition, RTs were guided by cue-associated reward magnitudes, i.e. RTs of responses were significantly shorter for expected high vs low reward. Thereafter, cue-reward magnitude contingencies were reversed. Reversal learning was tested for 12 daily sessions with intra-AcbC micro-infusions being given on sessions 1-6. Subjects received pre-trial infusions of the selective D1 or D2 receptor antagonists, SCH23390 (0.5, 2 microg per side) or raclopride (1, 4 microg per side), or vehicle (0.5 microl). Intra-AcbC infusion of SCH23390 (0.5, 2 microg) or raclopride (1, 4 microg) did not inhibit discrimination reversal learning, but the higher dose of each drug increased RTs of instrumental responses. In a visual discrimination task as used here, D1 and D2 receptor-mediated signals in the AcbC seem to be unnecessary in updating the reward-predictive significance of cues, rather, they serve to activate instrumental behaviour.

  7. Detection of Heteromers Formed by Cannabinoid CB1, Dopamine D2, and Adenosine A2A G-Protein-Coupled Receptors by Combining Bimolecular Fluorescence Complementation and Bioluminescence Energy Transfer

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    Gemma Navarro

    2008-01-01

    Full Text Available Functional interactions in signaling occur between dopamine D2 (D2R and cannabinoid CB1 (CB1R receptors, between CB1R and adenosine A2A (A2AR receptors, and between D2R and A2AR. Furthermore, direct molecular interactions have been reported for the pairs CB1R-D2R, A2AR-D2R, and CB1R-A2AR. Here a combination of bimolecular fluorescence complementation and bioluminescence energy transfer techniques was used to identify the occurrence of D2R-CB1R-A2AR hetero-oligomers in living cells.

  8. Lysergic acid diethylamide (LSD) is a partial agonist of D2 dopaminergic receptors and it potentiates dopamine-mediated prolactin secretion in lactotrophs in vitro.

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    Giacomelli, S; Palmery, M; Romanelli, L; Cheng, C Y; Silvestrini, B

    1998-01-01

    The hallucinogenic effects of lysergic acid diethylamide (LSD) have mainly been attributed to the interaction of this drug with the serotoninergic system, but it seems more likely that they are the result of the complex interactions of the drug with both the serotoninergic and dopaminergic systems. The aim of the present study was to investigate the functional actions of LSD at dopaminergic receptors using prolactin secretion by primary cultures of rat pituitary cells as a model. LSD produced a dose-dependent inhibition of prolactin secretion in vitro with an IC50 at 1.7x10(-9) M. This action was antagonized by spiperone but not by SKF83566 or cyproheptadine, which indicates that LSD has a specific effect on D2 dopaminergic receptors. The maximum inhibition of prolactin secretion achieved by LSD was lower than that by dopamine (60% versus 80%). Moreover, the fact that LSD at 10(-8)-10(-6) M antagonized the inhibitory effect of dopamine (10(-7) M) and bromocriptine (10(-11) M) suggests that LSD acts as a partial agonist at D2 receptors on lactotrophs in vitro. Interestingly, LSD at 10(-13)-10(-10) M, the concentrations which are 10-1000-fold lower than those required to induce direct inhibition on pituitary prolactin secretion, potentiated the dopamine (10(-10)-2.5x10(-9) M)-mediated prolactin secretion by pituitary cells in vitro. These results suggest that LSD not only interacts with dopaminergic receptors but also has a unique capacity for modulating dopaminergic transmission. These findings may offer new insights into the hallucinogenic effect of LSD.

  9. Different effects of chronic THC on the neuroadaptive response of dopamine D2/3 receptor-mediated signaling in roman high- and roman low-avoidance rats.

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    Tournier, Benjamin B; Dimiziani, Andrea; Tsartsalis, Stergios; Millet, Philippe; Ginovart, Nathalie

    2018-04-01

    The Roman high (RHA)- and low (RLA)-avoidance rat sublines have been identified as an addiction-prone and addiction-resistant phenotype based on their high vs. low locomotor responsiveness to novelty and high vs. low ability to develop neurochemical and behavioral sensitization to psychostimulants, respectively. Most studies though have focused on psychostimulants and little is known about the neuroadaptive response of these two lines to cannabinoids. This study investigated the effects of chronic exposure to Δ 9 -tetrahydrocannabinol (THC) on dopamine D 2/3 receptor (D 2/3 R) availabilities and functional sensitivity in the mesostriatal system of RHA and RLA rats. At baseline, RLA rats exhibited higher densities of mesostriatal D2/3R but lower levels of striatal CB 1 R mRNA and displayed a lower locomotor response to acute THC as compared to RHAs. Following chronic THC treatment, striking changes in D 2/3 R signaling were observed in RLA but not in RHA rats, namely an increased availability and functional supersensitivity of striatal D 2/3 R, as evidenced by a supersensitive psychomotor response to the D 2/3 R agonist quinpirole. Moreover, in RLA rats, the lower was the locomotor response to acute THC, the higher was the psychomotor response to quinpirole following chronic THC. These results showing a greater neuroadaptive response of RLA vs. RHA rats to chronic THC thus contrast with previous studies showing a resistance to neuroadaptive response of RLAs to psychostimulants, This suggests that, contrasting with their low proneness to psychostimulant drug-seeking, RLAs may exhibit a heightened proneness to cannabinoid drug-seeking as compared to RHA rats. © 2017 Wiley Periodicals, Inc.

  10. Dopamine D2-Receptor Antagonists Down-Regulate CYP1A1/2 and CYP1B1 in the Rat Liver.

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    P Harkitis

    Full Text Available Dopaminergic systems regulate the release of several hormones including growth hormone (GH, thyroid hormones, insulin, glucocorticoids and prolactin (PRL that play significant roles in the regulation of various Cytochrome P450 (CYP enzymes. The present study investigated the role of dopamine D2-receptor-linked pathways in the regulation of CYP1A1, CYP1A2 and CYP1B1 that belong to a battery of genes controlled by the Aryl Hydrocarbon Receptor (AhR and play a crucial role in the metabolism and toxicity of numerous environmental toxicants. Inhibition of dopamine D2-receptors with sulpiride (SULP significantly repressed the constitutive and benzo[a]pyrene (B[a]P-induced CYP1A1, CYP1A2 and CYP1B expression in the rat liver. The expression of AhR, heat shock protein 90 (HSP90 and AhR nuclear translocator (ARNT was suppressed by SULP in B[a]P-treated livers, whereas the AhRR expression was increased by the drug suggesting that the SULP-mediated repression of the CYP1 inducibility is due to inactivation of the AhR regulatory system. At signal transduction level, the D2-mediated down-regulation of constitutive CYP1A1/2 and CYP1B1 expression appears to be mediated by activation of the insulin/PI3K/AKT pathway. PRL-linked pathways exerting a negative control on various CYPs, and inactivation of the glucocorticoid-linked pathways that positively control the AhR-regulated CYP1 genes, may also participate in the SULP-mediated repression of both, the constitutive and induced CYP1 expression. The present findings indicate that drugs acting as D2-dopamine receptor antagonists can modify several hormone systems that regulate the expression of CYP1A1, CYP1A2 and CYP1B1, and may affect the toxicity and carcinogenicity outcome of numerous toxicants and pre-carcinogenic substances. Therefore, these drugs could be considered as a part of the strategy to reduce the risk of exposure to environmental pollutants and pre-carcinogens.

  11. Pleiotrophin overexpression regulates amphetamine-induced reward and striatal dopaminergic denervation without changing the expression of dopamine D1 and D2 receptors: Implications for neuroinflammation.

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    Vicente-Rodríguez, Marta; Rojo Gonzalez, Loreto; Gramage, Esther; Fernández-Calle, Rosalía; Chen, Ying; Pérez-García, Carmen; Ferrer-Alcón, Marcel; Uribarri, María; Bailey, Alexis; Herradón, Gonzalo

    2016-11-01

    It was previously shown that mice with genetic deletion of the neurotrophic factor pleiotrophin (PTN-/-) show enhanced amphetamine neurotoxicity and impair extinction of amphetamine conditioned place preference (CPP), suggesting a modulatory role of PTN in amphetamine neurotoxicity and reward. We have now studied the effects of amphetamine (10mg/kg, 4 times, every 2h) in the striatum of mice with transgenic PTN overexpression (PTN-Tg) in the brain and in wild type (WT) mice. Amphetamine caused an enhanced loss of striatal dopaminergic terminals, together with a highly significant aggravation of amphetamine-induced increase in the number of GFAP-positive astrocytes, in the striatum of PTN-Tg mice compared to WT mice. Given the known contribution of D1 and D2 dopamine receptors to the neurotoxic effects of amphetamine, we also performed quantitative receptor autoradiography of both receptors in the brains of PTN-Tg and WT mice. D1 and D2 receptors binding in the striatum and other regions of interest was not altered by genotype or treatment. Finally, we found that amphetamine CPP was significantly reduced in PTN-Tg mice. The data demonstrate that PTN overexpression in the brain blocks the conditioning effects of amphetamine and enhances the characteristic striatal dopaminergic denervation caused by this drug. These results indicate for the first time deleterious effects of PTN in vivo by mechanisms that are probably independent of changes in the expression of D1 and D2 dopamine receptors. The data also suggest that PTN-induced neuroinflammation could be involved in the enhanced neurotoxic effects of amphetamine in the striatum of PTN-Tg mice. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

  12. Dopamine acting at D1-like, D2-like and α1-adrenergic receptors differentially modulates theta and gamma oscillatory activity in primary motor cortex.

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    Özkan, Mazhar; Johnson, Nicholas W; Sehirli, Umit S; Woodhall, Gavin L; Stanford, Ian M

    2017-01-01

    The loss of dopamine (DA) in Parkinson's is accompanied by the emergence of exaggerated theta and beta frequency neuronal oscillatory activity in the primary motor cortex (M1) and basal ganglia. DA replacement therapy or deep brain stimulation reduces the power of these oscillations and this is coincident with an improvement in motor performance implying a causal relationship. Here we provide in vitro evidence for the differential modulation of theta and gamma activity in M1 by DA acting at receptors exhibiting conventional and non-conventional DA pharmacology. Recording local field potentials in deep layer V of rat M1, co-application of carbachol (CCh, 5 μM) and kainic acid (KA, 150 nM) elicited simultaneous oscillations at a frequency of 6.49 ± 0.18 Hz (theta, n = 84) and 34.97 ± 0.39 Hz (gamma, n = 84). Bath application of DA resulted in a decrease in gamma power with no change in theta power. However, application of either the D1-like receptor agonist SKF38393 or the D2-like agonist quinpirole increased the power of both theta and gamma suggesting that the DA-mediated inhibition of oscillatory power is by action at other sites other than classical DA receptors. Application of amphetamine, which promotes endogenous amine neurotransmitter release, or the adrenergic α1-selective agonist phenylephrine mimicked the action of DA and reduced gamma power, a result unaffected by prior co-application of D1 and D2 receptor antagonists SCH23390 and sulpiride. Finally, application of the α1-adrenergic receptor antagonist prazosin blocked the action of DA on gamma power suggestive of interaction between α1 and DA receptors. These results show that DA mediates complex actions acting at dopamine D1-like and D2-like receptors, α1 adrenergic receptors and possibly DA/α1 heteromultimeric receptors to differentially modulate theta and gamma activity in M1.

  13. Dopamine acting at D1-like, D2-like and α1-adrenergic receptors differentially modulates theta and gamma oscillatory activity in primary motor cortex.

    Directory of Open Access Journals (Sweden)

    Mazhar Özkan

    Full Text Available The loss of dopamine (DA in Parkinson's is accompanied by the emergence of exaggerated theta and beta frequency neuronal oscillatory activity in the primary motor cortex (M1 and basal ganglia. DA replacement therapy or deep brain stimulation reduces the power of these oscillations and this is coincident with an improvement in motor performance implying a causal relationship. Here we provide in vitro evidence for the differential modulation of theta and gamma activity in M1 by DA acting at receptors exhibiting conventional and non-conventional DA pharmacology. Recording local field potentials in deep layer V of rat M1, co-application of carbachol (CCh, 5 μM and kainic acid (KA, 150 nM elicited simultaneous oscillations at a frequency of 6.49 ± 0.18 Hz (theta, n = 84 and 34.97 ± 0.39 Hz (gamma, n = 84. Bath application of DA resulted in a decrease in gamma power with no change in theta power. However, application of either the D1-like receptor agonist SKF38393 or the D2-like agonist quinpirole increased the power of both theta and gamma suggesting that the DA-mediated inhibition of oscillatory power is by action at other sites other than classical DA receptors. Application of amphetamine, which promotes endogenous amine neurotransmitter release, or the adrenergic α1-selective agonist phenylephrine mimicked the action of DA and reduced gamma power, a result unaffected by prior co-application of D1 and D2 receptor antagonists SCH23390 and sulpiride. Finally, application of the α1-adrenergic receptor antagonist prazosin blocked the action of DA on gamma power suggestive of interaction between α1 and DA receptors. These results show that DA mediates complex actions acting at dopamine D1-like and D2-like receptors, α1 adrenergic receptors and possibly DA/α1 heteromultimeric receptors to differentially modulate theta and gamma activity in M1.

  14. A Novel Mechanism of Cocaine to Enhance Dopamine D2-Like Receptor Mediated Neurochemical and Behavioral Effects. An In Vivo and In Vitro Study

    Science.gov (United States)

    Ferraro, Luca; Frankowska, Malgorzata; Marcellino, Daniel; Zaniewska, Magdalena; Beggiato, Sarah; Filip, Malgorzata; Tomasini, Maria Cristina; Antonelli, Tiziana; Tanganelli, Sergio; Fuxe, Kjell

    2012-01-01

    Recent in vitro results suggest that cocaine may exert direct and/or indirect allosteric enhancing actions at dopamine (DA) D2 receptors (D2Rs). In the present paper we tested the hypothesis that cocaine in vivo can enhance the effects of the D2-likeR agonist quinpirole in rats by using microdialysis and pharmacological behavioral studies. Furthermore, in vitro D2-likeR binding characteristics and Gαi/o-protein coupling, in the absence and in the presence of cocaine, have been investigated in rat striatal membranes. Intra-nucleus accumbens perfusion of the D2-likeR agonist quinpirole (10 μM) reduced local dialysate glutamate levels, whereas cocaine (10 and 100 nM) was ineffective. At a low concentration (100 nM), cocaine significantly enhanced quinpirole-induced reduction of accumbal extracellular glutamate levels. The behavioral experiments showed that cocaine (0.625 mg/kg), but not the DA uptake blocker GBR 12783 (1.25 mg/kg), enhanced quinpirole (1 mg/kg)-induced hyperlocomotion. Finally, cocaine (100 nM), but not GBR 12783 (200 nM), produced a small, but significant increase in the efficacy of DA to stimulate binding of GTPγS to striatal D2-likeRs, whereas the D2-likeR binding characteristics were unchanged in striatal membranes by cocaine in the nM range. The significant increase in the maximal response to DA-stimulated GTPγS binding to D2-likeRs by 100 nM cocaine remained in the presence of GBR 12783. The observed cocaine-induced enhancement of the Gαi/o-protein coupling of D2Rs may be in part because of allosteric direct and/or indirect enhancing effects of cocaine at these receptors. These novel actions of cocaine may have relevance for understanding the actions of cocaine upon accumbal DA, and/or glutamate transmission and thus its rewarding as well as relapsing effects. PMID:22453136

  15. Rebalance of striatal NMDA/AMPA receptor ratio underlies the reduced emergence of dyskinesia during D2-like dopamine agonist treatment in experimental Parkinson's disease.

    Science.gov (United States)

    Bagetta, Vincenza; Sgobio, Carmelo; Pendolino, Valentina; Del Papa, Giulia; Tozzi, Alessandro; Ghiglieri, Veronica; Giampà, Carmela; Zianni, Elisa; Gardoni, Fabrizio; Calabresi, Paolo; Picconi, Barbara

    2012-12-05

    Dopamine replacement with levodopa (L-DOPA) represents the mainstay of Parkinson’s disease (PD) therapy. Nevertheless, this well established therapeutic intervention loses efficacy with the progression of the disease and patients develop invalidating side effects, known in their complex as L-DOPA-induced dyskinesia (LID). Unfortunately, existing therapies fail to prevent LID and very few drugs are available to lessen its severity, thus representing a major clinical problem inPDtreatment. D2-like receptor (D2R) agonists are a powerful clinical option as an alternative to L-DOPA, especially in the early stages of the disease, being associated to a reduced risk of dyskinesia development. D2R agonists also find considerable application in the advanced stages of PD, in conjunction with L-DOPA, which is used in this context at lower dosages, to delay the appearance and the extent of the motor complications. In advanced stages of PD, D2R agonists are often effective in delaying the appearance and the extent of motor complications. Despite the great attention paid to the family of D2R agonists, the main reasons underlying the reduced risk of dyskinesia have not yet been fully characterized. Here we show that the striatal NMDA/AMPAreceptor ratio and theAMPAreceptor subunit composition are altered in experimental parkinsonism in rats. Surprisingly, while L-DOPA fails to restore these critical synaptic alterations, chronic treatment with pramipexole is associated not only with a reduced risk of dyskinesia development but is also able to rebalance, in a dose-dependent fashion, the physiological synaptic parameters, thus providing new insights into the mechanisms of dyskinesia.

  16. Roles of adrenergic α1 and dopamine D1 and D2 receptors in the mediation of the desynchronization effects of modafinil in a mouse EEG synchronization model.

    Science.gov (United States)

    Chen, Chang-Rui; Yang, Su-Rong; Liu, Yuan-Yuan; Qu, Wei-Min; Urade, Yoshihiro; Huang, Zhi-Li

    2013-01-01

    Synchronized electroencephalogram (EEG) activity is observed in pathological stages of cognitive impairment and epilepsy. Modafinil, known to increase the release of catecholamines, is a potent wake-promoting agent, and has shown some abilities to desynchronize EEG,but its receptor mechanisms by which modafinil induces desynchoronization remain to be elucidated. Here we used a pharmacological EEG synchronization model to investigate the involvement of adrenergic α1 receptors (R, α1R) and dopamine (DA) D1 and D2 receptors (D1Rs and D2Rs) on modafinil-induced desynchronization in mice. Mice were treated with cholinergic receptor antagonist scopolamine and monoamine depletor reserpine to produce experimental EEG synchronization characterized by continuous large-amplitude synchronized activity, with prominent increased delta and decreased theta, alpha, and beta power density. The results showed that modafinil produced an EEG desynchronization in the model. This was characterized by a general decrease in amplitude of all the frequency bands between 0 and 20 Hz, a prominent reduction in delta power density, and an increase in theta power density. Adrenergic α1R antagonist terazosin (1 mg/kg, i.p.) completely antagonized the EEG desynchronization effects of modafinil at 90 mg/kg. However, DA D1R and D2R blockers partially attenuated the effects of modafinil. The modafinil-induced decrease in the amplitudes of the delta, theta, alpha, and beta waves and in delta power density were completely abolished by pretreatment with a combination of the D1R antagonist SCH 23390 (30 µg/kg) and the D2R antagonist raclopride (2 mg/kg, i.p.). These results suggest that modafinil-mediated desynchronization may be attributed to the activation of adrenergic α1R, and dopaminergic D1R and D2R in a model of EEG synchronization.

  17. Roles of adrenergic α1 and dopamine D1 and D2 receptors in the mediation of the desynchronization effects of modafinil in a mouse EEG synchronization model.

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    Chang-Rui Chen

    Full Text Available BACKGROUND: Synchronized electroencephalogram (EEG activity is observed in pathological stages of cognitive impairment and epilepsy. Modafinil, known to increase the release of catecholamines, is a potent wake-promoting agent, and has shown some abilities to desynchronize EEG,but its receptor mechanisms by which modafinil induces desynchoronization remain to be elucidated. Here we used a pharmacological EEG synchronization model to investigate the involvement of adrenergic α1 receptors (R, α1R and dopamine (DA D1 and D2 receptors (D1Rs and D2Rs on modafinil-induced desynchronization in mice. METHODOLOGY/PRINCIPAL FINDINGS: Mice were treated with cholinergic receptor antagonist scopolamine and monoamine depletor reserpine to produce experimental EEG synchronization characterized by continuous large-amplitude synchronized activity, with prominent increased delta and decreased theta, alpha, and beta power density. The results showed that modafinil produced an EEG desynchronization in the model. This was characterized by a general decrease in amplitude of all the frequency bands between 0 and 20 Hz, a prominent reduction in delta power density, and an increase in theta power density. Adrenergic α1R antagonist terazosin (1 mg/kg, i.p. completely antagonized the EEG desynchronization effects of modafinil at 90 mg/kg. However, DA D1R and D2R blockers partially attenuated the effects of modafinil. The modafinil-induced decrease in the amplitudes of the delta, theta, alpha, and beta waves and in delta power density were completely abolished by pretreatment with a combination of the D1R antagonist SCH 23390 (30 µg/kg and the D2R antagonist raclopride (2 mg/kg, i.p.. CONCLUSIONS/SIGNIFICANCE: These results suggest that modafinil-mediated desynchronization may be attributed to the activation of adrenergic α1R, and dopaminergic D1R and D2R in a model of EEG synchronization.

  18. Dopamine D2/3 Receptor Occupancy Following Dose Reduction Is Predictable With Minimal Plasma Antipsychotic Concentrations: An Open-Label Clinical Trial.

    Science.gov (United States)

    Nakajima, Shinichiro; Uchida, Hiroyuki; Bies, Robert R; Caravaggio, Fernando; Suzuki, Takefumi; Plitman, Eric; Mar, Wanna; Gerretsen, Philip; Pollock, Bruce G; Mulsant, Benoit H; Mamo, David C; Graff-Guerrero, Ariel

    2016-01-01

    Population pharmacokinetics can predict antipsychotic blood concentrations at a given time point prior to a dosage change. Those predicted blood concentrations could be used to estimate the corresponding dopamine D2/3 receptors (D2/3R) occupancy by antipsychotics based on the tight relationship between blood and brain pharmacokinetics. However, this 2-step prediction has never been tested. Two blood samples were collected at separate time points from 32 clinically stable outpatients with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; mean ± SD age: 60.1 ± 7.3 years) to measure plasma concentrations of olanzapine or risperidone at baseline. Then, subjects underwent a dose reduction of olanzapine or risperidone and completed a [(11)C]-raclopride positron emission tomography scan to measure D2/3R occupancy in the putamen. The plasma concentration at the time of the scan was predicted with the 2 samples based on population pharmacokinetic model, using NONMEM. D2/3R occupancy was then estimated by incorporating the predicted plasma concentration in a hyperbole saturation model. The predicted occupancy was compared to the observed value. The mean (95% CI) prediction errors for the prediction of D2/3R occupancy were -1.76% (-5.11 to 1.58) for olanzapine and 0.64% (-6.18 to 7.46) for risperidone. The observed and predicted D2/3R occupancy levels were highly correlated (r = 0.67, P = .001 for olanzapine; r = 0.67, P = .02 for risperidone). D2/3R occupancy levels can be predicted from blood drug concentrations collected prior to dosage change. Although this 2-step model is subject to a small degree of error, it could be used to select oral doses aimed at achieving optimal D2/3R occupancy on an individual basis. © The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  19. Cocaine-induced dendritic remodeling occurs in both D1 and D2 dopamine receptor-expressing neurons in the nucleus accumbens.

    Science.gov (United States)

    Li, Juan; Liu, Nuyun; Lu, Kangrong; Zhang, Lei; Gu, Jingjing; Guo, Fukun; An, Shengli; Zhang, Lin; Zhang, Lu

    2012-05-31

    Repeated exposure to cocaine can induce persistent alterations in the brain's reward system, including increases in the number of dendrites and spine density on medium-sized spiny neurons (MSNs) in the nucleus accumbens (NAc). The structural remodeling of dendrites and spines in the NAc is thought to play a critical role in cocaine addiction. MSNs in the NAc can be classified by expression of either D1 or D2 dopamine receptors, which are localized to the direct and indirect pathway, respectively. It is unknown whether the dendritic changes induced by repeated cocaine treatment occur in MSNs of the direct or indirect pathway. Because the traditional Golgi-Cox impregnation of neurons precludes identifying particular subpopulations of MSNs, we performed dendritic morphology analysis after biocytin-labeling and Golgi-Cox impregnation. We found that the biocytin staining MSNs showed higher dendritic spine density and higher number of dendrites than that in Golgi impregnation group. In addition, we found that the increasing spine density induced by repeated cocaine treatment in female mice was higher than that in male mice. Next we used biocytin staining and dynorphin/D2 receptor colocalization to determine which cell type(s) displayed dendritic changes after repeated cocaine treatment. We found that cocaine-induced changes in dendritic parameters occurred in MSNs of both the direct (D1-expressing) and indirect (D2-expressing) pathways. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  20. Interaction of clozapine and its nitrenium ion with rat D2 dopamine receptors: in vitro binding and computational study

    Science.gov (United States)

    Dilly, Sébastien; Liégeois, Jean-François

    2011-02-01

    The interaction of diazepine analogues like clozapine or olanzapine with D2 receptor was greatly affected by a mixture of HRP/H2O2 known to induce the formation of nitrenium ion. Unlike diazepine derivatives, the oxidative mixture had low impact on the affinity of oxa- and thiazepine derivatives such as loxapine, clothiapine or JL13 for the D2 receptor. Molecular docking simulations revealed a huge difference between the mode of interaction of clozapine nitrenium ion and the parent drug. Electronic and geometric changes of the tricyclic ring system caused by the oxidation appeared to prevent the compound finding the correct binding mode and could therefore explain the difference observed in binding affinities.

  1. Effects of a partial dopamine D2-like agonist on the cocaine-induced behavioral sensitization of preweanling rats.

    Science.gov (United States)

    Sibole, Janet M; Matea, Pam J; Krall, Catherine M; McDougall, Sanders A

    2003-08-01

    Partial D(2)-like receptor agonists act as functional antagonists when given during periods of high dopaminergic tone (e.g., when self-administering cocaine or amphetamine). For this reason, we determined whether pretreatment with the partial D(2)-like agonist terguride would block the induction and/or expression of cocaine-induced behavioral sensitization in preweanling rats. More specifically, we examined (a). whether repeated administration of terguride alone (0.4-1.6 mg/kg) would support behavioral sensitization (Experiment 1); (b). whether injecting preweanling rats with terguride (0.1-1.6 mg/kg) during the pretreatment phase would block the induction and ultimate expression of cocaine-induced behavioral sensitization (Experiment 2); and (c). whether injecting rats with terguride (0.2-0.8 mg/kg) on the test day would block the expression of cocaine sensitization (Experiment 3). Results showed that repeated terguride administration did not induce behavioral sensitization by itself, nor did it block the induction of cocaine sensitization in preweanling rats. Interestingly, terguride reduced, but did not fully attenuate, the locomotor activity of cocaine-treated rats during the pretreatment phase. When given on the test day, terguride also depressed cocaine-induced locomotor activity, but rather than blocking the expression of behavioral sensitization, terguride seemed to cause a general reduction in locomotion. Because partial D(2)-like agonists attenuate cocaine- and amphetamine-induced reward, it has been proposed that this class of drug might serve as an effective pharmacotherapy for psychostimulant abuse. Although partial D(2)-like agonists may prove useful in this regard, results from the present study suggest that terguride would not block sensitization components of the addiction process.

  2. Auswirkung genetischer Varianz im Dopamin-Rezeptor-D2-Gen auf Arbeitsgedächtnis- und Fehlermonitoringprozesse

    OpenAIRE

    Odorfer, Thorsten Michael

    2011-01-01

    In dieser Studie sollte die Bedeutung von genetischer Varianz im Gen des Dopaminrezeptors D2 (DRD2) insbesondere für Fehlermonitoring- und Arbeitsgedächtnisprozesse untersucht werden. Vorstudien implizieren die Relevanz der dopaminergen Neurotransmission für diese Systeme und geben Hinweise, dass Defizite in entsprechenden kognitiven Prozessen für psychiatrische Erkrankungen prädisponieren. Daher wurden die Verhaltensdaten in zwei verschiedenen kognitiven Leistungstests, als auch parallel daz...

  3. Behavioral and Neural Manifestations of Reward Memory in Carriers of Low-Expressing versus High-Expressing Genetic Variants of the Dopamine D2 Receptor

    Directory of Open Access Journals (Sweden)

    Anni Richter

    2017-05-01

    Full Text Available Dopamine is critically important in the neural manifestation of motivated behavior, and alterations in the human dopaminergic system have been implicated in the etiology of motivation-related psychiatric disorders, most prominently addiction. Patients with chronic addiction exhibit reduced dopamine D2 receptor (DRD2 availability in the striatum, and the DRD2 TaqIA (rs1800497 and C957T (rs6277 genetic polymorphisms have previously been linked to individual differences in striatal dopamine metabolism and clinical risk for alcohol and nicotine dependence. Here, we investigated the hypothesis that the variants of these polymorphisms would show increased reward-related memory formation, which has previously been shown to jointly engage the mesolimbic dopaminergic system and the hippocampus, as a potential intermediate phenotype for addiction memory. To this end, we performed functional magnetic resonance imaging (fMRI in 62 young, healthy individuals genotyped for DRD2 TaqIA and C957T variants. Participants performed an incentive delay task, followed by a recognition memory task 24 h later. We observed effects of both genotypes on the overall recognition performance with carriers of low-expressing variants, namely TaqIA A1 carriers and C957T C homozygotes, showing better performance than the other genotype groups. In addition to the better memory performance, C957T C homozygotes also exhibited a response bias for cues predicting monetary reward. At the neural level, the C957T polymorphism was associated with a genotype-related modulation of right hippocampal and striatal fMRI responses predictive of subsequent recognition confidence for reward-predicting items. Our results indicate that genetic variations associated with DRD2 expression affect explicit memory, specifically for rewarded stimuli. We suggest that the relatively better memory for rewarded stimuli in carriers of low-expressing DRD2 variants may reflect an intermediate phenotype of

  4. -141C Ins/Del polymorphism of the dopamine D2 receptor gene is associated with schizophrenia in a Spanish population.

    Science.gov (United States)

    Lafuente, Amalia; Bernardo, Miquel; Mas, Sergi; Crescenti, Anna; Aparici, Monica; Gassó, Patricia; Goti, Javier; Sanchez, Vanessa; Catalan, Rosa; Carne, Xavier

    2008-06-01

    In this study we examined the relationship between dopamine D2 receptor (DRD2) polymorphisms (TaqIA, TaqIB, -141C Ins/Del) and dopamine D3 receptor (DRD3) Ser9Gly polymorphism and the risk of schizophrenia in a Spanish population. Two hundred and forty-three schizophrenia patients and 291 healthy controls from the general population participated in a case-control study. No significant differences were observed in the allele or genotype frequencies of TaqIA, TaqIB or Ser9Gly polymorphisms between the schizophrenia patients and the healthy controls. The frequency of the -141C Del allele was significantly lower in the former group (odds ratio=0.4, P=0.01). The -141C Del allele, which produces lower expression of DRD2, may protect against dopaminergic hyperactivity in schizophrenia. This study is one of the few studies of Caucasian participants that supports the results obtained in the original Japanese study, in which the -141C Ins/Del polymorphism was first described. Furthermore, our findings reinforce the hypothesis that excess dopaminergic activity leads to schizophrenia.

  5. Lack of association between dopaminergic antagonism and negative symptoms in schizophrenia: a positron emission tomography dopamine D2/3 receptor occupancy study.

    Science.gov (United States)

    Fervaha, Gagan; Caravaggio, Fernando; Mamo, David C; Mulsant, Benoit H; Pollock, Bruce G; Nakajima, Shinichiro; Gerretsen, Philip; Rajji, Tarek K; Mar, Wanna; Iwata, Yusuke; Plitman, Eric; Chung, Jun Ku; Remington, Gary; Graff-Guerrero, Ariel

    2016-10-01

    Several pre-clinical studies suggest that antipsychotic medications cause secondary negative symptoms. However, direct evidence for a relationship among antipsychotic medications, their direct effects on neurotransmitter systems, and negative symptoms in schizophrenia remains controversial. The objective of this study was to examine the relationship between antipsychotic-related dopamine D2/3 receptor occupancy and negative symptoms in patients with schizophrenia. Forty-one clinically stable outpatients with schizophrenia participated in this prospective dose reduction positron emission tomography (PET) study. Clinical assessments and [11C]-raclopride PET scans were performed before and after participants underwent gradual dose reduction of their antipsychotic medication by up to 40 % from the baseline dose. No significant relationship was found between antipsychotic-related dopamine D2/3 receptor occupancy and negative symptom severity at baseline or follow-up. Similar null findings were found for subdomains of negative symptoms (amotivation and diminished expression). Occupancy was significantly lower following dose reduction; however, negative symptom severity did not change significantly, though a trend toward reduction was noted. Examination of change scores between these two variables revealed no systematic relationship. Our cross-sectional and longitudinal results failed to find a significant dose-dependent relationship between severity of negative symptoms and antipsychotic-related dopaminergic antagonism in schizophrenia. These findings argue against the notion that antipsychotics necessarily cause secondary negative symptoms. Our results are also in contrast with the behavioral effects of dopaminergic antagonism routinely reported in pre-clinical investigations, suggesting that the role of this variable in the context of chronic treatment and schizophrenia needs to be re-examined.

  6. Effects of early methylphenidate exposure on morphine- and sucrose-reinforced behaviors in adult rats: relationship to dopamine D2 receptors.

    Science.gov (United States)

    Crawford, Cynthia A; Villafranca, Steve W; Cyr, Michelle C; Farley, Cristal M; Reichel, Carmela M; Gheorghe, Stacy L; Krall, Catherine M; McDougall, Sanders A

    2007-03-30

    Methylphenidate is commonly used to treat Attention Deficit Hyperactivity Disorder (ADHD) in school-aged children, and there is an increasing trend to prescribe methylphenidate to younger preschool-aged children. While the efficacy of methylphenidate is not in question, there is evidence that early methylphenidate treatment may have long-term effects on later drug responsiveness. The goal of this study was to determine whether early exposure to methylphenidate would alter morphine-induced conditioned place preference (CPP) and sucrose-reinforced lever-pressing in young adult rats. We also assessed whether early methylphenidate exposure would impact dopamine D(2) binding sites. Sprague-Dawley rats were treated with methylphenidate (0, 2, or 5 mg/kg) once a day from PD 11-PD 20. On PD 60, morphine-induced CPP or sucrose-reinforced lever-pressing was assessed. A 10-day CPP procedure was used, which included 1 preconditioning day, 8 conditioning days, and 1 test day. After CPP testing, D(2) receptor binding was determined in striatal and accumbal tissue samples. In the sucrose experiment, rats were trained to lever-press on a progressive ratio schedule for one sucrose pellet. Results showed that early exposure to methylphenidate (5 mg/kg) increased the magnitude of morphine-induced CPP. Exposure to methylphenidate did not alter the number of D(2) binding sites, however, there were positive correlations between the number of D(2) binding sites and the strength of the CPP. In the sucrose-reinforced lever-press experiment, rats exposed to methylphenidate (2 and 5 mg/kg) had higher break points than saline controls. These results suggest that early exposure to methylphenidate alters reward system functioning, thereby making these systems more sensitive to appetitive stimuli.

  7. Regional CNS densities of serotonin 1A and dopamine D2 receptors in periadolescent alcohol-preferring P and alcohol-nonpreferring NP rat pups.

    Science.gov (United States)

    Strother, Wendy N; Lumeng, Larry; Li, Ting-Kai; McBride, William J

    2003-01-01

    The objective of the present study was to use quantitative autoradiography to determine binding densities of serotonin(1A) (5-HT(1A)) and dopamine (DA) D(2) receptors in alcohol-naive periadolescent P and NP rat pups. P (n=8) and NP (n=7) rat pups, 25 days of age, from different litters were used. Coronal brain sections were incubated with 2 nM [3H]8-OH-DPAT or 20 nM [3H]sulpiride for 5-HT(1A) or D(2) binding, respectively. Approximately 15-40% higher densities of [3H]8-OH-DPAT binding were observed in the anterior cortical regions of the periadolescent P rat compared with NP rat pups. Similar differences were also observed in posterior cortical regions with P rats having 25-40% higher [3H]8-OH-DPAT binding than NP rats. [3H]8-OH-DPAT binding was approximately 10-20% higher in posterior hippocampal regions of the P rat pups compared with the NP line. [3H]sulpiride binding was significantly different only in the ventral tegmental area (VTA), where binding was approximately 20% lower in the periadolescent P rats compared with the NP rat pups. Overall, these results are very similar to findings observed in adult alcohol-naive P and NP rats, and suggest that the innate differences in the neural systems implicated in high alcohol drinking behaviors may already be established in the periadolescent animal.

  8. Effects of Acute and Chronic Treatments with Dopamine D2and D3Receptor Ligands on Cocaine versus Food Choice in Rats.

    Science.gov (United States)

    Thomsen, Morgane; Barrett, Andrew C; Butler, Paul; Negus, S Stevens; Caine, S Barak

    2017-07-01

    Dopamine D 3 receptor ligands are potential medications for psychostimulant addiction. Medication assessment may benefit from preclinical studies that evaluate chronic medication effects on choice between an abused drug and an alternative, nondrug reinforcer. This study compared acute and chronic effects of dopamine D 2 - and D 3 -preferring ligands on choice between intravenous cocaine and palatable food in rats. Under baseline conditions, cocaine maintained dose-dependent increases in cocaine choice and reciprocal decreases in food choice. Acutely, the D 2 agonist R -(-)-norpropylapomorphine (NPA) and antagonist L-741,626 [3-[[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1 H -indole] produced leftward and rightward shifts in cocaine dose-effect curves, respectively, whereas the partial agonist terguride had no effect. All three drugs dose-dependently decreased food-maintained responding. Chronically, the effects of R -(-)-norpropylapomorphine and L-741,626 on cocaine self-administration showed marked tolerance, whereas suppression of food-reinforced behavior persisted. Acute effects of the D 3 ligands were less systematic and most consistent with nonselective decreases in cocaine- and food-maintained responding. Chronically, the D 3 agonist PF-592,379 [5-[(2 R ,5 S )-5-methyl-4-propylmorpholin-2-yl]pyridin-2-amine] increased cocaine choice, whereas an intermediate dose of the D 3 antagonist PG01037 [ N -[( E )-4-[4-(2,3-dichlorophenyl)piperazin-1-yl]but-2-enyl]-4-pyridin-2-ylbenzamide] produced a therapeutically desirable decrease in cocaine choice early in treatment; however, tolerance to this effect developed, and lower and higher doses were ineffective. D 3 ligands failed to significantly modify total cocaine intake but caused persistent decreases in food intake. Thus, D 2 -and D 3 -preferring ligands showed distinct profiles, consistent with different pharmacological actions. In addition, these results highlight the role of acute versus chronic treatment

  9. Dopamine D1/D2 Receptor Activity in the Nucleus Accumbens Core But Not in the Nucleus Accumbens Shell and Orbitofrontal Cortex Modulates Risk-Based Decision Making.

    Science.gov (United States)

    Mai, Bettina; Sommer, Susanne; Hauber, Wolfgang

    2015-04-23

    It is well known that brain dopamine (DA) signals support risk-based decision making; however, the specific terminal regions of midbrain DA neurons through which DA signals mediate risk-based decision making are unknown. Using microinfusions of the D1/D2 receptor antagonist flupenthixol, we sought to explore the role of D1/D2 receptor activity in the rat orbitofrontal cortex (OFC) and core and shell regions of the nucleus accumbens (AcbC and AcbS, respectively) in the regulation of risky choices. A risk-discounting task was used that involves choices between a certain small-reward lever that always delivered 1 pellet or a risky large-reward lever which delivered 4 pellets but had a decreasing probability of receiving the reward across 4 subsequent within-session trial blocks (100%, 50%, 25%, 12.5%). To validate task sensitivity to experimental manipulations of DA activity, we also examined the effects of systemic amphetamine and flupenthixol. Systemic amphetamine increased while systemic flupenthixol reduced risky choices. Results further demonstrate that rats that received intra-AcbC flupenthixol were able to track increasing risk associated with the risky lever but displayed a generally reduced preference for the risky lever across all trial blocks, including in the initial trial block (large reward at 100%). Microinfusions of flupenthixol into the AcbS or OFC did not alter risk-based decision making. Our data suggest that intra-AcbC D1/D2 receptor signaling does not support the ability to track shifts in reward probabilities but does bias risk-based decision making. That is, it increased the rats' preference for the response option known to be associated with higher risk-related costs. © The Author 2015. Published by Oxford University Press on behalf of CINP.

  10. PARAMETRIC IMAGING AND TEST-RETEST VARIABILITY OF 11C-(+)-PHNO BINDING TO D2/D3 DOPAMINE RECEPTORS IN HUMANS ON THE HRRT PET SCANNER

    Science.gov (United States)

    Gallezot, Jean-Dominique; Zheng, Ming-Qiang; Lim, Keunpoong; Lin, Shu-fei; Labaree, David; Matuskey, David; Huang, Yiyun; Ding, Yu-Shin; Carson, Richard E.; Malison, Robert T.

    2014-01-01

    11C-(+)-PHNO is an agonist radioligand for imaging dopamine D2 and D3 receptors in the human brain with PET. In this study we evaluated the reproducibility of 11C-(+)-PHNO binding parameters using a within-day design and assessed parametric imaging methods. Methods Repeated studies were performed in eight subjects, with simultaneous measurement of the arterial input function and plasma free fraction. Two 11C-(+)-PHNO scans on the same subject were separated by 5.4±0.7 h. After evaluating compartment models, 11C-(+)-PHNO volumes of distribution VT and VT/fP and binding potentials BPND, BPP and BPF were quantified using the multilinear analysis MA1, with the cerebellum as reference region. Parametric images of BPND were also computed using SRTM and SRTM2. Results The test-retest variability of 11C-(+)-PHNO BPND was 9% in D2-rich regions (caudate and putamen). Among D3-rich regions, variability was low in pallidum (6%), but higher in substantia nigra (19%), thalamus (14%) and hypothalamus (21%). No significant mass carry-over effect was observed in D3-rich regions, although a trend in BPND was present in substantia nigra (−14±15%). Due to the relatively fast kinetics, low noise BPND parametric images were obtained with both SRTM and SRTM2 without spatial smoothing. Conclusion 11C-(+)-PHNO can be used to compute low noise parametric images in both D2 and D3 rich regions in humans. PMID:24732151

  11. The hallucinogen d-lysergic diethylamide (LSD) decreases dopamine firing activity through 5-HT1A, D2 and TAAR1 receptors.

    Science.gov (United States)

    De Gregorio, Danilo; Posa, Luca; Ochoa-Sanchez, Rafael; McLaughlin, Ryan; Maione, Sabatino; Comai, Stefano; Gobbi, Gabriella

    2016-11-01

    d-lysergic diethylamide (LSD) is a hallucinogenic drug that interacts with the serotonin (5-HT) system binding to 5-HT1 and 5-HT2 receptors. Little is known about its potential interactions with the dopamine (DA) neurons of the ventral tegmental area (VTA). Using in-vivo electrophysiology in male adult rats, we evaluated the effects of cumulative doses of LSD on VTA DA neuronal activity, compared these effects to those produced on 5-HT neurons in the dorsal raphe nucleus (DRN), and attempted to identify the mechanism of action mediating the effects of LSD on VTA DA neurons. LSD, at low doses (5-20μg/kg, i.v.) induced a significant decrease of DRN 5-HT firing activity through 5-HT2A and D2 receptors. At these low doses, LSD did not alter VTA DA neuronal activity. On the contrary, at higher doses (30-120μg/kg, i.v.), LSD dose-dependently decreased VTA DA firing activity. The depletion of 5-HT with p-chlorophenylalanine did not modulate the effects of LSD on DA firing activity. The inhibitory effects of LSD on VTA DA firing activity were prevented by the D2 receptor antagonist haloperidol (50μg/kg, i.v.) and by the 5-HT1A receptor antagonist WAY-100,635 (500μg/kg, i.v.). Notably, pretreatment with the trace amine-associate receptor 1 (TAAR1) antagonist EPPTB (5mg/kg, i.v.) blocked the inhibitory effect of LSD on VTA DA neurons. These results suggest that LSD at high doses strongly affects DA mesolimbic neuronal activity in a 5-HT independent manner and with a pleiotropic mechanism of action involving 5-HT1A, D2 and TAAR1 receptors. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Dopamine D2 and D3 binding in people at clinical high risk for schizophrenia, antipsychotic-naive patients and healthy controls while performing a cognitive task

    Science.gov (United States)

    Suridjan, Ivonne; Rusjan, Pablo; Addington, Jean; Wilson, Alan A.; Houle, Sylvain; Mizrahi, Romina

    2013-01-01

    Background The dopamine (DA) D2 receptors exist in 2 states: a high-affinity state (D2high) that is linked to second messenger systems, responsible for functional effects, exhibits high affinity for agonists (e.g., DA), and a low-affinity state that is functionally inert exhibits lower affinity for agonists. The DA D3 receptor subtype exhibits high agonist affinity, whereas the existence of the multiple affinity states is controversial. Preclinical studies in animal models of psychosis have shown a selective increase of D2high as the common factor in psychosis, and the D3 receptor has been suggested to be involved in the pathophysiology of schizophrenia. Methods We studied D2high and D3 in people at clinical high risk (CHR) for schizophrenia and in antipsychotic-naive patients with schizophrenia using the novel positron emission tomography radiotracer, [11C]-(+)-PHNO. The binding potential nondisplaceable (BPND) was examined in the regions of interest (ROI; caudate, putamen, ventral striatum, globus pallidus, substantia nigra and thalamus) using an ROI and a voxel-wise approach while participants performed a cognitive task. Results We recruited 12 CHR individuals and 13 antipsychotic-naive patients with schizophrenia-spectrum disorder, whom we compared with 12 age- and sex-matched healthy controls. The BPND between patients and controls did not differ in any of the ROIs, consistent with the voxel-wise analysis. Correlations between the BPND in D3-rich regions and psychopathology warrant further investigation. Limitations In the absence of resting-state (baseline) BPND data, or following a depletion paradigm (i.e., α-methyl partyrosine), it is not possible to ascertain whether the lack of difference among the groups is owing to different levels of baseline DA or to release during the cognitive task. Conclusion To our knowledge, the present study represents the first effort to measure the D2 and D3 receptors under a cognitive challenge in individuals putative

  13. Validation of quantitative brain dopamine D2 receptor imaging with a conventional single-head SPET camera

    Energy Technology Data Exchange (ETDEWEB)

    Nikkinen, P. (Helsinki Univ. (Finland). Dept. of Clinical Chemistry); Liewendahl, K. (Helsinki Univ. (Finland). Dept. of Clinical Chemistry); Savolainen, S. (Helsinki Univ. (Finland). Dept. of Physics); Launes, J. (Helsinki Univ. (Finland). Dept. of Neurology)

    1993-08-01

    Phantom measurements were performed with a conventional single-head single-photon emission tomography (SPET) camera in order to validate the relevance of the basal ganglia/frontal cortex iodine-123 iodobenzamide (IBZM) uptake ratios measured in patients. Inside a cylindrical phantom (diameter 22 cm), two cylinders with a diameter of 3.3 cm were inserted. The activity concentrations of the cylinders ranged from 6.0 to 22.6 kBq/ml and the cylinder/background activity ratios varied from 1.4 to 3.8. From reconstructed SPET images the cylinder/background activity ratios were calculated using three different regions of interest (ROIs). A linear relationship between the measured activity ratio and the true activity ratio was obtained. In patient studies, basal ganglia/frontal cortex IBZM uptake ratios determined from the reconstructed slices using attentuation correction prior to reconstruction were 1.30 [+-]0.03 in idiopathic Parkinson's disease (n = 9), 1,33 [+-]0.09 in infantile and juvenile neuronal ceroid lipofuscinosis (n = 7) and 1.34 [+-]0.05 in narcolepsy (n = 8). Patients with Huntington's disease had significantly lower ratios (1.09 [+-]0.04, n = 5). The corrected basal ganglia/frontal cortex ratios, determined using linear regression, were about 80 % higher. The use of dual-window scatter correction increased the measured ratios by about 10 %. Although comprehensive correction methods can further improve the resolution in SPET images, the resolution of the SPET system used by us (1.5 - 2 cm) will determine what is achievable in basal ganglia D2 receptor imaging. (orig.)

  14. Striatal and extrastriatal dopamine D2 receptor occupancy by a novel antipsychotic, blonanserin: a PET study with [11C]raclopride and [11C]FLB 457 in schizophrenia.

    Science.gov (United States)

    Tateno, Amane; Arakawa, Ryosuke; Okumura, Masaki; Fukuta, Hajime; Honjo, Kazuyoshi; Ishihara, Keiichi; Nakamura, Hiroshi; Kumita, Shin-ichiro; Okubo, Yoshiro

    2013-04-01

    Blonanserin is a novel antipsychotic with high affinities for dopamine D(2) and 5-HT(2A) receptors, and it was recently approved for the treatment of schizophrenia in Japan and Korea. Although double-blind clinical trials have demonstrated that blonanserin has equal efficacy to risperidone, and with a better profile especially with respect to prolactin elevation, its profile of in vivo receptor binding has not been investigated in patients with schizophrenia. Using positron emission tomography (PET), we measured striatal and extrastriatal dopamine D(2) receptor occupancy by blonanserin in 15 patients with schizophrenia treated with fixed doses of blonanserin (ie, 8, 16, and 24 mg/d) for at least 4 weeks before PET scans, and in 15 healthy volunteers. Two PET scans, 1 with [(11)C]raclopride for the striatum and 1 with [(11)C]FLB 457 for the temporal cortex and pituitary, were performed on the same day. Striatal dopamine D(2) receptor occupancy by blonanserin was 60.8% (3.0%) [mean (SD)] at 8 mg, 73.4% (4.9%) at 16 mg, and 79.7% (2.3%) at 24 mg. The brain/plasma concentration ratio calculated from D(2) receptor occupancy in the temporal cortex and pituitary was 3.38, indicating good blood-brain barrier permeability. This was the first study to show clinical daily dose amounts of blonanserin occupying dopamine D(2) receptors in patients with schizophrenia. The clinical implications obtained in this study were the optimal therapeutic dose range of 12.9 to 22.1 mg/d of blonanserin required for 70% to 80% dopamine D(2) receptor occupancy in the striatum, and the good blood-brain barrier permeability that suggested a relatively lower risk of hyperprolactinemia.

  15. Genetically determined measures of striatal D2 signaling predict prefrontal activity during working memory performance.

    Directory of Open Access Journals (Sweden)

    Alessandro Bertolino

    2010-02-01

    Full Text Available Variation of the gene coding for D2 receptors (DRD2 has been associated with risk for schizophrenia and with working memory deficits. A functional intronic SNP (rs1076560 predicts relative expression of the two D2 receptors isoforms, D2S (mainly pre-synaptic and D2L (mainly post-synaptic. However, the effect of functional genetic variation of DRD2 on striatal dopamine D2 signaling and on its correlation with prefrontal activity during working memory in humans is not known.Thirty-seven healthy subjects were genotyped for rs1076560 (G>T and underwent SPECT with [123I]IBZM (which binds primarily to post-synaptic D2 receptors and with [123I]FP-CIT (which binds to pre-synaptic dopamine transporters, whose activity and density is also regulated by pre-synaptic D2 receptors, as well as BOLD fMRI during N-Back working memory.Subjects carrying the T allele (previously associated with reduced D2S expression had striatal reductions of [123I]IBZM and of [123I]FP-CIT binding. DRD2 genotype also differentially predicted the correlation between striatal dopamine D2 signaling (as identified with factor analysis of the two radiotracers and activity of the prefrontal cortex during working memory as measured with BOLD fMRI, which was positive in GG subjects and negative in GT.Our results demonstrate that this functional SNP within DRD2 predicts striatal binding of the two radiotracers to dopamine transporters and D2 receptors as well as the correlation between striatal D2 signaling with prefrontal cortex activity during performance of a working memory task. These data are consistent with the possibility that the balance of excitatory/inhibitory modulation of striatal neurons may also affect striatal outputs in relationship with prefrontal activity during working memory performance within the cortico-striatal-thalamic-cortical pathway.

  16. The associations among the dopamine D2 receptor Taq1, emotional intelligence, creative potential measured by divergent thinking, and motivational state and these associations' sex differences.

    Science.gov (United States)

    Takeuchi, Hikaru; Tomita, Hiroaki; Taki, Yasuyuki; Kikuchi, Yoshie; Ono, Chiaki; Yu, Zhiqian; Sekiguchi, Atsushi; Nouchi, Rui; Kotozaki, Yuka; Nakagawa, Seishu; Miyauchi, Carlos M; Iizuka, Kunio; Yokoyama, Ryoichi; Shinada, Takamitsu; Yamamoto, Yuki; Hanawa, Sugiko; Araki, Tsuyoshi; Hashizume, Hiroshi; Kunitoki, Keiko; Sassa, Yuko; Kawashima, Ryuta

    2015-01-01

    Previous neuroscientific studies have shown that the dopaminergic system plays an important role in creative potential measured by divergent thinking (CPMDT), emotional control, and motivational state. However, although associations between two of these four components have been previously established (e.g., the association between CPMDT and emotional control, the association between CPMDT and motivational state, etc.), the interactions between these four remain unknown. The purpose of this study was to reveal these interactions using path analyses. The Taq1A polymorphism of the dopamine D2 receptor (DRD2) gene was used for this purpose. For measuring emotional intelligence (EI), we used the Japanese version of the Emotional Intelligence Scale. CPMDT was measured using the S-A creativity test. Motivational state was measured using the Vigor subscale of the Japanese version of the Profile of Mood Scale (POMS). Data from 766 healthy, right-handed individuals (426 men and 340 women; 20.7 ± 1.9 years of age) were used in this study. There were significant and robust positive relationships among measures of CPMDT, EI, and motivational state across sex. In addition, the polymorphism of the DRD2 gene was significantly associated with EI, specifically in females. Path analysis in females indicates that the model in which (a) the DRD2 polymorphism primarily facilitates EI, (b) EI in turn facilitates CPMDT and leads to a better motivational state, and (c) a better motivational state also directly facilitates CPMDT explains the data in the most accurate manner. This study suggested a comprehensive picture of the cascade of the associations among dopamine, EI, motivational state, and CPMDT at least in females.

  17. The associations among the dopamine D2 receptor Taq1, emotional intelligence, creative potential measured by divergent thinking, and motivational state and these associations’ sex differences

    Directory of Open Access Journals (Sweden)

    Hikaru eTakeuchi

    2015-07-01

    Full Text Available Previous neuroscientific studies have shown that the dopaminergic system plays an important role in creativity potential measured by divergent thinking (CPMDT, emotional control, and motivational state. However, although associations between two of these four components have been previously established (e.g., the association between CPMDT and emotional control, the association between CPMDT and motivational state, etc., the interactions between these four remain unknown. The purpose of this study was to reveal these interactions using path analyses. The Taq1A polymorphism of the dopamine D2 receptor (DRD2 gene was used for this purpose. For measuring emotional intelligence (EI, we used the Japanese version of the Emotional Intelligence Scale. CPMDT was measured using the S-A creativity test. Motivational state was measured using the Vigor subscale of the Japanese version of the Profile of Mood Scale (POMS. Data from 766 healthy, right-handed individuals (426 men and 340 women; 20.7 ± 1.9 years of age were used in this study. There were significant and robust positive relationships among measures of CPMDT, EI, and motivational state across sex. In addition, the polymorphism of the DRD2 gene was significantly associated with EI, specifically in females. Path analysis in females indicates that the model in which (a the DRD2 polymorphism primarily facilitates EI, (b EI in turn facilitates CPMDT and leads to a better motivational state, and (c a better motivational state also directly facilitates CPMDT explains the data in the most accurate manner. This study suggested a comprehensive picture of the cascade of the associations among dopamine, EI, motivational state, and CPMDT at least in females.

  18. Reduction of dopamine D2/3receptor binding in the striatum after a single administration of esketamine, but not R-ketamine: a PET study in conscious monkeys.

    Science.gov (United States)

    Hashimoto, Kenji; Kakiuchi, Takeharu; Ohba, Hiroyuki; Nishiyama, Shingo; Tsukada, Hideo

    2017-03-01

    R-ketamine appears to be a potent, long-lasting and safer antidepressant, relative to esketamine (S-ketamine), since it might be free of psychotomimetic side effects. Using [ 11 C]raclopride and positron emission tomography (PET), we investigated whether esketamine and R-ketamine can affect dopamine D 2/3 receptor binding in the conscious monkey brain. A single infusion of esketamine (0.5 mg/kg), but not R-ketamine (0.5 mg/kg), caused a reduction of binding availability of dopamine D 2/3 receptor in the monkey striatum. This study suggests that unlike to R-ketamine, esketamine can cause dopamine release in the striatum, and that its release might be associated with psychotomimetic effects of esketamine.

  19. Role of Dopamine Receptors Subtypes, D1-Like and D2-Like, within the Nucleus Accumbens Subregions, Core and Shell, on Memory Consolidation in the One-Trial Inhibitory Avoidance Task

    Science.gov (United States)

    Manago, Francesca; Castellano, Claudio; Oliverio, Alberto; Mele, Andrea; De Leonibus, Elvira

    2009-01-01

    Recent evidence demonstrated that dopamine within the nucleus accumbens mediates consolidation of both associative and nonassociative memories. However, the specific contribution of the nucleus accumbens subregions, core and shell, and of D1 and D2 receptors subtypes has not been yet clarified. The aim of this study was, therefore, to directly…

  20. Spatial Working Memory in Male Rats: Pre-Experience and Task Dependent Roles of Dopamine D1- and D2-Like Receptors

    Directory of Open Access Journals (Sweden)

    Mekite Bezu

    2017-10-01

    Full Text Available The dopaminergic system is known to be involved in working memory processed by several brain regions like prefrontal cortex (PFC, hippocampus, striatum. In an earlier study we could show that Levodopa but not Modafinil enhanced working memory in a T-maze only during the early phase of training (day 3, whereas the later phase remained unaffected. Rats treated with a higher dose performed better than low dose treated rats. Here we could more specifically segregate the contributions of dopamine type 1- and 2- like receptors (D1R; D2R to the training state dependent modulation of spatial working memory by intracerebroventricular (ICV application of a D1R-like (SKF81297 and D2R-like agonist (Sumanirole and antagonist (SCH23390, Remoxipride at a low and high dose through 3 days of training. The D1R-like-agonist at both doses enhanced working memory at day 1 but only in the low dose treated rats enhancement persists over training compared to control rats. Rats treated with a high dose of a D1R-like-antagonist show persistent enhancement of working memory over training, whereas in low dose treated rats no statistical difference at any time point could be determined compared to controls. The D2R-like-agonist at both doses does not show an effect at any time point when compared to control animals, whereas the D2R-like antagonist at a low dose enhanced working memory at day 2. For the most effective D1R-like agonist, we repeated the experiments in a water maze working memory task, to test for task dependent differences in working memory modulations. Treated rats at both doses did not differ as compared to controls, but the temporal behavioral performance of all groups was different compared to T-maze trained rats. The results are in line with the view that spatial working memory is optimized within a limited range of dopaminergic transmission, however suggest that these ranges vary during spatial training.

  1. The effects of intra-locus coeruleus injection of dopamine D2 receptor agents on Naloxone withdrawal signs in Morphine-dependent rats

    Directory of Open Access Journals (Sweden)

    Mirzaii Dizgah I

    2007-07-01

    Full Text Available Background: Opiate-induced addiction is a main social problem in Iran. As treatment of this problem is a health priority among the medical community, studies on this topic are very crucial. The exact mechanism of dependence on opiates and their withdrawal syndrome remain unclear. It seems that dopaminergic system and locus coeruleus (LC have an important role in the expression of somatic signs during opioids withdrawal. The LC has been shown to contain significant levels of dopamine (DA. In the present study, the effects of different D2 dopaminergic receptor agonist and antagonist administration in the LC on withdrawal sign expression in morphine dependence is investigated in rats. Methods: Adult male Wistar rats, weighing 220–280 g were divided into eight groups (n=8. Two cannulae were stereotaxically implanted bilaterally into the LC of each rat. After a one-week recovery, seven groups were rendered dependent on morphine by subcutaneous injection during a seven-day period. Non-dependent control animals received saline according to the same protocol. Animals received bilateral intra-LC injections of saline (1 μg/site and quinpirole (0.1, 0.3 and 0.5 μg/site, a D2 agonist 15 min and sulpiride (5, 15 and 30 μg/site, a D2 antagonist 30 min prior to naloxone injection about 24 hours after the last dose of morphine or saline according to their respective group. To calculate the total withdrawal score, as an index of withdrawal syndrome, 20 different withdrawal signs were assessed and the scores of the intensity of these withdrawal signs were added. Results: Total withdrawal scores were significantly decreased by quinpirole (0.1µg/site and sulpiride (15 and 30 µg/site. Conclusion: The D2 dopaminergic system in the LC may be involved in the morphine-induced dependency in rats. Further studies are needed to define the mechanism of this dependency in order to improve methods for the rehabilitation of addicts.

  2. High fat/carbohydrate ratio but not total energy intake induces lower striatal dopamine D2/3 receptor availability in diet-induced obesity.

    Science.gov (United States)

    van de Giessen, E; la Fleur, S E; Eggels, L; de Bruin, K; van den Brink, W; Booij, J

    2013-05-01

    High-energy diets that induce obesity decrease striatal dopamine D2/3 receptor (DRD2/3) availability. It is however poorly understood which components of these diets are underlying this decrease. This study assessed the role of saturated fat intake on striatal DRD2/3 availability. Forty rats were randomized to a free-choice high-fat high-sugar diet (HFHS) or a standard chow diet for 28 days. Striatal DRD2/3 availability was measured using (123)I-IBZM storage phosphor imaging at day 29. The HFHS group was split in a HFHS-high-fat (HFHS-hf) and HFHS-low-fat (HFHS-lf) group based on the percentage energy intake from fat. Rats of both HFHS subgroups had increased energy intake, abdominal fat stores and plasma leptin levels compared with controls. DRD2/3 availability in the nucleus accumbens (NAcc) was significantly lower in HFHS-hf than in HFHS-lf rats, whereas it was similar for HFHS-lf and control rats. Furthermore, DRD2/3 availability in the NAcc was positively correlated with the percentage energy intake from sugar. Total energy intake was lower for HFHS-hf than for HFHS-lf rats. Together these results suggest that a diet with a high fat/carbohydrate ratio, but not total energy intake or the level of adiposity, is the best explanation for the decrease in striatal DRD2/3 availability observed in diet-induced obesity.

  3. Acute withdrawal-related hypophagia elicited by amphetamine is attenuated by pretreatment with selective dopamine D1 or D2 receptor antagonists in rats.

    Science.gov (United States)

    White, Wesley; Beyer, Jason D; White, Ilsun M

    2015-11-01

    After receiving 2.0mg/kg amphetamine, rats show two phases of reduced food intake, short-term hypophagia, during the first several hours after treatment, and longer-term hypophagia, approximately 19 to 26 h after treatment. The longer-term hypophagia may be an indicator of an acute withdrawal. This study assessed whether D1 and D2 receptor activation were important early events in the elicitation of longer-term hypophagia. Throughout a series of five-day tests, rats could lever press for food pellets for one-hour periods beginning every 3h. On test day 1, rats were given a saline pretreatment, and 15 min later they were given a saline treatment. On test day 3, they were given a pretreatment of either saline or a selective dopamine receptor antagonist, and 15 min later they were given a treatment of either saline or amphetamine (2.0mg/kg). In Experiment 1, pretreatments included 3, 12, 31, and 50 μg/kg of the selective D1 receptor antagonist SCH 23390. In Experiment 2, pretreatments included 25, 50, and 100 μg/kg of the selective D2 receptor antagonist eticlopride. Distance moved was monitored for the first 6h following pretreatment-treatment combinations to obtain an indirect behavioral measure of receptor blockade (antagonist attenuation of amphetamine hyperactivity). Food intake at each meal opportunity was monitored throughout each five day test. Patterns of food intake following day 1 saline-saline and day 3 pretreatment-treatment were compared. The combination saline-amphetamine produced short-term and longer-term hypophagia. Combinations involving antagonist-saline did not produce longer-term changes in food intake. Pretreatment with 12 to 50 μg/kg of SCH 23390 produced substantial blockade of amphetamine hyperactivity and prevented amphetamine-induced acute-withdrawal-related longer-term hypophagia. Eticlopride produced a partial blockade of longer-term hypophagia. Both D1 and D2 receptor activation are required for full expression of longer

  4. Polymorphism of dopamine D2 receptor (TaqIA, TaqIB, and-141C Ins/Del) and dopamine degradation enzyme (COMT G158A, A-278G) genes and extrapyramidal symptoms in patients with schizophrenia and bipolar disorders.

    Science.gov (United States)

    Lafuente, Amalia; Bernardo, Miquel; Mas, Sergi; Crescenti, Anna; Aparici, Monica; Gasso, Patricia; Deulofeu, Ramon; Mane, Anna; Catalan, Rosa; Carne, Xavier

    2008-11-30

    The relationship is examined of the dopamine D2 receptor (DRD2) polymorphism (TaqIA, TaqIB, -141 C Ins/Del) and the catechol-O-methyltransferase (COMT) polymorphism (A-278G, G158A) to the risk of antipsychotic-induced extrapyramidal symptoms (EPS) in schizophrenia and bipolar disorders. Participants comprised 80 cases presenting with EPS (Simpson-Angus Scale score >3) and 188 controls presenting without EPS (Simpson-Angus Scale score

  5. Brain histamine depletion enhances the behavioural sequences complexity of mice tested in the open-field: Partial reversal effect of the dopamine D2/D3 antagonist sulpiride.

    Science.gov (United States)

    Santangelo, Andrea; Provensi, Gustavo; Costa, Alessia; Blandina, Patrizio; Ricca, Valdo; Crescimanno, Giuseppe; Casarrubea, Maurizio; Passani, M Beatrice

    2017-02-01

    Markers of histaminergic dysregulation were found in several neuropsychiatric disorders characterized by repetitive behaviours, thoughts and stereotypies. We analysed the effect of acute histamine depletion by means of i. c.v. injections of alpha-fluoromethylhistidine, a blocker of histidine decarboxylase, on the temporal organization of motor sequences of CD1 mice behaviour in the open-field test. An ethogram encompassing 9 behavioural components was employed. Durations and frequencies were only slightly affected by treatments. However, as revealed by multivariate t-pattern analysis, histamine depletion was associated with a striking increase in the number of behavioural patterns. We found 42 patterns of different composition occurring, on average, 520.90 ± 50.23 times per mouse in the histamine depleted (HD) group, whereas controls showed 12 different patterns occurring on average 223.30 ± 20.64 times. Exploratory and grooming behaviours clustered separately, and the increased pattern complexity involved exclusively exploratory patterns. To test the hypothesis of a histamine-dopamine interplay on behavioural pattern phenotype, non-sedative doses of the D2/D3 antagonist sulpiride (12.5-25-50 mg/kg) were additionally administered to different groups of HD mice. Sulpiride counterbalanced the enhancement of exploratory patterns of different composition, but it did not affect the mean number of patterns at none of the doses used. Our results provide new insights on the role of histamine on repetitive behavioural sequences of freely moving mice. Histamine deficiency is correlated with a general enhancement of pattern complexity. This study supports a putative involvement of histamine in the pathophysiology of tics and related disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Associations Between Dopamine D2 Receptor (DRD2) Gene, Maternal Positive Parenting and Trajectories of Depressive Symptoms from Early to Mid-Adolescence.

    Science.gov (United States)

    Cao, Cong; Rijlaarsdam, Jolien; van der Voort, Anja; Ji, Linqin; Zhang, Wenxin; Bakermans-Kranenburg, Marian J

    2017-04-13

    Using data from the Longitudinal Study of Chinese Children and Adolescents (LSCCA), this study is the first to examine the roles of the dopamine D2 receptor (DRD2) gene polymorphisms (i.e., TaqIA and A241G) and maternal positive parenting at ages 10 and 11 years in the trajectories of depressive symptoms from early to mid-adolescence (ages 11 to 16 years). In a sample of 1090 Chinese adolescents (50% girls), three trajectories of depressive symptoms were identified: (i) low-stable (36.1%), (ii) moderate-increasing (44.5%), and (iii) high-increasing (19.4%). A241G AA homozygotes and youth exposed to lower levels of maternal positive parenting were both at increased odds to follow the high-increasing vs. low-stable trajectory. Moreover, the A241G polymorphism interacted with maternal positive parenting to distinguish the moderate-increasing trajectory from the high-increasing and the low-stable trajectories. For A241G G-allele carriers, but not AA homozygotes, exposure to high quality of maternal parenting decreased the odds to follow the high-increasing vs. moderate-increasing trajectory of depressive symptoms. For AA homozygotes, but not G-allele carriers, high quality of maternal parenting increased the odds to follow the low-stable vs. moderate-increasing trajectory. The DRD2 TaqIA polymorphism had neither a direct nor an interactive effect with maternal positive parenting on trajectory membership. The current findings highlight the importance of investigating gene-by-environment interactions (G × E) in trajectories of depressive symptoms over adolescence, and support a developmental versus static nature of G × E effects.

  7. D1- and D2-like dopamine receptors in the CA1 region of the hippocampus are involved in the acquisition and reinstatement of morphine-induced conditioned place preference.

    Science.gov (United States)

    Assar, Nasim; Mahmoudi, Dorna; Farhoudian, Ali; Farhadi, Mohammad Hasan; Fatahi, Zahra; Haghparast, Abbas

    2016-10-01

    The hippocampus plays a vital role in processing contextual memories and reward related learning tasks, such as conditioned place preference (CPP). Among the neurotransmitters in the hippocampus, dopamine is deeply involved in reward-related processes. This study assessed the role of D1- and D2-like dopamine receptors within the CA1 region of the hippocampus in the acquisition and reinstatement of morphine-CPP. To investigate the role of D1 and D2 receptors in morphine acquisition, the animals received different doses of D1- and/or D2-like dopamine receptor antagonists (SCH23390 and sulpiride, respectively) into the CA1, 5min before the administration of morphine (5mg/kg, subcutaneously) during a 3-days conditioning phase. To evaluate the involvement of these receptors in morphine reinstatement, the animals received different doses of SCH23390 or sulpiride (after extinction period) 5min before the administration of a low dose of morphine (1mg/kg) in order to reinstate the extinguished morphine-CPP. Conditioning scores were recorded by Ethovision software. The results of this study showed that the administration of SCH23390 or sulpiride, significantly decreased the acquisition of morphine-CPP. Besides, the injection of these antagonists before the administration of a priming dose of morphine, following the extinction period, decreased the reinstatement of morphine-CPP in sacrificed rats. However, the effect of sulpiride on the acquisition and reinstatement of morphine-CPP was more significant than that of SCH23390. These findings suggested that D1- and D2-like dopamine receptors in the CA1 are involved in the acquisition and reinstatement of morphine-CPP, and antagonism of these receptors can reduce the rewarding properties of morphine. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. 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.

  9. Syntheses and in vitro evaluation of fluorinated naphthoxazines as dopamine D2/D3 receptor agonists: radiosynthesis, ex vivo biodistribution and autoradiography of [{sup 18}F]F-PHNO

    Energy Technology Data Exchange (ETDEWEB)

    Vasdev, Neil [PET Centre for Addiction and Mental Health, Toronto, Ontario, Canada, M5T-1R8 (Canada) and Department of Psychiatry, University of Toronto, Toronto, Ontario, M5T-1R8 (Canada)]. E-mail: neil.vasdev@camhpet.ca; Seeman, Philip [Department of Psychiatry, University of Toronto, Toronto, Ontario, M5T-1R8 (Canada); Department of Pharmacology, University of Toronto, Toronto, Ontario, M5S-1A8 (Canada); Garcia, Armando [PET Centre for Addiction and Mental Health, Toronto, Ontario, M5T-1R8 (Canada); Stableford, Winston T. [PET Centre for Addiction and Mental Health, Toronto, Ontario, M5T-1R8 (Canada); Nobrega, Jose N. [PET Centre for Addiction and Mental Health, Toronto, Ontario, M5T-1R8 (Canada); Department of Psychiatry, University of Toronto, Toronto, Ontario, M5T-1R8 (Canada); Department of Pharmacology, University of Toronto, Toronto, Ontario, M5S-1A8 (Canada); Houle, Sylvain [PET Centre for Addiction and Mental Health, Toronto, Ontario, M5T-1R8 (Canada); Department of Psychiatry, University of Toronto, Toronto, Ontario, M5T-1R8 (Canada); Wilson, Alan A. [PET Centre for Addiction and Mental Health, Toronto, Ontario, M5T-1R8 (Canada); Department of Psychiatry, University of Toronto, Toronto, Ontario, M5T-1R8 (Canada)

    2007-02-15

    Introduction: Carbon-11-labeled (+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol ([{sup 11}C]-(+)-PHNO) is a dopamine D2/D3 agonist radioligand that is currently used to image the high-affinity state of dopamine receptors in humans with positron emission tomography (PET). The present study reports the preparation and evaluation of fluorinated (+)-PHNO derivatives. Methods: Five fluorinated (+)-PHNO derivatives were synthesized and tested in vitro for inhibition of binding of [{sup 3}H]domperidone in homogenates of rat striatum and inhibition of binding to [{sup 3}H]-(+)-PHNO in homogenates of human-cloned D2Long receptors in Chinese hamster ovary cells and rat striatum. Radiolabeling with fluorine-18 was carried out for the most promising candidate, N-fluoropropyl-(+)-HNO (F-PHNO), and ex vivo biodistribution and autoradiography studies with this radiopharmaceutical were performed in rodents. Results: (+)-PHNO and the fluorinated analogs inhibited binding of [{sup 3}H]domperidone and [{sup 3}H]-(+)-PHNO to the high- and low-affinity states of dopamine D2 receptors, consistent with D2 agonist behavior. The average dissociation constant at the high-affinity state of D2, K {sub i} {sup High}, was 0.4 nM for F-PHNO and proved to be equipotent with (+)-PHNO (0.7 nM). All other fluorinated derivatives were significantly less potent (K {sub i} {sup High}=2-102 nM). The most promising candidate, F-PHNO, was labeled with fluorine-18 in 5% uncorrected radiochemical yield, with respect to starting fluoride. Ex vivo biodistribution and autoradiography studies in rodents revealed that [{sup 18}F]F-PHNO rapidly enters the rodent brain. However, this radiotracer does not reveal specific binding in the brain and is rapidly cleared. Conclusions: Five novel dopamine D2/D3 agonists based on (+)-PHNO were synthesized and evaluated in vitro. F-PHNO was shown to behave as a potent D2 agonist in vitro and was therefore radiolabeled with fluorine-18. Despite the

  10. ARF6 and GASP-1 are post-endocytic sorting proteins selectively involved in the intracellular trafficking of dopamine D2 receptors mediated by GRK and PKC in transfected cells

    Science.gov (United States)

    Cho, DI; Zheng, M; Min, C; Kwon, KJ; Shin, CY; Choi, HK; Kim, KM

    2013-01-01

    Background and Purpose GPCRs undergo both homologous and heterologous regulatory processes in which receptor phosphorylation plays a critical role. The protein kinases responsible for each pathway are well established; however, other molecular details that characterize each pathway remain unclear. In this study, the molecular mechanisms that determine the differences in the functional roles and intracellular trafficking between homologous and PKC-mediated heterologous internalization pathways for the dopamine D2 receptor were investigated. Experimental Approach All of the S/T residues located within the intracellular loops of D2 receptor were mutated, and the residues responsible for GRK- and PKC-mediated internalization were determined in HEK-293 cells and SH-SY5Y cells. The functional role of receptor internalization and the cellular components that determine the post-endocytic fate of internalized D2 receptors were investigated in the transfected cells. Key Results T134, T225/S228/S229 and S325 were involved in PKC-mediated D2 receptor desensitization. S229 and adjacent S/T residues mediated the PKC-dependent internalization of D2 receptors, which induced down-regulation and desensitization. S/T residues within the second intracellular loop and T225 were the major residues involved in GRK-mediated internalization of D2 receptors, which induced receptor resensitization. ARF6 mediated the recycling of D2 receptors internalized in response to agonist stimulation. In contrast, GASP-1 mediated the down-regulation of D2 receptors internalized in a PKC-dependent manner. Conclusions and Implications GRK- and PKC-mediated internalizations of D2 receptors occur through different intracellular trafficking pathways and mediate distinct functional roles. Distinct S/T residues within D2 receptors and different sorting proteins are involved in the dissimilar regulation of D2 receptors by GRK2 and PKC. PMID:23082996

  11. Anticipatory and foraging behaviors in response to palatable food reward in chickens: Effects of dopamine D2 receptor blockade and domestication

    NARCIS (Netherlands)

    Moe, R.O.; Nordgreen, J.; Janczak, A.M.; Bakken, M.; Spruijt, Berry; Jensen, P.

    2014-01-01

    Behaviors associated with anticipation and search for palatable food may provide information about dopaminergic reward processes and positive motivational affect in animals. The overall aim was to investigate the involvement of dopamine signaling in the regulation of cue-induced anticipation and

  12. [11C]raclopride and positron emission tomography in previously untreated patients with Parkinson's disease: Influence of L-dopa and lisuride therapy on striatal dopamine D2-receptors.

    Science.gov (United States)

    Antonini, A; Schwarz, J; Oertel, W H; Beer, H F; Madeja, U D; Leenders, K L

    1994-07-01

    We studied cerebral dopamine D2-receptor binding using [11C]raclopride and PET in 18 previously untreated patients with Parkinson's disease (PD) and 14 healthy volunteer subjects. Sixteen patients were scanned before and after 3 to 4 months of stable oral therapy with either L-dopa (300 mg/d) (n = 7) or lisuride (0.8 to 1.2 mg/d) (n = 9). Two additional patients were investigated before and after a continuous IV infusion of L-dopa. In addition, we studied the effect of acute IV L-dopa and lisuride administration on [11C]raclopride binding in a healthy rhesus monkey. At baseline, PD patients showed higher uptake values in the putamen than did healthy subjects (p < 0.0001). Oral lisuride treatment lowered [11C]raclopride uptake in the putamen (-19%) and in the caudate nucleus (-15%) compared with baseline, but the difference did not reach significance upon Bonferroni correction for multiple comparisons. However, putamen tracer uptake returned to baseline in two patients when we repeated [11C]raclopride scans 4 days after lisuride withdrawal. Oral L-dopa treatment did not induce changes in the putamen or caudate nucleus indices. Acute lisuride (25 micrograms) administration in a healthy monkey reduced striatal uptake values, but acute injection of L-dopa (300 mg) did not. The results suggest that lisuride blocks [11C]raclopride binding at dopamine D2-receptor sites and demonstrate that 3 to 4 months' oral therapy with L-dopa or lisuride does not change striatal dopamine D2-receptor density in PD patients.

  13. Frontal dopamine D(2/3) receptor binding in drug-naive first-episode schizophrenic patients correlates with positive psychotic symptoms and gender

    DEFF Research Database (Denmark)

    Glenthoj, Birte Y; Mackeprang, Torben; Svarer, Claus

    2006-01-01

    with single-photon emission computerized tomography (SPECT) using the D(2/3)-receptor ligand [123I]epidepride. RESULTS: In the hitherto largest study on extrastriatal D(2/3) receptors we detected a significant correlation between frontal D(2/3) BP values and positive schizophrenic symptoms in the larger group...... of male schizophrenic patients, higher frontal BP values in male (n = 17) compared to female (n = 8) patients, and - in accordance with this - significantly fewer positive schizophrenic symptoms in the female patients. No significant differences in BP values were observed between patients and controls......; the patients, however, had significantly higher BP in the right compared to the left thalamus, whereas no significant hemispheric imbalances were observed in the healthy subjects. CONCLUSIONS: The present data are the first to confirm a significant correlation between frontal D(2/3) receptor BP values...

  14. Variation in Dopamine D2 and Serotonin 5-HT2A Receptor Genes is Associated with Working Memory Processing and Response to Treatment with Antipsychotics

    National Research Council Canada - National Science Library

    Blasi, Giuseppe; Selvaggi, Pierluigi; Fazio, Leonardo; Antonucci, Linda Antonella; Taurisano, Paolo; Masellis, Rita; Romano, Raffaella; Mancini, Marina; Zhang, Fengyu; Caforio, Grazia; Popolizio, Teresa; Apud, Jose; Weinberger, Daniel R; Bertolino, Alessandro

    2015-01-01

    .... In particular, the DRD2 rs1076560 T allele predicts a lower ratio of expression of D2 short/long isoforms, suboptimal working memory processing, and better response to antipsychotic treatment compared with the G allele...

  15. Comparison of dopamine D3 and D2 receptor occupancies by a single dose of blonanserin in healthy subjects: A positron emission tomography study with [11C]-(+)-PHNO.

    Science.gov (United States)

    Tateno, Amane; Sakayori, Takeshi; Kim, Woo-Chan; Honjo, Kazuyoshi; Nakayama, Haruo; Arakawa, Ryosuke; Okubo, Yoshiro

    2018-01-13

    Blockade of D3 receptor, a member of the dopamine D2-like receptor family, has been suggested as a possible medication for schizophrenia. Blonanserin has high affinity in vitro for D3 as well as D2 receptors. We investigated whether a single dose of 12 mg blonanserin, which was within the daily clinical dose range (i.e., 8-24 mg) for the treatment of schizophrenia, occupies D3 as well as D2 receptors in healthy subjects. Six healthy males (mean 35.7±7.6 years) received two positron emission tomography scans, the first prior to taking blonanserin, and the second 2 hours after the administration of a single dose of 12 mg blonanserin. Dopamine receptor occupancies by blonanserin were evaluated by [11C]-(+)-PHNO. Occupancy of each region by 12 mg blonanserin was: caudate (range 64.3-81.5%; mean±SD, 74.3±5.6%), putamen (range 60.4-84.3%; mean±SD, 73.3±8.2%), ventral striatum (range 40.1-88.2%; mean±SD, 60.8±17.1%), globus pallidus (range 65.8-87.6%; mean±SD, 75.7±8.6%), and substantia nigra (range 56.0-88.7%; mean±SD, 72.4±11.0%). Correlation analysis between plasma concentration of blonanserin and receptor occupancy in D2-rich (caudate and putamen) and D3-rich (globus pallidus and substantia nigra) regions showed that EC50 for D2-rich region was 0.39 ng/mL (r=0.43) and EC50 for D3-rich region was 0.40 ng/mL (r=0.79). A single dose of 12 mg blonanserin occupied D3 receptor to the same degree as D2 receptor in vivo. Our results were consistent with previous studies that reported that some of the pharmacological effect of blonanserin is mediated via D3 receptor antagonism.

  16. The dopamine D2/D3 receptor agonist quinpirole increases checking-like behaviour in an operant observing response task with uncertain reinforcement: A novel possible model of OCD?

    Science.gov (United States)

    Eagle, Dawn M.; Noschang, Cristie; d’Angelo, Laure-Sophie Camilla; Noble, Christie A.; Day, Jacob O.; Dongelmans, Marie Louise; Theobald, David E.; Mar, Adam C.; Urcelay, Gonzalo P.; Morein-Zamir, Sharon; Robbins, Trevor W.

    2014-01-01

    Excessive checking is a common, debilitating symptom of obsessive-compulsive disorder (OCD). In an established rodent model of OCD checking behaviour, quinpirole (dopamine D2/3-receptor agonist) increased checking in open-field tests, indicating dopaminergic modulation of checking-like behaviours. We designed a novel operant paradigm for rats (observing response task (ORT)) to further examine cognitive processes underpinning checking behaviour and clarify how and why checking develops. We investigated i) how quinpirole increases checking, ii) dependence of these effects on D2/3 receptor function (following treatment with D2/3 receptor antagonist sulpiride) and iii) effects of reward uncertainty. In the ORT, rats pressed an ‘observing’ lever for information about the location of an ‘active’ lever that provided food reinforcement. High- and low-checkers (defined from baseline observing) received quinpirole (0.5 mg/kg, 10 treatments) or vehicle. Parametric task manipulations assessed observing/checking under increasing task demands relating to reinforcement uncertainty (variable response requirement and active-lever location switching). Treatment with sulpiride further probed the pharmacological basis of long-term behavioural changes. Quinpirole selectively increased checking, both functional observing lever presses (OLPs) and non-functional extra OLPs (EOLPs). The increase in OLPs and EOLPs was long-lasting, without further quinpirole administration. Quinpirole did not affect the immediate ability to use information from checking. Vehicle and quinpirole-treated rats (VEH and QNP respectively) were selectively sensitive to different forms of uncertainty. Sulpiride reduced non-functional EOLPs in QNP rats but had no effect on functional OLPs. These data have implications for treatment of compulsive checking in OCD, particularly for serotonin-reuptake-inhibitor treatment-refractory cases, where supplementation with dopamine receptor antagonists may be

  17. The dopamine D2/D3 receptor agonist quinpirole increases checking-like behaviour in an operant observing response task with uncertain reinforcement: a novel possible model of OCD.

    Science.gov (United States)

    Eagle, Dawn M; Noschang, Cristie; d'Angelo, Laure-Sophie Camilla; Noble, Christie A; Day, Jacob O; Dongelmans, Marie Louise; Theobald, David E; Mar, Adam C; Urcelay, Gonzalo P; Morein-Zamir, Sharon; Robbins, Trevor W

    2014-05-01

    Excessive checking is a common, debilitating symptom of obsessive-compulsive disorder (OCD). In an established rodent model of OCD checking behaviour, quinpirole (dopamine D2/3-receptor agonist) increased checking in open-field tests, indicating dopaminergic modulation of checking-like behaviours. We designed a novel operant paradigm for rats (observing response task (ORT)) to further examine cognitive processes underpinning checking behaviour and clarify how and why checking develops. We investigated i) how quinpirole increases checking, ii) dependence of these effects on D2/3 receptor function (following treatment with D2/3 receptor antagonist sulpiride) and iii) effects of reward uncertainty. In the ORT, rats pressed an 'observing' lever for information about the location of an 'active' lever that provided food reinforcement. High- and low-checkers (defined from baseline observing) received quinpirole (0.5mg/kg, 10 treatments) or vehicle. Parametric task manipulations assessed observing/checking under increasing task demands relating to reinforcement uncertainty (variable response requirement and active-lever location switching). Treatment with sulpiride further probed the pharmacological basis of long-term behavioural changes. Quinpirole selectively increased checking, both functional observing lever presses (OLPs) and non-functional extra OLPs (EOLPs). The increase in OLPs and EOLPs was long-lasting, without further quinpirole administration. Quinpirole did not affect the immediate ability to use information from checking. Vehicle and quinpirole-treated rats (VEH and QNP respectively) were selectively sensitive to different forms of uncertainty. Sulpiride reduced non-functional EOLPs in QNP rats but had no effect on functional OLPs. These data have implications for treatment of compulsive checking in OCD, particularly for serotonin-reuptake-inhibitor treatment-refractory cases, where supplementation with dopamine receptor antagonists may be beneficial

  18. Chronic administration of the dopamine D2/3 agonist ropinirole invigorates performance of a rodent slot machine task, potentially indicative of less distractible or compulsive-like gambling behaviour.

    Science.gov (United States)

    Cocker, Paul J; Tremblay, M; Kaur, S; Winstanley, Catharine A

    2017-01-01

    Whilst dopamine agonist therapies can successfully manage the symptoms of diseases such as Parkinson's disease (PD), fibromyalgia and restless leg syndrome, they can also cause impulse control and addiction disorders such as gambling disorder (GD). These compulsive behaviours seriously undermine the utility of such treatments. The objective of the study was to model this phenomenon using a rodent slot machine task (rSMT) in order to investigate the neurobiological basis underlying such behavioural changes. Male Long Evans rats were trained to perform the rSMT. The D2-like agonist ropinirole, or saline, was then delivered continuously for 28 days via osmotic mini-pump. The effects of ropinirole on baseline rSMT performance, as well as extinction and reinstatement sessions, were determined during this time. Brain samples from key frontostriatal regions implicated in GD and PD were then harvested immediately or after a 4-week washout period during which behaviour returned to pre-drug baseline. Ropinirole invigorated task performance, in that drug treatment resulted in a robust and sustained increase in the number of trials completed. Ex vivo analyses revealed that chronic ropinirole treatment led to a pattern of changes indicative of upregulation within the β-arrestin-AKT-GSK3β intracellular cascade, recently theorised to dominate D2-mediated signalling under hyperdopaminergic conditions, in the dorsal striatum, rather than the canonical PKA-dependent signalling pathway associated with D2 receptor activation. Such findings provide novel insight into the role of dopamine signalling in mediating compulsive-like gambling behaviour and may inform more directed pharmacotherapies for the treatment of both idiopathic and iatrogenic GD.

  19. Multiple D2 heteroreceptor complexes: new targets for treatment of schizophrenia

    Science.gov (United States)

    Borroto-Escuela, Dasiel O.; Pintsuk, Julia; Schäfer, Thorsten; Friedland, Kristina; Ferraro, Luca; Tanganelli, Sergio; Liu, Fang; Fuxe, Kjell

    2016-01-01

    The dopamine (DA) neuron system most relevant for schizophrenia is the meso-limbic-cortical DA system inter alia densely innervating subcortical limbic regions. The field of dopamine D2 receptors and schizophrenia changed markedly with the discovery of many types of D2 heteroreceptor complexes in subcortical limbic areas as well as the dorsal striatum. The results indicate that the D2 is a hub receptor which interacts not only with many other G protein-coupled receptors (GPCRs) including DA isoreceptors but also with ion-channel receptors, receptor tyrosine kinases, scaffolding proteins and DA transporters. Disturbances in several of these D2 heteroreceptor complexes may contribute to the development of schizophrenia through changes in the balance of diverse D2 homo- and heteroreceptor complexes mediating the DA signal, especially to the ventral striato-pallidal γ-aminobutyric acid (GABA) pathway. This will have consequences for the control of this pathway of the glutamate drive to the prefrontal cortex via the mediodorsal thalamic nucleus which can contribute to psychotic processes. Agonist activation of the A2A protomer in the A2A–D2 heteroreceptor complex inhibits D2 Gi/o mediated signaling but increases the D2 β-arrestin2 mediated signaling. Through this allosteric receptor–receptor interaction, the A2A agonist becomes a biased inhibitory modulator of the Gi/o mediated D2 signaling, which may the main mechanism for its atypical antipsychotic properties especially linked to the limbic A2A–D2 heterocomplexes. The DA and glutamate hypotheses of schizophrenia come together in the signal integration in D2–N-methyl-d-aspartate (NMDA) and A2A–D2–metabotropic glutamate receptor 5 (mGlu5) heteroreceptor complexes, especially in the ventral striatum. 5-Hydroxytryptamine 2A (5-HT2A)–D2 heteroreceptor complexes are special targets for atypical antipsychotics with high potency to block their 5-HT2A protomer signaling in view of the potential development of

  20. Thalamic alexia with agraphia

    Directory of Open Access Journals (Sweden)

    Fábio Henrique de Gobbi Porto

    2012-02-01

    Full Text Available Alexia with agraphia is defined as an acquired impairment affecting reading and writing ability. It can be associated with aphasia, but can also occur as an isolated entity. This impairment has classically been associated with a left angular gyrus lesion In the present study, we describe a case involving a patient who developed alexia with agraphia and other cognitive deficits after a thalamic hemorrhage. In addition, we discuss potential mechanisms of this cortical dysfunction syndrome caused by subcortical injury. We examined a patient who presented with alexia with agraphia and other cognitive deficits due to a hemorrhage in the left thalamus. Neuropsychological evaluation showed attention, executive function, arithmetic and memory impairments. In addition, language tests revealed severe alexia with agraphia in the absence of aphasia. Imaging studies disclosed an old thalamic hemorrhage involving the anterior, dorsomedial and pulvinar nuclei. Tractography revealed asymmetric thalamocortical radiations in the parietal region (left - right, and single photon emission computed tomography demonstrated hypoperfusion in the left thalamus that extended to the frontal and parietal cortices. Cortical cognitive deficits, including alexia with agraphia, may occur as the result of thalamic lesions. The probable mechanism is a diaschisis phenomenon involving thalamic tract disconnections.

  1. Thalamic semantic paralexia

    Directory of Open Access Journals (Sweden)

    Michael Hoffmann

    2012-03-01

    Full Text Available Alexia may be divided into different subtypes, with semantic paralexia being particularly rare. A 57 year old woman with a discreet left thalamic stroke and semantic paralexia is described. Language evalution with the Boston Diagnostic Aphasia Battery confirmed the semantic paralexia (deep alexia. Multimodality magnetic resonance imaging brain scanning excluded other cerebral lesions. A good recovery ensued.

  2. Post-training dopamine receptor agonists and antagonists affect memory storage in mice irrespective of their selectivity for D1 or D2 receptors.

    Science.gov (United States)

    Castellano, C; Cestari, V; Cabib, S; Puglisi-Allegra, S

    1991-11-01

    Post-training administration of the selective D1 and D2 agonists SKF 38393 and LY 171555 dose-dependently facilitated retention of an inhibitory avoidance response in mice, while the selective D1 or D2 antagonists SCH 23390 and (-)sulpiride produced an impairment of retention. These effects are not to be ascribed to a nonspecific action of the drugs on retention performance, as the latencies during the retention test of those mice that had not received a footshock during the training were not increased by the post-training drug administration. The effects on retention performance induced by DA agonists and antagonists seem to be due to an effect on memory consolidation, since they have been observed when drugs were given at short, but not at long, periods of time after training. These results showing a similar role of D1 and D2 receptor types on memory storage appear not to be consistent with a body of neuropharmacological, neurophysiological, and behavioral evidence pointing to a different functional role of these types of DA receptors. This discrepancy is discussed in terms of possible involvement of different brain systems, peripheral systems, or possible second messenger processes activated by the two receptor types and leading to similar effects on memory processes.

  3. Dopamine receptor D2 and catechol-O-methyltransferase gene polymorphisms associated with anorexia nervosa in Chinese Han population: DRD2 and COMT gene polymorphisms were associated with AN.

    Science.gov (United States)

    Peng, Sufang; Yu, Shunying; Wang, Qian; Kang, Qing; Zhang, Yanxia; Zhang, Ran; Jiang, Wenhui; Qian, Yiping; Zhang, Haiyin; Zhang, Mingdao; Xiao, Zeping; Chen, Jue

    2016-03-11

    Dopamine receptor D2 (DRD2) and catechol-O-methyltransferase (COMT) are important in dopamine system which is proved to be associated with food-anticipatory behavior, food restriction, reward and motivation. This has made them good candidates for anorexia nervosa (AN). The aim of this work is to explore the roles of DRD2 (rs1800497) and COMT (rs4680, rs4633, rs4818) gene polymorphisms in the susceptibility of AN within the Chinese Han population. We recruited 260AN patients with DSM-IV diagnosis criteria, and 247 unrelated, normal weight controls. DRD2 (rs1800497) and COMT (rs4680, rs4633, rs4818) were genotyped in all subjects. We found rs1800497 and rs4633 were associated with the susceptibility of AN within the Chinese Han sample, and allele C of rs1800497 was a protective factor. There was a gene-gene interaction between rs1800497 of DRD2 gene and rs4633 of COMT gene. We concluded that rs1800497 and rs4633 play important roles in the AN susceptibility with respect to the Chinese Han population. The gene-gene interaction between DRD2 and COMT contributes to the risk of AN. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  4. The relationship between subcortical brain volume and striatal dopamine D2/3 receptor availability in healthy humans assessed with [11 C]-raclopride and [11 C]-(+)-PHNO PET.

    Science.gov (United States)

    Caravaggio, Fernando; Ku Chung, Jun; Plitman, Eric; Boileau, Isabelle; Gerretsen, Philip; Kim, Julia; Iwata, Yusuke; Patel, Raihaan; Chakravarty, M Mallar; Remington, Gary; Graff-Guerrero, Ariel

    2017-11-01

    Abnormalities in dopamine (DA) and brain morphology are observed in several neuropsychiatric disorders. However, it is not fully understood how these abnormalities may relate to one another. For such in vivo findings to be used as biomarkers for neuropsychiatric disease, it must be understood how variability in DA relates to brain structure under healthy conditions. We explored how the availability of striatal DA D2/3 receptors (D2/3 R) is related to the volume of subcortical brain structures in a sample of healthy humans. Differences in D2/3 R availability measured with an antagonist radiotracer ([11 C]-raclopride) versus an agonist radiotracer ([11 C]-(+)-PHNO) were examined. Data from 62 subjects scanned with [11 C]-raclopride (mean age = 38.98 ± 14.45; 23 female) and 68 subjects scanned with [11 C]-(+)-PHNO (mean age = 38.54 ± 14.59; 25 female) were used. Subcortical volumes were extracted from T1-weighted images using the Multiple Automatically Generated Templates (MAGeT-Brain) algorithm. Partial correlations were used controlling for age, gender, and total brain volume. For [11 C]-(+)-PHNO, ventral caudate volumes were positively correlated with BPND in the dorsal caudate and globus pallidus (GP). Ventral striatum (VS) volumes were positively correlated with BPND in the VS. With [11 C]-raclopride, BPND in the VS was negatively correlated with subiculum volume of the hippocampus. Moreover, BPND in the GP was negatively correlated with the volume of the lateral posterior nucleus of the thalamus. Findings are purely exploratory and presented corrected and uncorrected for multiple comparisons. We hope they will help inform the interpretation of future PET studies where concurrent changes in D2/3 R and brain morphology are observed. Hum Brain Mapp 38:5519-5534, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  5. Food deprivation facilitates reinstatement of morphine-induced conditioned place preference: Role of intra-accumbal dopamine D2-like receptors in associating reinstatement of morphine CPP with stress.

    Science.gov (United States)

    Sadeghzadeh, Fatemeh; Babapour, Vahab; Haghparast, Abbas

    2017-04-01

    The high rate of relapse to drug use is one of the main problems in the treatment of addiction. Stress plays the essential role in drug abuse and relapse; nevertheless, little is known about the mechanisms underlying stress and relapse. Accordingly, the effects of intra-accumbal administration of Sulpiride, as a dopamine D2-like receptor antagonist, on an ineffective morphine dose + food deprivation(FD)- and morphine priming-induced reinstatement of conditioned place preference (CPP). About 104 adult male albino Wistar rats weighing 200-280 g were bilaterally implanted by cannula into the nucleus accumbens (NAc). Subcutaneous (sc) injection of morphine (5 mg kg -1 ) was used daily during a 3-day conditioning phase. After a 24-hr "off" period following achievement of extinction criterion, rats were tested for FD- and priming-induced reinstatement of morphine CPP by an ineffective (0.5 mg kg -1 , sc) and priming (1 mg kg -1 , sc) dose of morphine, respectively. In the next experiments, animals received different doses of intra-accumbal Sulpiride (0.25, 1, and 4 µg/0.5 µL saline) bilaterally and were subsequently tested for morphine reinstatement. Our findings indicated that the 24-hr FD facilitated reinstatement of morphine CPP. Furthermore, the D2-like receptor antagonist attenuated the ineffective morphine dose+ FD- and priming-induced reinstatement of morphine CPP dose-dependently. Also, contribution of D2-like receptors in mediation of the ineffective morphine dose+ FD-induced reinstatement of CPP was greater than morphine priming-induced reinstatement of CPP. The role of dopaminergic system in morphine reinstatement through a neural pathway in the NAc provides the evidence that D2-like receptor antagonist can be useful therapeutic targets for reinstatement of morphine CPP. © 2016 Wiley Periodicals, Inc.

  6. Broca's area - thalamic connectivity.

    Science.gov (United States)

    Bohsali, Anastasia A; Triplett, William; Sudhyadhom, Atchar; Gullett, Joseph M; McGregor, Keith; FitzGerald, David B; Mareci, Thomas; White, Keith; Crosson, Bruce

    2015-02-01

    Broca's area is crucially involved in language processing. The sub-regions of Broca's area (pars triangularis, pars opercularis) presumably are connected via corticocortical pathways. However, growing evidence suggests that the thalamus may also be involved in language and share some of the linguistic functions supported by Broca's area. Functional connectivity is thought to be achieved via corticothalamic/thalamocortical white matter pathways. Our study investigates structural connectivity between Broca's area and the thalamus, specifically ventral anterior nucleus and pulvinar. We demonstrate that Broca's area shares direct connections with these thalamic nuclei and suggest a local Broca's area-thalamus network potentially involved in linguistic processing. Thalamic connectivity with Broca's area may serve to selectively recruit cortical regions storing multimodal features of lexical items and to bind them together during lexical-semantic processing. In addition, Broca's area-thalamic circuitry may enable cortico-thalamo-cortical information transfer and modulation between BA 44 and 45 during language comprehension and production. Published by Elsevier Inc.

  7. cis- and trans-2,3,3a,4,5,9b-Hexahydro-1H-benz[e]indoles: synthesis and evaluation of dopamine D2, and D3 receptor binding affinity

    DEFF Research Database (Denmark)

    Song, Xiaodong; Crider, Michael A.; Cruse, Sharon F.

    1999-01-01

    receptors was shown by compounds substituted with N-n-propyl or N-allyl groups. The cis-(+-)-N-allyl derivative 21e demonstrated a D2S/D3 selectivity of 290. Resolution of cis-(+-)-5 and trans-(+-)- 21c into individual enantiomers showed that in both series the more active isomer had 3aR absolute......cis- and trans-2,3,3a,4,5,9b-hexahydro-1H-benz [e]indoles were synthesized as conformationally rigid analogues of 3-phenylpyrrolidine and evaluated for dopamine (DA) D2S and D3 receptor binding affinity. The tricyclic benz[e]indole nucleus was constructed by a previously reported reductive...... amination-cyclization procedure. Several unexpectedside products were isolated and characterized using the general method. The trans-diastereoisomers exhibited greater affinities for the DA D3 receptor than the corresponding cis-isomers. In both the cis- and trans- series the greatest affinity for DA D3...

  8. Comparative effect of lurasidone and blonanserin on cortical glutamate, dopamine, and acetylcholine efflux: role of relative serotonin (5-HT)2A and DA D2 antagonism and 5-HT1A partial agonism.

    Science.gov (United States)

    Huang, Mei; Panos, John J; Kwon, Sunoh; Oyamada, Yoshihiro; Rajagopal, Lakshmi; Meltzer, Herbert Y

    2014-03-01

    Atypical antipsychotic drugs (AAPDs) have been suggested to be more effective in improving cognitive impairment in schizophrenia than typical APDs, a conclusion supported by differences in receptor affinities and neurotransmitter efflux in the cortex and the hippocampus. More potent serotonin (5-HT)2A than dopamine (DA) D2 receptors antagonism, and direct or indirect 5-HT1A agonism, characterize almost all AAPDs. Blonanserin, an AAPD, has slightly greater affinity for D2 than 5-HT2A receptors. Using microdialysis and ultra performance liquid chromatography-mass spectrometry/mass spectrometry, we compared the abilities of the typical APD, haloperidol, three AAPDs, blonanserin, lurasidone, and olanzapine, and a selective 5-HT1A partial agonist, tandospirone, and all, except haloperidol, were found to ameliorate the cognitive deficits produced by the N-methyl-d-aspartate antagonist, phencyclidine, altering the efflux of neurotransmitters and metabolites in the rat cortex and nucleus accumbens. Blonanserin, lurasidone, olanzapine, and tandospirone, but not haloperidol, increased the efflux of cortical DA and its metabolites, homovanillic acid and 3,4-dihydroxyphenylacetic acid. Olanzapine and lurasidone increased the efflux of acetylcholine; lurasidone increased glutamate as well. None of the compounds significantly altered the efflux of 5-HT or its metabolite, 5-hydroxyindole acetic acid, or GABA, serine, and glycine. The ability to increase cortical DA efflux was the only shared effect of the compounds which ameliorates the deficit in cognition in rodents following phencyclidine. © 2013 International Society for Neurochemistry.

  9. The decrease of dopamine D2/D3 receptor densities in the putamen and nucleus caudatus goes parallel with maintained levels of CB1 cannabinoid receptors in Parkinson's disease: a preliminary autoradiographic study with the selective dopamine D2/D3 antagonist [3H]raclopride and the novel CB1 inverse agonist [125I]SD7015

    OpenAIRE

    Farkas Szabolcs (1983-) (orvos); Nagy Katalin; Jia, Zhisheng; Harkány Tibor; Palkovits Miklós; Donohue, Sean; Pike, Victor; Halldin, Christer; Máthé Domokos; Csiba László (1952-) (neurológus, pszichiáter); Gulyás Balázs

    2012-01-01

    Cannabinoid type-1 receptors (CB1Rs) modulate synaptic neurotransmission by participating in retrograde signaling in the adult brain. Increasing evidence suggests that cannabinoids through CB1Rs play an important role in the regulation of motor activities in the striatum. In the present study, we used human brain samples to examine the relationship between CB1R and dopamine receptor density in case of Parkinson’s disease (PD).

  10. Thalamic Lesions: A Radiological Review

    Directory of Open Access Journals (Sweden)

    Dimitri Renard

    2014-01-01

    Full Text Available Background. Thalamic lesions are seen in a multitude of disorders including vascular diseases, metabolic disorders, inflammatory diseases, trauma, tumours, and infections. In some diseases, thalamic involvement is typical and sometimes isolated, while in other diseases thalamic lesions are observed only occasionally (often in the presence of other typical extrathalamic lesions. Summary. In this review, we will mainly discuss the MRI characteristics of thalamic lesions. Identification of the origin of the thalamic lesion depends on the exact localisation inside the thalamus, the presence of extrathalamic lesions, the signal changes on different MRI sequences, the evolution of the radiological abnormalities over time, the history and clinical state of the patient, and other radiological and nonradiological examinations.

  11. Protection against cocaine toxicity in mice by the dopamine D-3/D-2 agonist R-(+)-trans-3,4a,10b-Tetrahydro-4-propyl-2H,5H[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol[(+)-PD 128,907

    NARCIS (Netherlands)

    Witkin, JM; Dijkstra, D; Levant, B; Akunne, HC; Zapata, A; Peters, S; Shannon, HE; Gasior, M

    2004-01-01

    Cocaine abuse is a public health concern with seizures and death being one consequence of overdose. In the present study, dopamine D-3/D-2 receptor agonists dose dependently and completely prevented the convulsant and lethal effects of cocaine. The D-3-preferring agonists

  12. Dopamine D1/D5, But not D2/D3, Receptor Dependency of Synaptic Plasticity at Hippocampal Mossy Fiber Synapses that Is Enabled by Patterned Afferent Stimulation, or Spatial Learning.

    Science.gov (United States)

    Hagena, Hardy; Manahan-Vaughan, Denise

    2016-01-01

    Although the mossy fiber (MF) synapses of the hippocampal CA3 region display quite distinct properties in terms of the molecular mechanisms that underlie synaptic plasticity, they nonetheless exhibit persistent (>24 h) synaptic plasticity that is akin to that observed at the Schaffer collateral (SCH)-CA1 and perforant path (PP)-dentate gyrus (DG) synapses of freely behaving rats. In addition, they also respond to novel spatial learning with very enduring forms of long-term potentiation (LTP) and long-term depression (LTD). These latter forms of synaptic plasticity are directly related to the learning behavior: novel exploration of generalized changes in space facilitates the expression of LTP at MF-CA3 synapses, whereas exploration of novel configurations of large environmental features facilitates the expression of LTD. In the absence of spatial novelty, synaptic plasticity is not expressed. Motivation is a potent determinant of whether learning about the spatial experience effectively occurs and the neuromodulator dopamine (DA) plays a key role in motivation-based learning. Prior research on the regulation by DA receptors of long-term synaptic plasticity in CA1 and DG synapses in vivo suggests that whereas D2/D3 receptors may modulate a general predisposition toward expressing plasticity, D1/D5 receptors may directly regulate the direction of change in synaptic strength that occurs during learning. Although the CA3 region is believed to play a pivotal role in many forms of learning, the role of dopamine receptors in persistent (>24 h) forms of synaptic plasticity at MF-CA3 synapses is unknown. Here, we report that whereas pharmacological antagonism of D2/D3 receptors had no impact on LTP or LTD, antagonism of D1/D5 receptors significantly impaired LTP and LTD that were induced by solely by means of patterned afferent stimulation, or LTP/LTD that are typically enhanced by the conjunction of afferent stimulation and novel spatial learning. These data indicate an

  13. Differential expression of dopamine D2 and D4 receptor and tyrosine hydroxylase mRNA in mice prone, or resistant, to chronic high-fat diet-induced obesity.

    Science.gov (United States)

    Huang, Xu-Feng; Yu, Yinghua; Zavitsanou, Katerina; Han, Mei; Storlien, Len

    2005-04-27

    The present study examined brain dopamine D2 and D4 receptor and tyrosine hydroxylase (TH) mRNA expression in chronic high-fat diet-induced obese (cDIO) and obese-resistant (cDR) mice. Twenty-eight mice were fed a high-fat diet (HF: 40% of calories from fat) for 6 weeks and then classified as cDIO (n = 8) or cDR (n = 8) mice according to the highest and lowest body weight gainers, respectively. Seven mice were fed a low-fat diet (LF: 10% of calories from fat) and used as controls. After 20 weeks of feeding, visceral fat per gram of initial body weight was significantly higher in the cDIO group (ratio: 0.25, 0.09, and 0.04; P AcbC, +16%) and ventral parts of caudate putamen (CPu, 21% and 24%) compared to the cDR and LF mice. The levels of D2 receptor mRNA expression in the AcbC and ventromedial part of the CPu were positively related to the final body weight. This study is the first to systematically examine the D4 mRNA expression in the mouse brain using in situ hybridization method. D4 receptor mRNA expression in the ventromedial hypothalamic nucleus (VMH) and the ventral part of the lateral septal nucleus were also significantly higher in the cDIO mice compared to the cDR and LF mice (+31% and +60%; P < 0.05). TH mRNA expression was significantly higher in the ventral tegmental area (+17%, P D2 and D4 receptor and TH mRNA expression in specific brain regions of cDIO and cDR mice. It provides evidence that D4 receptors may play an important role influencing satiety via the mesohypothalamic pathway while the D2 receptor may regulate reward and motor centers via mesolimbic and nigrostriatal pathways. These findings contribute to the understanding of the role of these receptors in susceptibility, or resistance, to diet-induced obesity.

  14. Genetic Variation of the Mu Opioid Receptor (OPRM1) and Dopamine D2 Receptor (DRD2) is Related to Smoking Differences in Patients with Schizophrenia but not Bipolar Disorder.

    Science.gov (United States)

    Hirasawa-Fujita, Mika; Bly, Michael J; Ellingrod, Vicki L; Dalack, Gregory W; Domino, Edward F

    It is not known why mentally ill persons smoke excessively. Inasmuch as endogenous opioid and dopaminergic systems are involved in smoking reinforcement, it is important to study mu opioid receptor (OPRM1) A118G (rs1799971), dopamine D2 receptor (DRD2) Taq1A (rs1800497) genotypes, and sex differences among patients with schizophrenia or bipolar disorder. Smokers and nonsmokers with schizophrenia (n=177) and bipolar disorder (n=113) were recruited and genotyped. They were classified into three groups: current smoker, former smoker, and never smoker by tobacco smoking status self-report. The number of cigarettes smoked per day was used as the major tobacco smoking parameter. In patients with schizophrenia, tobacco smoking prevalence was greater in males than in females as expected, but women had greater daily cigarette consumption (pschizophrenia who had the OPRM1 *G genotype smoked more cigarettes per day than the AA allele carriers with schizophrenia (pschizophrenia who were GG homozygous of the DRD2 receptor smoked more than the *A male smokers with schizophrenia (pschizophrenia. Alteration of DRD2 receptor function also increased smoking behavior in females with schizophrenia.

  15. Alcohol drinking increases the dopamine-stimulating effects of ethanol and reduces D2 auto-receptor and group II metabotropic glutamate receptor function within the posterior ventral tegmental area of alcohol preferring (P) rats.

    Science.gov (United States)

    Ding, Zheng-Ming; Ingraham, Cynthia M; Rodd, Zachary A; McBride, William J

    2016-10-01

    Repeated local administration of ethanol (EtOH) sensitized the posterior ventral tegmental area (pVTA) to the local dopamine (DA)-stimulating effects of EtOH. Chronic alcohol drinking increased nucleus accumbens (NAC) DA transmission and pVTA glutamate transmission in alcohol-preferring (P) rats. The objectives of the present study were to determine the effects of chronic alcohol drinking by P rats on the (a) sensitivity and response of the pVTA DA neurons to the DA-stimulating actions of EtOH, and (b) negative feedback control of DA (via D2 auto-receptors) and glutamate (via group II mGlu auto-receptors) release in the pVTA. EtOH (50 or 150 mg%) or the D2/3 receptor antagonist sulpiride (100 or 200 μM) was microinjected into the pVTA while DA was sampled with microdialysis in the NAC shell (NACsh). The mGluR2/3 antagonist LY341495 (1 or 10 μM) was perfused through the pVTA via reverse microdialysis and local extracellular glutamate and DA levels were measured. EtOH produced a more robust increase of NACsh DA in the 'EtOH' than 'Water' groups (e.g., 150 mg% EtOH: to ∼ 210 vs 150% of baseline). In contrast, sulpiride increased DA release in the NACsh more in the 'Water' than 'EtOH' groups (e.g., 200 μM sulpiride: to ∼ 190-240 vs 150-160% of baseline). LY341495 (at 10 μM) increased extracellular glutamate and DA levels in the 'Water' (to ∼ 150-180% and 180-230% of baseline, respectively) but not the 'EtOH' groups. These results indicate that alcohol drinking enhanced the DA-stimulating effects of EtOH, and attenuated the functional activities of D2 auto-receptors and group II mGluRs within the pVTA. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. Association between Dopamine Receptor D2 (DRD2) Variations rs6277 and rs1800497 and Cognitive Performance According to Risk Type for Psychosis: A Nested Case Control Study in a Finnish Population Sample.

    Science.gov (United States)

    Ramsay, Hugh; Barnett, Jennifer H; Miettunen, Jouko; Mukkala, Sari; Mäki, Pirjo; Liuhanen, Johanna; Murray, Graham K; Jarvelin, Marjo-Riitta; Ollila, Hanna; Paunio, Tiina; Veijola, Juha

    2015-01-01

    There is limited research regarding the association between genes and cognitive intermediate phenotypes in those at risk for psychotic disorders. We measured the association between established psychosis risk variants in dopamine D2 receptor (DRD2) and cognitive performance in individuals at age 23 years and explored if associations between cognition and these variants differed according to the presence of familial or clinical risk for psychosis. The subjects of the Oulu Brain and Mind Study were drawn from the general population-based Northern Finland 1986 Birth Cohort (NFBC 1986). Using linear regression, we compared the associations between cognitive performance and two candidate DRD2 polymorphisms (rs6277 and rs1800497) between subjects having familial (n=61) and clinical (n=45) risk for psychosis and a random sample of participating NFBC 1986 controls (n=74). Cognitive performance was evaluated using a comprehensive battery of tests at follow-up. Principal components factor analysis supported a three-factor model for cognitive measures. The minor allele of rs6277 was associated with poorer performance on a verbal factor (p=0.003) but this did not significantly interact with familial or clinical risk for psychosis. The minor allele of rs1800497 was associated with poorer performance on a psychomotor factor (p=0.038), though only in those at familial risk for psychotic disorders (interaction p=0.049). The effect of two DRD2 SNPs on cognitive performance may differ according to risk type for psychosis, suggesting that cognitive intermediate phenotypes differ according to the type (familial or clinical) risk for psychosis.

  17. Decreased striatal and enhanced thalamic dopaminergic responsivity in detoxified cocaine abusers

    Energy Technology Data Exchange (ETDEWEB)

    Volkow, N.D.; Wang, G.J.; Fowler, J.S. [Brookhaven National Lab., Stony Brook, NY (United States)] [and others

    1997-05-01

    It has been hypothesized that cocaine addiction could result from decreased brain dopamine (DA) function. However, little is known about changes in (DA) neurotransmission in human cocaine addiction. We used PET and [C-11]raclopride, a DA D2 receptor ligand sensitive to competition with endogenous DA, to measure relative changes in extracellular DA induced by methylphenidate (MP) in 20 cocaine abusers (3-6 weeks after cocaine discontinuation) and 23 controls. MP did not affect the transport of [C-11]raclopride from blood to brain (K1); however it induced a significant reduction in DA D2 receptor availability (Bmax/Kd) in striatum. The magnitude of ND-induced changes in striatal [C-11]raclopride binding were significantly larger in controls (21 + 13% change from baseline) than in cocaine abusers (9 {+-} 13 %) (ANOVA p < 0.005). In cocaine abusers, but not in controls, MP also decreased Bmax/Kd values in thalamus (29 {+-} 35 %) (ANOVA p < 0.005). There were no differences in plasma MP concentration between the groups. In striatum MP-induced changes in Bmax/Kd were significantly correlated with MP-induced changes in self reports of restlessness (r = 0.49, df 42, p < 0.002). In thalamus MP-induced changes in Bmax/Kd were significantly correlated with ND-induced changes in self reports of cocaine craving (r = 0.57, df 42, p < 0.0001). These results are compatible with a decrease in striatal DA brain function in cocaine abusers. They also suggest a participation of thalamic DA pathways in cocaine addiction.

  18. Altered thalamic functional connectivity in multiple sclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Yaou; Liang, Peipeng; Duan, Yunyun; Huang, Jing; Ren, Zhuoqiong; Jia, Xiuqin [Department of Radiology, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Dong, Huiqing; Ye, Jing [Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Shi, Fu-Dong [Department of Neurology and Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052 (China); Butzkueven, Helmut [Department of Medicine, University of Melbourne, Parkville 3010 (Australia); Li, Kuncheng, E-mail: kunchengli55@gmail.com [Department of Radiology, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China)

    2015-04-15

    Highlights: •We demonstrated decreased connectivity between thalamus and cortical regions in MS. •Increased intra- and inter-thalamic connectivity was also observed in MS. •The increased functional connectivity is attenuated by increasing disease duration. -- Abstract: Objective: To compare thalamic functional connectivity (FC) in patients with multiple sclerosis (MS) and healthy controls (HC), and correlate these connectivity measures with other MRI and clinical variables. Methods: We employed resting-state functional MRI (fMRI) to examine changes in thalamic connectivity by comparing thirty-five patients with MS and 35 age- and sex-matched HC. Thalamic FC was investigated by correlating low frequency fMRI signal fluctuations in thalamic voxels with voxels in all other brain regions. Additionally thalamic volume fraction (TF), T2 lesion volume (T2LV), EDSS and disease duration were recorded and correlated with the FC changes. Results: MS patients were found to have a significantly lower TF than HC in bilateral thalami. Compared to HC, the MS group showed significantly decreased FC between thalamus and several brain regions including right middle frontal and parahippocampal gyri, and the left inferior parietal lobule. Increased intra- and inter-thalamic FC was observed in the MS group compared to HC. These FC alterations were not correlated with T2LV, thalamic volume or lesions. In the MS group, however, there was a negative correlation between disease duration and inter-thalamic connectivity (r = −0.59, p < 0.001). Conclusion: We demonstrated decreased FC between thalamus and several cortical regions, while increased intra- and inter-thalamic connectivity in MS patients. These complex functional changes reflect impairments and/or adaptations that are independent of T2LV, thalamic volume or presence of thalamic lesions. The negative correlation between disease duration and inter-thalamic connectivity could indicate an adaptive role of thalamus that is

  19. Sex differences in high fat diet-induced impairments to striatal Akt signaling and enhanced sensitivity to the behavioral effects of dopamine D2/D3 receptor agonist quinpirole.

    Science.gov (United States)

    Ramos, Jeremiah; Hernandez-Casner, Caroline; Cruz, Bryan; Serafine, Katherine M

    2017-11-14

    Eating a high fat laboratory chow enhances sensitivity of rats to the behavioral effects of drugs that act on dopamine systems (e.g., cocaine). Further, in male rats, eating high fat chow impairs expression of insulin signaling phosphorylated protein kinase B (pAkt), which is vital for maintaining dopamine homeostasis. Eating high fat chow enhances sensitivity of female rats to drugs that act indirectly on dopamine receptors (e.g., cocaine); however, less is known about sensitivity of females to drugs that act directly on dopamine receptors (e.g., quinpirole). Further, it is not known if pAkt expression is impaired in female rats eating high fat chow. Some quinpirole-induced behaviors (e.g., penile erections and yawning) are either absent or occur at very low frequency in adult female rats. It is not known if quinpirole sensitivity in adolescent rats is more comparable between sexes. The present report examined another unconditioned behavioral effect (i.e., rearing) induced by once-weekly cumulative doses of quinpirole (0.0032-0.32mg/kg) in male and female Sprague-Dawley rats eating standard laboratory chow (17% kcal from fat) or high fat chow (60% kcal from fat), for several weeks throughout development, (spanning adolescence and early adulthood). Following behavioral assessments, pAkt expression was examined using western blot protein analysis. Eating high fat chow increased sensitivity of male rats to the quinpirole-induced yawning, as compared to male rats eating standard chow. However, other unconditioned behavioral effects of quinpirole (yawning and hypothermia) remained unchanged. Female rats yawned significantly less than male rats, and eating a high fat chow had no effect on any quinpirole-induced unconditioned behavioral effect in female rats. Eating high fat chow also reduced pAkt levels in male, but not female rats. Taken together, these data suggest that alternative behavioral and biochemical assays should be considered to measure sensitivity of female

  20. 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...

  1. Synthesis and biological evaluation of the binding of dopamine D2/D3 receptor agonist, (R,S)-5-hydroxy-2-(N-propyl-N-5'-{sup 18}F-fluoropentyl)aminotetralin ({sup 18}F-5-OH-FPPAT) in rodents and nonhuman primates

    Energy Technology Data Exchange (ETDEWEB)

    Shi Bingzhi; Narayanan, Tanjore K.; Christian, Bradley T.; Chattopadhyay, Sankha; Mukherjee, Jogeshwar E-mail: mukherjj@uci.edu

    2004-04-01

    We have synthesized a new fluorinated dopamine D2 receptor agonist, (R,S)-2-(N-propyl-N-5'-fluoropentyl)amino-5-hydroxytetralin (5-OH-FPPAT). The radiosynthesis of the fluorine-18 analog, {sup 18}F-5-OH-FPPAT was achieved in decay corrected yields of 10 to 15% in specific activities of approx. 1.5 to 2 Ci/{mu}mol. In vitro binding and autoradiographic studies of this new radiotracer have been investigated. Using rat striatal homogenate binding assay, 5-OH-FPPAT exhibited an affinity of IC{sub 50} = 6.95 nM. The octanol-buffer partition coefficient, Log P was found to be 1.60. In vitro autoradiographs in rat brain slices with {sup 18}F-5-OH-FPPAT revealed selective binding to the dopaminergic regions in the striata that was displaceable by sulpiride. This selective binding to the striata was also removed in the presence of the GTP analog, 5'-guanylylimidodiphosphate, indicative of predominant binding of {sup 18}F-5-OH-FPPAT to the high-affinity state of the D2 receptor. In vivo regional distribution of {sup 18}F-5-OH-FPPAT in rat brains revealed selective localization in the striata with striata/cortex ratio of 1.5 and striata/cerebellum ratio of 1.8 to 2.0. The binding of {sup 18}F-5-OH-FPPAT in the striata was reduced upon pretreatment with the antagonist, risperidone and the agonist, PPHT. A PET study in rhesus monkeys showed selective localization of {sup 18}F-5-OH-FPPAT in the striata and the ratio between striata and cerebellum approached approximately 2 at 40 min post-injection. Keywords: {sup 18}F-5-OH-FPPAT; Dopamine D-2 Receptor Agonist; In vitro Autoradiography; PET.

  2. Presynaptic Dopamine D2 Receptors Modulate [3H]GABA Release at StriatoPallidal Terminals via Activation of PLC → IP3 → Calcineurin and Inhibition of AC → cAMP → PKA Signaling Cascades.

    Science.gov (United States)

    Jijón-Lorenzo, Rafael; Caballero-Florán, Isaac Hiram; Recillas-Morales, Sergio; Cortés, Hernán; Avalos-Fuentes, José Arturo; Paz-Bermúdez, Francisco Javier; Erlij, David; Florán, Benjamín

    2018-02-21

    Striatal dopamine D2 receptors activate the PLC → IP3 → Calcineurin-signaling pathway to modulate the neural excitability of En+ Medium-sized Spiny GABAergic neurons (MSN) through the regulation of L-type Ca 2+ channels. Presynaptic dopaminergic D2 receptors modulate GABA release at striatopallidal terminals through L-type Ca 2+ channels as well, but their signaling pathway is still undetermined. Since D2 receptors are Gi/o-coupled and negatively modulate adenylyl cyclase (AC), we investigated whether presynaptic D2 receptors modulate GABA release through the same signaling cascade that controls excitability in the striatum or by the inhibition of AC and decreased PKA activity. Activation of D2 receptors stimulated formation of [ 3 H]IP 1 and decreased Forskolin-stimulated [ 3 H]cAMP accumulation in synaptosomes from rat Globus Pallidus. D2 receptor activation with Quinpirole in the presence of L 745,870 decreased, in a dose-dependent manner, K + -induced [ 3 H]GABA release in pallidal slices. The effect was prevented by the pharmacological blockade of Gi/o βγ subunit effects with Gallein, PLC with U 73122, IP3 receptor activation with 4-APB, Calcineurin with FK506. In addition, when release was stimulated with Forskolin to activate AC, D2 receptors also decreased K + -induced [ 3 H]GABA release, an effect occluded with the effect of the blockade of PKA with H89 or stimulation of release with the cAMP analog 8-Br-cAMP. These data indicate that D2 receptors modulate [ 3 H]GABA release at striatopallidal terminals by activating the PLC → IP3 → Calcineurin-signaling cascade, the same one that modulates excitability in soma. Additionally, D2 receptors inhibit release when AC is active. Both mechanisms appear to converge to regulate the activity of presynaptic L-type Ca 2+ channels. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

  3. Patterns of age related changes for phosphodiesterase type-10A in comparison with dopamine D2/3receptors and sub-cortical volumes in the human basal ganglia: A PET study with18F-MNI-659 and11C-raclopride with correction for partial volume effect.

    Science.gov (United States)

    Fazio, Patrik; Schain, Martin; Mrzljak, Ladislav; Amini, Nahid; Nag, Sangram; Al-Tawil, Nabil; Fitzer-Attas, Cheryl J; Bronzova, Juliana; Landwehrmeyer, Bernhard; Sampaio, Cristina; Halldin, Christer; Varrone, Andrea

    2017-05-15

    Phosphodiesterase 10A enzyme (PDE10A) is an important striatal target that has been shown to be affected in patients with neurodegenerative disorders, particularly Huntington´s disease (HD). PDE10A is expressed on striatal neurones in basal ganglia where other known molecular targets are enriched such as dopamine D 2/3 receptors (D 2/3 R). The aim of this study was to examine the availability of PDE10A enzyme in relation with age and gender and to compare those changes with those related to D 2/3 R and volumes in different regions of the basal ganglia. As a secondary objective we examined the relative distribution of D 2/3 R and PDE10A enzyme in the striatum and globus pallidus. Forty control subjects (20F/20M; age: 44±11y, age range 27-69) from an ongoing positron emission tomography (PET) study in HD gene expansion carriers were included. Subjects were examined with PET using the high-resolution research tomograph (HRRT) and with 3T magnetic resonance imaging (MRI). The PDE10A radioligand 18 F-MNI-659 and D 2/3 R radioligand 11 C-raclopride were used. The outcome measure was the binding potential (BP ND ) estimated with the two-tissue compartment model ( 18 F-MNI-659) and the simplified reference tissue model ( 11 C-raclopride) using the cerebellum as reference region. The PET data were corrected for partial volume effects. In the striatum, PDE10A availability showed a significant age-related decline that was larger compared to the age-related decline of D 2/3 R availability and to the age-related decline of volumes measured with MRI. In the globus pallidus, a less pronounced decline of PDE10A availability was observed, whereas D 2/3 R availability and volumes seemed to be rather stable with aging. The distribution of the PDE10A enzyme was different from the distribution of D 2/3 R, with higher availability in the globus pallidus. These results indicate that aging is associated with a considerable physiological reduction of the availability of PDE10A enzyme in

  4. Ropinirole hydrochloride, a dopamine agonist.

    Science.gov (United States)

    Ravikumar, Krishnan; Sridhar, Balasubramanian

    2006-05-01

    Ropinirole hydrochloride, or diethyl[2-(2-oxo-2,3-dihydro-1H-indol-4-yl)ethyl]ammonium chloride, C16H25N2O+.Cl-, belongs to a class of new non-ergoline dopamine agonists which bind specifically to D2-like receptors with a selectivity similar to that of dopamine (D3 > D2 > D4). The N atom in the ethylamine side chain is protonated and there is a hydrogen bond between it and the Cl- ion. In the crystal structure, two cations and two anions form inversion-related cyclic dimers via N-H...Cl hydrogen bonds.

  5. Clozapine, a Fast-Off-D2 Antipsychotic

    Science.gov (United States)

    2013-01-01

    Ever since clozapine was first synthesized and tested, it showed the unique property of having antipsychotic action but no Parkinson-like motor side effects. The antipsychotic basis of clozapine is to transiently occupy dopamine D2 receptors in the human striatum, in contrast to haloperidol and chlorpromazine, which have a prolonged occupation of D2 receptors. The chemical structure of clozapine facilitates a relatively rapid dissociation from D2 receptors. After short-term occupation of D2 receptors, peak neural activity raises synaptic dopamine, which then displaces clozapine. While clozapine also occupies other types of receptors, they may not have a significant role in preventing parkinsonism. Clozapine’s transient occupation of D2 receptors permits patients to move easily and comfortably. PMID:24219174

  6. D2-tree

    DEFF Research Database (Denmark)

    Brodal, Gerth Stølting; Sioutas, Spyros; Pantazos, Kostas

    2015-01-01

    We present a new overlay, called the Deterministic Decentralized tree (D2-tree). The D2-tree compares favorably to other overlays for the following reasons: (a) it provides matching and better complexities, which are deterministic for the supported operations; (b) the management of nodes (peers...

  7. Bilateral paramedian thalamic syndrome after infection.

    Science.gov (United States)

    Kamaşak, Tülay; Sahin, Sevim; Eyüboğlu, İlker; Reis, Gökce Pinar; Cansu, Ali

    2015-02-01

    Although bilateral paramedian thalamic infarctions occur more frequently in adults than in children, they are rare entities at any age. The syndrome is thought to result from occlusion of the artery of Percheron, which arises as a common trunk from one of the posterior cerebral arteries to supply both paramedian thalamic regions. We describe two children with acute ischemic infarction involving both paramedian thalami developing after infection. The first patient developed mutism with ataxia after chicken pox infection. The second child developed headache, somnolence, agitation, and speech dysfunction following an upper respiratory tract infection. Bilateral thalamic lesions were documented on magnetic resonance imaging of both children. Bilateral infarctions of the paramedian thalamus may result in severe illness and impairment. Common clinical manifestations include disorientation, confusion, hypersomnolence, deep coma and "coma vigil," or akinetic mutism (awake unresponsiveness), as well as severe memory impairment. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Language disturbances from mesencephalo-thalamic infarcts. Identification of thalamic nuclei by CT-reconstructions

    Energy Technology Data Exchange (ETDEWEB)

    Lazzarino, L.G.; Nicolai, A.; Valassi, F. (Ospedale Civile di Gorizia (Italy). Div. di Neurologia); Biasizzo, E. (Ospedale di Udine (Italy). Servizio di Neuroradiologia)

    1991-08-01

    The authors report the cases of two patients with CT-documented paramedian mesencephalo-thalamic infarcts, showing language disturbances. The first patient showed a non fluent, transcortical motor-like aphasia, the other had a fluent but severely paraphasic language disorder. The CT study disclosed that it was the dorso-median thalamic nucleus that was mostly involved in both cases. These findings agree with a few previous pathological studies suggesting that the paramedian thalamic nuclei, particlularly the dorso-median nucleus may play some role in language disturbances. However the anatomical basis for thalamic aphasia remains speculative, taking into account the importantce of cortical connections in the origin of subcortical neuropsychological disturbances. (orig.).

  9. Thalamic morphology in schizophrenia and schizoaffective disorder.

    Science.gov (United States)

    Smith, Matthew J; Wang, Lei; Cronenwett, Will; Mamah, Daniel; Barch, Deanna M; Csernansky, John G

    2011-03-01

    Biomarkers are needed that can distinguish between schizophrenia and schizoaffective disorder to inform the ongoing debate over the diagnostic boundary between these two disorders. Neuromorphometric abnormalities of the thalamus have been reported in individuals with schizophrenia and linked to core features of the disorder, but have not been similarly investigated in individuals with schizoaffective disorder. In this study, we examine whether individuals with schizoaffective disorder have a pattern of thalamic deformation that is similar or different to the pattern found in individuals with schizophrenia. T1-weighted magnetic resonance images were collected from individuals with schizophrenia (n = 47), individuals with schizoaffective disorder (n = 15), and controls (n = 42). Large-deformation, high-dimensional brain mapping was used to obtain three-dimensional surfaces of the thalamus. Multiple analyses of variance were used to test for group differences in volume and measures of surface shape. Individuals with schizophrenia or schizoaffective disorder have similar thalamic volumes. Thalamic surface shape deformation associated with schizophrenia suggests selective involvement of the anterior and posterior thalamus, while deformations in mediodorsal and ventrolateral regions were observed in both groups. Schizoaffective disorder had distinct deformations in medial and lateral thalamic regions. Abnormalities distinct to schizoaffective disorder suggest involvement of the central and ventroposterior medial thalamus which may be involved in mood circuitry, dorsolateral nucleus which is involved in recall processing, and the lateral geniculate nucleus which is involved in visual processing. Copyright © 2010 Elsevier Ltd. All rights reserved.

  10. Dopamine receptor agonists modulate voluntary alcohol intake independently of individual levels of alcohol intake in rats

    OpenAIRE

    Spoelder, Marcia; Annemarie M Baars; Rotte, Marthe D.; Vanderschuren, Louk J.M.J.; Lesscher, Heidi M. B.

    2016-01-01

    RATIONALE: Individual susceptibility to alcohol use disorder has been related to functional changes in dopaminergic neurotransmission. OBJECTIVES: The aim of the current work was to assess the effects of selective dopamine D1 and D2 receptor agonists and antagonists on alcohol consumption in rats that differ in individual levels of alcohol intake. METHODS: The effects of the dopamine D1 receptor agonist SKF 82958, the dopamine D1 receptor antagonist SCH 23390, the dopamine D2 receptor agonist...

  11. Dopamine inhibits mitochondrial motility in hippocampal neurons.

    Directory of Open Access Journals (Sweden)

    Sigeng Chen

    2008-07-01

    Full Text Available The trafficking of mitochondria within neurons is a highly regulated process. In an earlier study, we found that serotonin (5-HT, acting through the 5-HT1A receptor subtype, promotes axonal transport of mitochondria in cultured hippocampal neurons by increasing Akt activity, and consequently decreasing glycogen synthase kinase (GSK3beta activity. This finding suggests a critical role for neuromodulators in the regulation of mitochondrial trafficking in neurons. In the present study, we investigate the effects of a second important neuromodulator, dopamine, on mitochondrial transport in hippocampal neurons.Here, we show that dopamine, like 5-HT, regulates mitochondrial motility in cultured hippocampal neurons through the Akt-GSK3beta signaling cascade. But, in contrast to the stimulatory effect of 5-HT, administration of exogenous dopamine or bromocriptine, a dopamine 2 receptor (D2R agonist, caused an inhibition of mitochondrial movement. Moreover, pretreatment with bromocriptine blocked the stimulatory effect of 5-HT on mitochondrial movement. Conversely, in cells pretreated with 5-HT, no further increases in movement were observed after administration of haloperidol, a D2R antagonist. In contrast to the effect of the D2R agonist, addition of SKF38393, a dopamine 1 receptor (D1R agonist, promoted mitochondrial transport, indicating that the inhibitory effect of dopamine was actually the net summation of opposing influences of the two receptor subtypes. The most pronounced effect of dopamine signals was on mitochondria that were already moving directionally. Western blot analysis revealed that treatment with either a D2R agonist or a D1R antagonist decreased Akt activity, and conversely, treatment with either a D2R antagonist or a D1R agonist increased Akt activity.Our observations strongly suggest a role for both dopamine and 5-HT in regulating mitochondrial movement, and indicate that the integrated effects of these two neuromodulators may be

  12. Orbitofrontal Dopamine Depletion Upregulates Caudate Dopamine and Alters Behavior via Changes in Reinforcement Sensitivity

    Science.gov (United States)

    Cardinal, R. N.; Rygula, R.; Hong, Y. T.; Fryer, T. D.; Sawiak, S. J.; Ferrari, V.; Cockcroft, G.; Aigbirhio, F. I.; Robbins, T. W.; Roberts, A. C.

    2014-01-01

    Schizophrenia is associated with upregulation of dopamine (DA) release in the caudate nucleus. The caudate has dense connections with the orbitofrontal cortex (OFC) via the frontostriatal loops, and both areas exhibit pathophysiological change in schizophrenia. Despite evidence that abnormalities in dopaminergic neurotransmission and prefrontal cortex function co-occur in schizophrenia, the influence of OFC DA on caudate DA and reinforcement processing is poorly understood. To test the hypothesis that OFC dopaminergic dysfunction disrupts caudate dopamine function, we selectively depleted dopamine from the OFC of marmoset monkeys and measured striatal extracellular dopamine levels (using microdialysis) and dopamine D2/D3 receptor binding (using positron emission tomography), while modeling reinforcement-related behavior in a discrimination learning paradigm. OFC dopamine depletion caused an increase in tonic dopamine levels in the caudate nucleus and a corresponding reduction in D2/D3 receptor binding. Computational modeling of behavior showed that the lesion increased response exploration, reducing the tendency to persist with a recently chosen response side. This effect is akin to increased response switching previously seen in schizophrenia and was correlated with striatal but not OFC D2/D3 receptor binding. These results demonstrate that OFC dopamine depletion is sufficient to induce striatal hyperdopaminergia and changes in reinforcement learning relevant to schizophrenia. PMID:24872570

  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. Morphological Abnormalities of Thalamic Subnuclei in Migraine

    DEFF Research Database (Denmark)

    Magon, Stefano; May, Arne; Stankewitz, Anne

    2015-01-01

    . SIGNIFICANCE STATEMENT: This multicenter imaging study shows morphological thalamic abnormalities in a large cohort of patients with episodic migraine compared with healthy subjects using state-of-the-art MRI and advanced, fully automated multiatlas segmentation techniques. The results stress that migraine...... is a disorder of the CNS in which not only is brain function abnormal, but also brain structure is undergoing significant remodeling....... techniques in substantial patient populations are lacking. In the present study, we investigated changes of thalamic volume and shape in a large multicenter cohort of patients with migraine. High-resolution T1-weighted MRI data acquired at 3 tesla in 131 patients with migraine (38 with aura; 30.8 ± 9 years...

  15. Two Case Report With Bilateral Thalamic Infarct

    Directory of Open Access Journals (Sweden)

    Utku Cenikli

    2017-04-01

    Full Text Available Bilateral thalamic infarction is a rare clinical condition. Thalamo-perforan arteries are arise from the same vascular territory in nearly one third of the cases and oclussion of it causes bilateral infacts. Clinical presentation can be altered mental status, decrease alertness, memory problems, mood disorders, cognitive problems and vertical gaze palsy. In this report we present two cases with different clinical status.

  16. 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.

  17. Light microscope autoradiography of peripheral dopamine receptor subtypes.

    Science.gov (United States)

    Amenta, F

    1997-01-01

    Radioligand binding assay techniques associated with light microscope autoradiography were used for investigating the pharmacological profile and the micro anatomical localization of peripheral dopamine receptor subtypes. In systemic arteries, the predominant dopamine D1-like receptor belongs to the D5 (or D1B) subtype. It is located within smooth muscle of the tunica media. In pulmonary arteries, dopamine D1-like receptors have primarily an endothelial localization and belong to the dopamine D1 (or D1A) receptor subtype. Both systemic and pulmonary arteries express a dopamine D2-like receptor belonging to the D2 receptor subtype. It has a prejunctional localization in the majority of vascular beds investigated. In cerebral, coronary and mesenteric arteries, it has also an endothelial localization. In the heart, a dopamine D4 receptor was identified. It is expressed by atrial tissue and has a widespread distribution overall atrial musculature. The kidney expresses both dopamine D1-like and D2-like receptors. Renal dopamine D1-like receptors have a vascular and tubular localization. The majority of these sites belongs to the D5 receptor subtype. A smaller D1 receptor population has primarily a tubular localization. Renal dopamine D2-like receptors belong to the dopamine D3 subtype and in lesser amounts to the D2 and D4 receptor subtypes. Renal dopamine D3 receptor has to a greater extent a tubular localization, whereas the D4 receptor is located within glomerular arterioles. The above results suggest that radioligand binding assay and autoradiographic techniques, if performed in the presence of compounds displaying specific receptor subtype selectivity, may contribute to characterize, mainly from a quantitative point of view, peripheral dopamine receptors.

  18. Dopamine receptors - physiological understanding to therapeutic intervention potential

    NARCIS (Netherlands)

    Emilien, G; Maloteaux, JM; Hoogenberg, K; Cragg, S

    1999-01-01

    There are two families of dopamine (DA) receptors, called D(1) and D(2), respectively. The D(1) family consists of D(1)- and D(5)-receptor subtypes and the D(2) family consists of D(2)-, D(3)-, and D(4)-receptor subtypes. The amino acid sequences of these receptors show that they all belong to a

  19. 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.

  20. Dopamine, vesicular transporters, and dopamine receptor expression in rat major salivary glands.

    Science.gov (United States)

    Tomassoni, Daniele; Traini, Enea; Mancini, Manuele; Bramanti, Vincenzo; Mahdi, Syed Sarosh; Amenta, Francesco

    2015-09-01

    The localization of dopamine stores and the expression and localization of dopamine (DAT) and vesicular monoamine transporters (VMAT) type-1 and -2 and of dopamine D1-like and D2-like receptor subtypes were investigated in rat submandibular, sublingual, and parotid salivary glands by HPLC with electrochemical detection, as well as immunochemical and immunohistochemical techniques. Male Wistar rats of 2 mo of age were used. The highest dopamine levels were measured in the parotid gland, followed by the submandibular and sublingual glands. Western blot analysis revealed DAT, VMAT-1, VMAT-2, and dopamine receptors immunoreactivity in membrane preparations obtained from the three glands investigated. Immunostaining for dopamine and transporters was developed within striated ducts. Salivary glands processed for dopamine receptors immunohistochemistry developed an immunoreaction primarily in striated and excretory ducts. In the submandibular gland, acinar cells displayed strong immunoreactivity for the D2 receptor, while cells of the convoluted granular tubules were negative for both D1-like and D2-like receptors. Parotid glands acinar cells displayed the highest immunoreactivity for both D1 and D2 receptors compared with other salivary glands. The above localization of dopamine and dopaminergic markers investigated did not correspond closely with neuron-specific enolase (NSE) localization. This indicates that at least in part, catecholamine stores and dopaminergic markers are independent from glandular innervation. These findings suggest that rat major salivary glands express a dopaminergic system probably involved in salivary secretion. The stronger immunoreactivity for dopamine transporters and receptors in striated duct cells suggests that the dopaminergic system could regulate not only quality, but also volume and ionic concentration of saliva. Copyright © 2015 the American Physiological Society.

  1. Thalamic hemorrhage. A prospective study of 100 patients.

    Science.gov (United States)

    Kumral, E; Kocaer, T; Ertübey, N O; Kumral, K

    1995-06-01

    The clinical features of thalamic hemorrhage in terms of localization are of great interest in many studies. To better understand the relationship between the localization of thalamic hemorrhage and clinical features. we evaluated the characteristics of patients with four different topographic types of thalamic hemorrhage. We prospectively studied 100 patients with thalamic hemorrhage who were admitted consecutively to our primary care unit. We divided them into two groups according to large (> 2 cm in diameter and/or > 4 mL in volume) and small thalamic hemorrhage. Four topographic subgroups (large and small) were compared to identify clinical syndromes associated with distinct lesion locations. All patients with posterolateral thalamic hemorrhage had severe sensorimotor deficit. Neuropsychological disturbances in patients with posterolateral thalamic hemorrhage were prominent, with primarily transcortical aphasia in those with left-sided lesions and hemineglect and anosognosia in those with right-sided lesions. Several variants of vertical gaze dysfunction, skew ocular deviation, gaze preference toward the site of the lesion, and miotic pupils were frequent in posterolateral thalamic hemorrhage, particularly in the large type. Patients with small and large anterolateral thalamic hemorrhage were characterized by severe motor and sensory deficits; language and oculomotor disturbances were also observed, although less frequently than in posterolateral hemorrhage. Sensorimotor deficits were observed in patients with medial thalamic hemorrhage (moderate in small hemorrhages and severe in large hemorrhages because of involvement of the adjacent internal capsule). Language disturbances in patients with left-sided lesions and neglect in patients with right-sided lesions were seen only in large medial thalamic hemorrhage. Dorsal thalamic hemorrhage was rare and characterized by mild and transient sensorimotor disturbances. Among patients with dorsal thalamic hemorrhages

  2. Dopamine receptor expression and function in corticotroph pituitary tumors

    NARCIS (Netherlands)

    R. Pivonello (Rosario); S.W.J. Lamberts (Steven); D. Ferone (Diego); W.W. de Herder (Wouter); J.M. Kros (Johan); M.L. de Caro; M. Arvigo; L. Annunziato; G. Lombardi (Gaetano); A. Colao (Annamaria); L.J. Hofland (Leo)

    2004-01-01

    textabstractThe role of dopamine agonist treatment in corticotroph pituitary tumors is controversial. The aim of this study was to evaluate D(2) receptor expression in 20 corticotroph pituitary tumors and to correlate it to the in vitro effect of dopamine agonists on ACTH secretion

  3. No association between striatal dopamine transporter binding and body mass index

    DEFF Research Database (Denmark)

    van de Giessen, Elsmarieke; Hesse, Swen; Caan, Matthan W A

    2013-01-01

    Dopamine is one among several neurotransmitters that regulate food intake and overeating. Thus, it has been linked to the pathophysiology of obesity and high body mass index (BMI). Striatal dopamine D(2) receptor availability is lower in obesity and there are indications that striatal dopamine...

  4. Contributions of the Paraventricular Thalamic Nucleus in the Regulation of Stress, Motivation, and Mood

    Directory of Open Access Journals (Sweden)

    David Tai Hsu

    2014-03-01

    Full Text Available The purpose of this review is to describe how the function and connections of the paraventricular thalamic nucleus (Pa may play a role in the regulation of stress and negative emotional behavior. Located in the dorsal midline thalamus, the Pa is heavily innervated by serotonin, norepinephrine, dopamine, corticotropin-releasing hormone, and orexins, and is the only thalamic nucleus connected to the group of structures comprising the amygdala, bed nucleus of the stria terminalis, nucleus accumbens, and infralimbic/subgenual anterior cingulate cortex. These neurotransmitter systems and structures are involved in regulating motivation and mood, and display abnormal functioning in several psychiatric disorders including anxiety, substance use, and major depressive disorders. Furthermore, rodent studies show that the Pa is consistently and potently activated following a variety of stressors and has a unique role in regulating responses to chronic stressors. These observations provide a compelling rationale for investigating the Pa in the link between stress and negative emotional behavior, and for including the Pa in the neural pathways of stress-related psychiatric disorders.

  5. Dopamine controls Parkinson's tremor by inhibiting the cerebellar thalamus.

    Science.gov (United States)

    Dirkx, Michiel F; den Ouden, Hanneke E M; Aarts, Esther; Timmer, Monique H M; Bloem, Bastiaan R; Toni, Ivan; Helmich, Rick C

    2017-03-01

    Parkinson's resting tremor is related to altered cerebral activity in the basal ganglia and the cerebello-thalamo-cortical circuit. Although Parkinson's disease is characterized by dopamine depletion in the basal ganglia, the dopaminergic basis of resting tremor remains unclear: dopaminergic medication reduces tremor in some patients, but many patients have a dopamine-resistant tremor. Using pharmacological functional magnetic resonance imaging, we test how a dopaminergic intervention influences the cerebral circuit involved in Parkinson's tremor. From a sample of 40 patients with Parkinson's disease, we selected 15 patients with a clearly tremor-dominant phenotype. We compared tremor-related activity and effective connectivity (using combined electromyography-functional magnetic resonance imaging) on two occasions: ON and OFF dopaminergic medication. Building on a recently developed cerebral model of Parkinson's tremor, we tested the effect of dopamine on cerebral activity associated with the onset of tremor episodes (in the basal ganglia) and with tremor amplitude (in the cerebello-thalamo-cortical circuit). Dopaminergic medication reduced clinical resting tremor scores (mean 28%, range -12 to 68%). Furthermore, dopaminergic medication reduced tremor onset-related activity in the globus pallidus and tremor amplitude-related activity in the thalamic ventral intermediate nucleus. Network analyses using dynamic causal modelling showed that dopamine directly increased self-inhibition of the ventral intermediate nucleus, rather than indirectly influencing the cerebello-thalamo-cortical circuit through the basal ganglia. Crucially, the magnitude of thalamic self-inhibition predicted the clinical dopamine response of tremor. Dopamine reduces resting tremor by potentiating inhibitory mechanisms in a cerebellar nucleus of the thalamus (ventral intermediate nucleus). This suggests that altered dopaminergic projections to the cerebello-thalamo-cortical circuit have a role

  6. 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...

  7. Potential for targeting dopamine/DARPP-32 signaling in neuropsychiatric and neurodegenerative disorders.

    Science.gov (United States)

    Nishi, Akinori; Shuto, Takahide

    2017-03-01

    Alterations in dopamine neurotransmission has been implicated in pathophysiology of neuropsychiatric and neurodegenerative disorders, and DARPP-32 plays a pivotal role in dopamine neurotransmission. DARPP-32 likely influences dopamine-mediated behaviors in animal models of neuropsychiatric and neurodegenerative disorders and therapeutic effects of pharmacological treatment. Areas covered: We will review animal studies on the biochemical and behavioral roles of DARPP-32 in drug addiction, schizophrenia and Parkinson's disease. In general, under physiological and pathophysiological conditions, DARPP-32 in D1 receptor expressing (D1R) -medium spiny neurons (MSNs) promotes dopamine/D1 receptor/PKA signaling, whereas DARPP-32 in D2 receptor expressing (D2R)-MSNs counteracts dopamine/D2 receptor signaling. However, the function of DARPP-32 is differentially regulated in acute and chronic phases of drug addiction; DARPP-32 enhances D1 receptor/PKA signaling in the acute phase, whereas DARPP-32 suppresses D1 receptor/PKA signaling in the chronic phase through homeostatic mechanisms. Therefore, DARPP-32 plays a bidirectional role in dopamine neurotransmission, depending on the cell type and experimental conditions, and is involved in dopamine-related behavioral abnormalities. Expert opinion: DARPP-32 differentially regulates dopamine signaling in D1R- and D2R-MSNs, and a shift of balance between D1R- and D2R-MSN function is associated with behavioral abnormalities. An adjustment of this imbalance is achieved by therapeutic approaches targeting DARPP-32-related signaling molecules.

  8. Reduced noradrenaline, but not dopamine and serotonin in motor thalamus of the MPTP primate: relation to severity of parkinsonism.

    Science.gov (United States)

    Pifl, Christian; Hornykiewicz, Oleh; Blesa, Javier; Adánez, Rebeca; Cavada, Carmen; Obeso, José A

    2013-06-01

    We recently found severe noradrenaline deficits throughout the thalamus of patients with Parkinson's disease [C. Pifl, S. J. Kish and O. Hornykiewicz Mov Disord. 27, 2012, 1618.]. As this noradrenaline loss was especially severe in nuclei of the motor thalamus normally transmitting basal ganglia motor output to the cortex, we hypothesized that this noradrenaline loss aggravates the motor disorder of Parkinson's disease. Here, we analysed noradrenaline, dopamine and serotonin in motor (ventrolateral and ventroanterior) and non-motor (mediodorsal, centromedian, ventroposterior lateral and reticular) thalamic nuclei in MPTP-treated monkeys who were always asymptomatic; who recovered from mild parkinsonism; and monkeys with stable, either moderate or severe parkinsonism. We found that only the symptomatic parkinsonian animals had significant noradrenaline losses specifically in the motor thalamus, with the ventroanterior motor nucleus being affected only in the severe parkinsonian animals. In contrast, the striatal dopamine loss was identical in both the mild and severe symptom groups. MPTP-treatment had no significant effect on noradrenaline in non-motor thalamic nuclei or dopamine and serotonin in any thalamic subregion. We conclude that in the MPTP primate model, loss of noradrenaline in the motor thalamus may also contribute to the clinical expression of the parkinsonian motor disorder, corroborating experimentally our hypothesis on the role of thalamic noradrenaline deficit in Parkinson's disease. © 2013 International Society for Neurochemistry.

  9. Modeling influences of dopamine on synchronization behavior of striatum.

    Science.gov (United States)

    Çakir, Yüksel

    2017-01-01

    A network model of striatum that comprises medium spiny neurons (MSNs) and fast spiking interneurons (FSIs) is constructed following the work of Humphries et al. (2009). The dynamic behavior of striatum microcircuit is investigated using a dopamine-modulated modified Izhikevich neuron model. The influences of dopamine on the synchronization behavior of the striatal microcircuit and the dependence on receptor type are investigated with and without time delay. To investigate the role of two types of dopamine receptors, D1 and D2, on the overall activity of the striatum microcircuit, the activities of two groups are considered as disconnected and connected. When the connection exists between D1 and D2 sub-networks with zero dopamine and time delay, neuronal activity decreases because of an inhibitory effect of the connected neurons of the other sub-network. In the presence of dopamine, an increase in the activity of D1 type MSNs and quiescent behavior of D2 type MSNs are observed when the time delay is zero. However, the diversity in synchronization of D1 and D2 type MSNs is observed for different synaptic time delays and synaptic strengths in the case that dopamine is present.

  10. Predominance of D2 Receptors in Mediating Dopamine’s Effects in Brain Metabolism: Effects of Alcoholism

    Science.gov (United States)

    Volkow, Nora D.; Tomasi, Dardo; Wang, Gene-Jack; Telang, Frank; Fowler, Joanna S.; Logan, Jean; Maynard, L. Jayne; Wong, Christopher T.

    2013-01-01

    Dopamine signals through D1-like and D2-like receptors, which can stimulate or inhibit, respectively, neuronal activity. Here we assessed the balance between D1 or D2 receptor signaling in the human brain and how it is affected in alcoholism. Using PET, we measured the relationship between changes in dopamine and brain glucose metabolism induced by methylphenidate in controls and alcoholics. We show that methylphenidate induced significant DA increases in striatum, amygdala, and medial orbitofrontal cortex, whereas it decreased metabolism in these brain regions. Methylphenidate-induced dopamine increases were greater in controls than in alcoholics, whereas methylphenidate-induced metabolic decreases were greater in alcoholics. For both groups, methylphenidate-induced dopamine increases were associated with decreases in regional brain metabolism, and the correlations were strongest in subthalamic nuclei, anterior cingulate, and medial orbitofrontal cortex. These correlations were more extensive and robust and the slopes steeper in alcoholics than in controls despite their attenuated dopamine responses to methylphenidate, which suggests an impaired modulation of dopamine signals in the brain of alcoholic subjects. These findings are consistent with a predominant inhibitory effect of dopamine in the human brain that is likely mediated by the prominence of dopamine D2/D3 receptors. PMID:23467368

  11. Relationship of frontal D2/3 binding potentials to cognition

    DEFF Research Database (Denmark)

    Fagerlund, Birgitte; Pinborg, Lars H; Mortensen, Erik Lykke

    2013-01-01

    Studies of in vivo dopamine receptors in schizophrenia have mostly focused on D2 receptors in striatal areas or on D1 receptors in cortex. No previous study has examined the correlation between cortical dopamine D2/3 receptor binding potentials and cognition in schizophrenia patients. The objective...... single-photon emission computerized tomography with the D2/3-receptor ligand [123I]epidepride, co-registered with structural magnetic resonance imaging and correlated to cognitive measures. Participants were 24 antipsychotic-naive, first-episode schizophrenia patients and 20 healthy controls matched......, in schizophrenia patients compared to healthy people. The results suggest that cortical D2/3 receptor function may be more involved in some cognitive functions (i.e. attention, fluency and planning) in patients with schizophrenia than in healthy people, suggesting that information processing in schizophrenia may...

  12. [Brain dopamine receptors: structure, functional role, and modulation by psychotropic substances].

    Science.gov (United States)

    Raevskiĭ, K S

    1997-01-01

    Recent advances in molecular neurobiology led to a new understanding on mammalian brain dopaminergic system which plays a major role in the regulation of motor, cognitive, emotional, neuroendocrine functions as well as in the pathogenesis of several pathological conditions, including neurodegenerative diseases, affective disorders, schizophrenia, drug addiction etc. Functional, biochemical and pharmacological heterogeneity of dopamine receptors, which were divided into D1-like (D1 and D5 subtypes) and D2-like (D2, D3 and D4) families of receptors has been postulated. The article reviews the recent advances including author's own results concerning the structure and function of main dopaminergic brain system, i.e. nigrostriatal and mesolimbic. The problem of autoreceptor regulation of dopaminergic neurotransmission, particularly, the processes of dopamine synthesis, release and metabolism has been specially discussed. An involvement of D2 and D3 dopamine autoreceptors in the control of these processes and differences in the mode of action of typical and atypical neuroleptics demonstrating various affinities to D2 and D3 dopamine receptors are analysed in detail. Dopamine and its metabolites have been determined on freely moving rats using brain microdialysis and high performance liquid chromatography. It is hypothesized that dopamine D3 autoreceptor is preferentially involved in the regulation of dopamine release while D2 one is responsible for the control of dopamine synthesis and metabolism in rat basal ganglia in vivo.

  13. Efecto de la inactivación de los receptores dopaminérgicos D2 y de la manipulación del núcleo subtalámico sobre la conducta motora en modelos de hemiparkinsonismo en roedores

    OpenAIRE

    Nancy Pavón Fuentes

    2007-01-01

    El tratamiento actual de la enfermedad de Parkinson (EP) se basa en la utilización de fármacos que intentan compensar el déficit dopaminérgico nigroestriatal. La levodopa constituye el tratamiento sintomático más eficaz, sin embargo, con el uso prolongado de este medicamento aparecen complicaciones motoras como los movimientos involuntarios (disquinesias) y las fluctuaciones en la respuesta motora. Consecuentemente después de 5 años de tratamiento los efectos beneficiosos de la levodopa dismi...

  14. Polimorfismos en los receptores dopaminérgicos D2 y D3, y en el transportador de dopamina DAT, y su relación con el riesgo de síntomas extrapiramidales inducidos por tratamiento AP en la esquizofrenia

    OpenAIRE

    Aparici Virgili, Mònica

    2006-01-01

    La esquizofrenia es una enfermedad mental en la que se producen trastornos del lenguaje, delirios, alucinaciones, así como trastornos afectivos y trastornos de la conducta. Su causa todavía se desconoce, aunque la susceptibilidad individual parece tener una base genética, con una herencia estimada del 80% (Miyamoto S. et al. 2003). La hipótesis más aceptada de la etiopatogenia es la que postula que en la enfermedad se daría una hiperactividad dopaminérgica.El tratamiento de los pacientes esqu...

  15. 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

  16. Global suppression of electrocortical activity in unilateral perinatal thalamic stroke.

    LENUS (Irish Health Repository)

    Kharoshankaya, Liudmila

    2014-07-01

    We present an unusual case of persistent generalized electroencephalography (EEG) suppression and right-sided clonic seizures in a male infant born at 40(+2) weeks\\' gestation, birthweight 3240g, with an isolated unilateral thalamic stroke. The EEG at 13 hours after birth showed a generalized very low amplitude background pattern, which progressed to frequent electrographic seizures over the left hemisphere. The interictal background EEG pattern remained grossly abnormal over the next 48 hours, showing very low background amplitudes (<10μV). Magnetic resonance imaging revealed an isolated acute left-sided thalamic infarction. This is the first description of severe global EEG suppression caused by an isolated unilateral thalamic stroke and supports the role of the thalamus as the control centre for cortical electrical activity.

  17. Bilateral thalamic infarction with psychiatric symptoms: case report

    Directory of Open Access Journals (Sweden)

    Betül Tekin Güveli

    2016-04-01

    Full Text Available Introduction: Thalamus is a mass of gray matter, which plays a role in the transmission of sensory and motor information to the primary sensory and motor centers of the cerebral cortex, cerebellum and basal ganglia. Vascular lesions of thalamus may occur in different syndromes depending on the affected nuclei. In this report, a case with acute evolving personality and behavior changes and detected bilateral thalamic infarction will be presented. Case: A 40-year-old male patient was brought to the psychiatric ER with complaints of acute excessive sleep and behavioral changing. His neurological examination was normal except for limited cooperation and dysarthria. There was hyperintensity in bilateral paramedian thalamic regions in diffusion MRI and hypointensity in the right side in the ADC. During clinical observation the patient occasionally had visual hallucinations and attempted suicide. The psychiatrist diagnosed the patient with psychotic disorder due to his general medical condition and olanzapine 10 mg / day was prescribed. Etiological tests were normal. The patient was discharged after clinical improvement on the tenth day of hospitalization. Conclusion: Bilateral thalamic infarcts are very rare in all ischemic cerebrovascular diseases and typically result in changing of consciousness, gaze palsy and memory. The most common etiological cause of bilateral thalamic infarct is cardioembolism and the prognosis is generally good. Thalamic infarcts have a clinical spectrum varying according to the location of the lesion and may even just be present with psychiatric symptoms. In acute or subacute personality and behavior changes in a patient with no history of psychiatric disorders, thalamic lesions should be considered.

  18. Intrinsic properties and neuropharmacology of midline paraventricular thalamic nucleus neurons.

    Directory of Open Access Journals (Sweden)

    Miloslav eKolaj

    2014-04-01

    Full Text Available Neurons in the midline and intralaminar thalamic nuclei are components of an interconnected brainstem, limbic and prefrontal cortex neural network that is engaged during arousal, vigilance, motivated and addictive behaviors, and stress. To better understand the cellular mechanisms underlying these functions, here we review some of the recently characterized electrophysiological and neuropharmacological properties of neurons in the paraventricular thalamic nucleus (PVT, derived from whole cell patch clamp recordings in acute rat brain slice preparations. PVT neurons display firing patterns and ionic conductances (IT and IH that exhibit significant diurnal change. Their resting membrane potential is maintained by various ionic conductances that include inward rectifier (Kir, hyperpolarization-activated nonselective cation (HCN and TWIK-related acid sensitive (TASK K+ channels. Firing patterns are regulated by high voltage-activated (HVA and low voltage-activated (LVA Ca2+ conductances. Moreover, transient receptor potential (TRP-like nonselective cation channels together with Ca2+- and Na+-activated K+ conductances (KCa; KNa contribute to unique slow afterhyperpolarizing potentials (sAHPs that are generally not detectable in lateral thalamic or reticular thalamic nucleus neurons. We also report on receptor-mediated actions of GABA, glutamate, monoamines and several neuropeptides: arginine vasopressin, gastrin-releasing peptide, thyrotropin releasing hormone and the orexins (hypocretins. This review represents an initial survey of intrinsic and transmitter-sensitive ionic conductances that are deemed to be unique to this population of midline thalamic neurons, information that is fundamental to an appreciation of the role these thalamic neurons may play in normal central nervous system (CNS physiology and in CNS disorders that involve the dorsomedial thalamus.

  19. Bilateral paramedian thalamic artery infarcts: report of 10 cases.

    Science.gov (United States)

    Jiménez Caballero, Pedro Enrique

    2010-01-01

    The paramedian thalamic arteries can arise as a pair from each P1 of the posterior cerebral artery, but they may also arise equally from a common trunk off one P1, thus supplying thalamus bilaterally. Such a common trunk is called the artery of Percheron and supplies the mesial aspects of both thalami and the rostral midbrain. This is a retrospective review of 1,253 consecutive patients with ischemic stroke enrolled in a stroke registry within an 8-year period (January 2001-December 2008). All were evaluated with detailed clinical and neuropsychological evaluation, magnetic resonance imaging (MRI), blood studies, electrocardiogram, and transthoracic echocardiography. All standard risk factors were recorded in these patients. Ten patients (0.7%) in this series presented with a first-ever thalamic stroke demonstrating bilateral paramedian thalamic lesions on MRI. The main cause of bilateral paramedian thalamic infarctions was small artery disease (60%), followed by cardioembolism (40%). A well-defined clinical picture is shown in bilateral paramedian thalamic artery infarcts. These patients had disorder's consisting of consciousness, memory dysfunctions, various types of vertical gaze paresis, and psychological changes. Although neurologic deficits and hypersomnia recovered to large extent in patients with paramedian thalamic infarcts, cognitive deficits that were mainly linked with bilateral and left-sided lesions often persisted. Vertical gaze paresis tended to improve and never seriously disturbed the patient's activities. We believe that these kinds of strokes have been commonly overlooked, especially without widespread use of MRI. Copyright (c) 2010 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  20. Orthostatic tremor responds to bilateral thalamic deep brain stimulation.

    Science.gov (United States)

    Lyons, Mark K; Behbahani, Mandana; Boucher, Orland K; Caviness, John N; Evidente, Virgilio Gerald H

    2012-01-01

    Orthostatic tremor (OT) is a disabling movement disorder manifested by postural and gait disturbance. Primarily a condition of elderly people, it can be progressive in up to 15% of patients. The primary treatments are medications that are often ineffective. A 75-year-old male presented with a 10-year history of progressive and disabling OT. He had tried various medications without significant benefits. He underwent bilateral thalamic Vim deep brain stimulation (DBS). At 30-month follow-up, he has had continued significant improvement of his OT. Bilateral thalamic DBS may be a viable option for medically refractory OT.

  1. Thalamic syndrome as the heralding manifestation of atlantoaxial dislocation

    Science.gov (United States)

    Verma, Rajesh; Sahu, Ritesh; Ojha, B K; Junewar, Vivek

    2013-01-01

    In India, Atlantoaxial dislocation (AAD) is the commonest skeletal craniovertebral junction (CVJ) anomaly, followed by occipitalisation of atlas and basilar invagination. The usual presentation is progressive neurological deficit (76–95% cases) involving the high cervical cord, lower brainstem and cranial nerves. The association between vertebro-basilar insufficiency and skeletal CVJ anomalies is well recognised and angiographic abnormalities of the vertebrobasilar arteries and their branches have been reported; however, initial presentation of CVJ anomaly as thalamic syndrome due to posterior circulation stroke is extremely rare. Here, we report one such rare case of thalamic syndrome as the initial presentation of CVJ anomaly with AAD. PMID:23314448

  2. Thalamic theta phase alignment predicts human memory formation and anterior thalamic cross-frequency coupling.

    Science.gov (United States)

    Sweeney-Reed, Catherine M; Zaehle, Tino; Voges, Jürgen; Schmitt, Friedhelm C; Buentjen, Lars; Kopitzki, Klaus; Hinrichs, Hermann; Heinze, Hans-Jochen; Rugg, Michael D; Knight, Robert T; Richardson-Klavehn, Alan

    2015-05-20

    Previously we reported electrophysiological evidence for a role for the anterior thalamic nucleus (ATN) in human memory formation (Sweeney-Reed et al., 2014). Theta-gamma cross-frequency coupling (CFC) predicted successful memory formation, with the involvement of gamma oscillations suggesting memory-relevant local processing in the ATN. The importance of the theta frequency range in memory processing is well-established, and phase alignment of oscillations is considered to be necessary for synaptic plasticity. We hypothesized that theta phase alignment in the ATN would be necessary for memory encoding. Further analysis of the electrophysiological data reveal that phase alignment in the theta rhythm was greater during successful compared with unsuccessful encoding, and that this alignment was correlated with the CFC. These findings support an active processing role for the ATN during memory formation.

  3. Inverted-U-shaped correlation between dopamine receptor availability in striatum and sensation seeking

    DEFF Research Database (Denmark)

    Gjedde, Albert; Kumakura, Yoshitaka; Cumming, Paul

    2010-01-01

    Sensation seeking is a core personality trait that declines with age in both men and women, as do also both density and availability of the dopamine D(2/3) receptors in striatum and cortical regions. In contrast, novelty seeking at a given age relates inversely to dopamine receptor availability....... The simplest explanation of these findings is an inverted-U-shaped correlation between ratings of sensation seeking on the Zuckerman scale and dopamine D(2/3) receptor availability. To test the claim of an inverted-U-shaped relation between ratings of the sensation-seeking personality and measures of dopamine....... The inverted-U shape is consistent with a negative correlation between sensation seeking and the reactivity ("gain") of dopaminergic neurotransmission to dopamine. The correlation reflects Zuckerman scores that are linearly linked to dopamine receptor densities in the striatum but nonlinearly linked...

  4. Low level of dopaminergic D2 receptor binding in obsessive-compulsive disorder

    NARCIS (Netherlands)

    Denys, Damiaan; van der Wee, Nic; Janssen, Joost; de Geus, Femke; Westenberg, Herman G. M.

    2004-01-01

    BACKGROUND: Despite growing evidence for involvement of the dopaminergic system in obsessive-compulsive disorder (OCD), the functional anatomy of the dopaminergic system in the basal ganglia has been investigated sparsely. METHODS: Dopamine D(2) receptor binding was assessed in 10 medication-free

  5. Thalamic abscess caused by a rare pathogen: streptococcus ...

    African Journals Online (AJOL)

    Streptococcus constellatus is a microorganism that lives commensally in the oropharyngeal region, urogenital region, and intestinal tract. However, it can cause infection in patients with certain predisposing factors. Rarely, this microorganism can cause a brain abscess. Thalamic localization of brain abscesses is much rarer ...

  6. Communication skills and thalamic lesion: Strategies of rehabilitation.

    Science.gov (United States)

    Amaddii, Luisa; Centorrino, Santi; Cambi, Jacopo; Passali, Desiderio

    2014-01-01

    To describe the speech rehabilitation history of patients with thalamic lesions. Thalamic lesions can affect speech and language according to diverse thalamic nuclei involved. Because of the strategic functional position of the thalamus within the cognitive networks, its lesion can also interfere with other cognitive processes, such as attention, memory and executive functions. Alterations of these cognitive domains contribute significantly to language deficits, leading to communicative inefficacy. This fact must be considered in the rehabilitation efforts. Whereas evaluation of cognitive functions and communicative efficiency is different from that of aphasic disorder, treatment should also be different. The treatment must be focused on specific cognitive deficits with belief in the regaining of communicative ability, as well as it occurs in therapy of pragmatic disorder in traumatic brain injury: attention process training, mnemotechnics and prospective memory training. According to our experience: (a) there is a close correlation between cognitive processes and communication skills; (b) alterations of attention, memory and executive functions cause a loss of efficiency in the language use; and (c) appropriate cognitive treatment improves pragmatic competence and therefore the linguistic disorder. For planning a speech-therapy it is important to consider the relationship between cognitive functions and communication. The cognitive/behavioral treatment confirms its therapeutic efficiency for thalamic lesions. Copyright © 2014 Polish Otorhinolaryngology - Head and Neck Surgery Society. Published by Elsevier Urban & Partner Sp. z.o.o. All rights reserved.

  7. Neuroanatomical considerations of isolated hearing loss in thalamic hemorrhage

    Directory of Open Access Journals (Sweden)

    Nitin Agarwal, M.D.

    2016-12-01

    Conclusion: Presumably, this neurological deficit was caused by a hypertensive hemorrhage in the posterior right thalamus. The following case and discussion will review the potential neuroanatomical pathways that we suggest could make isolated hearing loss be part of a “thalamic syndrome.”

  8. Effects of Intralaminar Thalamic Stimulation on Language Functions

    Science.gov (United States)

    Bhatnagar, Subhash C.; Mandybur, George T.

    2005-01-01

    Fifteen neurosurgical subjects, who were undergoing thalamic chronic electrode implants as a treatment for dyskinesia and chronic pain, were evaluated on a series of neurolinguistic functions to determine if the stimulation of the centromedianum nucleus of the thalamus affected language and cognitive processing. Analysis of the data revealed that…

  9. Hypertensive thalamic hemorrhage. Clinical symptoms and outcomes in 40 cases

    Energy Technology Data Exchange (ETDEWEB)

    Munaka, Masahiro; Nishikawa, Michio; Hirai, Osamu; Kaneko, Takaaki; Watanabe, Syu; Fukuma, Jun; Handa, Hajime

    1988-12-01

    In the past six years, we have had experience with 40 patients with hypertensive thalamic hemorrhages, as verified by CT scan at our hospital within 24 hours. These patients were classified into the following three groups according to the location of the bleeding point and the size of the hematoma: (1) anteromedial (4 cases), (2) posterolateral (16 cases), and (3) massive (20 cases). The (1) and (2) hematomas were small (less than 3 cm in diameter), while those in (3) were large (more than 3 cm in diameter). Twenty cases (50% of all the thalamic hematomas) were small hematomas. The characteristic clinical symptoms of the anteromedial type were a mild disturbance of consciousness and thalamic dementia, while those of the posterolateral type were motor and sensory disturbance, and thalamic aphasia, respectively. Twenty cases (50%) were large hematomas. The clinical symptoms of these cases were mainly consciousness disturbance; 7 of them expired. Based on this experience, it may be considered that the patients whose hematoma size was larger than 3 cm had a poor prognosis and that the patients with the posterolateral type had a poor functional diagnosis.

  10. PKCβ Inhibitors Attenuate Amphetamine-Stimulated Dopamine Efflux.

    Science.gov (United States)

    Zestos, Alexander G; Mikelman, Sarah R; Kennedy, Robert T; Gnegy, Margaret E

    2016-06-15

    Amphetamine abuse afflicts over 13 million people, and there is currently no universally accepted treatment for amphetamine addiction. Amphetamine serves as a substrate for the dopamine transporter and reverses the transporter to cause an increase in extracellular dopamine. Activation of the beta subunit of protein kinase C (PKCβ) enhances extracellular dopamine in the presence of amphetamine by facilitating the reverse transport of dopamine and internalizing the D2 autoreceptor. We previously demonstrated that PKCβ inhibitors block amphetamine-stimulated dopamine efflux in synaptosomes from rat striatum in vitro. In this study, we utilized in vivo microdialysis in live, behaving rats to assess the effect of the PKCβ inhibitors, enzastaurin and ruboxistaurin, on amphetamine-stimulated locomotion and increases in monoamines and their metabolites. A 30 min perfusion of the nucleus accumbens core with 1 μM enzastaurin or 1 μM ruboxistaurin reduced efflux of dopamine and its metabolite 3-methoxytyramine induced by amphetamine by approximately 50%. The inhibitors also significantly reduced amphetamine-stimulated extracellular levels of norepinephrine. The stimulation of locomotor behavior by amphetamine, measured simultaneously with the analytes, was comparably reduced by the PKCβ inhibitors. Using a stable isotope label retrodialysis procedure, we determined that ruboxistaurin had no effect on basal levels of dopamine, norepinephrine, glutamate, or GABA. In addition, normal uptake function through the dopamine transporter was unaltered by the PKCβ inhibitors, as measured in rat synaptosomes. Our results support the utility of using PKCβ inhibitors to reduce the effects of amphetamine.

  11. 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…

  12. 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

  13. 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...

  14. Corticotropin-releasing hormone and dopamine release in healthy individuals.

    Science.gov (United States)

    Payer, Doris; Williams, Belinda; Mansouri, Esmaeil; Stevanovski, Suzanna; Nakajima, Shinichiro; Le Foll, Bernard; Kish, Stephen; Houle, Sylvain; Mizrahi, Romina; George, Susan R; George, Tony P; Boileau, Isabelle

    2017-02-01

    Corticotropin-releasing hormone (CRH) is a key component of the neuroendocrine response to stress. In animal models, CRH has been shown to modulate dopamine release, and this interaction is believed to contribute to stress-induced relapse in neuropsychiatric disorders. Here we investigated whether CRH administration induces dopamine release in humans, using positron emission tomography (PET). Eight healthy volunteers (5 female, 22-48 years old) completed two PET scans with the dopamine D2/3 receptor radioligand [11C]-(+)-PHNO: once after saline injection, and once after injection of corticorelin (synthetic human CRH). We also assessed subjective reports and measured plasma levels of endocrine hormones (adrenocorticotropic hormone and cortisol). Relative to saline, corticorelin administration decreased binding of the D2/3 PET probe [11C]-(+)-PHNO, suggesting dopamine release. Endocrine stress markers were also elevated, in line with activation of the hypothalamic-pituitary-adrenal axis, but we detected no changes in subjective ratings. Preliminary results from this proof-of-concept study suggests that CRH challenge in combination with [11C]-(+)-PHNO PET may serve as an assay of dopamine release, presenting a potential platform for evaluating CRH/dopamine interactions in neuropsychiatric disorders and CRH antagonists as potential treatment avenues. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Sleep onset uncovers thalamic abnormalities in patients with idiopathic generalised epilepsy

    Directory of Open Access Journals (Sweden)

    Andrew P. Bagshaw

    2017-01-01

    Full Text Available The thalamus is crucial for sleep regulation and the pathophysiology of idiopathic generalised epilepsy (IGE, and may serve as the underlying basis for the links between the two. We investigated this using EEG-fMRI and a specific emphasis on the role and functional connectivity (FC of the thalamus. We defined three types of thalamic FC: thalamocortical, inter-hemispheric thalamic, and intra-hemispheric thalamic. Patients and controls differed in all three measures, and during wakefulness and sleep, indicating disorder-dependent and state-dependent modification of thalamic FC. Inter-hemispheric thalamic FC differed between patients and controls in somatosensory regions during wakefulness, and occipital regions during sleep. Intra-hemispheric thalamic FC was significantly higher in patients than controls following sleep onset, and disorder-dependent alterations to FC were seen in several thalamic regions always involving somatomotor and occipital regions. As interactions between thalamic sub-regions are indirect and mediated by the inhibitory thalamic reticular nucleus (TRN, the results suggest abnormal TRN function in patients with IGE, with a regional distribution which could suggest a link with the thalamocortical networks involved in the generation of alpha rhythms. Intra-thalamic FC could be a more widely applicable marker beyond patients with IGE.

  16. D2 Inertial Measurement Unit

    Science.gov (United States)

    Dewar, Patrick; Gido, Joseph; Carroll, Joseph

    1993-06-01

    The D2 Hypervelocity Projectile is a Strategic Defense Initiative sponsored technology program that is designed to provide low endo-atmospheric, kinetic kill defense against strategic reentry vehicles. The D2 program is funded through the U.S. Army Space and Strategic Defense Command (SSDC) in Huntsville, AL and contracted through the U.S. Army Armament Research and Development Engineering Center (ARDEC) at Picatinny Arsenal, NJ. In GFY 93 the program began an integration and flight demonstration phase with the Hypervelocity Fire Control System (HVFC) and the Solid Propellant Electro Thermal Chemical (SPETC) launcher. The Inertial Measurement Unit (IMU) necessary to perform the autopilot and guidance data gathering must be extremely small, lightweight and shock hardened. The IMU is comprised of three Honeywell GG1308 miniature Ring Laser Gyros (RLG), and three Endevco 7290-M19 miniature silicon accelerometers. The IMU has self-contained high voltage Power Supply (HVPS) processor and memory electronics providing a complete stand alone, three axis measurement package. This Inertial Cluster Assembly (ICA) is then packaged into a cylindrical housing, approximately 1.9 inches in diameter and 1.3 inches in length.

  17. Transient overexpression of striatal D2 receptors impairs operant motivation and interval timing.

    Science.gov (United States)

    Drew, Michael R; Simpson, Eleanor H; Kellendonk, Christoph; Herzberg, William G; Lipatova, Olga; Fairhurst, Stephen; Kandel, Eric R; Malapani, Chara; Balsam, Peter D

    2007-07-18

    The striatum receives prominent dopaminergic innervation that is integral to appetitive learning, performance, and motivation. Signaling through the dopamine D2 receptor is critical for all of these processes. For instance, drugs with high affinity for the D2 receptor potently alter timing of operant responses and modulate motivation. Recently, in an attempt to model a genetic abnormality encountered in schizophrenia, mice were generated that reversibly overexpress D2 receptors specifically in the striatum (Kellendonk et al., 2006). These mice have impairments in working memory and behavioral flexibility, components of the cognitive symptoms of schizophrenia, that are not rescued when D2 overexpression is reversed in the adult. Here we report that overexpression of striatal D2 receptors also profoundly affects operant performance, a potential index of negative symptoms. Mice overexpressing D2 exhibited impairments in the ability to time food rewards in an operant interval timing task and reduced motivation to lever press for food reward in both the operant timing task and a progressive ratio schedule of reinforcement. The motivational deficit, but not the timing deficit, was rescued in adult mice by reversing D2 overexpression with doxycycline. These results suggest that early D2 overexpression alters the organization of interval timing circuits and confirms that striatal D2 signaling in the adult regulates motivational process. Moreover, overexpression of D2 under pathological conditions such as schizophrenia and Parkinson's disease could give rise to motivational and timing deficits.

  18. Altered thalamic connectivity during spontaneous attacks of migraine without aura

    DEFF Research Database (Denmark)

    Amin, Faisal Mohammad; Hougaard, Anders; Magon, Stefano

    2017-01-01

    Background Functional connectivity of brain networks may be altered in migraine without aura patients. Functional magnetic resonance imaging (fMRI) studies have demonstrated changed activity in the thalamus, pons and cerebellum in migraineurs. Here, we investigated the thalamic, pontine and cereb......Background Functional connectivity of brain networks may be altered in migraine without aura patients. Functional magnetic resonance imaging (fMRI) studies have demonstrated changed activity in the thalamus, pons and cerebellum in migraineurs. Here, we investigated the thalamic, pontine...... and cerebellar network connectivity during spontaneous migraine attacks. Methods Seventeen patients with episodic migraine without aura underwent resting-state fMRI scan during and outside of a spontaneous migraine attack. Primary endpoint was a difference in functional connectivity between the attack...

  19. Pseudocortical and dissociate discriminative sensory dysfunction in a thalamic stroke.

    Science.gov (United States)

    Notturno, Francesca; Sepe, Rosamaria; Caulo, Massimo; Uncini, Antonino; Committeri, Giorgia

    2013-01-01

    In thalamic lesions a pseudocortical syndrome has been occasionally described but the effect of the lesion on the cortical network of tactile recognition has never been studied. We report a patient who developed tactile agnosia in the left hand after right thalamic stroke, configuring a pseudocortical sensory syndrome. The discriminative sensory dysfunction was dissociate because only tactile agnosia and mild pseudoathetosis were present. A functional magnetic resonance imaging (fMRI) study showed that tactile recognition with the unaffected hand recruited a bilateral fronto-parietal network. During recognition with the left hand the activation was restricted and lateralized to the ipsilateral hemisphere. In this patient with pseudocortical discriminative sensory dysfunction the lack of activation of the whole cortical network, implicated in tactile recognition, demonstrates that pseudocortical is functionally equivalent to cortical tactile agnosia. Copyright © 2012 Elsevier Ltd. All rights reserved.

  20. Effects of dopamine-related gene-gene interactions on working memory component processes.

    Science.gov (United States)

    Stelzel, Christine; Basten, Ulrike; Montag, Christian; Reuter, Martin; Fiebach, Christian J

    2009-03-01

    Dopamine modulates complex cognitive functions like working memory and cognitive control. It is widely accepted that an optimal level of prefrontal dopamine supports working memory performance. In the present study we used a molecular genetic approach to test whether the optimal activity of the dopamine system for different component processes of working memory is additionally related to the availability of dopamine D2 receptors. We sought evidence for this assumption by investigating the interaction effect (epistasis) of variations in two dopaminergic candidate genes: the catechol-O-methyltransferase (COMT) Val(158)Met polymorphism, which has been shown to influence prefrontal dopamine concentration, and the DRD2/ANKK1-Taq-Ia polymorphism, which has been related to the density of D2 receptors. Our results show that COMT effects on working memory performance are modulated by the DRD2/ANKK1-TAQ-Ia polymorphism and the specific working memory component process under investigation. Val-participants--supposedly characterized by increased prefrontal dopamine concentrations--outperformed Val+ participants in the manipulation of working memory contents, but only when D2 receptor density could be considered to be high. No such effect was present for passive maintenance of working memory contents or for maintenance in the face of distracting information. This beneficial effect of a balance between prefrontal dopamine availability and D2 receptor density reveals the importance of considering epistasis effects and different working memory subprocesses in genetic association studies.

  1. Differential diagnosis of bilateral thalamic lesions; Differenzialdiagnose bilateral Thalamuslaesionen

    Energy Technology Data Exchange (ETDEWEB)

    Linn, J.; Brueckmann, H. [Universitaetsklinikum Muenchen (Germany). Abt. fuer Neuroradiologie; Hoffmann, L.A. [Universitaetsklinikum Muenchen (Germany). Inst. fuer Klinische Neuroimmunologie; Danek, A. [Universitaetsklinikum Muenchen (Germany). Klinik und Poliklinik fuer Neurologie

    2007-03-15

    A multitude of different diseases can result in bilateral thalamic lesions. These include vascular pathologies requiring prompt therapeutic intervention, such as basilar thrombosis or thrombosis of the internal cerebral veins, as well as tumors, infectious or demyelinating diseases, and toxic-metabolic lesions. Therefore, detailed knowledge of the typical radiological findings for the various diseases is essential for determining the correct diagnosis. This review provides a synopsis of the radiological findings for the most important bithalamic lesions and an overview of the literature.

  2. Thalamic volume as a biomarker for disorders of consciousness

    Science.gov (United States)

    Rubeaux, Mathieu; Mahalingam, Jamuna Jayashri; Gomez, Francisco; Nelson, Marvin; Vanhaudenhuyse, Audrey; Bruno, Marie-Aurélie; Gosseries, Olivia; Laureys, Steven; Soddu, Andrea; Lepore, Natasha

    2015-01-01

    Disorders of consciousness (DOC) may be characterized by the degree at which consciousness is impaired, and include for example vegetative state (VS) and minimally conscious state (MCS) patients. Using a reliable marker as a measure of the level of consciousness in such patients is of utmost necessity and importance for their appropriate diagnosis and prognosis. Identification of VS and MCS states based on their behaviors sometimes leads to incorrect inferences due to the influence of a range of factors like motor impairment, fluctuating arousal levels and rapidly habituating responses to name a few.1 The extent of damage in the thalamus, a structure known for its role in arousal regulation, may provide an imaging biomarker to better differentiate between VS and MCS. In this study, we manually segmented the thalamus from T1-weighted brain MRI images in a large cohort of 19 VS and 23 MCS subjects that were examined using the French version of the Coma Recovery Scale Revised (CRS-R).2 This scale is the most trustworthy behavioural diagnosis tool3 for patients with DOC available. The aim was to determine whether a relationship between thalamus volume and consciousness level exists. Results show that total thalamic volume tends to decrease over time after a severe brain injury. Moreover, for subjects in chronic state, the thalamic volume seems to differ with respect to the degree of consciousness that was diagnosed. Finally, for these same chronic patients, the total thalamic volume is varying linearly as a function of the CRS-R score obtained, indicating that thalamic volume may be used as a biomarker to measure the level of consciousness.

  3. Injury of the mammillothalamic tract in patients with thalamic hemorrhage

    Directory of Open Access Journals (Sweden)

    Hyeok Gyu eKwon

    2014-04-01

    Full Text Available Objective:Injury of the mammillothalamic tract(MTT has been suggested as one of the plausible pathogenic mechanisms of memory impairment in patients with thalamic hemorrhage; however, it has not been clearly demonstrated so far. We attempted to investigate whether injury of the MTT documented by diffusion tensor tractography(DTT following thalamic hemorrhage correlates with cognitive impairment. Methods:We recruited 22 patients with a thalamic hemorrhage and 20 control subjects. MTTs were reconstructed using the probabilistic tractography method. Patients were classified into two subgroups: Reconstructed group-patients whose MTT was reconstructed in the affected hemisphere and Non-reconstructed group-patients whose MTT was not reconstructed.Results:MTT was reconstructed in five(22.7%,Reconstructed group patients in the affected hemisphere and was not reconstructed in the remaining 17 patients(77.3%,Non-reconstructed group. In addition, the MTT was not reconstructed even in the unaffected hemisphere in four patients(23.5% in Non-reconstructed group. Fractional anisotropy and mean diffusivity values of the affected hemisphere in Reconstructed group also did not show significant differences from those in the unaffected hemisphere of Reconstructed group and the control group(p>0.05. However, the tract volume of the affected hemisphere in Reconstructed group was significantly lower than that of the unaffected hemisphere in Reconstructed group and the control group(pConclusion:A large portion of patients with thalamic hemorrhage appeared to suffer severe injury of the ipsi-lesional MTT(77.3% and 18.2% of these patients appeared to suffer severe injury even in the contra-lesional MTT. In addition, the remaining 22.7% of patients who had preserved integrity of the ipsi-lesional MTT appeared to suffer partial injury of the ipsi-lesional MTT.

  4. 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.

  5. Decrease of thalamic gray matter following limb amputation.

    Science.gov (United States)

    Draganski, B; Moser, T; Lummel, N; Gänssbauer, S; Bogdahn, U; Haas, F; May, A

    2006-07-01

    Modern neuroscience has elucidated general mechanisms underlying the functional plasticity of the adult mammalian brain after limb deafferentation. However, little is known about possible structural alterations following amputation and chronic loss of afferent input in humans. Using voxel-based morphometry (VBM), based on high-resolution magnetic resonance images, we investigated the brain structure of 28 volunteers with unilateral limb amputation and compared them to healthy controls. Subjects with limb amputation exhibited a decrease in gray matter of the posterolateral thalamus contralateral to the side of the amputation. The thalamic gray matter differences were positively correlated with the time span after the amputation but not with the frequency or magnitude of coexisting phantom pain. Phantom limb pain was unrelated to thalamic structural variations, but was positively correlated to a decrease in brain areas related to the processing of pain. No gray matter increase was detected. The unilateral thalamic differences may reflect a structural correlate of the loss of afferent input as a secondary change following deafferentation.

  6. Immunomodulatory Effects Mediated by Dopamine

    Science.gov (United States)

    Alvarez-Herrera, Samantha; Pérez-Sánchez, Gilberto; Becerril-Villanueva, Enrique; Cruz-Fuentes, Carlos; Flores-Gutierrez, Enrique Octavio; Quintero-Fabián, Saray

    2016-01-01

    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. PMID:27795960

  7. 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.

  8. SPECT imaging of D{sub 2} dopamine receptors and endogenous dopamine release in mice

    Energy Technology Data Exchange (ETDEWEB)

    Jongen, Cynthia [University Medical Center Utrecht, Image Sciences Institute, Q0S.459, P.O. Box 85500, Utrecht (Netherlands); Bruin, Kora de; Booij, Jan [University of Amsterdam, Academic Medical Center, Department of Nuclear Medicine, Amsterdam (Netherlands); Beekman, Freek [University Medical Center Utrecht, Image Sciences Institute, Q0S.459, P.O. Box 85500, Utrecht (Netherlands); University Medical Center Utrecht, Department of Neuroscience and Pharmacology, Utrecht (Netherlands); Technical University Delft, Department R3, Section Radiation, Detection and Matter, Delft (Netherlands)

    2008-09-15

    The dopamine D{sub 2} receptor (D2R) is important in the mediation of addiction. [{sup 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, [{sup 123}I]IBZM has not been used in mice SPECT studies. This study evaluates the use of [{sup 123}I]IBZM for measuring D2R availability in mice. Pharmacokinetics of [{sup 123}I]IBZM in mice were studied with pinhole SPECT imaging after intravenous (i.v.) injection of [{sup 123}I]IBZM (20, 40, and 70 MBq). In addition, the ability to measure the release of endogenous dopamine after amphetamine administration with [{sup 123}I]IBZM SPECT was investigated. Thirdly, i.v. administration, the standard route of administration, and intraperitoneal (i.p.) administration of [{sup 123}I]IBZM were compared. Specific binding of [{sup 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 [{sup 123}I]IBZM decreased significantly (-27.2%; n=6; p=0.046). Intravenous administration of [{sup 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 [{sup 123}I]IBZM might result in acute ethanol intoxication because ethanol is used as a preparative aid for the routine production of [{sup 123}I]IBZM. Imaging of D2R availability and endogenous dopamine release in mice is feasible using [{sup 123}I]IBZM single pinhole SPECT. Using commercially produced [{sup 123}I]IBZM, a dose of 40 MBq injected i.v. can be recommended. (orig.)

  9. 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...

  10. Kappa-opioid receptor signaling in the striatum as a potential modulator of dopamine transmission in cocaine dependence

    Directory of Open Access Journals (Sweden)

    Pierre eTrifilieff

    2013-06-01

    Full Text Available Cocaine addiction is accompanied by a decrease in striatal dopamine signaling, measured as a decrease in dopamine D2 receptor binding as well as blunted dopamine release in the striatum. These alterations in dopamine transmission have clinical relevance, and have been shown to correlate with cocaine-seeking behavior and response to treatment for cocaine dependence. However, the mechanisms contributing to the hypodopaminergic state in cocaine addiction remain unknown. Here we review the Positron Emission Tomography (PET imaging studies showing alterations in D2 receptor binding potential and dopamine transmission in cocaine abusers and their significance in cocaine-seeking behavior. Based on animal and human studies, we propose that the kappa receptor/dynorphin system, because of its impact on dopamine transmission and upregulation following cocaine exposure, could contribute to the hypodopaminergic state reported in cocaine addiction, and could thus be a relevant target for treatment development.

  11. Thalamic Spindles Promote Memory Formation during Sleep through Triple Phase-Locking of Cortical, Thalamic, and Hippocampal Rhythms.

    Science.gov (United States)

    Latchoumane, Charles-Francois V; Ngo, Hong-Viet V; Born, Jan; Shin, Hee-Sup

    2017-07-19

    While the interaction of the cardinal rhythms of non-rapid-eye-movement (NREM) sleep-the thalamo-cortical spindles, hippocampal ripples, and the cortical slow oscillations-is thought to be critical for memory consolidation during sleep, the role spindles play in this interaction is elusive. Combining optogenetics with a closed-loop stimulation approach in mice, we show here that only thalamic spindles induced in-phase with cortical slow oscillation up-states, but not out-of-phase-induced spindles, improve consolidation of hippocampus-dependent memory during sleep. Whereas optogenetically stimulated spindles were as efficient as spontaneous spindles in nesting hippocampal ripples within their excitable troughs, stimulation in-phase with the slow oscillation up-state increased spindle co-occurrence and frontal spindle-ripple co-occurrence, eventually resulting in increased triple coupling of slow oscillation-spindle-ripple events. In-phase optogenetic suppression of thalamic spindles impaired hippocampus-dependent memory. Our results suggest a causal role for thalamic sleep spindles in hippocampus-dependent memory consolidation, conveyed through triple coupling of slow oscillations, spindles, and ripples. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Predictions of in vivo prolactin levels from in vitro k I values of d 2 receptor antagonists using an agonist-antagonist interaction model

    NARCIS (Netherlands)

    Petersson, K.J.; Vermeulen, A.M.J.; Friberg, L.E.

    2013-01-01

    Prolactin elevation is a side effect of all currently available D2 receptor antagonists used in the treatment of schizophrenia. Prolactin elevation is the result of a direct antagonistic D2 effect blocking the tonic inhibition of prolactin release by dopamine. The aims of this work were to assess

  13. Loss of Plasticity in the D2-Accumbens Pallidal Pathway Promotes Cocaine Seeking.

    Science.gov (United States)

    Heinsbroek, Jasper A; Neuhofer, Daniela N; Griffin, William C; Siegel, Griffin S; Bobadilla, Ana-Clara; Kupchik, Yonatan M; Kalivas, Peter W

    2017-01-25

    Distinct populations of D1- and D2-dopamine receptor-expressing medium spiny neurons (D1-/D2-MSNs) comprise the nucleus accumbens, and activity in D1-MSNs promotes, whereas activity in D2-MSNs inhibits, motivated behaviors. We used chemogenetics to extend D1-/D2-MSN cell specific regulation to cue-reinstated cocaine seeking in a mouse model of self-administration and relapse, and found that either increasing activity in D1-MSNs or decreasing activity in D2-MSNs augmented cue-induced reinstatement. Both D1- and D2-MSNs provide substantial GABAergic innervation to the ventral pallidum, and chemogenetic inhibition of ventral pallidal neurons blocked the augmented reinstatement elicited by chemogenetic regulation of either D1- or D2-MSNs. Because D1- and D2-MSNs innervate overlapping populations of ventral pallidal neurons, we next used optogenetics to examine whether changes in synaptic plasticity in D1- versus D2-MSN GABAergic synapses in the ventral pallidum could explain the differential regulation of VP activity. In mice trained to self-administer cocaine, GABAergic LTD was abolished in D2-, but not in D1-MSN synapses. A μ opioid receptor antagonist restored GABA currents in D2-, but not D1-MSN synapses of cocaine-trained mice, indicating that increased enkephalin tone on presynaptic μ opioid receptors was responsible for occluding the LTD. These results identify a behavioral function for D1-MSN innervation of the ventral pallidum, and suggest that losing LTDGABA in D2-MSN, but not D1-MSN input to ventral pallidum may promote cue-induced reinstatement of cocaine-seeking. More than 90% of ventral striatum is composed of two cell types, those expressing dopamine D1 or D2 receptors, which exert opposing roles on motivated behavior. Both cell types send GABAergic projections to the ventral pallidum and were found to differentially promote cue-induced reinstatement of cocaine seeking via the ventral pallidum. Furthermore, after cocaine self-administration, synaptic

  14. Cannabis use and striatal D2 receptor density in untreated first-episode psychosis: an in vivo SPECT study.

    Science.gov (United States)

    Safont, Gemma; Corripio, Iluminada; Escartí, María J; Portella, Maria J; Pérez, Víctor; Ferrer, Marc; Camacho, Valle; Sauras, Rosa B; Alonso, Anna; Grasa, Eva M; Arranz, Belén; San, Luis; Dueñas, Rosa; Carrió, Ignasi; Álvarez, Enric

    2011-07-01

    The biological basis of the association between cannabis-induced dopamine dysregulation and psychosis remains poorly understood. This (123)I-IBZM SPECT study assessed striatal dopamine D2 receptor (D2R) binding in 37 untreated first-episode psychosis (FEP) subjects, and 18 healthy controls. The aim was to examine if there were differences between FEP subjects with (n=14) and without (n=23) cannabis use in uptake ratios in the D2R. Striatal/Frontal cortex (S/F) uptake ratios were obtained. Healthy controls showed the lowest D2R binding ratios. No differences were found in S/F ratios between users and non-users, suggesting similar dopaminergic mechanisms underlying psychotic symptoms in both groups. Copyright © 2011 Elsevier B.V. All rights reserved.

  15. Testosterone induces molecular changes in dopamine signaling pathway molecules in the adolescent male rat nigrostriatal pathway.

    Science.gov (United States)

    Purves-Tyson, Tertia D; Owens, Samantha J; Double, Kay L; Desai, Reena; Handelsman, David J; Weickert, Cynthia Shannon

    2014-01-01

    Adolescent males have an increased risk of developing schizophrenia, implicating testosterone in the precipitation of dopamine-related psychopathology. Evidence from adult rodent brain indicates that testosterone can modulate nigrostriatal dopamine. However, studies are required to understand the role testosterone plays in maturation of dopamine pathways during adolescence and to elucidate the molecular mechanism(s) by which testosterone exerts its effects. We hypothesized that molecular indices of dopamine neurotransmission [synthesis (tyrosine hydroxylase), breakdown (catechol-O-methyl transferase; monoamine oxygenase), transport [vesicular monoamine transporter (VMAT), dopamine transporter (DAT)] and receptors (DRD1-D5)] would be changed by testosterone or its metabolites, dihydrotestosterone and 17β-estradiol, in the nigrostriatal pathway of adolescent male rats. We found that testosterone and dihydrotestosterone increased DAT and VMAT mRNAs in the substantia nigra and that testosterone increased DAT protein at the region of the cell bodies, but not in target regions in the striatum. Dopamine receptor D2 mRNA was increased and D3 mRNA was decreased in substantia nigra and/or striatum by androgens. These data suggest that increased testosterone at adolescence may change dopamine responsivity of the nigrostriatal pathway by modulating, at a molecular level, the capacity of neurons to transport and respond to dopamine. Further, dopamine turnover was increased in the dorsal striatum following gonadectomy and this was prevented by testosterone replacement. Gene expression changes in the dopaminergic cell body region may serve to modulate both dendritic dopamine feedback inhibition and reuptake in the dopaminergic somatodendritic field as well as dopamine release and re-uptake dynamics at the presynaptic terminals in the striatum. These testosterone-induced changes of molecular indices of dopamine neurotransmission in males are primarily androgen receptor

  16. Testosterone induces molecular changes in dopamine signaling pathway molecules in the adolescent male rat nigrostriatal pathway.

    Directory of Open Access Journals (Sweden)

    Tertia D Purves-Tyson

    Full Text Available Adolescent males have an increased risk of developing schizophrenia, implicating testosterone in the precipitation of dopamine-related psychopathology. Evidence from adult rodent brain indicates that testosterone can modulate nigrostriatal dopamine. However, studies are required to understand the role testosterone plays in maturation of dopamine pathways during adolescence and to elucidate the molecular mechanism(s by which testosterone exerts its effects. We hypothesized that molecular indices of dopamine neurotransmission [synthesis (tyrosine hydroxylase, breakdown (catechol-O-methyl transferase; monoamine oxygenase, transport [vesicular monoamine transporter (VMAT, dopamine transporter (DAT] and receptors (DRD1-D5] would be changed by testosterone or its metabolites, dihydrotestosterone and 17β-estradiol, in the nigrostriatal pathway of adolescent male rats. We found that testosterone and dihydrotestosterone increased DAT and VMAT mRNAs in the substantia nigra and that testosterone increased DAT protein at the region of the cell bodies, but not in target regions in the striatum. Dopamine receptor D2 mRNA was increased and D3 mRNA was decreased in substantia nigra and/or striatum by androgens. These data suggest that increased testosterone at adolescence may change dopamine responsivity of the nigrostriatal pathway by modulating, at a molecular level, the capacity of neurons to transport and respond to dopamine. Further, dopamine turnover was increased in the dorsal striatum following gonadectomy and this was prevented by testosterone replacement. Gene expression changes in the dopaminergic cell body region may serve to modulate both dendritic dopamine feedback inhibition and reuptake in the dopaminergic somatodendritic field as well as dopamine release and re-uptake dynamics at the presynaptic terminals in the striatum. These testosterone-induced changes of molecular indices of dopamine neurotransmission in males are primarily androgen

  17. Dopamine Autoreceptor Regulation of a Hypothalamic Dopaminergic Network

    Directory of Open Access Journals (Sweden)

    Stefanos Stagkourakis

    2016-04-01

    Full Text Available How autoreceptors contribute to maintaining a stable output of rhythmically active neuronal circuits is poorly understood. Here, we examine this issue in a dopamine population, spontaneously oscillating hypothalamic rat (TIDA neurons, that underlie neuroendocrine control of reproduction and neuroleptic side effects. Activation of dopamine receptors of the type 2 family (D2Rs at the cell-body level slowed TIDA oscillations through two mechanisms. First, they prolonged the depolarizing phase through a combination of presynaptic increases in inhibition and postsynaptic hyperpolarization. Second, they extended the discharge phase through presynaptic attenuation of calcium currents and decreased synaptic inhibition. Dopamine reuptake blockade similarly reconfigured the oscillation, indicating that ambient somatodendritic transmitter concentration determines electrical behavior. In the absence of D2R feedback, however, discharge was abolished by depolarization block. These results indicate the existence of an ultra-short feedback loop whereby neuroendocrine dopamine neurons tune network behavior to echoes of their own activity, reflected in ambient somatodendritic dopamine, and also suggest a mechanism for antipsychotic side effects.

  18. Pharmacological characterisation and autoradiographic localisation of dopamine receptor subtypes in the cardiovascular system and in the kidney.

    Science.gov (United States)

    Amenta, F; Ferrante, F; Ricci, A

    1995-06-01

    Combined radioligand binding and light microscope autoradiography techniques were used for investigating the pharmacological profile and the microanatomical localisation of dopamine receptor subtypes in the cardiovascular system and in the kidney. In superior mesenteric and renal arteries the predominant dopamine D1-like receptor belongs to the D5 (or D1b) subtype. This site is located within smooth muscle of the tunica media. The same receptor subtype predominates in the kidney, where it has a vascular and tubular localisation. The dopamine D2-like receptor subtype expressed by systemic arteries belongs to the D2 receptor subtype. It has a prejunctional and endothelial localisation. In the kidney the predominating dopamine D2-like receptor belongs to the dopamine D3 subtype. Atria but not ventricles express dopamine D2-like receptors belonging to the D4 receptor subtype. The above results suggest that in spite of the emerging complexity of the dopamine receptor profile demonstrated by molecular biology techniques, radioligand binding and autoradiographic techniques, if performed with appropriate radioligands and/or in the presence of compounds active on specific receptor subtypes, may represent a useful tool for better understanding the biological significance of peripheral dopamine receptors.

  19. Modeling of prolactin response following dopamine Dreceptor antagonists in rats : can it be translated to clinical dosing?

    NARCIS (Netherlands)

    Taneja, Amit; Vermeulen, An; Huntjens, Dymphy R H; Danhof, Meindert; De Lange, Elizabeth C M; Proost, Johannes H

    2017-01-01

    Prolactin release is a side effect of antipsychotic therapy with dopamine antagonists, observed in rats as well as humans. We examined whether two semimechanistic models could describe prolactin response in rats and subsequently be translated to predict pituitary dopamine D2receptor occupancy and

  20. 7 CFR 15d.2 - Discrimination prohibited.

    Science.gov (United States)

    2010-01-01

    ..., religion, sex, age, national origin, marital status, familial status, sexual orientation, or disability, or... 7 Agriculture 1 2010-01-01 2010-01-01 false Discrimination prohibited. 15d.2 Section 15d.2... THE UNITED STATES DEPARTMENT OF AGRICULTURE § 15d.2 Discrimination prohibited. (a) No agency, officer...

  1. Transient Relay Function of Midline Thalamic Nuclei during Long-Term Memory Consolidation in Humans

    Science.gov (United States)

    Thielen, Jan-Willem; Takashima, Atsuko; Rutters, Femke; Tendolkar, Indira; Fernández, Guillén

    2015-01-01

    To test the hypothesis that thalamic midline nuclei play a transient role in memory consolidation, we reanalyzed a prospective functional MRI study, contrasting recent and progressively more remote memory retrieval. We revealed a transient thalamic connectivity increase with the hippocampus, the medial prefrontal cortex (mPFC), and a…

  2. Thalamic activity and biochemical changes in individuals with neuropathic pain following spinal cord injury

    Science.gov (United States)

    Gustin, S.M.; Wrigley, P.J.; Youssef, A.M.; McIndoe, L.; Wilcox, S.L.; Rae, C.D.; Edden, R; Siddall, P.J.; Henderson, L.A.

    2015-01-01

    There is increasing evidence relating thalamic changes to the generation and/or maintenance of neuropathic pain. We have recently reported that neuropathic orofacial pain is associated with altered thalamic anatomy, biochemistry and activity, which may result in disturbed thalamocortical oscillatory circuits. Despite this evidence, it is possible that these thalamic changes are not responsible for the presence of pain per se, but result as a consequence of the injury. To clarify this subject, we compared brain activity and biochemistry in 12 people with below-level neuropathic pain after complete thoracic spinal cord injury to 11 people with similar injuries and no neuropathic pain and 21 age and gender matched healthy controls. Quantitative arterial spinal labelling was used to measure thalamic activity and magnetic resonance spectroscopy was used to determine changes in neuronal variability quantifying N-acetylaspartate and alterations in inhibitory function quantifying gamma amino butyric acid. This study revealed that the presence of neuropathic pain is associated with significant changes in thalamic biochemistry and neuronal activity. More specifically, the presence of neuropathic pain following spinal cord injury is associated with significant reductions in thalamic N-acetylaspartate, gamma amino butyric acid content and blood flow in the region of the thalamic reticular nucleus. Spinal cord injury on its own did not account for these changes. These findings support the hypothesis that neuropathic pain is associated with altered thalamic structure and function, which may disturb central processing and play a key role in the experience of neuropathic pain. PMID:24530612

  3. Clinical analysis of electrolyte imbalance in thalamic hemorrhage patients within 24 h after admission.

    Science.gov (United States)

    Guo, Zhenwei; Wang, Tianzhu; Zhang, John H; Qin, Xinyue

    2011-01-01

    We have observed that patients with thalamic hemorrhage are more likely to have electrolyte disturbances than those with non-thalamic hemorrhage. Here, we are attempting to provide some comprehensive information on electrolyte disturbances in patients with thalamic hemorrhage. Retrospectively, 67 patients with thalamic hemorrhage (TH group) and 256 with non-thalamic hemorrhage (N-TH group) were found from computer tomography images. Electrolytes of these patients were tested within 24 h after hospitalization. Chi-square test was used to compare the incidence of electrolyte imbalance. Serum K+ levels were found to be abnormal in 37.31% of the patients in the TH group and 24.21% in the N-TH group, and the difference was significant (pelectrolyte disturbances (42.50%) was higher than that of patients with normal electrolyte levels (14.81%, pelectrolyte imbalance is higher in patients with thalamic hemorrhage than in those with non-thalamic hemorrhage. The reason may be partly related to the location of the hemorrhage. Electrolyte disturbance may contribute to the higher mortality of patients with thalamic hemorrhage.

  4. Multicentre European study of thalamic stimulation in parkinsonian and essential tremor

    NARCIS (Netherlands)

    Limousin, P.; Speelman, J. D.; Gielen, F.; Janssens, M.

    1999-01-01

    Thalamic stimulation has been proposed to treat disabling tremor. The aims of this multicentre study were to evaluate the efficacy and the morbidity of thalamic stimulation in a large number of patients with parkinsonian or essential tremor. One hundred and eleven patients were included in the study

  5. Correlation between ethanol behavioral sensitization and midbrain dopamine neuron reactivity to ethanol.

    Science.gov (United States)

    Didone, Vincent; Masson, Sébastien; Quoilin, Caroline; Seutin, Vincent; Quertemont, Etienne

    2016-03-01

    Repeated ethanol injections lead to a sensitization of its stimulant effects in mice. Some recent results argue against a role for ventral tegmental area (VTA) dopamine neurons in ethanol behavioral sensitization. The aim of the present study was to test whether in vivo ethanol locomotor sensitization correlates with changes in either basal- or ethanol-evoked firing rates of dopamine neurons in vitro. Female Swiss mice were daily injected with 2.5 g/kg ethanol (or saline in the control group) for 7 days and their locomotor activity was recorded. At the end of the sensitization procedure, extracellular recordings were made from dopaminergic neurons in midbrain slices from these mice. Significantly higher spontaneous basal firing rates of dopamine neurons were recorded in ethanol-sensitized mice relative to control mice, but without correlations with the behavioral effects. The superfusion of sulpiride, a dopamine D2 antagonist, induced a stronger increase of dopamine neuron firing rates in ethanol-sensitized mice. This shows that the D2 feedback in dopamine neurons is preserved after chronic ethanol administration and argues against a reduced D2 feedback as an explanation for the increased dopamine neuron basal firing rates in ethanol-sensitized mice. Finally, ethanol superfusion (10-100 mM) significantly increased the firing rates of dopamine neurons and this effect was of higher magnitude in ethanol-sensitized mice. Furthermore, there were significant correlations between such a sensitization of dopamine neuron activity and ethanol behavioral sensitization. These results support the hypothesis that changes in brain dopamine neuron activity contribute to the behavioral sensitization of the stimulant effects of ethanol. © 2014 Society for the Study of Addiction.

  6. Dopamine Modulates the Functional Organization of the Orbitofrontal Cortex.

    Science.gov (United States)

    Kahnt, Thorsten; Tobler, Philippe N

    2017-02-08

    Neuromodulators such as dopamine can alter the intrinsic firing properties of neurons and may thereby change the configuration of larger functional circuits. The primate orbitofrontal cortex (OFC) receives dopaminergic input from midbrain nuclei, but the role of dopamine in the OFC is still unclear. Here we tested the idea that dopaminergic activity changes the pattern of connectivity between the OFC and the rest of the brain and thereby reconfigures functional networks in the OFC. To this end, we combined double-blind, placebo-controlled pharmacology [D2 receptor (D2R) antagonist amisulpride] in humans with resting-state functional magnetic resonance imaging and clustering methods. In the placebo group, we replicated previously observed parcellations of the OFC into two and six subregions based on connectivity patterns with the rest of the brain. Most importantly, while the twofold clustering did not differ significantly between groups, blocking D2Rs significantly changed the composition of the sixfold parcellation, suggesting a dopamine-dependent reconfiguration of functional OFC subregions. Moreover, multivariate decoding analyses revealed that amisulpride changed the whole-brain connectivity patterns of individual OFC subregions. In particular, D2R blockade shifted the balance of OFC connectivity from associative areas in the temporal and parietal lobe toward functional connectivity with the frontal cortex. In summary, our results suggest that dopamine alters the composition of functional OFC circuits, possibly indicating a broader role for neuromodulators in the dynamic reconfiguration of functional brain networks.SIGNIFICANCE STATEMENT A key role of any neuromodulator may be the reconfiguration of functional brain circuits. Here we test this idea with regard to dopamine and the organization of functional networks in the orbitofrontal cortex (OFC). We show that blockade of dopamine D2 receptors has profound effects on the functional connectivity patterns of

  7. Thalamic mechanisms in language: a reconsideration based on recent findings and concepts.

    Science.gov (United States)

    Crosson, Bruce

    2013-07-01

    Recent literature on thalamic aphasia and thalamic activity during neuroimaging is selectively reviewed followed by a consideration of recent anatomic and physiological findings regarding thalamic structure and functions. It is concluded that four related corticothalamic and/or thalamocortical mechanisms impact language processing: (1) selective engagement of task-relevant cortical areas in a heightened state of responsiveness in part through the nucleus reticularis (NR), (2) passing information from one cortical area to another through corticothalamo-cortical mechanisms, (3) sharpening the focus on task-relevant information through corticothalamo-cortical feedback mechanisms, and (4) selection of one language unit over another in the expression of a concept, accomplished in concert with basal ganglia loops. The relationship and interaction of these mechanisms is discussed and integrated with thalamic aphasia and neuroimaging data into a theory of thalamic functions in language. Published by Elsevier Inc.

  8. D1 dopamine receptor signaling is modulated by the R7 RGS protein EAT-16 and the R7 binding protein RSBP-1 in Caenoerhabditis elegans motor neurons.

    Directory of Open Access Journals (Sweden)

    Khursheed A Wani

    Full Text Available Dopamine signaling modulates voluntary movement and reward-driven behaviors by acting through G protein-coupled receptors in striatal neurons, and defects in dopamine signaling underlie Parkinson's disease and drug addiction. Despite the importance of understanding how dopamine modifies the activity of striatal neurons to control basal ganglia output, the molecular mechanisms that control dopamine signaling remain largely unclear. Dopamine signaling also controls locomotion behavior in Caenorhabditis elegans. To better understand how dopamine acts in the brain we performed a large-scale dsRNA interference screen in C. elegans for genes required for endogenous dopamine signaling and identified six genes (eat-16, rsbp-1, unc-43, flp-1, grk-1, and cat-1 required for dopamine-mediated behavior. We then used a combination of mutant analysis and cell-specific transgenic rescue experiments to investigate the functional interaction between the proteins encoded by two of these genes, eat-16 and rsbp-1, within single cell types and to examine their role in the modulation of dopamine receptor signaling. We found that EAT-16 and RSBP-1 act together to modulate dopamine signaling and that while they are coexpressed with both D1-like and D2-like dopamine receptors, they do not modulate D2 receptor signaling. Instead, EAT-16 and RSBP-1 act together to selectively inhibit D1 dopamine receptor signaling in cholinergic motor neurons to modulate locomotion behavior.

  9. 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

  10. Dopamine Receptor-Specific Contributions to the Computation of Value.

    Science.gov (United States)

    Burke, Christopher J; Soutschek, Alexander; Weber, Susanna; Beharelle, Anjali R; Fehr, Ernst; Haker, Helene; Tobler, Philippe N

    2017-12-18

    Dopamine is thought to play a crucial role in value-based decision making. However, the specific contributions of different dopamine receptor subtypes to the computation of subjective value remain unknown. Here we demonstrate how the balance between D1 and D2 dopamine receptor subtypes shapes subjective value computation during risky decision-making. We administered the D2 receptor antagonist amisulpride or placebo before participants made choices between risky options. Compared to placebo, D2 receptor blockade resulted in more frequent choice of higher risk and higher expected value options. Using a novel model fitting procedure, we concurrently estimated the three parameters that define individual risk attitude according to an influential theoretical account of risky decision making. This analysis revealed that the observed reduction in risk aversion under amisulpride was driven by increased sensitivity to reward magnitude and decreased distortion of outcome probability, resulting in more linear value coding. Our data suggest that different components that govern individual risk attitude are under dopaminergic control, such that D2 receptor blockade facilitates risk taking and expected value processing.Neuropsychopharmacology accepted article preview online, 18 December 2017. doi:10.1038/npp.2017.302.

  11. Dopamine hypothesis of mania

    OpenAIRE

    Cookson, John

    2013-01-01

    s­of­the­Speakers­/­Konuşmacı­leriThe discovery of dopamine and its pathwaysDopamine (DA) was first synthesized in 1910 from 3,4-dihydroxy phenyl alanine (DOPA) by Barger and Ewens at Wellcome Laboratories in London. It is a cathecholamine and in the 1940s Blaschko in Cambridge proposed that DA was a precursor in synthesis of the cat-echolamine neurotransmitters noradrenaline (norepinephrine) and adrenaline (epinephrine). In 1957 it was shown to be present in the brain with other catecholamin...

  12. Thalamic, brainstem, and cerebellar glucose metabolism in the hemiplegic monkey

    Energy Technology Data Exchange (ETDEWEB)

    Shimoyama, I.; Dauth, G.W.; Gilman, S.; Frey, K.A.; Penney, J.B. Jr.

    1988-12-01

    Unilateral ablation of cerebral cortical areas 4 and 6 of Brodmann in the macaque monkey results in a contralateral hemiplegia that resolves partially with time. During the phase of dense hemiplegia, local cerebral metabolic rate for glucose (1CMRG1c) is decreased significantly in most of the thalamic nuclei ipsilateral to the ablation, and there are slight contralateral decreases. The lCMRGlc is reduced bilaterally in most of the brainstem nuclei and bilaterally in the deep cerebellar nuclei, but only in the contralateral cerebellar cortex. During the phase of partial motor recovery, lCMRGlc is incompletely restored in many of the thalamic nuclei ipsilateral to the ablation and completely restored in the contralateral nuclei. In the brainstem and deep cerebellar nuclei, poor to moderate recovery occurs bilaterally. Moderate recovery occurs in the contralateral cerebellar cortex. The findings demonstrate that a unilateral cerebral cortical lesion strongly affects lCMRGlc in the thalamus ipsilaterally and in the cerebellar cortex contralaterally, but in the brainstem bilaterally. Partial recovery of lCMRGlc accompanies the progressive motor recovery. The structures affected include those with direct, and also those with indirect, connections to the areas ablated.

  13. Isolated thalamic agraphia with impaired grapheme formation and micrographia.

    Science.gov (United States)

    Sakurai, Yasuhisa; Yoshida, Yukinaga; Sato, Koki; Sugimoto, Izumi; Mannen, Toru

    2011-08-01

    Two patients with isolated thalamic agraphia are described. Both showed kanji (Japanese morphograms) agraphia due to impaired character recall, grapheme deformity and micrographia (progressive reduction in character size during writing) after a lesion that involved the ventral lateral and ventroposterolateral nuclei. Single photon emission computed tomography with a (99m)Tc-ethylcysteinate dimer revealed hypoperfusion in the left precentral gyrus (Brodmann Area 6) and anterior supramarginal gyrus in both. Six months later, the extent of blood flow reduction decreased in the supramarginal gyrus in both patients and the precentral gyrus in patient 1. By this time, the writing impairment improved to nearly the normal range. Our study suggests that kanji agraphia (corresponding to lexical agraphia in Western countries) with poor grapheme formation and micrographia arises from a lesion in the ventral lateral and ventroposterolateral nuclei in the left thalamus. The accompaniment of poor grapheme formation and micrographia may reflect disruption of the cortico-subcortical motor circuit involving the putamen, thalamus, premotor cortex and sensorimotor cortex. It is also suggested that multiple cortical sites can be a target for secondary dysfunction that yields agraphia in a thalamic lesion, and that the recovery of reduced cortical blood flow does not always proceed in parallel with that of agraphia.

  14. Thalamocortical projections of the anteroventral thalamic nucleus in the rabbit.

    Science.gov (United States)

    Shibata, Hideshi; Yoshiko, Honda

    2015-04-01

    The anterior thalamic nuclei are one of the regions that play critical roles in behavioral learning and memory functions. A part of the anterior thalamic nuclei, the anteroventral nucleus (AV) is well developed and differentiated into the parvocellular (AVp) and magnocellular (AVm) division in the rabbit. The AV is crucial for learning discriminative avoidance conditioning. Although communication between the AV and cortex is considered important in learning, little is known about the neural connections of the AV in the rabbit. Thus, this study used anterograde tracer biotinylated dextran amine and the retrograde tracer cholera toxin B subunit to examine the organization of the thalamocortical projections of the AV. Our data show that each division of the AV provides a unique set of projections to restricted regions and layers of the retrosplenial cortex and presubiculum. In addition, the AVp projects to layers I and IV of retrosplenial areas 29 and 30 and to layers I and VI of the presubiculum. The dorsolateral AVm projects to layers I and IV of area 29 and to layers I, III, and V of the presubiculum. However, the ventromedial AVm only projects to layer I of area 29. These projections are generally organized such that the rostral-to-caudal axis of the AV corresponds to the caudal-to-rostral axis of the retrosplenial cortex and to the temporal-to-septal axis of the presubiculum. These findings suggest distinct functional roles played by each division of the AV in the learning and memory functions. © 2014 Wiley Periodicals, Inc.

  15. State-dependent architecture of thalamic reticular subnetworks.

    Science.gov (United States)

    Halassa, Michael M; Chen, Zhe; Wimmer, Ralf D; Brunetti, Philip M; Zhao, Shengli; Zikopoulos, Basilis; Wang, Fan; Brown, Emery N; Wilson, Matthew A

    2014-08-14

    Behavioral state is known to influence interactions between thalamus and cortex, which are important for sensation, action, and cognition. The thalamic reticular nucleus (TRN) is hypothesized to regulate thalamo-cortical interactions, but the underlying functional architecture of this process and its state dependence are unknown. By combining the first TRN ensemble recording with psychophysics and connectivity-based optogenetic tagging, we found reticular circuits to be composed of distinct subnetworks. While activity of limbic-projecting TRN neurons positively correlates with arousal, sensory-projecting neurons participate in spindles and show elevated synchrony by slow waves during sleep. Sensory-projecting neurons are suppressed by attentional states, demonstrating that their gating of thalamo-cortical interactions is matched to behavioral state. Bidirectional manipulation of attentional performance was achieved through subnetwork-specific optogenetic stimulation. Together, our findings provide evidence for differential inhibition of thalamic nuclei across brain states, where the TRN separately controls external sensory and internal limbic processing facilitating normal cognitive function. PAPERFLICK: Copyright © 2014 Elsevier Inc. All rights reserved.

  16. 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

  17. Naltrexone modulates dopamine release following chronic, but not acute amphetamine administration: a translational study.

    Science.gov (United States)

    Jayaram-Lindström, N; Guterstam, J; Häggkvist, J; Ericson, M; Malmlöf, T; Schilström, B; Halldin, C; Cervenka, S; Saijo, T; Nordström, A-L; Franck, J

    2017-04-25

    The opioid antagonist naltrexone has been shown to attenuate the subjective effects of amphetamine. However, the mechanisms behind this modulatory effect are currently unknown. We hypothesized that naltrexone would diminish the striatal dopamine release induced by amphetamine, which is considered an important mechanism behind many of its stimulant properties. We used positron emission tomography and the dopamine D2-receptor radioligand [11C]raclopride in healthy subjects to study the dopaminergic effects of an amphetamine injection after pretreatment with naltrexone or placebo. In a rat model, we used microdialysis to study the modulatory effects of naltrexone on dopamine levels after acute and chronic amphetamine exposure. In healthy humans, naltrexone attenuated the subjective effects of amphetamine, confirming our previous results. Amphetamine produced a significant reduction in striatal radioligand binding, indicating increased levels of endogenous dopamine. However, there was no statistically significant effect of naltrexone on dopamine release. The same pattern was observed in rats, where an acute injection of amphetamine caused a significant rise in striatal dopamine levels, with no effect of naltrexone pretreatment. However, in a chronic model, naltrexone significantly attenuated the dopamine release caused by reinstatement of amphetamine. Collectively, these data suggest that the opioid system becomes engaged during the more chronic phase of drug use, evidenced by the modulatory effect of naltrexone on dopamine release following chronic amphetamine administration. The importance of opioid-dopamine interactions in the reinforcing and addictive effects of amphetamine is highlighted by the present findings and may help to facilitate medication development in the field of stimulant dependence.

  18. 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.

  19. Addiction: beyond dopamine reward circuitry.

    Science.gov (United States)

    Volkow, Nora D; Wang, Gene-Jack; Fowler, Joanna S; Tomasi, Dardo; Telang, Frank

    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.

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

    Science.gov (United States)

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

    2014-01-01

    of powerful dopamine D2 agonists have failed due to chronic down regulation of D2 receptors newer targets based on 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 reward deficiency.

  1. Effects of GTP and sodium on rat striatal dopamine receptors labeled with lisuride.

    Science.gov (United States)

    Uzumaki, H; Govoni, S; Memo, M; Carruba, M O; Trabucchi, M; Spano, P F

    1982-09-23

    [3H]Lisuride binding to rat striatal membranes appeared to be stereospecifically displaced by the dopamine antagonist butaclamol. Sodium increased the number of [3H]lisuride binding sites (Bmax) without changing the dissociation constant (Kd). GTP did not affect [3H]lisuride binding characteristics, either with or without sodium. These results suggest that dopamine receptor sites labeled by lisuride are at least in part sodium-dependent, possibly the D2-receptors not involved in adenylate cyclase stimulation.

  2. Anatomical Variations in the Posterior Circle of Willis and Vascular Pathologies in Isolated Unilateral Thalamic Infarction.

    Science.gov (United States)

    Goerlitz, Johannes; Wenz, Holger; Al-Zghloul, Mansour; Kerl, Hans U; Groden, Christoph; Förster, Alex

    2015-01-01

    To characterize relations between configurations of the posterior part of the Circle of Willis (CoW) and the occurrence of unilateral thalamic infarction. From a magnetic resonance imaging report database, we identified and analyzed 111 patients with acute isolated unilateral thalamic infarction on diffusion-weighted imaging (DWI). Vascular pathologies were noted on magnetic resonance angiography (MRA) and the diameter of the posterior communicating artery (PComA) and the P1 and P2 segments of the posterior cerebral artery determined. Most infarctions were observed in the territory of the inferolateral arteries (70.2%), followed by the paramedian (16.3%), tuberothalamic (8.7%), and posterior choroidal arteries (4.8%). Relevant vascular pathologies included stenosis of the basilar artery (4.5%), P1 segment stenosis (4.5%)/occlusion (.9%), and P2 segment stenosis (14.4%)/occlusion (4.5%). Paramedian thalamic infarction was associated with ipsilateral P1 segment hypoplasia/absence (P < .001); tuberothalamic infarction with ipsilateral PComA hypoplasia/absence (P = .08). Furthermore, the diameter of the relevant CoW segment was smaller in patients with ipsilateral thalamic infarction. Assessment of CoW configuration on MRA may be helpful to understand the appearance of unilateral thalamic stroke independent from stroke etiology. A smaller diameter of the relevant CoW segment might be a risk factor for ipsilateral thalamic stroke in the corresponding thalamic vascular territory. Copyright © 2015 by the American Society of Neuroimaging.

  3. Unified thalamic model generates multiple distinct oscillations with state-dependent entrainment by stimulation.

    Science.gov (United States)

    Li, Guoshi; Henriquez, Craig S; Fröhlich, Flavio

    2017-10-01

    The thalamus plays a critical role in the genesis of thalamocortical oscillations, yet the underlying mechanisms remain elusive. To understand whether the isolated thalamus can generate multiple distinct oscillations, we developed a biophysical thalamic model to test the hypothesis that generation of and transition between distinct thalamic oscillations can be explained as a function of neuromodulation by acetylcholine (ACh) and norepinephrine (NE) and afferent synaptic excitation. Indeed, the model exhibited four distinct thalamic rhythms (delta, sleep spindle, alpha and gamma oscillations) that span the physiological states corresponding to different arousal levels from deep sleep to focused attention. Our simulation results indicate that generation of these distinct thalamic oscillations is a result of both intrinsic oscillatory cellular properties and specific network connectivity patterns. We then systematically varied the ACh/NE and input levels to generate a complete map of the different oscillatory states and their transitions. Lastly, we applied periodic stimulation to the thalamic network and found that entrainment of thalamic oscillations is highly state-dependent. Our results support the hypothesis that ACh/NE modulation and afferent excitation define thalamic oscillatory states and their response to brain stimulation. Our model proposes a broader and more central role of the thalamus in the genesis of multiple distinct thalamo-cortical rhythms than previously assumed.

  4. In vivo measurement of somatodendritic release of dopamine in the ventral tegmental area.

    Science.gov (United States)

    Kita, Justin M; Kile, Brian M; Parker, Lauren E; Wightman, R Mark

    2009-11-01

    The ventral tegmental area (VTA), the locus of mesolimbic dopamine cell bodies, contains dopamine. Experiments in brain slices have demonstrated that VTA dopamine can be released by local electrical stimulation. Measurements with both push-pull cannula and microdialysis in intact animals have also obtained evidence for releasable dopamine. Here we demonstrate that dopamine release in the VTA can be evoked by remote stimulations of the medial forebrain bundle (MFB) in the anesthetized rat. In initial experiments, the MFB was electrically stimulated while a carbon-fiber electrode was lowered to the VTA, with recording by fast-scan cyclic voltammetry. While release was not observed with the carbon fiber 4-6 mm below dura, a voltammetric response was observed at 6-8 mm below dura, but the voltammogram was poorly defined. At lower depths, in the VTA, dopamine release was evoked. Immunohistochemistry experiments with antibodies for tyrosine hydroxylase (TH) confirmed that dopamine processes were primarily found below 8 mm. Similarly, tissue content determined by liquid chromatography revealed serotonin but not dopamine dorsal to 8 mm with both dopamine and serotonin at lower depths. Evaluation of the VTA signal by pharmacological means showed that it increased with inhibitors of dopamine uptake, but release was not altered by D2 agents. Dopamine release in the VTA was frequency dependent and could be exhausted by stimulations longer than 5 s. Thus, VTA dopamine release can be evoked in vivo by remote stimulations and it resembles release in terminal regions, possessing a similar uptake mechanism and a finite releasable storage pool.

  5. 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

  6. Genetic contributions to avoidance-based decisions: striatal D2 receptor polymorphisms.

    Science.gov (United States)

    Frank, M J; Hutchison, K

    2009-11-24

    Individuals differ in their tendencies to seek positive decision outcomes or to avoid negative ones. At the neurobiological level, our model suggests that phasic changes in dopamine support learning to reinforce good decisions via striatal D1 receptors, and to avoid maladaptive choices via striatal D2 receptors. Accordingly, in a previous study individual differences in positive and negative learning were strongly modulated by two genetic polymorphisms factors related to striatal D1 and D2 function, respectively. Nevertheless, whereas the role for dopamine in positive learning is relatively well accepted, that in learning to avoid negative outcomes is more controversial. Here we further explore D2-receptor-related genetic contributions to probabilistic avoidance in humans, in light of recent data showing that particular DRD2 polymorphisms are associated with functional modulation of receptor expression [Zhang Y, Bertolino A, Fazio L, Blasi G, Rampino A, Romano R, Lee M-LT, Xiao T, Papp A, Wang D, Sadée W (2007) Polymorphisms in human dopamine d2 receptor gene affect gene expression, splicing, and neuronal activity during working memory. Proc Natl Acad Sci U S A 104(51):20552-20557]. We find that a promoter polymorphism rs12364283 associated with transcription and D2 receptor density was strongly and selectively predictive of avoidance-based decisions. Two further polymorphisms (rs2283265 and rs1076560) associated with relatively reduced presynaptic relative to postsynaptic D2 receptor expression were predictive of relative impairments in negative compared to positive decisions. These previously undocumented effects of DRD2 polymorphisms were largely independent of those we reported previously for the C957T polymorphism (rs6277) associated with striatal D2 density. In contrast, effects of the commonly studied Taq1A polymorphism on reinforcement-based decisions were due to indirect association with C957T. Taken together these findings suggest multiple D2-dependent

  7. Effects of donepezil on behavioural manifestations of thalamic infarction: a single case observation

    Directory of Open Access Journals (Sweden)

    Rodrigo eRiveros

    2011-03-01

    Full Text Available Objective: To examine the effect of donepezil for the treatment of cognitive and behavioural disorders associated with thalamic lesions in a 45 years old male who suffered an infarct in the left thalamus. Background: Recent studies suggest that donepezil may improve executive functions impairments due to subcortical ischemic lesionsMethod: The crossover effects of donepezil were analyzed in a single case of thalamic infarction with cognitive and behavioural alterations. Results: Significant behavioural modifications related to improved performances in executive functions were observed with the treatment. Conclusions: The results suggest that donepezil may have significant effect on executive functions that can alter behavioural outcomes after thalamic infarctions

  8. Frontal D2/3 Receptor Availability in Schizophrenia Patients Before and After Their First Antipsychotic Treatment: Relation to Cognitive Functions and Psychopathology.

    Science.gov (United States)

    Nørbak-Emig, Henrik; Ebdrup, Bjørn H; Fagerlund, Birgitte; Svarer, Claus; Rasmussen, Hans; Friberg, Lars; Allerup, Peter N; Rostrup, Egill; Pinborg, Lars H; Glenthøj, Birte Y

    2016-05-01

    We have previously reported associations between frontal D2/3 receptor binding potential positive symptoms and cognitive deficits in antipsychotic-naïve schizophrenia patients. Here, we examined the effect of dopamine D2/3 receptor blockade on cognition. Additionally, we explored the relation between frontal D2/3 receptor availability and treatment effect on positive symptoms. Twenty-five antipsychotic-naïve first-episode schizophrenia patients were examined with the Positive and Negative Syndrome Scale, tested with the cognitive test battery Cambridge Neuropsychological Test Automated Battery, scanned with single-photon emission computerized tomography using the dopamine D2/3 receptor ligand [(123)I]epidepride, and scanned with MRI. After 3 months of treatment with either risperidone (n=13) or zuclopenthixol (n=9), 22 patients were reexamined. Blockade of extrastriatal dopamine D2/3 receptors was correlated with decreased attentional focus (r = -0.615, P=.003) and planning time (r = -0.436, P=.048). Moreover, baseline frontal dopamine D2/3 binding potential and positive symptom reduction correlated positively (D2/3 receptor binding potential left frontal cortex rho = 0.56, P=.003; D2/3 receptor binding potential right frontal cortex rho = 0.48, P=.016). Our data support the hypothesis of a negative influence of D2/3 receptor blockade on specific cognitive functions in schizophrenia. This is highly clinically relevant given the well-established association between severity of cognitive disturbances and a poor functional outcome in schizophrenia. Additionally, the findings support associations between frontal D2/3 receptor binding potential at baseline and the effect of antipsychotic treatment on positive symptoms. © The Author 2016. Published by Oxford University Press on behalf of CINP.

  9. Dopamine receptors antagonistically regulate behavioral choice between conflicting alternatives in C. elegans.

    Directory of Open Access Journals (Sweden)

    Daoyong Wang

    Full Text Available Caenorhabditis elegans is a useful model to study the neuronal or molecular basis for behavioral choice, a specific form of decision-making. Although it has been implied that both D1-like and D2-like dopamine receptors may contribute to the control of decision-making in mammals, the genetic interactions between D1-like and D2-like dopamine receptors in regulating decision-making are still largely unclear. In the present study, we investigated the molecular control of behavioral choice between conflicting alternatives (diacetyl and Cu2+ by D1-like and D2-like dopamine receptors and their possible genetic interactions with C. elegans as the assay system. In the behavioral choice assay system, mutation of dop-1 gene encoding D1-like dopamine receptor resulted in the enhanced tendency to cross the Cu2+ barrier compared with wild-type. In contrast, mutations of dop-2 or dop-3 gene encoding D2-like dopamine receptor caused the weak tendency to cross the Cu2+ barrier compared with wild-type. During the control of behavioral choice, DOP-3 antagonistically regulated the function of DOP-1. The behavioral choice phenotype of dop-2; dop-1dop-3 triple mutant further confirmed the possible antagonistic function of D2-like dopamine receptor on D1-like dopamine receptor in regulating behavioral choice. The genetic assays further demonstrate that DOP-3 might act through Gαo signaling pathway encoded by GOA-1 and EGL-10, and DOP-1 might act through Gαq signaling pathway encoded by EGL-30 and EAT-16 to regulate the behavioral choice. DOP-1 might function in cholinergic neurons to regulate the behavioral choice, whereas DOP-3 might function in GABAergic neurons, RIC, and SIA neurons to regulate the behavioral choice. In this study, we provide the genetic evidence to indicate the antagonistic relationship between D1-like dopamine receptor and D2-like dopamine receptor in regulating the decision-making of animals. Our data will be useful for understanding the

  10. Blunted Dopamine Transmission in Addiction: Potential Mechanisms and Implications for Behavior.

    Science.gov (United States)

    Trifilieff, Pierre; Ducrocq, Fabien; van der Veldt, Suzanne; Martinez, Diana

    2017-01-01

    Positron emission tomography (PET) imaging consistently shows blunted striatal dopamine release and decreased dopamine D2 receptor availability in addiction. Here, we review the preclinical and clinical studies indicating that this neurobiological phenotype is likely to be both a consequence of chronic drug consumption and a vulnerability factor in the development of addiction. We propose that, behaviorally, blunted striatal dopamine transmission could reflect the increased impulsivity and altered cost/benefit computations that are associated with addiction. The factors that influence blunted striatal dopamine transmission in addiction are unknown. Herein, we give an overview of various factors, genetic, environmental, and social, that are known to affect dopamine transmission and that have been associated with the vulnerability to develop addiction. Altogether, these data suggest that blunted dopamine transmission and decreased D2 receptor availability are biomarkers both for the development of addiction and resistance to treatment. These findings support the view that blunted dopamine reflects impulsive behavior and deficits in motivation, which lead to the escalation of drug use. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Severe personality changes after unilateral left paramedian thalamic infarct.

    Science.gov (United States)

    Fukutake, Toshio; Akada, Koichi; Ito, Shoichi; Okuda, Tomoko; Ueki, Yoshihiro

    2002-01-01

    Personality changes are not uncommon after paramedian thalamic infarction, but usually bilateral or relatively large lesions, often complicated by other neurological or neuropsychological deficits, are present. 'Pure' cases of unilateral lesions are extremely rare. We report that a right-handed, 48-year-old man, who was hypertensive and diabetic but had no prior psychiatric history, developed severe personality changes and a frontal-like syndrome after recovery from acute-onset impairment of consciousness at the age of 43. Other neurological and neuropsychological disturbances, especially verbal and visual amnesia, were unremarkable. MRI showed a very small infarct in the left paramedian area of the thalamus, mainly involving the dorsomedial nucleus. Copyright 2002 S. Karger AG, Basel

  12. Thalamic Ventral Intermediate Nucleus Deep Brain Stimulation for Orthostatic Tremor

    Directory of Open Access Journals (Sweden)

    Alexander C. Lehn

    2017-07-01

    Full Text Available Background: Orthostatic tremor (OT was first described in 1977. It is characterized by rapid tremor of 13–18 Hz and can be recorded in the lower limbs and trunk muscles. OT remains difficult to treat, although some success has been reported with deep brain stimulation (DBS.Case Report: We report a 68-year-old male with OT who did not improve significantly after bilateral thalamic stimulation.Discussion: Although some patients were described who improved after DBS surgery, more information is needed about the effect of these treatment modalities on OT, ideally in the form of randomized trial data. 

  13. 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)

  14. Increased dopamine tone during meditation-induced change of consciousness

    DEFF Research Database (Denmark)

    Kjaer, Troels W; Bertelsen, Camilla; Piccini, Paola

    2002-01-01

    This is the first in vivo demonstration of an association between endogenous neurotransmitter release and conscious experience. Using 11C-raclopride PET we demonstrated increased endogenous dopamine release in the ventral striatum during Yoga Nidra meditation. Yoga Nidra is characterized by a dep......This is the first in vivo demonstration of an association between endogenous neurotransmitter release and conscious experience. Using 11C-raclopride PET we demonstrated increased endogenous dopamine release in the ventral striatum during Yoga Nidra meditation. Yoga Nidra is characterized...... the frontal cortex to striatal neurons, which in turn project back to the frontal cortex via the pallidum and ventral thalamus. The present study was designed to investigate whether endogenous dopamine release increases during loss of executive control in meditation. Participants underwent two 11C......-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...

  15. Dissociable effects of dopamine on neuronal firing rate and synchrony in the dorsal striatum

    Directory of Open Access Journals (Sweden)

    John M Burkhardt

    2009-10-01

    Full Text Available Previous studies showed that dopamine depletion leads to both changes in firing rate and in neuronal synchrony in the basal ganglia. Since dopamine D1 and D2 receptors are preferentially expressed in striatonigral and striatopallidal medium spiny neurons, respectively, we investigated the relative contribution of lack of D1 and/or D2-type receptor activation to the changes in striatal firing rate and synchrony observed after dopamine depletion. Similar to what was observed after dopamine depletion, co-administration of D1 and D2 antagonists to mice chronically implanted with multielectrode arrays in the striatum caused significant changes in firing rate, power of the local field potential (LFP oscillations, and synchrony measured by the entrainment of neurons to striatal local field potentials. However, although blockade of either D1 or D2 type receptors produced similarly severe akinesia, the effects on neural activity differed. Blockade of D2 receptors affected the firing rate of medium spiny neurons and the power of the LFP oscillations substantially, but it did not affect synchrony to the same extent. In contrast, D1 blockade affected synchrony dramatically, but had less substantial effects on firing rate and LFP power. Furthermore, there was no consistent relation between neurons changing firing rate and changing LFP entrainment after dopamine blockade. Our results suggest that the changes in rate and entrainment to the LFP observed in medium spiny neurons after dopamine depletion are somewhat dissociable, and that lack of D1- or D2-type receptor activation can exert independent yet interactive pathological effects during the progression of Parkinson’s disease.

  16. Synthesis, pharmacological evaluation and molecular modeling studies of triazole containing dopamine D3 receptor ligands.

    Science.gov (United States)

    Peng, Xin; Wang, Qi; Mishra, Yogesh; Xu, Jinbin; Reichert, David E; Malik, Maninder; Taylor, Michelle; Luedtke, Robert R; Mach, Robert H

    2015-02-01

    A series of 2-methoxyphenyl piperazine analogues containing a triazole ring were synthesized and their in vitro binding affinities at human dopamine D2 and D3 receptors were evaluated. Compounds 5b, 5c, 5d, and 4g, demonstrate high affinity for dopamine D3 receptors and moderate selectivity for the dopamine D3 versus D2 receptor subtypes. To further examine their potential as therapeutic agents, their intrinsic efficacy at both D2 and D3 receptors was determined using a forskolin-dependent adenylyl cyclase inhibition assay. Affinity at dopamine D4 and serotonin 5-HT1A receptors was also determined. In addition, information from previous molecular modeling studies of the binding of a panel of 163 structurally-related benzamide analogues at dopamine D2 and D3 receptors was applied to this series of compounds. The results of the modeling studies were consistent with our previous experimental data. More importantly, the modeling study results explained why the replacement of the amide linkage with the hetero-aromatic ring leads to a reduction in the affinity of these compounds at D3 receptors. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. Radiochemical synthesis of [123I]2-iodo-lisuride for dopamine D2-receptor studies.

    Science.gov (United States)

    Bier, D; Dutschka, K; Knust, E J

    1996-04-01

    By variation of reaction parameters iodination of 3-(9,10-didehydro-6-methyl-8 alpha-ergolinyl)-1,1-diethylurea (lisuride) was performed with the radiohalogen [123I]iodine (t1/2 = 13.3 h). For comparative experiments and stability studies the beta(-)-emitting radioisotope [131I]iodine (t1/2 = 8.04 d) was also used. Reaction occurs at the activated position 2 of the molecule, thus leading to [123I]3-(9,10-didehydro-2-iodo-6-methyl-8 alpha-ergolinyl)-1,1-diethylurea ([123I]2-iodo-lisuride, [123I]ILIS) or the analogous [131I]iodine-labeled compound, respectively. Electrophilic radioactive species were generated by oxidation of no-carrier-added (n.c.a.) iodide with IODOGEN (1,3,4,6-tetrachloro-3 alpha,6 alpha-diphenylglycouril) fixed on the glass wall of the reaction vial prior to iodination. After optimization of reaction parameters [123I]2-iodo-lisuride after HPLC-purification was obtained with radiochemical yields of 70 +/- 5% and a radiochemical purity of > 97%. In n.c.a. syntheses, specific activities of the product were in the range between 4440 and 7400 GBq/mumol (120-200 Ci/mumol) corresponding to 50-85% of the theoretical value.

  18. Radiochemical synthesis of [{sup 123}I]2-iodo-lisuride for dopamine D2-receptor studies

    Energy Technology Data Exchange (ETDEWEB)

    Bier, Dirk; Dutschka, Klaus; Knust, E. Joachim

    1996-04-01

    By variation of reaction parameters iodination of 3-(9-10-didehydro-6-methyl-8{alpha}-ergolinyl)-1,1-diethylurea (lusuride) was performed with the radiohalogen [{sup 123}I]iodine (t{sub (1(2))} = 13.3 h). For comparative experiments and stability studies the {beta}{sup -}-emitting radioisotope [{sup 131}I]iodine (t{sub (1(2))} = 8.04 d) was also used. Reaction occurs at the activated position 2 of the molecule, thus leading to [{sup 123}I]3-(9,10-didehydro-2-iodo-6-methyl-8{alpha}-ergolinyl)-1,1-diethylurea= = ([{sup 123}I]2-iodo-lisuride, [{sup 123}I]ILIS) or the analogous [{sup 131}I]iodine-labeled compound, respectively. Electrophilic radioactive species were generated by oxidation of no-carrier-added (n.c.a.) iodide with IODOGEN (1,3,4,6-tetrachloro-3{alpha},6{alpha}-diphenylglycouril) fixed on the glass wall of the reaction vial prior to iodination. After optimization of reaction parameters [{sup 123}I]2-iodo-lisuride after HPLC-purification was obtained with radiochemical yields of 70 {+-} 5% and a radiochemical purity of >97%. In n.c.a. syntheses, specific activities of the product were in the range between 4440 and 7400 GBq/{mu}mol (120-200 Ci/{mu}mol) corresponding to 50-85% of the theoretical value.

  19. Striatal dopamine D2 receptors, metabolism, and volume in preclinical Huntington disease

    NARCIS (Netherlands)

    van Oostrom, JCH; Maguire, RP; Verschuuren-Bemelmans, CC; van der Duin, LV; Pruim, J; Roos, RAC; Leenders, KL

    2005-01-01

    Among 27 preclinical carriers of the Huntington disease mutation (PMC), the authors found normal striatal values for MRI volumetry in 88% and for fluorodesoxyglucose PET metabolic index in 67%. Raclopride PET binding potential (RAC-BP) was decreased in 50% and correlated with increases in the

  20. Subjective experience and dopamine D2 receptor occupancy in patients treated with antipsychotics: clinical implications

    NARCIS (Netherlands)

    de Haan, Lieuwe; Lavalaye, Jules; van Bruggen, Marion; van Nimwegen, Lonneke; Booij, Jan; van Amelsvoort, Therese; Linszen, Don

    2004-01-01

    OBJECTIVES: This paper gives an overview of studies on the association between dopaminergic neurotransmission and the subjective experience of patients with schizophrenia. METHODS: We undertook a review of the literature. RESULTS: Dopaminergic neurotransmission may be relevant for subjective

  1. D2 receptor blockade by risperidone correlates with attention deficits in late-life schizophrenia.

    Science.gov (United States)

    Uchida, Hiroyuki; Rajji, Tarek K; Mulsant, Benoit H; Kapur, Shitij; Pollock, Bruce G; Graff-Guerrero, Ariel; Menon, Mahesh; Mamo, David C

    2009-12-01

    The negative impact of antipsychotic drugs on attention is expected to be greater in late-life schizophrenia because of the age-related changes in the dopamine receptor reserve. The objective of this study was to examine the relationship between dopamine D2 receptor blockade by risperidone and the cognitive function in late-life schizophrenia. Subjects with schizophrenia or schizoaffective disorder aged 50 or older who were receiving risperidone completed a [C]raclopride positron emission tomography scan to measure D2-binding potential in the striatum. The D2 receptor blockade by risperidone was calculated using age-corrected measures from healthy individuals and region of interest analysis of dynamic positron emission tomography data coregistered to the subjects' magnetic resonance imaging scans. Cognitive function was assessed using a battery of neuropsychological tests that included the Dementia Rating Scale-2 (DRS). Eleven subjects (mean +/- SD age, 64 +/- 8 years) participated in this study. The mean +/- SD D2 receptor blockade was 69% +/- 14% (range, 34%-80%). The age-corrected score on the attention subscale in the DRS was negatively correlated with the D2 receptor blockade. The DRS attention subscale score was lower in the subjects who experienced 74.9% or higher D2 blockade (median value, corresponding to a daily risperidone dose of >3.0 mg) than in those who did not. Although a causal attribution cannot be made in light of the cross-sectional nature of this study, the results suggest the critical importance of identifying the lowest effective dose of antipsychotic drugs in older patients with schizophrenia.

  2. 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.

  3. Seasonal Variation of Provitamin D2 and Vitamin D2 in Perennial Ryegrass (Lolium perenne L.)

    DEFF Research Database (Denmark)

    Jäpelt, Rie Bak; Didion, Thomas; Smedsgaard, Jørn

    2011-01-01

    Ergosterol (provitamin D(2)) is converted to vitamin D(2) in grass by exposure to UV light. Six varieties of perennial ryegrass (Lolium perenne L.) were harvested four times during the season, and the contents of vitamin D(2) and ergosterol were analyzed by a sensitive and selective liquid...

  4. Thalamic Stroke and Associated Behavior Disorders. Possibilities for Integral Management: Case Report

    National Research Council Canada - National Science Library

    Camargo, Loida Camargo; Sánchez, Katherine Parra

    2012-01-01

    .... Case report of a 56-year male patient with thalamic ischemia. The intervention with integral strategies involving pharmacological management and cognitive interventions was decisive for the satisfactory evolution of the patient...

  5. Prenatal thalamic waves regulate cortical area size prior to sensory processing

    Science.gov (United States)

    Moreno-Juan, Verónica; Filipchuk, Anton; Antón-Bolaños, Noelia; Mezzera, Cecilia; Gezelius, Henrik; Andrés, Belen; Rodríguez-Malmierca, Luis; Susín, Rafael; Schaad, Olivier; Iwasato, Takuji; Schüle, Roland; Rutlin, Michael; Nelson, Sacha; Ducret, Sebastien; Valdeolmillos, Miguel; Rijli, Filippo M.; López-Bendito, Guillermina

    2017-01-01

    The cerebral cortex is organized into specialized sensory areas, whose initial territory is determined by intracortical molecular determinants. Yet, sensory cortical area size appears to be fine tuned during development to respond to functional adaptations. Here we demonstrate the existence of a prenatal sub-cortical mechanism that regulates the cortical areas size in mice. This mechanism is mediated by spontaneous thalamic calcium waves that propagate among sensory-modality thalamic nuclei up to the cortex and that provide a means of communication among sensory systems. Wave pattern alterations in one nucleus lead to changes in the pattern of the remaining ones, triggering changes in thalamic gene expression and cortical area size. Thus, silencing calcium waves in the auditory thalamus induces Rorβ upregulation in a neighbouring somatosensory nucleus preluding the enlargement of the barrel-field. These findings reveal that embryonic thalamic calcium waves coordinate cortical sensory area patterning and plasticity prior to sensory information processing. PMID:28155854

  6. Characteristics of thalamic local field potentials in patients with disorders of consciousness.

    Science.gov (United States)

    Huang, Yongzhi; He, Jianghong; Green, Alexander L; Aziz, Tipu Z; Stein, John F; Wang, Shouyan

    2015-08-01

    A functioning thalamus is essential for treatment of patients with disorders of consciousness (DOC) using deep brain stimulation (DBS). This work aims to identify the potential biomarkers related to consciousness from the thalamic deep brain local field potentials (LFPs) in DOC patients. The frequency features of central thalamic LFPs were characterized with spectral analysis. The features were further compared to those of LFPs from the ventroposterior lateral nucleus of the thalamus (VPL) in patients with pain. There are several distinct characteristics of thalamic LFPs found in patients with DOC. The most important feature is the oscillation around 10Hz which could be relevant to the existence of residual consciousness, whereas high power below 8Hz seemed to be associated with loss of consciousness. The invasive deep brain recording tool opens a unique way to explore the brain function in consciousness, awareness and alertness and clarify the potential mechanisms of thalamic stimulation in DOC.

  7. Reduced Slc6a15 in Nucleus Accumbens D2-Neurons Underlies Stress Susceptibility.

    Science.gov (United States)

    Chandra, Ramesh; Francis, T Chase; Nam, Hyungwoo; Riggs, Lace M; Engeln, Michel; Rudzinskas, Sarah; Konkalmatt, Prasad; Russo, Scott J; Turecki, Gustavo; Iniguez, Sergio D; Lobo, Mary Kay

    2017-07-05

    Previous research demonstrates that Slc6a15, a neutral amino acid transporter, is associated with depression susceptibility. However, no study examined Slc6a15 in the ventral striatum [nucleus accumbens (NAc)] in depression. Given our previous characterization of Slc6a15 as a striatal dopamine receptor 2 (D2)-neuron-enriched gene, we examined the role of Slc6a15 in NAc D2-neurons in mediating susceptibility to stress in male mice. First, we showed that Slc6a15 mRNA was reduced in NAc of mice susceptible to chronic social defeat stress (CSDS), a paradigm that produces behavioral and molecular adaptations that resemble clinical depression. Consistent with our preclinical data, we observed Slc6a15 mRNA reduction in NAc of individuals with major depressive disorder (MDD). The Slc6a15 reduction in NAc occurred selectively in D2-neurons. Next, we used Cre-inducible viruses combined with D2-Cre mice to reduce or overexpress Slc6a15 in NAc D2-neurons. Slc6a15 reduction in D2-neurons caused enhanced susceptibility to a subthreshold social defeat stress (SSDS) as observed by reduced social interaction, while a reduction in social interaction following CSDS was not observed when Slc6a15 expression in D2-neurons was restored. Finally, since both D2-medium spiny neurons (MSNs) and D2-expressing choline acetyltransferase (ChAT) interneurons express Slc6a15, we examined Slc6a15 protein in these interneurons after CSDS. Slc6a15 protein was unaltered in ChAT interneurons. Consistent with this, reducing Slc5a15 selectively in NAc D2-MSNs, using A2A-Cre mice that express Cre selectively in D2-MSNs, caused enhanced susceptibility to SSDS. Collectively, our data demonstrate that reduced Slc6a15 in NAc occurs in MDD individuals and that Slc6a15 reduction in NAc D2-neurons underlies stress susceptibility. SIGNIFICANCE STATEMENT Our study demonstrates a role for reduced Slc6a15, a neutral amino acid transporter, in nucleus accumbens (NAc) in depression and stress susceptibility. The

  8. Thalamic physiology of intentional essential tremor is more like cerebellar tremor than postural essential tremor

    OpenAIRE

    Zakaria, R; Lenz, FA; Hua, S; Avin, BH; Liu, CC; Mari, Z

    2013-01-01

    The neuronal physiological correlates of clinical heterogeneity in human essential tremor are unknown. We now test the hypothesis that thalamic neuronal and EMG activities during intention essential tremor are similar to those of the intention tremor which is characteristic of cerebellar lesions. Thalamic neuronal firing was studied in a cerebellar relay nucleus (ventral intermediate, Vim) and in a pallidal relay nucleus (ventral oral posterior, Vop) during stereotactic surgery for the treatm...

  9. 5-HT modulation of dopamine release in basal ganglia in psilocybin-induced psychosis in man - A PET study with [C-11]raclopride

    NARCIS (Netherlands)

    Vollenweider, FX; Vontobel, P; Hell, D; Leenders, KL

    The modulating effects of serotonin on dopamine neurotransmission are not well understood, particularly in acute psychotic states. Positron emission tomography was used to examine the effect of psilocybin on the in vivo binding of [C-11]raclopride to D-2-dopamine receptors in the striatum in healthy

  10. One-pass deep brain stimulation of dentato-rubro-thalamic tract and subthalamic nucleus for tremor-dominant or e