Oral Administration of Methylphenidate Blocks the Effect of Cocaine on Uptake at the Drosophila Dopamine Transporter

PubMed Central

2013-01-01

Although our understanding of the actions of cocaine in the brain has improved, an effective drug treatment for cocaine addiction has yet to be found. Methylphenidate binds the dopamine transporter and increases extracellular dopamine levels in mammalian central nervous systems similar to cocaine, but it is thought to elicit fewer addictive and reinforcing effects owing to slower pharmacokinetics for different routes of administration between the drugs. This study utilizes the fruit fly model system to quantify the effects of oral methylphenidate on dopamine uptake during direct cocaine exposure to the fly CNS. The effect of methylphenidate on the dopamine transporter has been explored by measuring the uptake of exogenously applied dopamine. The data suggest that oral consumption of methylphenidate inhibits the Drosophila dopamine transporter and the inhibition is concentration dependent. The peak height increased to 150% of control when cocaine was used to block the dopamine transporter for untreated flies but only to 110% for methylphenidate-treated flies. Thus, the dopamine transporter is mostly inhibited for the methylphenidate-fed flies before the addition of cocaine. The same is true for the rate of the clearance of dopamine measured by amperometry. For untreated flies the rate of clearance changes 40% when the dopamine transporter is inhibited with cocaine, and for treated flies the rate changes only 10%. The results were correlated to the in vivo concentration of methylphenidate determined by CE-MS. Our data suggest that oral consumption of methylphenidate inhibits the Drosophila dopamine transporter for cocaine uptake, and the inhibition is concentration dependent. PMID:23402315

Olfactory discrimination deficits in mice lacking the dopamine transporter or the D2 dopamine receptor.

PubMed

Tillerson, Jennifer L; Caudle, W Michael; Parent, Jack M; Gong, C; Schallert, Timothy; Miller, Gary W

2006-09-15

Previous pharmacological studies have implicated dopamine as a modulator of olfactory bulb processing. Several disorders characterized by altered dopamine homeostasis in olfaction-related brain regions display olfactory deficits. To further characterize the role of dopamine in olfactory processing, we subjected dopamine transporter knockout mice (DAT -/-) and dopamine receptor 2 knockout mice (D2 -/-) to a battery of olfactory tests. In addition to behavioral characterization, several neurochemical markers of olfactory bulb integrity and function were examined. DAT -/- mice displayed an olfactory discrimination deficit, but did not differ detectably from DAT wildtype (DAT +/+) mice in odor habituation, olfactory sensitivity, or odor recognition memory. Neurochemically, DAT -/- mice have decreased D2 receptor staining in the periglomerular layer of the olfactory bulb and increased tyrosine hydroxylase immunoreactivity compared to DAT +/+ controls. D2 -/- mice exhibited the same olfactory deficit as the DAT -/- mice, further supporting the role of dopamine at the D2 synapse in olfactory discrimination processing. The findings presented in this paper reinforce the functional significance of dopamine and more specifically the D2 receptor in olfactory discrimination and may help explain the behavioral phenotype in the DAT and D2 knockout mice.

Dopamine Transporter Blockade Increases LTP in the CA1 Region of the Rat Hippocampus via Activation of the D3 Dopamine Receptor

ERIC Educational Resources Information Center

Swant, Jarod; Wagner, John J.

2006-01-01

Dopamine has been demonstrated to be involved in the modulation of long-term potentiation (LTP) in the CA1 region of the hippocampus. As monoamine transporter blockade will increase the actions of endogenous monoamine neurotransmitters, the effect of a dopamine transporter (DAT) antagonist on LTP was assessed using field excitatory postsynaptic…

Atypical Dopamine Uptake Inhibitors that Provide Clues About Cocaine's Mechanism at the Dopamine Transporter

NASA Astrophysics Data System (ADS)

Hauck Newman, Amy; Katz, Jonathan L.

The dopamine transporter (DAT) has been a primary target for cocaine abuse/addiction medication discovery. However predicted addiction liability and limited clinical evaluation has provided a formidable challenge for development of these agents for human use. The unique and atypical pharmacological profile of the benztropine (BZT) class of dopamine uptake inhibitors, in preclinical models of cocaine effects and abuse, has encouraged further development of these agents. Moreover, in vivo studies have challenged the original DAT hypothesis and demonstrated that DAT occupancy and subsequent increases in dopamine produced by BZT analogues are significantly delayed and long lasting, as compared to cocaine. These important and distinctive elements are critical to the lack of abuse liability among BZT analogues, and improve their potential for development as treatments for cocaine abuse and possibly other neuropsychiatric disorders.

Disruption of dopamine transport by DDT and its metabolites

PubMed Central

Hatcher, Jaime M.; Delea, Kristin C.; Richardson, Jason R.; Pennell, Kurt D.; Miller, Gary W.

2016-01-01

Epidemiological studies suggest a link between pesticide exposure and an increased risk of developing Parkinson’s disease (PD). Although studies have been unable to clearly identify specific pesticides that contribute to PD, a few human studies have reported higher levels of the organochlorine pesticides dieldrin and DDE (a metabolite of DDT) in post-mortem PD brains. Previously, we found that exposure of mice to dieldrin caused perturbations in the nigrostriatal dopamine system consistent with those seen in PD. Given the concern over the environmental persistence and reintroduction of DDT for the control of malaria-carrying mosquitoes and other pests, we sought to determine whether DDT and its two major metabolites, DDD and DDE, could damage the dopamine system. In vitro analyses in mouse synaptosomes and vesicles demonstrated that DDT and its metabolites inhibit the plasma membrane dopamine transporter (DAT) and the vesicular monoamine transporter (VMAT2). However, exposure of mice to either DDT or DDE failed to show evidence of nigrostriatal damage or behavioral abnormalities in any of the measures examined. Thus, we report that in vitro effects of DDT and its metabolites on components of the dopamine system do not translate into neurotoxicological outcomes in orally exposed mice and DDT appears to have less dopamine toxicity when compared to dieldrin. These data suggest elevated DDE levels in PD patients may represent a measure of general pesticide exposure and that other pesticides may be responsible for the association between pesticide exposure and PD. PMID:18533268

Glutamatergic modulation of hyperactivity in mice lacking the dopamine transporter

PubMed Central

Gainetdinov, Raul R.; Mohn, Amy R.; Bohn, Laura M.; Caron, Marc G.

2001-01-01

In the brain, dopamine exerts an important modulatory influence over behaviors such as emotion, cognition, and affect as well as mechanisms of reward and the control of locomotion. The dopamine transporter (DAT), which reuptakes the released neurotransmitter into presynaptic terminals, is a major determinant of the intensity and duration of the dopaminergic signal. Knockout mice lacking the dopamine transporter (DAT-KO mice) display marked changes in dopamine homeostasis that result in elevated dopaminergic tone and pronounced locomotor hyperactivity. A feature of DAT-KO mice is that their hyperactivity can be inhibited by psychostimulants and serotonergic drugs. The pharmacological effect of these drugs occurs without any observable changes in dopaminergic parameters, suggesting that other neurotransmitter systems in addition to dopamine might contribute to the control of locomotion in these mice. We report here that the hyperactivity of DAT-KO mice can be markedly further enhanced when N-methyl-d-aspartate receptor-mediated glutamatergic transmission is blocked. Conversely, drugs that enhance glutamatergic transmission, such as positive modulators of l-α-amino-3-hydroxy-5-methylisoxazole-4-propionate glutamate receptors, suppress the hyperactivity of DAT-KO mice. Interestingly, blockade of N- methyl-d-aspartate receptors prevented the inhibitory effects of both psychostimulant and serotonergic drugs on hyperactivity. These findings support the concept of a reciprocal functional interaction between dopamine and glutamate in the basal ganglia and suggest that agents modulating glutamatergic transmission may represent an approach to manage conditions associated with dopaminergic dysfunction. PMID:11572967

Dopamine transporter SPECT in patients with mitochondrial disorders

PubMed Central

Minnerop, M; Kornblum, C; Joe, A; Tatsch, K; Kunz, W; Klockgether, T; Wullner, U; Reinhardt, M

2005-01-01

Objective : To investigate the dopaminergic system in patients with known mitochondrial disorders and complex I deficiency. Methods: Dopamine transporter density was studied in 10 female patients with mitochondrial complex I deficiency by 123I-FP-CIT (N-ß-fluoropropyl-2ß-carbomethyl-3ß-(4-iodophenyl)-nortropane) SPECT. Results: No differences in 123I-FP-CIT striatal binding ratios were observed and no correlation of the degree of complex I deficiency and striatal binding ratios could be detected. Conclusions: These data argue against the possibility that mitochondrial complex I deficiency by itself is sufficient to elicit dopaminergic cell loss. PMID:15608010

β-Phenylethylamine requires the dopamine transporter to increase extracellular dopamine in Caenorhabditis elegans dopaminergic neurons.

PubMed

Hossain, Murad; Wickramasekara, Rochelle N; Carvelli, Lucia

2014-07-01

β-Phenylethylamine (βPEA) is an endogenous amine that has been shown to increase the synaptic levels of dopamine (DA). A number of in vitro and behavioral studies suggest the dopamine transporter (DAT) plays a role in the effects generated by βPEA, however the mechanism through which βPEA affects DAT has not yet been elucidated. Here, we used Caenorhabditis (C.) elegans DAT (DAT-1) expressing LLC-pk1 cells and neuronal cultures to investigate whether the βPEA-induced increase of extracellular DA required DAT-1. Our data show that βPEA increases extracellular dopamine both in DAT-1 transfected cells and cultures of differentiated neurons. RTI-55, a cocaine homologue and DAT inhibitor, completely blocked the βPEA-induced effect in transfected cells. However in neuronal cultures, RTI-55 only partly inhibited the increase of extracellular DA generated by βPEA. These results suggest that βPEA requires DAT-1 and other, not yet identified proteins, to increase extracellular DA when tested in a native system. Furthermore, our results suggest that βPEA-induced increase of extracellular DA does not require functional monoamine vesicles as genetic ablation of the C. elegans homologue vesicular monoamine transporter, cat-1, did not compromise the ability of βPEA to increase extracellular DA. Finally, our electrophysiology data show that βPEA caused fast-rising and self-inactivating amperometric currents in a subset of wild-type DA neurons but not in neurons isolated from dat-1 knockout animals. Taken together, these data demonstrate that in both DA neurons and heterogeneous cultures of differentiated C. elegans neurons, βPEA releases cytoplasmic DA through DAT-1 to ultimately increase the extracellular concentration of DA. Copyright © 2013 Elsevier Ltd. All rights reserved.

β-phenylethylamine Requires the Dopamine Transporter to Increase Extracellular Dopamine in C. elegans Dopaminergic Neurons

PubMed Central

Hossain, Murad; Wickramasekara, Rochelle N.; Carvelli, Lucia

2013-01-01

β-phenylethylamine (βPEA) is an endogenous amine that has been shown to increase the synaptic levels of dopamine (DA). A number of in vitro and behavioral studies suggest the dopamine transporter (DAT) plays a role in the effects generated by βPEA, however the mechanism through which βPEA affects DAT has not yet been elucidated. Here, we used Caenorhabditis (C.) elegans DAT (DAT-1) expressing LLC-pk1 cells and neuronal cultures to investigate whether the βPEA-induced increase of extracellular DA required DAT-1. Our data show that βPEA increases extracellular dopamine both in DAT-1 transfected cells and cultures of differentiated neurons. RTI-55, a cocaine homologue and DAT inhibitor, completely blocked the βPEA-induced effect in transfected cells. However in neuronal cultures, RTI-55 only partly inhibited the increase of extracellular DA generated by βPEA. These results suggest that βPEA requires DAT-1 and other, not yet identified proteins, to increase extracellular DA when tested in a native system. Furthermore, our results suggest that βPEA-induced increase of extracellular DA does not require functional monoamine vesicles as genetic ablation of the C. elegans homologue vesicular monoamine transporter, cat-1, did not compromise the ability of βPEA to increase extracellular DA. Finally, our electrophysiology data show that βPEA caused fast-rising and self-inactivating amperometric currents in a subset of wild-type DA neurons but not in neurons isolated from dat-1 knockout animals. Taken together, these data demonstrate that in both DA neurons and heterogeneous cultures of differentiated C. elegans neurons, βPEA releases cytoplasmic DA through DAT-1 to ultimately increase the extracellular concentration of DA. PMID:24161617

Dampened Amphetamine-Stimulated Behavior and Altered Dopamine Transporter Function in the Absence of Brain GDNF.

PubMed

Kopra, Jaakko J; Panhelainen, Anne; Af Bjerkén, Sara; Porokuokka, Lauriina L; Varendi, Kärt; Olfat, Soophie; Montonen, Heidi; Piepponen, T Petteri; Saarma, Mart; Andressoo, Jaan-Olle

2017-02-08

Midbrain dopamine neuron dysfunction contributes to various psychiatric and neurological diseases, including drug addiction and Parkinson's disease. Because of its well established dopaminotrophic effects, the therapeutic potential of glial cell line-derived neurotrophic factor (GDNF) has been studied extensively in various disorders with disturbed dopamine homeostasis. However, the outcomes from preclinical and clinical studies vary, highlighting a need for a better understanding of the physiological role of GDNF on striatal dopaminergic function. Nevertheless, the current lack of appropriate animal models has limited this understanding. Therefore, we have generated novel mouse models to study conditional Gdnf deletion in the CNS during embryonic development and reduction of striatal GDNF levels in adult mice via AAV-Cre delivery. We found that both of these mice have reduced amphetamine-induced locomotor response and striatal dopamine efflux. Embryonic GDNF deletion in the CNS did not affect striatal dopamine levels or dopamine release, but dopamine reuptake was increased due to increased levels of both total and synaptic membrane-associated dopamine transporters. Collectively, these results suggest that endogenous GDNF plays an important role in regulating the function of dopamine transporters in the striatum. SIGNIFICANCE STATEMENT Delivery of ectopic glial cell line-derived neurotrophic factor (GDNF) promotes the function, plasticity, and survival of midbrain dopaminergic neurons, the dysfunction of which contributes to various neurological and psychiatric diseases. However, how the deletion or reduction of GDNF in the CNS affects the function of dopaminergic neurons has remained unknown. Using conditional Gdnf knock-out mice, we found that endogenous GDNF affects striatal dopamine homeostasis and regulates amphetamine-induced behaviors by regulating the level and function of dopamine transporters. These data regarding the physiological role of GDNF are

Brain serotonin and dopamine transporter bindings in adults with high-functioning autism.

PubMed

Nakamura, Kazuhiko; Sekine, Yoshimoto; Ouchi, Yasuomi; Tsujii, Masatsugu; Yoshikawa, Etsuji; Futatsubashi, Masami; Tsuchiya, Kenji J; Sugihara, Genichi; Iwata, Yasuhide; Suzuki, Katsuaki; Matsuzaki, Hideo; Suda, Shiro; Sugiyama, Toshiro; Takei, Nori; Mori, Norio

2010-01-01

Autism is a neurodevelopmental disorder that is characterized by repetitive and/or obsessive interests and behavior and by deficits in sociability and communication. Although its neurobiological underpinnings are postulated to lie in abnormalities of the serotoninergic and dopaminergic systems, the details remain unknown. To determine the occurrence of changes in the binding of serotonin and dopamine transporters, which are highly selective markers for their respective neuronal systems. Using positron emission tomography, we measured the binding of brain serotonin and dopamine transporters in each individual with the radioligands carbon 11 ((11)C)-labeled trans-1,2,3,5,6,10-beta-hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]isoquinoline ([(11)C](+)McN-5652) and 2beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane ([(11)C]WIN-35,428), respectively. Statistical parametric mapping was used for between-subject analysis and within-subject correlation analysis with respect to clinical variables. Participants recruited from the community. Twenty men (age range, 18-26 years; mean [SD] IQ, 99.3 [18.1]) with autism and 20 age- and IQ-matched control subjects. Serotonin transporter binding was significantly lower throughout the brain in autistic individuals compared with controls (P < .05, corrected). Specifically, the reduction in the anterior and posterior cingulate cortices was associated with the impairment of social cognition in the autistic subjects (P < .05, corrected). A significant correlation was also found between repetitive and/or obsessive behavior and interests and the reduction of serotonin transporter binding in the thalamus (P < .05, corrected). In contrast, the dopamine transporter binding was significantly higher in the orbitofrontal cortex of the autistic group (P < .05, corrected in voxelwise analysis). In the orbitofrontal cortex, the dopamine transporter binding was significantly inversely correlated with serotonin transporter binding (r = -0.61; P

Serotonin and Dopamine Transporter Binding in Children with Autism Determined by SPECT

ERIC Educational Resources Information Center

Makkonen, Ismo; Riikonen, Raili; Kokki, Hannu; Airaksinen, Mauno M.; Kuikka, Jyrki T.

2008-01-01

Disturbances in the serotonergic system have been recognized in autism. To investigate the association between serotonin and dopamine transporters and autism, we studied 15 children (14 males, one female; mean age 8y 8mo [SD 3y 10mo]) with autism and 10 non-autistic comparison children (five males, five females; mean age 9y 10mo [SD 2y 8mo]) using…

Serotonin and dopamine transporter binding in children with autism determined by SPECT.

PubMed

Makkonen, Ismo; Riikonen, Raili; Kokki, Hannu; Airaksinen, Mauno M; Kuikka, Jyrki T

2008-08-01

Disturbances in the serotonergic system have been recognized in autism. To investigate the association between serotonin and dopamine transporters and autism, we studied 15 children (14 males, one female; mean age 8 y 8 mo [SD 3 y 10 mo]) with autism and 10 non-autistic comparison children (five males, five females; mean age 9 y 10 mo [SD 2 y 8 mo]) using single-photon emission computed tomography (SPECT) with [123 I] nor-beta-CIT. The children, with autism were studied during light sedation. They showed reduced serotonin transporter (SERT) binding capacity in the medial frontal cortex, midbrain, and temporal lobe areas. However, after correction due to the estimated effect of sedation, the difference remained significant only in the medial frontal cortex area (p=0.002). In the individuals with autism dopamine transporter (DAT) binding did not differ from that of the comparison group. The results indicate that SERT binding capacity is disturbed in autism. The reduction is more evident in adolescence than in earlier childhood. The low SERT binding reported here and the low serotonin synthesis capacity shown elsewhere may indicate maturation of a lesser number of serotonergic nerve terminals in individuals with autism.

Association of dopamine transporter loss in the orbitofrontal and dorsolateral prefrontal cortices with methamphetamine-related psychiatric symptoms.

PubMed

Sekine, Yoshimoto; Minabe, Yoshio; Ouchi, Yasuomi; Takei, Nori; Iyo, Masaomi; Nakamura, Kazuhiko; Suzuki, Katsuaki; Tsukada, Hideo; Okada, Hiroyuki; Yoshikawa, Etsuji; Futatsubashi, Masami; Mori, Norio

2003-09-01

The authors examined dopamine transporter density in the orbitofrontal cortex, dorsolateral prefrontal cortex, and amygdala in methamphetamine users and assessed the relationship of these measures to the subjects' clinical characteristics. Positron emission tomography with [(11)C]WIN 35,428 was used to examine the regions of interest in 11 methamphetamine users and nine healthy comparison subjects. Psychiatric symptoms were evaluated with the Brief Psychiatric Rating Scale. Dopamine transporter density in the three regions studied was significantly lower in the methamphetamine users than in the comparison subjects. The lower dopamine transporter density in the orbitofrontal and dorsolateral prefrontal cortex was significantly correlated with the duration of methamphetamine use and the severity of psychiatric symptoms. Chronic methamphetamine use may cause dopamine transporter reduction in the orbitofrontal cortex, dorsolateral prefrontal cortex, and amygdala in the brain. Psychiatric symptoms in methamphetamine users may be attributable to the decrease in dopamine transporter density in the orbitofrontal cortex and the dorsolateral prefrontal cortex.

Impact of disruption of secondary binding site S2 on dopamine transporter function.

PubMed

Zhen, Juan; Reith, Maarten E A

2016-09-01

The structures of the leucine transporter, drosophila dopamine transporter, and human serotonin transporter show a secondary binding site (designated S2 ) for drugs and substrate in the extracellular vestibule toward the membrane exterior in relation to the primary substrate recognition site (S1 ). The present experiments are aimed at disrupting S2 by mutating Asp476 and Ile159 to Ala. Both mutants displayed a profound decrease in [(3) H]DA uptake compared with wild-type associated with a reduced turnover rate kcat . This was not caused by a conformational bias as the mutants responded to Zn(2+) (10 μM) similarly as WT. The dopamine transporters with either the D476A or I159A mutation both displayed a higher Ki for dopamine for the inhibition of [3H](-)-2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane binding than did the WT transporter, in accordance with an allosteric interaction between the S1 and S2 sites. The results provide evidence in favor of a general applicability of the two-site allosteric model of the Javitch/Weinstein group from LeuT to dopamine transporter and possibly other monoamine transporters. X-ray structures of transporters closely related to the dopamine (DA) transporter show a secondary binding site S2 in the extracellular vestibule proximal to the primary binding site S1 which is closely linked to one of the Na(+) binding sites. This work examines the relationship between S2 and S1 sites. We found that S2 site impairment severely reduced DA transport and allosterically reduced S1 site affinity for the cocaine analog [(3) H]CFT. Our results are the first to lend direct support for the application of the two-site allosteric model, advanced for bacterial LeuT, to the human DA transporter. The model states that, after binding of the first DA molecule (DA1 ) to the primary S1 site (along with Na(+) ), binding of a second DA (DA2 ) to the S2 site triggers, through an allosteric interaction, the release of DA1 and Na(+) into the cytoplasm. © 2016

Recovery of dopamine transporters with methamphetamine detoxification is not linked to changes in dopamine release

DOE Office of Scientific and Technical Information (OSTI.GOV)

Volkow, Nora D.; Wang, Gene-Jack; Smith, Lisa

Metamphetamine’s widepread abuse and concerns that it may increase Parkinson’s disease led us to assess if the reported loss of dopamine transporters (DAT) in methamphetamine abusers (MA) reflected damage to dopamine neurons. Using PET with [ 11C]cocaine to measure DAT, and with [ 11C]raclopride to measure dopamine release (assessed as changes in specific binding of [ 11C]raclopride between placebo and methylphenidate), which was used as marker of dopamine neuronal function, we show that MA (n=16), tested during early detoxification, had lower DAT (20-30%) but overall normal DA release in striatum (except for a small decrease in left putamen), when comparedmore » to controls (n=15). In controls, DAT were positively correlated with DA release (higher DAT associated with larger DA increases), consistent with DAT serving as markers of DA terminals. In contrast, MA showed a trend for a negative correlation (p=0.07) (higher DAT associated with lower DA increases), consistent with reduced DA re-uptake following DAT downregulation. MA who remained abstinent nine-months later (n=9) showed significant increases in DAT (20%) but methylphenidate-induced dopamine increases did not change. In contrast, in controls, DAT did not change when retested 9 months later but methylphenidate-induced dopamine increases in ventral striatum were reduced (p=0.05). Baseline D2/D3 receptors in caudate were lower in MA than in controls and did not change with detoxification, nor did they change in the controls upon retest. The loss of DAT in the MA, which was not associated with a concomitant reduction in dopamine release as would have been expected if DAT loss reflected DA terminal degneration; as well as the recovery of DAT after protracted detoxification, which was not associated with increased dopamine release as would have been expected if DAT increases reflected terminal regeneration, indicate that the loss of DAT in these MA does not reflect degeneration of dopamine terminals.« less

Recovery of dopamine transporters with methamphetamine detoxification is not linked to changes in dopamine release.

PubMed

Volkow, Nora D; Wang, Gene-Jack; Smith, Lisa; Fowler, Joanna S; Telang, Frank; Logan, Jean; Tomasi, Dardo

2015-11-01

Methamphetamine's widepread abuse and concerns that it might increase Parkinson's disease led us to assess if the reported loss of dopamine transporters (DAT) in methamphetamine abusers (MA) reflected damage to dopamine neurons. Using PET with [(11)C]cocaine to measure DAT, and with [(11)C]raclopride to measure dopamine release (assessed as changes in specific binding of [(11)C]raclopride between placebo and methylphenidate), which was used as a marker of dopamine neuronal function, we show that MA (n=16), tested during early detoxification, had lower DAT (20-30%) but overall normal DA release in striatum (except for a small decrease in left putamen), when compared to controls (n=15). In controls, DAT were positively correlated with DA release (higher DAT associated with larger DA increases), consistent with DAT serving as markers of DA terminals. In contrast, MA showed a trend for a negative correlation (p=0.07) (higher DAT associated with lower DA increases), consistent with reduced DA re-uptake following DAT downregulation. MA who remained abstinent nine-months later (n=9) showed significant increases in DAT (20%) but methylphenidate-induced dopamine increases did not change. In contrast, in controls, DAT did not change when retested 9 months later but methylphenidate-induced dopamine increases in ventral striatum were reduced (p=0.05). Baseline D2/D3 receptors in caudate were lower in MA than in controls and did not change with detoxification, nor did they change in the controls upon retest. The loss of DAT in the MA, which was not associated with a concomitant reduction in dopamine release as would have been expected if DAT loss reflected DA terminal degneration; as well as the recovery of DAT after protracted detoxification, which was not associated with increased dopamine release as would have been expected if DAT increases reflected terminal regeneration, indicate that the loss of DAT in these MA does not reflect degeneration of dopamine terminals

Recovery of dopamine transporters with methamphetamine detoxification is not linked to changes in dopamine release

DOE PAGES

Volkow, Nora D.; Wang, Gene-Jack; Smith, Lisa; ...

2015-07-21

Metamphetamine’s widepread abuse and concerns that it may increase Parkinson’s disease led us to assess if the reported loss of dopamine transporters (DAT) in methamphetamine abusers (MA) reflected damage to dopamine neurons. Using PET with [ 11C]cocaine to measure DAT, and with [ 11C]raclopride to measure dopamine release (assessed as changes in specific binding of [ 11C]raclopride between placebo and methylphenidate), which was used as marker of dopamine neuronal function, we show that MA (n=16), tested during early detoxification, had lower DAT (20-30%) but overall normal DA release in striatum (except for a small decrease in left putamen), when comparedmore » to controls (n=15). In controls, DAT were positively correlated with DA release (higher DAT associated with larger DA increases), consistent with DAT serving as markers of DA terminals. In contrast, MA showed a trend for a negative correlation (p=0.07) (higher DAT associated with lower DA increases), consistent with reduced DA re-uptake following DAT downregulation. MA who remained abstinent nine-months later (n=9) showed significant increases in DAT (20%) but methylphenidate-induced dopamine increases did not change. In contrast, in controls, DAT did not change when retested 9 months later but methylphenidate-induced dopamine increases in ventral striatum were reduced (p=0.05). Baseline D2/D3 receptors in caudate were lower in MA than in controls and did not change with detoxification, nor did they change in the controls upon retest. The loss of DAT in the MA, which was not associated with a concomitant reduction in dopamine release as would have been expected if DAT loss reflected DA terminal degneration; as well as the recovery of DAT after protracted detoxification, which was not associated with increased dopamine release as would have been expected if DAT increases reflected terminal regeneration, indicate that the loss of DAT in these MA does not reflect degeneration of dopamine terminals.« less

ADHD-associated dopamine transporter, latrophilin and neurofibromin share a dopamine-related locomotor signature in Drosophila

PubMed Central

van der Voet, M; Harich, B; Franke, B; Schenck, A

2016-01-01

Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neuropsychiatric disorder with hyperactivity as one of the hallmarks. Aberrant dopamine signaling is thought to be a major theme in ADHD, but how this relates to the vast majority of ADHD candidate genes is illusive. Here we report a Drosophila dopamine-related locomotor endophenotype that is shared by pan-neuronal knockdown of orthologs of the ADHD-associated genes Dopamine transporter (DAT1) and Latrophilin (LPHN3), and of a gene causing a monogenic disorder with frequent ADHD comorbidity: Neurofibromin (NF1). The locomotor signature was not found in control models and could be ameliorated by methylphenidate, validating its relevance to symptoms of the disorder. The Drosophila ADHD endophenotype can be further exploited in high throughput to characterize the growing number of candidate genes. It represents an equally useful outcome measure for testing chemical compounds to define novel treatment options. PMID:25962619

De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder.

PubMed

Hamilton, P J; Campbell, N G; Sharma, S; Erreger, K; Herborg Hansen, F; Saunders, C; Belovich, A N; Sahai, M A; Cook, E H; Gether, U; McHaourab, H S; Matthies, H J G; Sutcliffe, J S; Galli, A

2013-12-01

De novo genetic variation is an important class of risk factors for autism spectrum disorder (ASD). Recently, whole-exome sequencing of ASD families has identified a novel de novo missense mutation in the human dopamine (DA) transporter (hDAT) gene, which results in a Thr to Met substitution at site 356 (hDAT T356M). The dopamine transporter (DAT) is a presynaptic membrane protein that regulates dopaminergic tone in the central nervous system by mediating the high-affinity reuptake of synaptically released DA, making it a crucial regulator of DA homeostasis. Here, we report the first functional, structural and behavioral characterization of an ASD-associated de novo mutation in the hDAT. We demonstrate that the hDAT T356M displays anomalous function, characterized as a persistent reverse transport of DA (substrate efflux). Importantly, in the bacterial homolog leucine transporter, substitution of A289 (the homologous site to T356) with a Met promotes an outward-facing conformation upon substrate binding. In the substrate-bound state, an outward-facing transporter conformation is required for substrate efflux. In Drosophila melanogaster, the expression of hDAT T356M in DA neurons-lacking Drosophila DAT leads to hyperlocomotion, a trait associated with DA dysfunction and ASD. Taken together, our findings demonstrate that alterations in DA homeostasis, mediated by aberrant DAT function, may confer risk for ASD and related neuropsychiatric conditions.

Pyrethroid pesticide-induced alterations in dopamine transporter function

DOE Office of Scientific and Technical Information (OSTI.GOV)

Elwan, Mohamed A.; Department of Environmental and Occupational Health, School of Medicine, Emory University, Atlanta, GA 30322; Richardson, Jason R.

Parkinson's disease (PD) is a progressive neurodegenerative disease affecting the nigrostriatal dopaminergic pathway. Several epidemiological studies have demonstrated an association between pesticide exposure and the incidence of PD. Studies from our laboratory and others have demonstrated that certain pesticides increase levels of the dopamine transporter (DAT), an integral component of dopaminergic neurotransmission and a gateway for dopaminergic neurotoxins. Here, we report that repeated exposure (3 injections over 2 weeks) of mice to two commonly used pyrethroid pesticides, deltamethrin (3 mg/kg) and permethrin (0.8 mg/kg), increases DAT-mediated dopamine uptake by 31 and 28%, respectively. Using cells stably expressing DAT, we determinedmore » that exposure (10 min) to deltamethrin and permethrin (1 nM-100 {mu}M) had no effect on DAT-mediated dopamine uptake. Extending exposures to both pesticides for 30 min (10 {mu}M) or 24 h (1, 5, and 10 {mu}M) resulted in significant decrease in dopamine uptake. This reduction was not the result of competitive inhibition, loss of DAT protein, or cytotoxicity. However, there was an increase in DNA fragmentation, an index of apoptosis, in cells exhibiting reduced uptake at 30 min and 24 h. These data suggest that up-regulation of DAT by in vivo pyrethroid exposure is an indirect effect and that longer-term exposure of cells results in apoptosis. Since DAT can greatly affect the vulnerability of dopamine neurons to neurotoxicants, up-regulation of DAT by deltamethrin and permethrin may increase the susceptibility of dopamine neurons to toxic insult, which may provide insight into the association between pesticide exposure and PD.« less

Zn(2+) site engineering at the oligomeric interface of the dopamine transporter.

PubMed

Norgaard-Nielsen, Kristine; Norregaard, Lene; Hastrup, Hanne; Javitch, Jonathan A; Gether, Ulrik

2002-07-31

Increasing evidence suggests that Na(+)/Cl(-)-dependent neurotransmitter transporters exist as homo-oligomeric proteins. However, the functional implication of this oligomerization remains unclear. Here we demonstrate the engineering of a Zn(2+) binding site at the predicted dimeric interface of the dopamine transporter (DAT) corresponding to the external end of transmembrane segment 6. Upon binding to this site, which involves a histidine inserted in position 310 (V310H) and the endogenous Cys306 within the same DAT molecule, Zn(2+) potently inhibits [(3)H]dopamine uptake. These data provide indirect evidence that conformational changes critical for the translocation process may occur at the interface between two transporter molecules in the oligomeric structure.

[Study of dopamine transporter imaging on the brain of children with autism].

PubMed

Sun, Xiaomian; Yue, Jing; Zheng, Chongxun

2008-04-01

This study was conducted to evaluate the applicability of 99mTc-2beta-[ N, N'-bis (2-mercaptoethyl) ethylenediamino]methyl,3beta(4-chlorophenyl)tropane(TRODAT-1) dopamine transporter(DAT) SPECT imaging in children with autism, and thus to provide an academic basis for the etiology, mechanism and clinical therapy of autism. Ten autistic children and ten healthy controls were examined with 99mTc-TRODAT-1 DAT SPECT imaging. Striatal specific uptake of 99mTc-TRODAT-1 was calculated with region of interest analysis according to the ratics between striatum and cerebellum [(STR-BKG)/BKG]. There was no statistically significant difference in semiquantitative dopamine transporter between the bilateral striata of autistic children (P=0.562), and between those of normal controls (p=0.573); Dopamine transporter in the brain of patients with autism increased significantly as compared with that in the brain of normal controls (P=0.017). Dopaminergic nervous system is dysfunctioning in the brain of children with autism, and DAT 99mTc-TRODAT-1 SPECT imaging on the brain will help the imaging diagnosis of childhcod autism.

Regulator of G protein signaling-12 modulates the dopamine transporter in ventral striatum and locomotor responses to psychostimulants.

PubMed

Gross, Joshua D; Kaski, Shane W; Schroer, Adam B; Wix, Kimberley A; Siderovski, David P; Setola, Vincent

2018-02-01

Regulators of G protein signaling are proteins that accelerate the termination of effector stimulation after G protein-coupled receptor activation. Many regulators of G protein signaling proteins are highly expressed in the brain and therefore considered potential drug discovery targets for central nervous system pathologies; for example, here we show that RGS12 is highly expressed in microdissected mouse ventral striatum. Given a role for the ventral striatum in psychostimulant-induced locomotor activity, we tested whether Rgs12 genetic ablation affected behavioral responses to amphetamine and cocaine. RGS12 loss significantly decreased hyperlocomotion to lower doses of both amphetamine and cocaine; however, other outcomes of administration (sensitization and conditioned place preference) were unaffected, suggesting that RGS12 does not function in support of the rewarding properties of these psychostimulants. To test whether observed response changes upon RGS12 loss were caused by changes to dopamine transporter expression and/or function, we prepared crude membranes from the brains of wild-type and RGS12-null mice and measured dopamine transporter-selective [ 3 H]WIN 35428 binding, revealing an increase in dopamine transporter levels in the ventral-but not dorsal-striatum of RGS12-null mice. To address dopamine transporter function, we prepared striatal synaptosomes and measured [ 3 H]dopamine uptake. Consistent with increased [ 3 H]WIN 35428 binding, dopamine transporter-specific [ 3 H]dopamine uptake in RGS12-null ventral striatal synaptosomes was found to be increased. Decreased amphetamine-induced locomotor activity and increased [ 3 H]WIN 35428 binding were recapitulated with an independent RGS12-null mouse strain. Thus, we propose that RGS12 regulates dopamine transporter expression and function in the ventral striatum, affecting amphetamine- and cocaine-induced increases in dopamine levels that specifically elicit acute hyperlocomotor responses.

Flipped Phenyl Ring Orientations of Dopamine Binding with Human and Drosophila Dopamine Transporters: Remarkable Role of Three Nonconserved Residues.

PubMed

Yuan, Yaxia; Zhu, Jun; Zhan, Chang-Guo

2018-03-09

Molecular modeling and molecular dynamics simulations were performed in the present study to examine the modes of dopamine binding with human and Drosophila dopamine transporters (hDAT and dDAT). The computational data revealed flipped binding orientations of dopamine in hDAT and dDAT due to the major differences in three key residues (S149, G153, and A423 of hDAT vs A117, D121, and S422 of dDAT) in the binding pocket. These three residues dictate the binding orientation of dopamine in the binding pocket, as the aromatic ring of dopamine tends to take an orientation with both the para- and meta-hydroxyl groups being close to polar residues and away from nonpolar residues of the protein. The flipped binding orientations of dopamine in hDAT and dDAT clearly demonstrate a generally valuable insight concerning how the species difference could drastically affect the protein-ligand binding modes, demonstrating that the species difference, which is a factor rarely considered in early drug design stage, must be accounted for throughout the ligand/drug design and discovery processes in general.

Diet-induced obesity: dopamine transporter function, impulsivity and motivation.

PubMed

Narayanaswami, V; Thompson, A C; Cassis, L A; Bardo, M T; Dwoskin, L P

2013-08-01

A rat model of diet-induced obesity (DIO) was used to determine dopamine transporter (DAT) function, impulsivity and motivation as neurobehavioral outcomes and predictors of obesity. To evaluate neurobehavioral alterations following the development of DIO induced by an 8-week high-fat diet (HF) exposure, striatal D2-receptor density, DAT function and expression, extracellular dopamine concentrations, impulsivity, and motivation for high- and low-fat reinforcers were determined. To determine predictors of DIO, neurobehavioral antecedents including impulsivity, motivation for high-fat reinforcers, DAT function and extracellular dopamine were evaluated before the 8-week HF exposure. Striatal D2-receptor density was determined by in vitro kinetic analysis of [(3)H]raclopride binding. DAT function was determined using in vitro kinetic analysis of [(3)H]dopamine uptake, methamphetamine-evoked [(3)H]dopamine overflow and no-net flux in vivo microdialysis. DAT cell-surface expression was determined using biotinylation and western blotting. Impulsivity and food-motivated behavior were determined using a delay discounting task and progressive ratio schedule, respectively. Relative to obesity-resistant (OR) rats, obesity-prone (OP) rats exhibited 18% greater body weight following an 8-week HF-diet exposure, 42% lower striatal D2-receptor density, 30% lower total DAT expression, 40% lower in vitro and in vivo DAT function, 45% greater extracellular dopamine and twofold greater methamphetamine-evoked [(3)H]dopamine overflow. OP rats exhibited higher motivation for food, and surprisingly, were less impulsive relative to OR rats. Impulsivity, in vivo DAT function and extracellular dopamine concentration did not predict DIO. Importantly, motivation for high-fat reinforcers predicted the development of DIO. Human studies are limited by their ability to determine if impulsivity, motivation and DAT function are causes or consequences of DIO. The current animal model shows that

Diet-induced obesity: dopamine transporter function, impulsivity and motivation

PubMed Central

Narayanaswami, V; Thompson, AC; Cassis, LA; Bardo, MT; Dwoskin, LP

2013-01-01

OBJECTIVE A rat model of diet-induced obesity (DIO) was used to determine dopamine transporter (DAT) function, impulsivity and motivation as neurobehavioral outcomes and predictors of obesity. DESIGN To evaluate neurobehavioral alterations following the development of DIO induced by an 8-week high-fat diet (HF) exposure, striatal D2-receptor density, DAT function and expression, extracellular dopamine concentrations, impulsivity, and motivation for high- and low-fat reinforcers were determined. To determine predictors of DIO, neurobehavioral antecedents including impulsivity, motivation for high-fat reinforcers, DAT function and extracellular dopamine were evaluated before the 8-week HF exposure. METHODS Striatal D2-receptor density was determined by in vitro kinetic analysis of [3H]raclopride binding. DAT function was determined using in vitro kinetic analysis of [3H]dopamine uptake, methamphetamine-evoked [3H]dopamine overflow and no-net flux in vivo microdialysis. DAT cell-surface expression was determined using biotinylation and western blotting. Impulsivity and food-motivated behavior were determined using a delay discounting task and progressive ratio schedule, respectively. RESULTS Relative to obesity-resistant (OR) rats, obesity-prone (OP) rats exhibited 18% greater body weight following an 8-week HF-diet exposure, 42% lower striatal D2-receptor density, 30% lower total DAT expression, 40% lower in vitro and in vivo DAT function, 45% greater extracellular dopamine and twofold greater methamphetamine-evoked [3H]dopamine overflow. OP rats exhibited higher motivation for food, and surprisingly, were less impulsive relative to OR rats. Impulsivity, in vivo DAT function and extracellular dopamine concentration did not predict DIO. Importantly, motivation for high-fat reinforcers predicted the development of DIO. CONCLUSION Human studies are limited by their ability to determine if impulsivity, motivation and DAT function are causes or consequences of DIO. The

Dopamine Transporter Genotype Predicts Attentional Asymmetry in Healthy Adults

ERIC Educational Resources Information Center

Newman, Daniel P.; O'Connell, Redmond G.; Nathan, Pradeep J.; Bellgrove, Mark A.

2012-01-01

A number of recent studies suggest that DNA variation in the dopamine transporter gene (DAT1) influences spatial attention asymmetry in clinical populations such as ADHD, but confirmation in non-clinical samples is required. Since non-spatial factors such as attentional load have been shown to influence spatial biases in clinical conditions, here…

Atrial Natriuretic Peptide Stimulates Dopamine Tubular Transport by Organic Cation Transporters: A Novel Mechanism to Enhance Renal Sodium Excretion

PubMed Central

Kouyoumdzian, Nicolás M.; Rukavina Mikusic, Natalia L.; Kravetz, María C.; Lee, Brenda M.; Carranza, Andrea; Del Mauro, Julieta S.; Pandolfo, Marcela; Gironacci, Mariela M.; Gorzalczany, Susana; Toblli, Jorge E.; Fernández, Belisario E.

2016-01-01

The aim of this study was to demonstrate the effects of atrial natriuretic peptide (ANP) on organic cation transporters (OCTs) expression and activity, and its consequences on dopamine urinary levels, Na+, K+-ATPase activity and renal function. Male Sprague Dawley rats were infused with isotonic saline solution during 120 minutes and randomized in nine different groups: control, pargyline plus tolcapone (P+T), ANP, dopamine (DA), D-22, DA+D-22, ANP+D-22, ANP+DA and ANP+DA+D-22. Renal functional parameters were determined and urinary dopamine concentration was quantified by HPLC. Expression of OCTs and D1-receptor in membrane preparations from renal cortex tissues were determined by western blot and Na+, K+-ATPase activity was determined using in vitro enzyme assay. 3H-DA renal uptake was determined in vitro. Compared to P+T group, ANP and dopamine infusion increased diuresis, urinary sodium and dopamine excretion significantly. These effects were more pronounced in ANP+DA group and reversed by OCTs blockade by D-22, demonstrating that OCTs are implied in ANP stimulated-DA uptake and transport in renal tissues. The activity of Na+, K+-ATPase exhibited a similar fashion when it was measured in the same experimental groups. Although OCTs and D1-receptor protein expression were not modified by ANP, OCTs-dependent-dopamine tubular uptake was increased by ANP through activation of NPR-A receptor and protein kinase G as signaling pathway. This effect was reflected by an increase in urinary dopamine excretion, natriuresis, diuresis and decreased Na+, K+-ATPase activity. OCTs represent a novel target that links the activity of ANP and dopamine together in a common mechanism to enhance their natriuretic and diuretic effects. PMID:27392042

Gβγ subunit activation promotes dopamine efflux through the dopamine transporter

PubMed Central

Garcia-Olivares, J; Baust, T; Harris, S; Hamilton, P; Galli, A; Amara, SG; Torres, GE

2018-01-01

The dopamine transporter (DAT) is an important regulator of brain dopamine (DA) homeostasis, controlling the intensity and duration of DA signaling. DAT is the target for psychostimulants—like cocaine and amphetamine—and plays an important role in neuropsychiatric disorders, including attention-deficit hyperactivity disorder and drug addiction. Thus, a thorough understanding of the mechanisms that regulate DAT function is necessary for the development of clinical interventions to treat DA-related brain disorders. Previous studies have revealed a plethora of protein–protein interactions influencing DAT cellular localization and activity, suggesting that the fine-tuning of DA homeostasis involves multiple mechanisms. We recently reported that G-protein beta-gamma (Gβγ) subunits bind directly to DAT and decrease DA clearance. Here we show that Gβγ induces the release of DA through DAT. Specifically, a Gβγ-binding/activating peptide, mSIRK, increases DA efflux through DAT in heterologous cells and primary dopaminergic neurons in culture. Addition of the Gβγ inhibitor gallein or DAT inhibitors prevents this effect. Residues 582 to 596 in the DAT carboxy terminus were identified as the primary binding site of Gβγ. A TAT peptide containing the Gβγ-interacting domain of DAT blocked the ability of mSIRK to induce DA efflux, consistent with a direct interaction of Gβγ with the transporter. Finally, activation of a G-protein-coupled receptor, the muscarinic M5R, results in DAT-mediated DA efflux through a Gβγ-dependent mechanism. Collectively, our data show that Gβγ interacts with DAT to promote DA efflux. This novel mechanism may have important implications in the regulation of brain DA homeostasis. PMID:28894302

Salvinorin A regulates dopamine transporter function via a kappa opioid receptor and ERK1/2-dependent mechanism.

PubMed

Kivell, Bronwyn; Uzelac, Zeljko; Sundaramurthy, Santhanalakshmi; Rajamanickam, Jeyaganesh; Ewald, Amy; Chefer, Vladimir; Jaligam, Vanaja; Bolan, Elizabeth; Simonson, Bridget; Annamalai, Balasubramaniam; Mannangatti, Padmanabhan; Prisinzano, Thomas E; Gomes, Ivone; Devi, Lakshmi A; Jayanthi, Lankupalle D; Sitte, Harald H; Ramamoorthy, Sammanda; Shippenberg, Toni S

2014-11-01

Salvinorin A (SalA), a selective κ-opioid receptor (KOR) agonist, produces dysphoria and pro-depressant like effects. These actions have been attributed to inhibition of striatal dopamine release. The dopamine transporter (DAT) regulates dopamine transmission via uptake of released neurotransmitter. KORs are apposed to DAT in dopamine nerve terminals suggesting an additional target by which SalA modulates dopamine transmission. SalA produced a concentration-dependent, nor-binaltorphimine (BNI)- and pertussis toxin-sensitive increase of ASP(+) accumulation in EM4 cells coexpressing myc-KOR and YFP-DAT, using live cell imaging and the fluorescent monoamine transporter substrate, trans 4-(4-(dimethylamino)-styryl)-N-methylpyridinium) (ASP(+)). Other KOR agonists also increased DAT activity that was abolished by BNI pretreatment. While SalA increased DAT activity, SalA treatment decreased serotonin transporter (SERT) activity and had no effect on norepinephrine transporter (NET) activity. In striatum, SalA increased the Vmax for DAT mediated DA transport and DAT surface expression. SalA up-regulation of DAT function is mediated by KOR activation and the KOR-linked extracellular signal regulated kinase-½ (ERK1/2) pathway. Co-immunoprecipitation and BRET studies revealed that DAT and KOR exist in a complex. In live cells, DAT and KOR exhibited robust FRET signals under basal conditions. SalA exposure caused a rapid and significant increase of the FRET signal. This suggests that the formation of KOR and DAT complexes is promoted in response to KOR activation. Together, these data suggest that enhanced DA transport and decreased DA release resulting in decreased dopamine signalling may contribute to the dysphoric and pro-depressant like effects of SalA and other KOR agonists. Copyright © 2014 Elsevier Ltd. All rights reserved.

miR-137 and miR-491 Negatively Regulate Dopamine Transporter Expression and Function in Neural Cells.

PubMed

Jia, Xiaojian; Wang, Feng; Han, Ying; Geng, Xuewen; Li, Minghua; Shi, Yu; Lu, Lin; Chen, Yun

2016-12-01

The dopamine transporter (DAT) is involved in the regulation of extracellular dopamine levels. A 40-bp variable-number tandem repeat (VNTR) polymorphism in the 3'-untranslated region (3'UTR) of the DAT has been reported to be associated with various phenotypes that are involved in the aberrant regulation of dopaminergic neurotransmission. In the present study, we found that miR-137 and miR-491 caused a marked reduction of DAT expression, thereby influencing neuronal dopamine transport. Moreover, the regulation of miR-137 and miR-491 on this transport disappeared after the DAT was silenced. The miR-491 seed region that is located on the VNTR sequence in the 3'UTR of the DAT and the regulatory effect of miR-491 on the DAT depended on the VNTR copy-number. These data indicate that miR-137 and miR-491 regulate DAT expression and dopamine transport at the post-transcriptional level, suggesting that microRNA may be targeted for the treatment of diseases associated with DAT dysfunction.

The structure and function of the dopamine transporter and its role in CNS diseases.

PubMed

McHugh, Patrick C; Buckley, David A

2015-01-01

In this chapter, we explore the basic science of the dopamine transporter (DAT), an integral component of a system that regulates dopamine homeostasis. Dopamine is a key neurotransmitter for several brain functions including locomotor control and reward systems. The transporter structure, function, mechanism of action, localization, and distribution, in addition to gene regulation, are discussed. Over many years, a wealth of information concerning the DAT has been accrued and has led to increased interest in the role of the DAT in a plethora of central nervous system diseases. These DAT characteristics are explored in relation to a range of neurological and neuropsychiatric diseases, with a particular focus on the genetics of the DAT. In addition, we discuss the pharmacology of the DAT and how this relates to disease and addiction. © 2015 Elsevier Inc. All rights reserved.

Striatal dopamine in Parkinson disease: A meta-analysis of imaging studies.

PubMed

Kaasinen, Valtteri; Vahlberg, Tero

2017-12-01

A meta-analysis of 142 positron emission tomography and single photon emission computed tomography studies that have investigated striatal presynaptic dopamine function in Parkinson disease (PD) was performed. Subregional estimates of striatal dopamine metabolism are presented. The aromatic L-amino-acid decarboxylase (AADC) defect appears to be consistently smaller than the dopamine transporter and vesicular monoamine transporter 2 defects, suggesting upregulation of AADC function in PD. The correlation between disease severity and dopamine loss appears linear, but the majority of longitudinal studies point to a negative exponential progression pattern of dopamine loss in PD. Ann Neurol 2017;82:873-882. © 2017 American Neurological Association.

Role of dopamine transporters in the behavioral effects of 3,4-methylenedioxymethamphetamine (MDMA) in nonhuman primates

PubMed Central

Fantegrossi, William E.; Bauzo, Rayna M.; Manvich, Daniel M.; Morales, Jose C.; Votaw, John R.; Goodman, Mark M.

2011-01-01

Rationale The interoceptive and reinforcing effects of 3,4-methylenedioxymethamphetamine (MDMA) are similar to those of psychostimulants, but the role of dopamine in the behavioral effects of MDMA is not well documented, especially in primates. Objective The aim of this study was to assess the role of dopamine in the behavioral effects of MDMA in two nonhuman primate species. Methods The behavioral effects of MDMA, with and without serotonergic or dopaminergic pretreatments, were studied in squirrel monkeys trained to respond under a fixed-interval schedule of stimulus termination; effects on caudate dopamine levels were studied in a separate group of squirrel monkeys using in vivo microdialysis. Positron emission tomography neuroimaging with the dopamine transporter (DAT) ligand [18F]FECNT was used to determine DAT occupancy by MDMA in rhesus monkeys. Results MDMA (0.5–1.5 mg/kg) did not induce behavioral stimulant effects, but the highest dose of MDMA suppressed responding. Pretreatment with fluoxetine (3.0 mg/kg) or the selective 5HT2A antagonist M100907 (0.03–0.3 mg/kg) attenuated the rate suppressing effects of MDMA. In contrast, pretreatment with the selective dopamine transporter inhibitor RTI-177 (0.1 mg/kg) did not alter the rate suppressing effects of MDMA. Administration of MDMA at a dose that suppressed operant behavior had negligible effects on extracellular dopamine. The percent DAT occupancy of MDMA at a dose that suppressed operant behavior also was marginal and reflected low in vivo potency for DAT binding. Conclusions Collectively, these results indicate that behaviorally relevant doses of MDMA do not induce behavioral stimulant or dopamine transporter-mediated effects in nonhuman primates. PMID:19421742

Role of dopamine transporters in the behavioral effects of 3,4-methylenedioxymethamphetamine (MDMA) in nonhuman primates.

PubMed

Fantegrossi, William E; Bauzo, Rayna M; Manvich, Daniel M; Morales, Jose C; Votaw, John R; Goodman, Mark M; Howell, Leonard L

2009-08-01

The interoceptive and reinforcing effects of 3,4-methylenedioxymethamphetamine (MDMA) are similar to those of psychostimulants, but the role of dopamine in the behavioral effects of MDMA is not well documented, especially in primates. The aim of this study was to assess the role of dopamine in the behavioral effects of MDMA in two nonhuman primate species. The behavioral effects of MDMA, with and without serotonergic or dopaminergic pretreatments, were studied in squirrel monkeys trained to respond under a fixed-interval schedule of stimulus termination; effects on caudate dopamine levels were studied in a separate group of squirrel monkeys using in vivo microdialysis. Positron emission tomography neuroimaging with the dopamine transporter (DAT) ligand [18F]FECNT was used to determine DAT occupancy by MDMA in rhesus monkeys. MDMA (0.5-1.5 mg/kg) did not induce behavioral stimulant effects, but the highest dose of MDMA suppressed responding. Pretreatment with fluoxetine (3.0 mg/kg) or the selective 5HT(2A) antagonist M100907 (0.03-0.3 mg/kg) attenuated the rate suppressing effects of MDMA. In contrast, pretreatment with the selective dopamine transporter inhibitor RTI-177 (0.1 mg/kg) did not alter the rate suppressing effects of MDMA. Administration of MDMA at a dose that suppressed operant behavior had negligible effects on extracellular dopamine. The percent DAT occupancy of MDMA at a dose that suppressed operant behavior also was marginal and reflected low in vivo potency for DAT binding. Collectively, these results indicate that behaviorally relevant doses of MDMA do not induce behavioral stimulant or dopamine transporter-mediated effects in nonhuman primates.

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

PubMed Central

Siciliano, Cody A.; Fordahl, Steve C.

2016-01-01

Cocaine addiction is a debilitating neuropsychiatric disorder characterized by uncontrolled cocaine intake, which is thought to be driven, at least in part, by cocaine-induced deficits in dopamine system function. A decreased ability of cocaine to elevate dopamine levels has been repeatedly observed as a consequence of cocaine use in humans, and preclinical work has highlighted tolerance to cocaine's effects as a primary determinant in the development of aberrant cocaine taking behaviors. Here we determined that cocaine self-administration in rats produced tolerance to the dopamine transporter-inhibiting effects of cocaine in the nucleus accumbens core, which was normalized following a 14 or 60 d abstinence period; however, although these rats appeared to be similar to controls, a single self-administered infusion of cocaine at the end of abstinence, even after 60 d, fully reinstated tolerance to cocaine's effects. A single cocaine infusion in a naive rat had no effect on cocaine potency, demonstrating that cocaine self-administration leaves the dopamine transporter in a “primed” state, which allows for cocaine-induced plasticity to be reinstated by a subthreshold cocaine exposure. Further, reinstatement of cocaine tolerance was accompanied by decreased cocaine-induced locomotion and escalated cocaine intake despite extended abstinence from cocaine. These data demonstrate that cocaine leaves a long-lasting imprint on the dopamine system that is activated by re-exposure to cocaine. Further, these results provide a potential mechanism for severe cocaine binge episodes, which occur even after sustained abstinence from cocaine, and suggest that treatments aimed at transporter sites may be efficacious in promoting binge termination following relapse. SIGNIFICANCE STATEMENT Tolerance is a DSM-V criterion for substance abuse disorders. Abusers consistently show reduced subjective effects of cocaine concomitant with reduced effects of cocaine at its main site of action

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

PubMed

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

2017-07-19

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

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

PubMed Central

Bisgaard, Heidi; Larsen, M. Andreas B.; Mazier, Sonia; Beuming, Thijs; Newman, Amy Hauck; Weinstein, Harel; Shi, Lei; Loland, Claus J.; Gether, Ulrik

2013-01-01

Analogues of benztropines (BZTs) are potent inhibitors of the dopamine transporter (DAT) but are less effective than cocaine as behavioral stimulants. As a result, there have been efforts to evaluate these compounds as leads for potential medication for cocaine addiction. Here we use computational modeling together with site-directed mutagenesis to characterize the binding site for BZTs in DAT. Docking into molecular models based on the structure of the bacterial homologue LeuT supported a BZT binding site that overlaps with the substrate binding pocket. In agreement, mutations of residues within the pocket, including Val1523.46* to Ala or Ile, Ser4228.60 to Ala and Asn1573.51 to Cys or Ala, resulted in decreased affinity for BZT and the analog JHW007, as assessed in [3H]dopamine uptake inhibition assays and/or [3H]CFT competition binding assay. A putative polar interaction of one of the phenyl ring fluorine substituents in JHW007 with Asn1573.51 was used as a criterion for determining likely binding poses and establish a structural context for the mutagenesis findings. The analysis positioned the other fluorine substituted phenyl ring of JHW007 in close proximity to Ala47910.51/Ala48010.52 in transmembrane segment (TM) 10. The lack of such an interaction for BZT led to a more tilted orientation, as compared to JHW007, bringing one of the phenyl rings even closer to Ala47910.51/Ala48010.52. Mutation of Ala47910.51 and Ala48010.52 to valines supported these predictions with a larger decrease in the affinity for BZT than for JHW007. Summarized, our data suggest that BZTs display a classical competitive binding mode with binding sites overlapping those of cocaine and dopamine. PMID:20816875

EFFECTS OF THE ORGANOCHLORINE PESTICIDE METHOXYCHLOR ON DOPAMINE METABOLITES AND TRANSPORTERS IN THE MOUSE BRAIN

PubMed Central

Schuh, Rosemary A.; Richardson, Jason R.; Gupta, Rupesh K.; Flaws, Jodi A.; Fiskum, Gary

2009-01-01

Pesticide exposure has been suggested as an increased risk factor in developing Parkinson’s disease (PD). While the molecular mechanism underlying this association is not clear, several studies have demonstrated a role for mitochondrial dysfunction and oxidative damage in PD. Although data on specific pesticides associated with PD are often lacking, several lines of evidence point to the potential involvement of the organochlorine class of pesticides. Previously, we have found that the organochlorine pesticide methoxychlor (mxc) causes mitochondrial dysfunction and oxidative stress in isolated mitochondria. Here, we sought to determine whether mxc-induced mitochondrial dysfunction results in oxidative damage and dysfunction of the dopamine system. Adult female CD1 mice were dosed with either vehicle (sesame oil) or mxc (16, 32, or 64 mg/kg/day) for 20 consecutive days. Following treatment, we observed a dose-related increase in protein carbonyl levels in non-synaptic mitochondria, indicating oxidative modification of mitochondrial proteins which may lead to mitochondrial dysfunction. Mxc exposure also caused a dose-related decrease in striatal levels of dopamine (16–31%), which were accompanied by decreased levels of the dopamine transporter (DAT; 35–48%) and the vesicular monoamine transporter 2 (VMAT2; 21–44%). Because mitochondrial dysfunction, oxidative damage, and decreased levels of DAT and VMAT2 are found in PD patients, our data suggests that mxc should be investigated as a possible candidate involved in the association of pesticides with increased risk for PD, particularly in highly-exposed populations. PMID:19459224

Serotonin and dopamine transporter PET changes in the premotor phase of LRRK2 parkinsonism: cross-sectional studies.

PubMed

Wile, Daryl J; Agarwal, Pankaj A; Schulzer, Michael; Mak, Edwin; Dinelle, Katherine; Shahinfard, Elham; Vafai, Nasim; Hasegawa, Kazuko; Zhang, Jing; McKenzie, Jessamyn; Neilson, Nicole; Strongosky, Audrey; Uitti, Ryan J; Guttman, Mark; Zabetian, Cyrus P; Ding, Yu-Shin; Adam, Mike; Aasly, Jan; Wszolek, Zbigniew K; Farrer, Matthew; Sossi, Vesna; Stoessl, A Jon

2017-05-01

People with Parkinson's disease can show premotor neurochemical changes in the dopaminergic and non-dopaminergic systems. Using PET, we assessed whether dopaminergic and serotonin transporter changes are similar in LRRK2 mutation carriers with Parkinson's disease and individuals with sporadic Parkinson's disease, and whether LRRK2 mutation carriers without motor symptoms show PET changes. We did two cross-sectional PET studies at the Pacific Parkinson's Research Centre in Vancouver, BC, Canada. We included LRRK2 mutation carriers with or without manifest Parkinson's disease, people with sporadic Parkinson's disease, and age-matched healthy controls, all aged 18 years or older. People with Parkinson's disease were diagnosed by a neurologist with movement disorder training, in accordance with the UK Parkinson's Disease Society Brain Bank criteria. LRRK2 carrier status was confirmed by bidirectional Sanger sequencing. In the first study, LRRK2 mutation carriers with or without manifest Parkinson's disease who were referred for investigation between July, 1999, and January, 2012, were scanned with PET tracers for the membrane dopamine transporter, and dopamine synthesis and storage ( 18 F-6-fluoro-L-dopa; 18 F-FDOPA). We compared findings with those in people with sporadic Parkinson's disease and age-matched healthy controls. In the second study, distinct groups of LRRK2 mutation carriers, individuals with sporadic Parkinson's disease, and age-matched healthy controls seen from November, 2012, to May, 2016, were studied with tracers for the serotonin transporter and vesicular monoamine transporter 2 (VMAT2). Striatal dopamine transporter binding, VMAT2 binding, 18 F-FDOPA uptake, and serotonin transporter binding in multiple brain regions were compared by ANCOVA, adjusted for age. Between January, 1997, and January, 2012, we obtained data for our first study from 40 LRRK2 mutation carriers, 63 individuals with sporadic Parkinson's disease, and 35 healthy controls. We

Brain Region-Specific Trafficking of the Dopamine Transporter

PubMed Central

Block, Ethan R.; Nuttle, Jacob; Balcita-Pedicino, Judith Joyce; Caltagarone, John; Watkins, Simon C.

2015-01-01

The dopamine (DA) transporter (DAT) controls dopaminergic neurotransmission by removing extracellular DA. Although DA reuptake is proposed to be regulated by DAT traffic to and from the cell surface, the membrane trafficking system involved in the endocytic cycling of DAT in the intact mammalian brain has not been characterized. Hence, we performed immunolabeling and quantitative analysis of the subcellular and regional distribution of DAT using the transgenic knock-in mouse expressing hemagglutinin (HA) epitope-tagged DAT (HA-DAT) and by using a combination of electron microscopy and a novel method for immunofluorescence labeling of HA-DAT in acute sagittal brain slices. Both approaches demonstrated that, in midbrain somatodendritic regions, HA-DAT was present in the plasma membrane, endoplasmic reticulum, and Golgi complex, with a small fraction in early and recycling endosomes and an even smaller fraction in late endosomes and lysosomes. In the striatum and in axonal tracts between the midbrain and striatum, HA-DAT was detected predominantly in the plasma membrane, and quantitative analysis revealed increased DAT density in striatal compared with midbrain plasma membranes. Endosomes were strikingly rare and lysosomes were absent in striatal axons, in which there was little intracellular HA-DAT. Acute administration of amphetamine in vivo (60 min) or to slices ex vivo (10–60 min) did not result in detectable changes in DAT distribution. Altogether, these data provide evidence for regional differences in DAT plasma membrane targeting and retention and suggest a surprisingly low level of endocytic trafficking of DAT in the striatum along with limited DAT endocytic activity in somatodendritic areas. SIGNIFICANCE STATEMENT The dopamine transporter (DAT) is the key regulator of the dopamine neurotransmission in the CNS. In the present study, we developed a new approach for studying DAT localization and dynamics in intact neurons in acute sagittal brain slices from

Synthesis and dopamine transporter imaging in rhesus monkeys with fluorine-18 labeled FECT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Keil, R.; Hoffman, J.M.; Eschima, D.

1996-05-01

Parkinson`s patients have been shown to suffer a 60-80% loss of dopamine transporters in the substantia nigra and striatum. Dopamine transporter ligands labeled with fluorine-18 (t {1/2}=110 min) are attractive probes for measuring the density of dopamine transporter sites n the striatum for the diagnosis and evaluation of Parkinson`s patients by PET. We have synthesized (Ki = 32 nM vs RTI-55), fluorine-18 labeled 2{beta}-carbomethoxy-3{beta}(4-chlorophenyl)-8-(3-fluoropropyl)nortropane (FECT), with favorable kinetics as a potential dopamine transporter PET imaging agent. Treatment of 2{beta}-carbomethoxy-3{beta}-(4-chlorophenyl)nortropane (1) with 1-bromo-2-fluoroethane (2) in CH3CN at 80{degrees}C gave FECT (3). [F-18]FECT (3) was prepared by treating 1,2-ditosyloxyethane (4) with NCAmore » K[F-18]/K222 (365 mCi) for 5 min in CH3CN at 85{degrees}C to give [F-18] 1-fluoro-2-tosyloxyethane (5) (175 mCi)in 59% E.O.B. yield. Coupling of [F-18] 5 with 1 in DMF at 135 {degrees}C for 45 min gave [F-18]FECT (41 mCi) in 25% yield E.O.B. following HPLC purification in a total synthesis time of 122 min. [F-18] 5 was >99% radiochemically pure with a specific activity of 5 Ci/{mu}mole. Following intravenous administration to a rhesus monkey [F-18]FECT (8.13 mCi) showed a peak uptake at 30 min in the striatum (S) followed by a slow clearance and a rapid washout from the cerebellum to afford a high S/C ratio = 11.0 at 125 min. Radio-HPLC analysis of the ether extracts form plasma samples for radioactive metabolites detected only the presence of [F-18]FECT. These results suggest that FECT is an Research supported by DOE.« less

Longitudinal imaging of the availability of dopamine transporter and D2 receptor in rat striatum following mild ischemia.

PubMed

Momosaki, Sotaro; Ito, Miwa; Yamato, Hiroko; Iimori, Hitoshi; Sumiyoshi, Hirokazu; Morimoto, Kenji; Imamoto, Natsumi; Watabe, Tadashi; Shimosegawa, Eku; Hatazawa, Jun; Abe, Kohji

2017-02-01

The changes in the availability of striatal dopamine transporter and dopamine D2 receptor after mild focal ischemia in rats were measured using a small animal positron emission tomography system. Mild focal ischemia was induced by 20-minute middle cerebral artery occlusion. [ 11 C]PE2I binding to dopamine transporter was transiently increased on the ipsilateral side of the striatum at 2 days after middle cerebral artery occlusion. On day 7 and 14 after middle cerebral artery occlusion, [ 11 C]PE2I binding levels were decreased. In contrast, [ 11 C]raclopride binding to dopamine D2 receptor in the ipsilateral striatum had not changed at 2 days after middle cerebral artery occlusion. [ 11 C]Raclopride binding was significantly decreased on the ischemic side of the striatum at 7 and 14 days after middle cerebral artery occlusion. Moreover, on day 1 and 2 after middle cerebral artery occlusion, significant circling behavior to the contralateral direction was induced by amphetamine challenge. This behavior disappeared at 7 days after middle cerebral artery occlusion. At 14 days, circling behavior to the ipsilateral direction (middle cerebral artery occlusion side) was significantly increased, and that to the contralateral direction also appeared again. The present study suggested that amphetamine-induced circling behavior indicated striatal dopaminergic alterations and that dopamine transporter and dopamine D2 receptor binding could be key markers for predicting motor dysfunction after mild focal ischemia.

Altered effect of dopamine transporter 3'UTR VNTR genotype on prefrontal and striatal function in schizophrenia.

PubMed

Prata, Diana P; Mechelli, Andrea; Picchioni, Marco M; Fu, Cynthia H Y; Toulopoulou, Timothea; Bramon, Elvira; Walshe, Muriel; Murray, Robin M; Collier, David A; McGuire, Philip

2009-11-01

The dopamine transporter plays a key role in the regulation of central dopaminergic transmission, which modulates cognitive processing. Disrupted dopamine function and impaired executive processing are robust features of schizophrenia. To examine the effect of a polymorphism in the dopamine transporter gene (the variable number of tandem repeats in the 3' untranslated region) on brain function during executive processing in healthy volunteers and patients with schizophrenia. We hypothesized that this variation would have a different effect on prefrontal and striatal activation in schizophrenia, reflecting altered dopamine function. Case-control study. Psychiatric research center. Eighty-five subjects, comprising 44 healthy volunteers (18 who were 9-repeat carriers and 26 who were 10-repeat homozygotes) and 41 patients with DSM-IV schizophrenia (18 who were 9-repeat carriers and 23 who were 10-repeat homozygotes). Regional brain activation during word generation relative to repetition in an overt verbal fluency task measured by functional magnetic resonance imaging. Main effects of genotype and diagnosis on activation and their interaction were estimated with analysis of variance in SPM5. Irrespective of diagnosis, the 10-repeat allele was associated with greater activation than the 9-repeat allele in the left anterior insula and right caudate nucleus. Trends for the same effect in the right insula and for greater deactivation in the rostral anterior cingulate cortex were also detected. There were diagnosis x genotype interactions in the left middle frontal gyrus and left nucleus accumbens, where the 9-repeat allele was associated with greater activation than the 10-repeat allele in patients but not controls. Insular, cingulate, and striatal function during an executive task is normally modulated by variation in the dopamine transporter gene. Its effect on activation in the dorsolateral prefrontal cortex and ventral striatum is altered in patients with schizophrenia

Missense dopamine transporter mutations associate with adult parkinsonism and ADHD

PubMed Central

Hansen, Freja H.; Skjørringe, Tina; Yasmeen, Saiqa; Arends, Natascha V.; Sahai, Michelle A.; Erreger, Kevin; Andreassen, Thorvald F.; Holy, Marion; Hamilton, Peter J.; Neergheen, Viruna; Karlsborg, Merete; Newman, Amy H.; Pope, Simon; Heales, Simon J.R.; Friberg, Lars; Law, Ian; Pinborg, Lars H.; Sitte, Harald H.; Loland, Claus; Shi, Lei; Weinstein, Harel; Galli, Aurelio; Hjermind, Lena E.; Møller, Lisbeth B.; Gether, Ulrik

2014-01-01

Parkinsonism and attention deficit hyperactivity disorder (ADHD) are widespread brain disorders that involve disturbances of dopaminergic signaling. The sodium-coupled dopamine transporter (DAT) controls dopamine homeostasis, but its contribution to disease remains poorly understood. Here, we analyzed a cohort of patients with atypical movement disorder and identified 2 DAT coding variants, DAT-Ile312Phe and a presumed de novo mutant DAT-Asp421Asn, in an adult male with early-onset parkinsonism and ADHD. According to DAT single-photon emission computed tomography (DAT-SPECT) scans and a fluoro-deoxy-glucose-PET/MRI (FDG-PET/MRI) scan, the patient suffered from progressive dopaminergic neurodegeneration. In heterologous cells, both DAT variants exhibited markedly reduced dopamine uptake capacity but preserved membrane targeting, consistent with impaired catalytic activity. Computational simulations and uptake experiments suggested that the disrupted function of the DAT-Asp421Asn mutant is the result of compromised sodium binding, in agreement with Asp421 coordinating sodium at the second sodium site. For DAT-Asp421Asn, substrate efflux experiments revealed a constitutive, anomalous efflux of dopamine, and electrophysiological analyses identified a large cation leak that might further perturb dopaminergic neurotransmission. Our results link specific DAT missense mutations to neurodegenerative early-onset parkinsonism. Moreover, the neuropsychiatric comorbidity provides additional support for the idea that DAT missense mutations are an ADHD risk factor and suggests that complex DAT genotype and phenotype correlations contribute to different dopaminergic pathologies. PMID:24911152

Essential Oils from the Medicinal Herbs Upregulate Dopamine Transporter in Rat Pheochromocytoma Cells.

PubMed

Choi, Min Sun; Choi, Bang-sub; Kim, Sang Heon; Pak, Sok Cheon; Jang, Chul Ho; Chin, Young-Won; Kim, Young-Mi; Kim, Dong-il; Jeon, Songhee; Koo, Byung-Soo

2015-10-01

The dopamine transporter (DAT) protein, a component of the dopamine system, undergoes adaptive neurobiological changes from drug abuse. Prevention of relapse and reduction of withdrawal symptoms are still the major limitations in the current pharmacological treatments of drug addiction. The present study aimed to investigate the effects of essential oils extracted from Elsholtzia ciliata, Shinchim, Angelicae gigantis Radix, and Eugenia caryophyllata, well-known traditional Korean medicines for addiction, on the modulation of dopamine system in amphetamine-treated cells and to explore the possible mechanism underlying its therapeutic effect. The potential cytotoxic effect of essential oils was evaluated in PC12 rat pheochromocytoma cells using cell viability assays. Quantification of DAT, p-CREB, p-MAPK, and p-Akt was done by immunoblotting. DAT was significantly reduced in cells treated with 50 μM of amphetamine in a time-dependent manner. No significant toxicity of essential oils from Elsholtzia ciliata and Shinchim was observed at doses of 10, 25, and 50 μg/mL. However, essential oils from A. gigantis Radix at a dose of 100 μg/mL and E. caryophyllata at doses of 50 and 100 μg/mL showed cytotoxicity. Treatment with GBR 12909, a highly selective DAT inhibitor, significantly increased DAT expression compared with that of amphetamine only by enhancing phosphorylation of mitogen-activated protein kinases (MAPK) and Akt. In addition, essential oils effectively induced hyperphosphorylation of cyclic-AMP response element-binding protein (CREB), MAPK, and Akt, which resulted in DAT upregulation. Our study implies that the essential oils may rehabilitate brain dopamine function through increased DAT availability in abstinent former drug users.

Serotonin and Dopamine Gene Variation and Theory of Mind Decoding Accuracy in Major Depression: A Preliminary Investigation.

PubMed

Zahavi, Arielle Y; Sabbagh, Mark A; Washburn, Dustin; Mazurka, Raegan; Bagby, R Michael; Strauss, John; Kennedy, James L; Ravindran, Arun; Harkness, Kate L

2016-01-01

Theory of mind-the ability to decode and reason about others' mental states-is a universal human skill and forms the basis of social cognition. Theory of mind accuracy is impaired in clinical conditions evidencing social impairment, including major depressive disorder. The current study is a preliminary investigation of the association of polymorphisms of the serotonin transporter (SLC6A4), dopamine transporter (DAT1), dopamine receptor D4 (DRD4), and catechol-O-methyl transferase (COMT) genes with theory of mind decoding in a sample of adults with major depression. Ninety-six young adults (38 depressed, 58 non-depressed) completed the 'Reading the Mind in the Eyes task' and a non-mentalistic control task. Genetic associations were only found for the depressed group. Specifically, superior accuracy in decoding mental states of a positive valence was seen in those homozygous for the long allele of the serotonin transporter gene, 9-allele carriers of DAT1, and long-allele carriers of DRD4. In contrast, superior accuracy in decoding mental states of a negative valence was seen in short-allele carriers of the serotonin transporter gene and 10/10 homozygotes of DAT1. Results are discussed in terms of their implications for integrating social cognitive and neurobiological models of etiology in major depression.

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

PubMed

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

2017-05-01

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

PET evaluation of the dopamine system of the human brain

DOE Office of Scientific and Technical Information (OSTI.GOV)

Volkow, N.D.; Fowler, J.S.; Gatley, S.

1996-07-01

Dopamine plays a pivotal role in the regulation and control of movement, motivation and cognition. It also is closely linked to reward, reinforcement and addiction. Abnormalities in brain dopamine are associated with many neurological and psychiatric disorders including Parkinson`s disease, schizophrenia and substance abuse. This close association between dopamine and neurological and psychiatric diseases and with substance abuse make it an important topic in research in the neurosciences and an important molecular target in drug development. PET enables the direct measurement of components of the dopamine system in the living human brain. It relies on radiotracers which label dopamine receptors,more » dopamine transporters, precursors of dopamine or compounds which have specificity for the enzymes which degrade dopamine. Additionally, by using tracers that provide information on regional brain metabolism or blood flow as well as neurochemically specific pharmacological interventions, PET can be used to assess the functional consequences of change in brain dopamine activity. PET dopamine measurements have been used to investigate the normal human brain and its involvement in psychiatric and neurological diseases. It has also been used in psychopharmacological research to investigate dopamine drugs used in the treatment of Parkinson`s disease and of schizophrenia as well as to investigate the effects of drugs of abuse on the dopamine system. Since various functional and neurochemical parameters can be studied in the same subject, PET enables investigation of the functional integrity of the dopamine system in the human brain and investigation of the interactions of dopamine with other neurotransmitters. This paper summarizes the different tracers and experimental strategies developed to evaluate the various elements of the dopamine system in the human brain with PET and their applications to clinical research. 254 refs., 7 figs., 3 tabs.« less

Dopamine Transporter Genotype Conveys Familial Risk of Attention-Deficit/Hyperactivity Disorder through Striatal Activation

ERIC Educational Resources Information Center

Durston, Sarah; Fossella, John A.; Mulder, Martijn J.; Casey B. J.; Ziermans, Tim B.; Vessaz, M. Nathalie; Van Engeland, Herman

2008-01-01

The study examines the effect of the dopamine transporter (DAT1) genotype in attention-deficit/hyperactivity disorder (ADHD). The results confirm that DAT1 translates the genetic risk of ADHD through striatal activation.

Molecular dynamics of conformation-specific dopamine transporter-inhibitor complexes.

PubMed

Jean, Bernandie; Surratt, Christopher K; Madura, Jeffry D

2017-09-01

The recreational psychostimulant cocaine inhibits dopamine reuptake from the synapse, resulting in excessive stimulation of postsynaptic dopamine receptors in brain areas associated with reward and addiction. Cocaine binds to and stabilizes the outward- (extracellular-) facing conformation of the dopamine transporter (DAT) protein, while the low abuse potential DAT inhibitor benztropine prefers the inward- (cytoplasmic-) facing conformation. A correlation has been previously postulated between psychostimulant abuse potential and preference for the outward-facing DAT conformation. The 3β-aryltropane cocaine analogs LX10 and LX11, however, differ only in stereochemistry and share a preference for the outward-facing DAT, yet are reported to vary widely in abuse potential in an animal model. In search of the molecular basis for DAT conformation preference, complexes of cocaine, benztropine, LX10 or LX11 bound to each DAT conformation were subjected to 100ns of all-atom molecular dynamics simulation. Results were consistent with previous findings from cysteine accessibility assays used to assess an inhibitor's DAT conformation preference. The respective 2β- and 2α-substituted phenyltropanes of LX10 and LX11 interacted with hydrophobic regions of the DAT S1 binding site that were inaccessible to cocaine. Solvent accessibility measurements also revealed subtle differences in inhibitor positioning within a given DAT conformation. This work serves to advance our understanding of the conformational selectivity of DAT inhibitors and suggests that MD may be useful in antipsychostimulant therapeutic design. Copyright © 2017 Elsevier Inc. All rights reserved.

Molecular mechanism: the human dopamine transporter histidine 547 regulates basal and HIV-1 Tat protein-inhibited dopamine transport

PubMed Central

Quizon, Pamela M.; Sun, Wei-Lun; Yuan, Yaxia; Midde, Narasimha M.; Zhan, Chang-Guo; Zhu, Jun

2016-01-01

Abnormal dopaminergic transmission has been implicated as a risk determinant of HIV-1-associated neurocognitive disorders. HIV-1 Tat protein increases synaptic dopamine (DA) levels by directly inhibiting DA transporter (DAT) activity, ultimately leading to dopaminergic neuron damage. Through integrated computational modeling prediction and experimental validation, we identified that histidine547 on human DAT (hDAT) is critical for regulation of basal DA uptake and Tat-induced inhibition of DA transport. Compared to wild type hDAT (WT hDAT), mutation of histidine547 (H547A) displayed a 196% increase in DA uptake. Other substitutions of histidine547 showed that DA uptake was not altered in H547R but decreased by 99% in H547P and 60% in H547D, respectively. These mutants did not alter DAT surface expression or surface DAT binding sites. H547 mutants attenuated Tat-induced inhibition of DA transport observed in WT hDAT. H547A displays a differential sensitivity to PMA- or BIM-induced activation or inhibition of DAT function relative to WT hDAT, indicating a change in basal PKC activity in H547A. These findings demonstrate that histidine547 on hDAT plays a crucial role in stabilizing basal DA transport and Tat-DAT interaction. This study provides mechanistic insights into identifying targets on DAT for Tat binding and improving DAT-mediated dysfunction of DA transmission. PMID:27966610

Atypical dopamine efflux caused by 3,4-methylenedioxypyrovalerone (MDPV) via the human dopamine transporter.

PubMed

Shekar, Aparna; Aguilar, Jenny I; Galli, Greta; Cozzi, Nicholas V; Brandt, Simon D; Ruoho, Arnold E; Baumann, Michael H; Matthies, Heinrich J G; Galli, Aurelio

2017-10-01

Synthetic cathinones are similar in chemical structure to amphetamines, and their behavioral effects are associated with enhanced dopaminergic signaling. The past ten years of research on the common constituent of bath salts, MDPV (the synthetic cathinone 3,4-methylenedioxypyrovalerone), has aided the understanding of how synthetic cathinones act at the dopamine (DA) transporter (DAT). Several groups have described the ability of MDPV to block the DAT with high-affinity. In this study, we demonstrate for the first time a new mode of action of MDPV, namely its ability to promote DAT-mediated DA efflux. Using single cell amperometric assays, we determined that low concentrations of MDPV (1nM) can cause reverse transport of DA via DAT. Notably, administration of MDPV leads to hyperlocomotion in Drosophila melanogaster. These data describe further how MDPV acts at the DAT, possibly paving the way for novel treatment strategies for individuals who abuse bath salts. Copyright © 2017 Elsevier B.V. All rights reserved.

Dopamine Transporter Neuroimaging as an Enrichment Biomarker in Early Parkinson's Disease Clinical Trials: A Disease Progression Modeling Analysis

PubMed Central

Nicholas, Timothy; Tsai, Kuenhi; Macha, Sreeraj; Sinha, Vikram; Stone, Julie; Corrigan, Brian; Bani, Massimo; Muglia, Pierandrea; Watson, Ian A.; Kern, Volker D.; Sheveleva, Elena; Marek, Kenneth; Stephenson, Diane T.; Romero, Klaus

2017-01-01

Abstract Given the recognition that disease‐modifying therapies should focus on earlier Parkinson's disease stages, trial enrollment based purely on clinical criteria poses significant challenges. The goal herein was to determine the utility of dopamine transporter neuroimaging as an enrichment biomarker in early motor Parkinson's disease clinical trials. Patient‐level longitudinal data of 672 subjects with early‐stage Parkinson's disease in the Parkinson's Progression Markers Initiative (PPMI) observational study and the Parkinson Research Examination of CEP‐1347 Trial (PRECEPT) clinical trial were utilized in a linear mixed‐effects model analysis. The rate of worsening in the motor scores between subjects with or without a scan without evidence of dopamine transporter deficit was different both statistically and clinically. The average difference in the change from baseline of motor scores at 24 months between biomarker statuses was –3.16 (90% confidence interval [CI] = –0.96 to –5.42) points. Dopamine transporter imaging could identify subjects with a steeper worsening of the motor scores, allowing trial enrichment and 24% reduction of sample size. PMID:28749580

Amphetamine Paradoxically Augments Exocytotic Dopamine Release and Phasic Dopamine Signals

PubMed Central

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

Persistent cognitive and dopamine transporter deficits in abstinent methamphetamine users.

PubMed

McCann, Una D; Kuwabara, Hiroto; Kumar, Anil; Palermo, Michael; Abbey, Rubyna; Brasic, James; Ye, Weiguo; Alexander, Mohab; Dannals, Robert F; Wong, Dean F; Ricaurte, George A

2008-02-01

Studies in abstinent methamphetamine (METH) users have demonstrated reductions in brain dopamine transporter (DAT) binding potential (BP), as well as cognitive and motor deficits, but it is not yet clear whether cognitive deficits and brain DAT reductions fully reverse with sustained abstinence, or whether behavioral deficits in METH users are related to dopamine (DA) deficits. This study was conducted to further investigate potential persistent psychomotor deficits secondary to METH abuse, and their relationship to brain DAT availability, as measured using quantitative PET methods with [(11)C]WIN 35428. Twenty-two abstinent METH users and 17 healthy non-METH using controls underwent psychometric testing to test the hypothesis that METH users would demonstrate selective deficits in neuropsychiatric domains known to involve DA neurons (e.g., working memory, executive function, motor function). A subset of subjects also underwent PET scanning with [(11)C]WIN 35428. METH users were found to have modest deficits in short-term memory, executive function, and manual dexterity. Exploratory correlational analyses revealed that deficits in memory, but not those in executive or motor function, were associated with decreases in striatal DAT BP. These results suggest a possible relationship between DAT BP and memory deficits in abstinent METH users, and lend support to the notion that METH produces lasting effects on central DA neurons in humans. As METH can also produce toxic effects on serotonin (5-HT) neurons, further study is needed to address the potential role of brain 5-HT depletion in cognitive deficits in abstinent METH users. (c) 2007 Wiley-Liss, Inc.

Dopamine transport by the serotonin transporter: a mechanistically distinct mode of substrate translocation

PubMed Central

Larsen, Mads Breum; Sonders, Mark S.; Mortensen, Ole Valente; Larson, Gaynor A.; Zahniser, Nancy R.; Amara, Susan G.

2011-01-01

The serotonin transporter (SERT) is the principal mechanism for terminating serotonin (5HT) signals in the nervous system and is a site of action for a variety of psychoactive drugs including antidepressants, amphetamines, and cocaine. Here we show that human SERTs (hSERTs) and rat SERTs are capable of robust dopamine (DA) uptake through a process that differs mechanistically from 5HT transport in several unanticipated ways. DA transport by hSERT has a higher maximum velocity than 5HT transport, requires significantly higher Na+ and Cl− concentrations to sustain transport, is inhibited non-competitively by 5HT and is more sensitive to SERT inhibitors, including selective serotonin reuptake inhibitors (SSRIs). We use a thiol reactive methane thiosulfonate (MTS) reagent to modify a conformationally-sensitive cysteine residue to demonstrate that hSERT spends more time in an outward facing conformation when transporting DA than when transporting 5HT. Co-transfection of an inactive or an MTS-sensitive SERT with wild type SERT subunits reveals an absence of cooperative interactions between subunits during DA, but not 5HT transport. To establish the physiological relevance of this mechanism for DA clearance, we show using in vivo high-speed chronoamperometry that SERT has the capacity to clear extracellularly applied DA in the hippocampal CA3 region of anesthetized rats. Together, these observations suggest the possibility that SERT serves as a DA transporter in vivo and highlight the idea that there can be distinct modes of transport of alternative physiological substrates by SERT. PMID:21525301

Differential action of methamphetamine on tyrosine hydroxylase and dopamine transport in the nigrostriatal pathway of μ-opioid receptor knockout mice.

PubMed

Park, Sang Won; He, Zhi; Shen, Xine; Roman, Richard J; Ma, Tangeng

2012-06-01

Extensive anatomical and functional interactions exist between central dopaminergic and opioidergic systems and both systems are proposed to be targets for amphetamine-like drugs. We have previously reported that μ-opioid receptor (μ-OR) knockout mice are resistant to the loss of dopamine in the striatum and the development of behavioral sensitization induced by repeated methamphetamine (METH) treatment. The present study assessed whether METH-treated μ-OR knockout mice exhibit a differential response of the expression of dopamine transporter and tyrosine hydroxylase (TH), the rate-limiting enzyme for dopamine synthesis and maintaining dopamine levels. Mice daily received intraperitoneal injection of METH (0, 0.6, 2.5, or 10 mg/kg) for 7 days and sacrificed on day 11 (4 days after the last injection). The expression of TH protein in the striatum and the levels of TH mRNA and number of TH positive neurons in the substantia nigra were reduced in wild-type mice treated with METH (2.5 and 10 mg/kg), but not in the μ-OR knockout mice. In contrast, METH exposure at the highest dose (10 mg/kg) reduced dopamine transporter levels in both strains of mice. These results suggest that the μ-OR contributes to METH-induced loss of dopamine and behavioral sensitization by decreasing the expression of TH.

Effects of a short-course MDMA binge on dopamine transporter binding and on levels of dopamine and its metabolites in adult male rats

PubMed Central

Biezonski, Dominik K.; Piper, Brian J.; Shinday, Nina M.; Kim, Peter J.; Ali, Syed F.; Meyer, Jerrold S.

2013-01-01

Although the recreational drug 3,4-methylenedioxymethamphetamine (MDMA) is often described as a selective serotonergic neurotoxin, some research has challenged this view. The objective of this study was to determine the influence of MDMA on subsequent levels of two different markers of dopaminergic function, the dopamine transporter (DAT) as well as dopamine and its major metabolites. In experiment I, adult male Sprague–Dawley rats were administered either a low or moderate dose MDMA binge (2.5 or 5.0 mg/kg × 4 with an inter-dose interval of 1 h) or saline, and were killed 1 week later. The moderate dose dramatically reduced [3H]WIN 35,428 binding to striatal DAT by 73.7% (P ≤ 0.001). In experiment II, animals were binged with a higher dose of MDMA (10 mg/kg × 4) to determine the drug’s effects on concentrations of serotonin (5-HT), dopamine, and their respective major metabolites 5-hydroxyindoleacetic acid (5-HIAA), dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in the striatum and frontal cortex 1 week later. As expected, MDMA significantly reduced 5-HT and 5-HIAA (≥ 50%) in these structures, while only a marginal decrease in dopamine was noted in the striatum. In contrast, levels of DOPAC (34.3%, P < 0.01) and HVA (33.5%, P < 0.001) were reduced by MDMA treatment, suggesting a decrease in dopamine turnover. Overall, these findings indicate that while serotonergic markers are particularly vulnerable to MDMA-induced depletion, significant dopaminergic deficits may also occur under some conditions. Importantly, DAT expression may be more vulnerable to perturbation by MDMA than dopamine itself. PMID:23276666

The effects of benzofury (5-APB) on the dopamine transporter and 5-HT2-dependent vasoconstriction in the rat.

PubMed

Dawson, Patrick; Opacka-Juffry, Jolanta; Moffatt, James D; Daniju, Yusuf; Dutta, Neelakshi; Ramsey, John; Davidson, Colin

2014-01-03

5-APB, commonly marketed as 'benzofury' is a new psychoactive substance and erstwhile 'legal high' which has been implicated in 10 recent drug-related deaths in the UK. This drug was available on the internet and in 'head shops' and was one of the most commonly sold legal highs up until its recent UK temporary ban (UK Home Office). Despite its prominence, very little is known about its pharmacology. This study was undertaken to examine the pharmacology of 5-APB in vitro. We hypothesised that 5-APB would activate the dopamine and 5-HT systems which may underlie its putative stimulant and hallucinogenic effects. Autoradiographic studies showed that 5-APB displaced both [(125)I] RTI-121 and [(3)H] ketanserin from rat brain tissue suggesting affinity at the dopamine transporter and 5-HT2 receptor sites respectively. Voltammetric studies in rat accumbens brain slices revealed that 5-APB slowed dopamine reuptake, and at high concentrations caused reverse transport of dopamine. 5-APB also caused vasoconstriction of rat aorta, an effect antagonised by the 5-HT2A receptor antagonist ketanserin, and caused contraction of rat stomach fundus, which was reversed by the 5-HT2B receptor antagonist RS-127445. These data show that 5-APB interacts with the dopamine transporter and is an agonist at the 5-HT2A and 5-HT2B receptors in the rat. Thus 5-APB's pharmacology is consistent with it having both stimulant and hallucinogenic properties. In addition, 5-APB's activity at the 5-HT2B receptor may cause cardiotoxicity. © 2013.

Long-term dopamine transporter expression and normal cellular distribution of mitochondria in dopaminergic neuron transplants in Parkinson’s disease patients

PubMed Central

Hallett, Penelope J; Cooper, Oliver; Sadi, Damaso; Robertson, Harold; Mendez, Ivar; Isacson, Ole

2014-01-01

Summary To determine the long-term health and function of transplanted dopamine neurons in Parkinson’s disease (PD) patients, the expression of dopamine transporters (DAT) and mitochondrial morphology was examined in human fetal midbrain cellular transplants. DAT was robustly expressed in transplanted dopamine neuron terminals in the reinnervated host putamen and caudate, for at least 14 years after transplantation. The transplanted dopamine neurons showed a healthy and non-atrophied morphology at all time points. Labeling of the mitochondrial outer membrane protein Tom20 and alpha-synuclein showed typical cellular pathology in the patients’ own substantia nigra, which was not observed in transplanted dopamine neurons. These results show that the vast majority of transplanted neurons remain healthy long-term in PD patients, consistent with the clinically maintained function of fetal dopamine neuron transplants for up to 15–18 years in patients. These findings are critically important for the rational development of stem cell-based dopamine neuronal replacement therapies for PD. PMID:24910427

Reversal of dopamine-mediated firing inhibition through activation of the dopamine transporter in substantia nigra pars compacta neurons.

PubMed

Aversa, Daniela; Martini, Alessandro; Guatteo, Ezia; Pisani, Antonio; Mercuri, Nicola Biagio; Berretta, Nicola

2018-06-22

One of the hallmarks of ventral midbrain dopamine (DA)-releasing neurons is membrane hyperpolarization in response to somato-dendritic D 2 receptors (D 2 Rs) stimulation. At early postnatal age, under sustained DA, this inhibitory response is followed by a slow recovery, resulting in dopamine inhibition reversal (DIR). In the present investigation we aimed to get a better insight onto the cellular mechanisms underlying DIR. We performed single unit extracellular recordings with a multi-electrode array (MEA) device and conventional patch-clamp recordings on midbrain mouse slices. While continuous DA (100 μM) perfusion gave rise to firing inhibition that recovered in 10 to 15 min, the same effect was not obtained with the D 2 R agonist quinpirole (100 nM). Moreover, firing inhibition caused by the GABA B receptor agonist baclofen (300 nM), was reverted by DA (100 μM), albeit D 2 Rs had been blocked by sulpiride (10 μM). Conversely, the block of the DA transporter (DAT) with cocaine (30 μM) prevented firing recovery by DA under GABA B receptor stimulation. Accordingly, in whole cell recordings from single cells the baclofen-induced outward current was counteracted by DA (100 μM) in the presence of sulpiride (10 μM), and this effect was prevented by the DAT antagonists cocaine (30 μM) and GBR12909 (2 μM). Our results indicate a major role played by DAT in causing DIR under conditions of sustained DA exposure and point to DAT as an important target for pharmacological therapies leading to prolonged enhancement of the DAergic signal. This article is protected by copyright. All rights reserved.

Methamphetamine Regulation of Firing Activity of Dopamine Neurons

PubMed Central

Lin, Min; Sambo, Danielle

2016-01-01

Methamphetamine (METH) is a substrate for the dopamine transporter that increases extracellular dopamine levels by competing with dopamine uptake and increasing reverse transport of dopamine via the transporter. METH has also been shown to alter the excitability of dopamine neurons. The mechanism of METH regulation of the intrinsic firing behaviors of dopamine neurons is less understood. Here we identified an unexpected and unique property of METH on the regulation of firing activity of mouse dopamine neurons. METH produced a transient augmentation of spontaneous spike activity of midbrain dopamine neurons that was followed by a progressive reduction of spontaneous spike activity. Inspection of action potential morphology revealed that METH increased the half-width and produced larger coefficients of variation of the interspike interval, suggesting that METH exposure affected the activity of voltage-dependent potassium channels in these neurons. Since METH has been shown to affect Ca2+ homeostasis, the unexpected findings that METH broadened the action potential and decreased the amplitude of afterhyperpolarization led us to ask whether METH alters the activity of Ca2+-activated potassium (BK) channels. First, we identified BK channels in dopamine neurons by their voltage dependence and their response to a BK channel blocker or opener. While METH suppressed the amplitude of BK channel-mediated unitary currents, the BK channel opener NS1619 attenuated the effects of METH on action potential broadening, afterhyperpolarization repression, and spontaneous spike activity reduction. Live-cell total internal reflection fluorescence microscopy, electrophysiology, and biochemical analysis suggest METH exposure decreased the activity of BK channels by decreasing BK-α subunit levels at the plasma membrane. SIGNIFICANCE STATEMENT Methamphetamine (METH) competes with dopamine uptake, increases dopamine efflux via the dopamine transporter, and affects the excitability of

Dopamine Transporter Neuroimaging as an Enrichment Biomarker in Early Parkinson's Disease Clinical Trials: A Disease Progression Modeling Analysis.

PubMed

Conrado, Daniela J; Nicholas, Timothy; Tsai, Kuenhi; Macha, Sreeraj; Sinha, Vikram; Stone, Julie; Corrigan, Brian; Bani, Massimo; Muglia, Pierandrea; Watson, Ian A; Kern, Volker D; Sheveleva, Elena; Marek, Kenneth; Stephenson, Diane T; Romero, Klaus

2018-01-01

Given the recognition that disease-modifying therapies should focus on earlier Parkinson's disease stages, trial enrollment based purely on clinical criteria poses significant challenges. The goal herein was to determine the utility of dopamine transporter neuroimaging as an enrichment biomarker in early motor Parkinson's disease clinical trials. Patient-level longitudinal data of 672 subjects with early-stage Parkinson's disease in the Parkinson's Progression Markers Initiative (PPMI) observational study and the Parkinson Research Examination of CEP-1347 Trial (PRECEPT) clinical trial were utilized in a linear mixed-effects model analysis. The rate of worsening in the motor scores between subjects with or without a scan without evidence of dopamine transporter deficit was different both statistically and clinically. The average difference in the change from baseline of motor scores at 24 months between biomarker statuses was -3.16 (90% confidence interval [CI] = -0.96 to -5.42) points. Dopamine transporter imaging could identify subjects with a steeper worsening of the motor scores, allowing trial enrichment and 24% reduction of sample size. Published 2017. This article is a U.S. Government work and is in the public domain in the USA. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

[18F]CFT [(18F)WIN 35,428], a radioligand to study the dopamine transporter with PET: characterization in human subjects.

PubMed

Laakso, A; Bergman, J; Haaparanta, M; Vilkman, H; Solin, O; Hietala, J

1998-03-01

We have characterized the usage of [18F]CFT (also known as [18F]WIN 35,428) as a radioligand for in vivo studies of human dopamine transporter by PET. CFT was labeled with 18F to a high specific activity, and dynamic PET scans were conducted in healthy volunteers at various time points up to 5 h from [18F]CFT injection. The regional distribution of [18F]CFT uptake correlated well with the known distribution of dopaminergic nerve terminals in the human brain and also with that of other dopamine transporter radioligands. Striatal binding peaked at 225 min after injection and declined thereafter, demonstrating the reversible nature of the binding to the dopamine transporter. Therefore, due to the relatively long half-life of 18F (109.8 min), PET scans with [18F]CFT could easily be conducted during the binding equilibrium, allowing estimation of Bmax/Kd values (i.e., binding potential). Binding potentials for putamen and caudate measured at equilibrium were 4.79+/-0.11 and 4.50+/-0.23, respectively. We were able to also visualize midbrain dopaminergic neurons (substantia nigra) with [18F]CFT in some subjects. In conclusion, the labeling of CFT with 18F allows PET scans to be conducted at binding equilibrium, and therefore a high signal-to-noise ratio and reliable quantification of binding potential can be achieved. With a high resolution 3D PET scanner, the quantification of extrastriatal dopamine transporters should become possible.

Influence of education on cognitive performance and dopamine transporter binding in dementia with Lewy bodies.

PubMed

Lamotte, Guillaume; Morello, Rémy; Lebasnier, Adrien; Agostini, Denis; Bouvard, Gérard; De La Sayette, Vincent; Defer, Gilles L

2016-07-01

Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) are the two most common forms of dementia. These two diseases share some clinical and pathological similarities, yet the loss of dopaminergic neurons confirmed by 123-I-Ioflupane Single Photon Emission Computed Tomography (SPECT) is a suggestive feature of DLB. Current evidence suggests that higher education has a protective effect on the risk of developing clinical AD. However, how education influences cognitive performance and the presynaptic dopamine transporter marker in DLB is unknown. We reviewed 56 consecutive patients with DLB who underwent a 123-I-Ioflupane SPECT from January 2009 to August 2013 at the University Hospital of Caen. We collected clinical and neuropsychological data from medical files and 123-I-Ioflupane SPECT data for all patients. There was no correlation between education and global cognitive performance in patients with DLB. However, there was a positive correlation between education and tests exploring visuoconstructive functions (Rey complex figure copy and recall) and verbal retrieval strategies (Grober and Buschke free recall test). There was also a positive correlation between education and dopamine transporter binding. Higher educated patients had higher binding in the striatum, putamen and caudate nucleus (p=0.001 for each regions of interest). Dopamine transporter binding in the striatum, putamen and caudate nucleus was lower in the subgroup of patients with REM sleep behavior disorder, but was not associated with other DLB symptoms. Higher education may have a protective effect on visuoconstructive performance and verbal retrieval strategies and may influence dopaminergic nigrostriatal neurodegeneration in patients with DLB. Copyright © 2016 Elsevier B.V. All rights reserved.

Interaction of Dopamine Transporter (DAT1) Genotype and Maltreatment for ADHD: A Latent Class Analysis

ERIC Educational Resources Information Center

Li, James J.; Lee, Steve S.

2012-01-01

Background: Although the association of the dopamine transporter (DAT1) gene and attention-deficit/hyperactivity disorder (ADHD) has been widely studied, far less is known about its potential interaction with environmental risk factors. Given that maltreatment is a replicated risk factor for ADHD, we explored the interaction between DAT1 and…

Occupancy of the Zinc-binding Site by Transition Metals Decreases the Substrate Affinity of the Human Dopamine Transporter by an Allosteric Mechanism*

PubMed Central

Li, Yang; Mayer, Felix P.; Hasenhuetl, Peter S.; Burtscher, Verena; Schicker, Klaus; Sitte, Harald H.; Freissmuth, Michael; Sandtner, Walter

2017-01-01

The human dopamine transporter (DAT) has a tetrahedral Zn2+-binding site. Zn2+-binding sites are also recognized by other first-row transition metals. Excessive accumulation of manganese or of copper can lead to parkinsonism because of dopamine deficiency. Accordingly, we examined the effect of Mn2+, Co2+, Ni2+, and Cu2+ on transport-associated currents through DAT and DAT-H193K, a mutant with a disrupted Zn2+-binding site. All transition metals except Mn2+ modulated the transport cycle of wild-type DAT with affinities in the low micromolar range. In this concentration range, they were devoid of any action on DAT-H193K. The active transition metals reduced the affinity of DAT for dopamine. The affinity shift was most pronounced for Cu2+, followed by Ni2+ and Zn2+ (= Co2+). The extent of the affinity shift and the reciprocal effect of substrate on metal affinity accounted for the different modes of action: Ni2+ and Cu2+ uniformly stimulated and inhibited, respectively, the substrate-induced steady-state currents through DAT. In contrast, Zn2+ elicited biphasic effects on transport, i.e. stimulation at 1 μm and inhibition at 10 μm. A kinetic model that posited preferential binding of transition metal ions to the outward-facing apo state of DAT and a reciprocal interaction of dopamine and transition metals recapitulated all experimental findings. Allosteric activation of DAT via the Zn2+-binding site may be of interest to restore transport in loss-of-function mutants. PMID:28096460

Importance of cholesterol in dopamine transporter function

PubMed Central

Jones, Kymry T.; Zhen, Juan; Reith, Maarten E.A.

2012-01-01

The conformation and function of the dopamine transporter (DAT) can be affected by manipulating membrane cholesterol, yet there is no agreement as to the impact of cholesterol on the activity of lipid-raft localized DATs compared to non-raft DATs. Given the paucity of information regarding the impact of cholesterol on substrate efflux by the DAT, this study explores its influence on the kinetics of DAT-mediated DA efflux induced by dextroamphetamine, as measured by rotating disk electrode voltammetry (RDEV). Treatment with methyl-β-cyclodextrin (mβCD), which effectively depletes total membrane cholesterol- uniformly affecting cholesterol-DAT interactions in both raft and non-raft membrane domains- reduced both DA uptake and efflux rate. In contrast, disruption of raft localized DAT by cholesterol chelation with nystatin had no effect, arguing against a vital role for raft-localized DAT in substrate uptake or efflux. Supra-normal repletion of cholesterol depleted cells with the analogue desmosterol, a non-raft promoting sterol, was as effective as cholesterol itself in restoring transport rates. Further studies with Zn2+ and the conformationally-biased W84L DAT mutant supported the idea that cholesterol is important for maintaining the outward-facing DAT with normal rates of conformational interconversions. Collectively, these results point to a role for direct cholesterol-DAT interactions in regulating DAT function. PMID:22957537

Preserved serotonin transporter binding in de novo Parkinson's disease: negative correlation with the dopamine transporter.

PubMed

Strecker, Karl; Wegner, Florian; Hesse, Swen; Becker, Georg-Alexander; Patt, Marianne; Meyer, Philipp M; Lobsien, Donald; Schwarz, Johannes; Sabri, Osama

2011-01-01

Recent imaging and neuropathological studies indicate reduced serotonin transporter (SERT) in advanced Parkinson's disease (PD). However, data on SERT in early PD patients are sparse. Following the hypothesis that the serotonergic system is damaged early in PD, the aim of our study was to investigate SERT availability by means of PET imaging. Since the loss of dopaminergic neurons is the pathologic hallmark of PD and SERT might be associated with psychiatric co-morbidity, we further sought to correlate SERT availability with the availability of dopamine transporter (DAT) and depressive or motor symptoms in early PD. We prospectively recruited nine early PD patients (4 female, 5 male; 42-76 years) and nine age matched healthy volunteers (5 female, 4 male; 42-72 years). Diagnosis of PD was confirmed by the UK brain bank criteria and DAT imaging. SERT availability was measured by means of [11C]DASB PET. For neuropsychiatric assessment done on the day of PET we applied UPDRS parts I, II and III, Beck's Depression Inventory, Hamilton Rating Scale for Depression, Mini-Mental State Examination and Demtect. SERT was not reduced in any of 14 investigated regions of interest in the nine PD patients compared to healthy controls (p>0.13). SERT was negatively associated with DAT in the striatum (r=-0.69; p=0.04) but not within the midbrain. There was no correlation of SERT availability with depressive symptoms. No alteration of SERT binding in our patients suggests that the serotonergic system is remarkably preserved in early PD. Correlation with DAT might point to a compensatory regulation of the serotonergic system in early stages of PD.

Intranasal Dopamine Reduces In Vivo [(123)I]FP-CIT Binding to Striatal Dopamine Transporter: Correlation with Behavioral Changes and Evidence for Pavlovian Conditioned Dopamine Response.

PubMed

de Souza Silva, Maria A; Mattern, Claudia; Decheva, Cvetana; Huston, Joseph P; Sadile, Adolfo G; Beu, Markus; Müller, H-W; Nikolaus, Susanne

2016-01-01

Dopamine (DA), which does not cross the blood-brain barrier, has central and behavioral effects when administered via the nasal route. Neither the mechanisms of central action of intranasal dopamine (IN-DA), nor its mechanisms of diffusion and transport into the brain are well understood. We here examined whether IN-DA application influences dopamine transporter (DAT) binding in the dorsal striatum and assessed the extent of binding in relation to motor and exploratory behaviors. We hypothesized that, based on the finding of increased extracellular DA in the striatum induced by application of IN-DA, binding of [(123)I]FP-CIT to the DAT should be decreased due to competition at the receptor. Rats were administered 3 mg/kg IN-DA and vehicle (VEH), with IN-DA injection either preceding or following VEH. Then motor and exploratory behaviors (traveled distance, velocity, center time, sitting, rearing, head-shoulder motility, grooming) were assessed for 30 min in an open field prior to administration of [(123)I]FP-CIT. DAT binding after IN-DA and VEH was measured with small animal SPECT 2 h following administration of the radioligand. (1) After IN-DA application, striatal DAT binding was significantly lower as compared to VEH, indicating that the nasally delivered DA had central action and increased DA levels comparable to that found previously with L-DOPA administration; and (2) DAT binding in response to intranasal VEH was lower when IN-DA application preceded VEH treatment. This finding is suggestive of Pavlovian conditioning of DA at the level of the DAT, since the DA treatment modified (decreased) the binding in response to the subsequent VEH treatment. VEH treatment also reduced motor and exploratory behaviors more when applied before, as compared to when it followed IN-DA application, also indicative of behavioral Pavlovian conditioning akin to that found upon application of various psychostimulant drugs. (a) demonstrate a direct central action of intranasally

Dysregulated glutamate and dopamine transporters in postmortem frontal cortex from bipolar and schizophrenic patients

PubMed Central

Rao, Jagadeesh Sridhara; Kellom, Matthew; Reese, Edmund Arthur; Rapoport, Stanley Isaac; Kim, Hyung-Wook

2012-01-01

Background Dysregulated glutamate, serotonin and dopamine neurotransmission has been reported in bipolar disorder (BD) and schizophrenia (SZ), but the underlying mechanisms of dysregulation are not clear. We hypothesized that they involve alterations in excitatory amino acid transporters (EAATs), the serotonin reuptake transporter (SERT), and the dopamine reuptake transporter (DAT). Methods To test this hypothesis, we determined protein and mRNA levels of EAAT subtypes 1–4, of the SERT and of the DAT in postmortem frontal cortex from BD (n=10) and SZ (n=10) patients and from healthy control (n=10) subjects. Results Compared to control levels, protein and mRNA levels of EAAT1 were increased significantly in cortex from both BD and SZ patients. EAAT2 protein and mRNA levels were decreased significantly in BD but not in SZ cortices. EAAT3 and EAAT 4 protein and mRNA levels were significantly higher in SZ but not in BD compared with control. DAT protein and mRNA levels were decreased significantly in both BD and SZ cortex. There was no significant change in SERT expression in either BD or SZ. Conclusions The altered EAATs and DAT expression could result in altered glutamatergic and hyperdopaminergic function in BD and SZ. Differently altered EAATs involved in glutamatergic transmission could be therapeutic targets for treating BD and SZ. PMID:21925739

Amphetamine activates Rho GTPase signaling to mediate dopamine transporter internalization and acute behavioral effects of amphetamine

PubMed Central

Wheeler, David S.; Underhill, Suzanne M.; Stolz, Donna B.; Murdoch, Geoffrey H.; Thiels, Edda; Romero, Guillermo; Amara, Susan G.

2015-01-01

Acute amphetamine (AMPH) exposure elevates extracellular dopamine through a variety of mechanisms that include inhibition of dopamine reuptake, depletion of vesicular stores, and facilitation of dopamine efflux across the plasma membrane. Recent work has shown that the DAT substrate AMPH, unlike cocaine and other nontransported blockers, can also stimulate endocytosis of the plasma membrane dopamine transporter (DAT). Here, we show that when AMPH enters the cytoplasm it rapidly stimulates DAT internalization through a dynamin-dependent, clathrin-independent process. This effect, which can be observed in transfected cells, cultured dopamine neurons, and midbrain slices, is mediated by activation of the small GTPase RhoA. Inhibition of RhoA activity with C3 exotoxin or a dominant-negative RhoA blocks AMPH-induced DAT internalization. These actions depend on AMPH entry into the cell and are blocked by the DAT inhibitor cocaine. AMPH also stimulates cAMP accumulation and PKA-dependent inactivation of RhoA, thus providing a mechanism whereby PKA- and RhoA-dependent signaling pathways can interact to regulate the timing and robustness of AMPH’s effects on DAT internalization. Consistent with this model, the activation of D1/D5 receptors that couple to PKA in dopamine neurons antagonizes RhoA activation, DAT internalization, and hyperlocomotion observed in mice after AMPH treatment. These observations support the existence of an unanticipated intracellular target that mediates the effects of AMPH on RhoA and cAMP signaling and suggest new pathways to target to disrupt AMPH action. PMID:26553986

Impulse control disorders in Parkinson's disease: decreased striatal dopamine transporter levels.

PubMed

Voon, Valerie; Rizos, Alexandra; Chakravartty, Riddhika; Mulholland, Nicola; Robinson, Stephanie; Howell, Nicholas A; Harrison, Neil; Vivian, Gill; Ray Chaudhuri, K

2014-02-01

Impulse control disorders are commonly associated with dopaminergic therapy in Parkinson's disease (PD). PD patients with impulse control disorders demonstrate enhanced dopamine release to conditioned cues and a gambling task on [(11)C]raclopride positron emission tomography (PET) imaging and enhanced ventral striatal activity to reward on functional MRI. We compared PD patients with impulse control disorders and age-matched and gender-matched controls without impulse control disorders using [(123)I]FP-CIT (2β-carbomethoxy-3β-(4-iodophenyl)tropane) single photon emission computed tomography (SPECT), to assess striatal dopamine transporter (DAT) density. The [(123)I]FP-CIT binding data in the striatum were compared between 15 PD patients with and 15 without impulse control disorders using independent t tests. Those with impulse control disorders showed significantly lower DAT binding in the right striatum with a trend in the left (right: F(1,24)=5.93, p=0.02; left: F(1,24)=3.75, p=0.07) compared to controls. Our findings suggest that greater dopaminergic striatal activity in PD patients with impulse control disorders may be partly related to decreased uptake and clearance of dopamine from the synaptic cleft. Whether these findings are related to state or trait effects is not known. These findings dovetail with reports of lower DAT levels secondary to the effects of methamphetamine and alcohol. Although any regulation of DAT by antiparkinsonian medication appears to be modest, PD patients with impulse control disorders may be differentially sensitive to regulatory mechanisms of DAT expression by dopaminergic medications.

Impulse control disorders in Parkinson's disease: decreased striatal dopamine transporter levels

PubMed Central

Voon, Valerie; Rizos, Alexandra; Chakravartty, Riddhika; Mulholland, Nicola; Robinson, Stephanie; Howell, Nicholas A; Harrison, Neil; Vivian, Gill; Ray Chaudhuri, K

2014-01-01

Objective Impulse control disorders are commonly associated with dopaminergic therapy in Parkinson's disease (PD). PD patients with impulse control disorders demonstrate enhanced dopamine release to conditioned cues and a gambling task on [11C]raclopride positron emission tomography (PET) imaging and enhanced ventral striatal activity to reward on functional MRI. We compared PD patients with impulse control disorders and age-matched and gender-matched controls without impulse control disorders using [123I]FP-CIT (2β-carbomethoxy-3β-(4-iodophenyl)tropane) single photon emission computed tomography (SPECT), to assess striatal dopamine transporter (DAT) density. Methods The [123I]FP-CIT binding data in the striatum were compared between 15 PD patients with and 15 without impulse control disorders using independent t tests. Results Those with impulse control disorders showed significantly lower DAT binding in the right striatum with a trend in the left (right: F(1,24)=5.93, p=0.02; left: F(1,24)=3.75, p=0.07) compared to controls. Conclusions Our findings suggest that greater dopaminergic striatal activity in PD patients with impulse control disorders may be partly related to decreased uptake and clearance of dopamine from the synaptic cleft. Whether these findings are related to state or trait effects is not known. These findings dovetail with reports of lower DAT levels secondary to the effects of methamphetamine and alcohol. Although any regulation of DAT by antiparkinsonian medication appears to be modest, PD patients with impulse control disorders may be differentially sensitive to regulatory mechanisms of DAT expression by dopaminergic medications. PMID:23899625

Tamoxifen protects male mice nigrostriatal dopamine against methamphetamine-induced toxicity.

PubMed

Bourque, Mélanie; Liu, Bin; Dluzen, Dean E; Di Paolo, Thérèse

2007-11-01

The selective estrogen receptor modulator tamoxifen and estradiol were shown to protect nigrostriatal dopamine concentration loss by methamphetamine in female mice whereas male mice were protected only by tamoxifen. The present study examined the protective properties of tamoxifen in male mice on several nigrostriatal dopaminergic markers and body temperature. Intact male mice were administered 12.5 or 50 microg tamoxifen 24 h before methamphetamine treatment. Basal body temperatures of male mice remained unchanged by the tamoxifen treatment. Methamphetamine reduced striatal dopamine and its metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid concentrations, striatal and substantia nigra dopamine and vesicular monoamine transporter specific binding as well substantia nigra dopamine and vesicular monoamine transporter mRNA levels and increased striatal preproenkephalin mRNA levels. These methamphetamine effects were not altered by 12.5 microg tamoxifen except for increased striatal dopamine metabolites and turnover. Tamoxifen at 50 microg reduced the methamphetamine effect on striatal dopamine concentration, dopamine transporter specific binding and prevented the increase in preproenkephalin mRNA levels; in the substantia nigra tamoxifen prevented the decrease of dopamine transporter mRNA levels. The present results show a tamoxifen dose-dependent prevention of loss of various dopaminergic markers against methamphetamine-induced toxicity in male mice. Since this is the only known hormonal protection of male mice against methamphetamine toxicity, these findings provide important new information on specific parameters of nigrostriatal dopaminergic function preserved by tamoxifen.

Putaminal dopamine depletion in de novo Parkinson's disease predicts future development of wearing-off.

PubMed

Chung, Su Jin; Lee, Yoonju; Oh, Jungsu S; Kim, Jae Seung; Lee, Phil Hyu; Sohn, Young H

2018-05-10

The present study aimed to investigate whether the level of presynaptic dopamine neuronal loss predicts future development of wearing-off in de novo Parkinson's disease. This retrospective cohort study included a total of 342 non-demented patients with de novo Parkinson's disease who underwent dopamine transporter positron emission tomography scans at their initial evaluation and received dopaminergic medications for 24 months or longer. Onset of wearing-off was determined based on patients' medical records at their outpatient clinic visits every 3-6 months. Predictive power of dopamine transporter activity in striatal subregions and other clinical factors for the development of wearing-off was evaluated by Cox proportional hazard models. During a median follow-up period of 50.2 ± 18.9 months, 69 patients (20.2%) developed wearing-off. Patients with wearing-off exhibited less dopamine transporter activity in the putamen, particularly the anterior and posterior putamens, compared to those without wearing-off. Multivariate Cox proportional hazard models revealed that dopamine transporter activities of the anterior (hazard ratio 0.556; p = 0.008) and whole putamens (hazard ratio 0.504; p = 0.025) were significant predictors of development of wearing-off. In addition, younger age at onset of Parkinson's disease, lower body weight, and a motor phenotype of postural instability/gait disturbance were also significant predictors for development of wearing-off. The present results provide in vivo evidence to support the hypothesis that presynaptic dopamine neuronal loss, particularly in the anterior putamen, leads to development of wearing-off in Parkinson's disease. Copyright © 2018. Published by Elsevier Ltd.

Dopamine-Independent Locomotor Actions of Amphetamines in a Novel Acute Mouse Model of Parkinson Disease

PubMed Central

Sotnikova, Tatyana D; Beaulieu, Jean-Martin; Barak, Larry S; Wetsel, William C; Gainetdinov, Raul R

2005-01-01

Brain dopamine is critically involved in movement control, and its deficiency is the primary cause of motor symptoms in Parkinson disease. Here we report development of an animal model of acute severe dopamine deficiency by using mice lacking the dopamine transporter. In the absence of transporter-mediated recycling mechanisms, dopamine levels become entirely dependent on de novo synthesis. Acute pharmacological inhibition of dopamine synthesis in these mice induces transient elimination of striatal dopamine accompanied by the development of a striking behavioral phenotype manifested as severe akinesia, rigidity, tremor, and ptosis. This phenotype can be reversed by administration of the dopamine precursor, L-DOPA, or by nonselective dopamine agonists. Surprisingly, several amphetamine derivatives were also effective in reversing these behavioral abnormalities in a dopamine-independent manner. Identification of dopamine transporter- and dopamine-independent locomotor actions of amphetamines suggests a novel paradigm in the search for prospective anti-Parkinsonian drugs. PMID:16050778

No association between schizophrenia and polymorphisms within the genes for debrisoquine 4-hydroxylase (CYP2D6) and the dopamine transporter (DAT)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Daniels, J.; Williams, J.; Asherson, P.

1995-02-27

It has been suggested that the cytochrome P450 mono-oxygenase, debrisoquine 4-hydroxylase, is involved in the catabolism and processing of neurotransmitters subsequent to their reuptake into target cells. It is also thought to be related to the dopamine transporter that acts to take released dopamine back up into presynaptic terminals. The present study used the association approach to test the hypothesis that mutations in the genes for debrisoquine 4-hydroxylase (CYP2D6) and the dopamine transporter (DAT) confer susceptibility to schizophrenia. There were no differences in allele or genotype frequencies between patients and controls in the mutations causing the poor metaboliser phenotype inmore » CYP2D6. In addition there was no association found between schizophrenia and a 48 bp repeat within the 3{prime} untranslated region of DAT. 18 refs., 2 tabs.« less

Alterations in brain extracellular dopamine and glycine levels following combined administration of the glycine transporter type-1 inhibitor Org-24461 and risperidone.

PubMed

Nagy, Katalin; Marko, Bernadett; Zsilla, Gabriella; Matyus, Peter; Pallagi, Katalin; Szabo, Geza; Juranyi, Zsolt; Barkoczy, Jozsef; Levay, Gyorgy; Harsing, Laszlo G

2010-12-01

The most dominant hypotheses for the pathogenesis of schizophrenia have focused primarily upon hyperfunctional dopaminergic and hypofunctional glutamatergic neurotransmission in the central nervous system. The therapeutic efficacy of all atypical antipsychotics is explained in part by antagonism of the dopaminergic neurotransmission, mainly by blockade of D(2) dopamine receptors. N-methyl-D-aspartate (NMDA) receptor hypofunction in schizophrenia can be reversed by glycine transporter type-1 (GlyT-1) inhibitors, which regulate glycine concentrations at the vicinity of NMDA receptors. Combined drug administration with D(2) dopamine receptor blockade and activation of hypofunctional NMDA receptors may be needed for a more effective treatment of positive and negative symptoms and the accompanied cognitive deficit in schizophrenia. To investigate this type of combined drug administration, rats were treated with the atypical antipsychotic risperidone together with the GlyT-1 inhibitor Org-24461. Brain microdialysis was applied in the striatum of conscious rats and determinations of extracellular dopamine, DOPAC, HVA, glycine, glutamate, and serine concentrations were carried out using HPLC/electrochemistry. Risperidone increased extracellular concentrations of dopamine but failed to influence those of glycine or glutamate measured in microdialysis samples. Org-24461 injection reduced extracellular dopamine concentrations and elevated extracellular glycine levels but the concentrations of serine and glutamate were not changed. When risperidone and Org-24461 were added in combination, a decrease in extracellular dopamine concentrations was accompanied with sustained elevation of extracellular glycine levels. Interestingly, the extracellular concentrations of glutamate were also enhanced. Our data indicate that coadministration of an antipsychotic with a GlyT-1 inhibitor may normalize hypofunctional NMDA receptor-mediated glutamatergic neurotransmission with reduced

A new synthetic drug 5-(2-aminopropyl)indole (5-IT) induces rewarding effects and increases dopamine D1 receptor and dopamine transporter mRNA levels.

PubMed

Botanas, Chrislean Jun; Yoon, Seong Shoon; de la Peña, June Bryan; Dela Peña, Irene Joy; Kim, Mikyung; Custodio, Raly James; Woo, Taeseon; Seo, Joung-Wook; Jang, Choon-Gon; Yang, Ji Seul; Yoon, Yoon Mi; Lee, Yong Sup; Kim, Hee Jin; Cheong, Jae Hoon

2018-04-02

In recent years, there has been a marked increase in the use of recreational synthetic psychoactive substances, which is a cause of concern among healthcare providers and legal authorities. In particular, there have been reports on the misuse of 5-(2-aminopropyl)indole (5-API; 5-IT), a new synthetic drug, and of fatal and non-fatal intoxication. Despite these reports, little is known about its psychopharmacological effects and abuse potential. Here, we investigated the abuse potential of 5-IT by evaluating its rewarding and reinforcing effects through conditioned place preference (CPP) (1, 10, and 30 mg/kg, i.p.) in mice and self-administration test (0.1, 0.3, 1, and 3 mg/kg/inf., i.v.) in rats. We also examined whether 5-IT (1, 3, and 10 mg/kg, i.p.) induces locomotor sensitization in mice following a 7-day treatment and drug challenge. Then, we explored the effects of 5-IT (10 mg/kg, i.p.) on dopamine-related genes in the striatum, prefrontal cortex (PFC), and substantia nigra pars compacta (SNc)/ventral tegmental (VTA) of mice by quantitative real-time polymerase chain reaction. 5-IT produced CPP in mice but was not reliably self-administered by rats. 5-IT also induced locomotor sensitization following repeated administration and drug challenge. Moreover, 5-IT increased mRNA levels of dopamine D1 receptor in the striatum and PFC and dopamine transporter in the SNc/VTA of mice. These results indicate that 5-IT has psychostimulant and rewarding properties, which may be attributed to its ability to affect the dopaminergic system in the brain. These findings suggest that 5-IT poses a substantial risk for abuse and addiction in humans. Copyright © 2017 Elsevier B.V. All rights reserved.

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

PubMed

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.

Maternal separation affects dopamine transporter function in the spontaneously hypertensive rat: an in vivo electrochemical study.

PubMed

Womersley, Jacqueline S; Hsieh, Jennifer H; Kellaway, Lauriston A; Gerhardt, Greg A; Russell, Vivienne A

2011-12-01

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

Lipopolysaccharide mitagates methamphetamine-induced striatal dopamine depletion via modulating local TNF-alpha and dopamine transporter expression.

PubMed

Lai, Yu-Ting; Tsai, Yen-Ping N; Cherng, Chianfang G; Ke, Jing-Jer; Ho, Ming-Che; Tsai, Chia-Wen; Yu, Lung

2009-04-01

Systemic lipopolysaccharide (LPS) treatment may affect methamphetamine (MA)-induced nigrostriatal dopamine (DA) depletion. This study was undertaken to determine the critical time window for the protective effects of LPS treatment and the underlying mechanisms. An LPS injection (1 mg/kg) 72 h before or 2 h after MA treatment [three consecutive, subcutaneous injections of MA (10 mg/kg each) at 2-h intervals] diminished the MA-induced DA depletion in mouse striatum. Such an LPS-associated effect was independent of MA-produced hyperthermia. TNF-alpha, IL-1beta, IL-6 expressions were all elevated in striatal tissues following a systemic injection with LPS, indicating that peripheral LPS treatment affected striatal pro-inflammatory cytokine expression. Striatal TNF-alpha expression was dramatically increased at 72 and 96 h after the MA treatment, while such TNF-alpha elevation was abolished by the LPS pretreatment protocol. Moreover, MA-produced activation of nuclear NFkappaB, a transcription factor following TNF-alpha activation, in striatum was abolished by the LPS (1 mg/kg) pretreatment. Furthermore, thalidomide, a TNF-alpha antagonist, treatment abolished the LPS pretreatment-associated protective effects. Pretreatment with mouse recombinant TNF-alpha in striatum diminished the MA-produced DA depletion. Finally, single LPS treatment caused a rapid down-regulation of dopamine transporter (DAT) in striatum. Taken together, we conclude that peripheral LPS treatment protects nigrostriatal DA neurons against MA-induced toxicity, in part, by reversing elevated TNF-alpha expression and subsequent signaling cascade and causing a rapid DAT down-regulation in striatum.

Neuronal Depolarization Drives Increased Dopamine Synaptic Vesicle Loading via VGLUT

PubMed Central

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

2017-01-01

SUMMARY The ability of presynaptic dopamine terminals to tune neurotransmitter release to meet the demands of neuronal activity is critical to neurotransmission. Although vesicle content has been assumed to be static, in vitro data increasingly suggest that cell activity modulates vesicle content. Here, we use a coordinated genetic, pharmacological, and imaging approach in Drosophila to study the presynaptic machinery responsible for these vesicular processes in vivo. We show that cell depolarization increases synaptic vesicle dopamine content prior to release via vesicular hyperacidification. This depolarization-induced hyperacidification is mediated by the vesicular glutamate transporter (VGLUT). Remarkably, both depolarization-induced dopamine vesicle hyperacidification and its dependence on VGLUT2 are seen in ventral midbrain dopamine neurons in the mouse. Together, these data suggest that in response to depolarization, dopamine vesicles utilize a cascade of vesicular transporters to dynamically increase the vesicular pH gradient, thereby increasing dopamine vesicle content. PMID:28823729

PRESYNAPTIC DOPAMINE MODULATION BY STIMULANT SELF ADMINISTRATION

PubMed Central

España, Rodrigo A.; Jones, Sara R.

2013-01-01

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

Novel L-Dopa and dopamine prodrugs containing a 2-phenyl-imidazopyridine moiety.

PubMed

Denora, Nunzio; Laquintana, Valentino; Lopedota, Angela; Serra, Mariangela; Dazzi, Laura; Biggio, Giovanni; Pal, Dhananjay; Mitra, Ashim K; Latrofa, Andrea; Trapani, Giuseppe; Liso, Gaetano

2007-07-01

The aim of this study was to gain insight into the feasibility of enhancing the delivery of L-Dopa and dopamine to the brain by linking these neurotransmitters and L-Dopa ethyl ester to 2-phenyl-3-carboxymethyl-imidazopyridine compounds giving rise to the so-called Dopimid compounds. A number of Dopimid compounds were synthesized and both stability and binding studies to dopaminergic and benzodiazepine receptors were performed. To evaluate whether Dopimid compounds are P-gp substrates, [(3)H]ritonavir uptake experiments and bi-directional transport studies on confluent MDCKII-MDR1 monolayers were carried out. The brain penetration properties of Dopimid compounds were estimated by the Clark's computational model and evaluated by investigation of their transport across BBMECs monolayers. The dopamine levels following the intraperitoneal administration of the selected Dopimid compounds were measured in vivo by using brain microdialysis in rat. Tested compounds were adequately stable in solution buffered at pH 7.4 but undergo faster cleavage in dilute rat serum at 37 degrees C. Receptor binding studies showed that Dopimid compounds are essentially devoid of affinity for dopaminergic and benzodiazepine receptors. [(3)H]ritonavir uptake experiments indicated that selected Dopimid compounds, like L-Dopa and dopamine hydrochloride, are not substrates of P-gp and it was also confirmed by bi-directional transport experiments across MDCKII-MDR1 monolayers. By Clark's model a significant brain penetration was deduced for L-Dopa ethyl ester and dopamine derivatives. Transport studies involving BBMECs monolayers indicated that some of these compounds should be able to cross the BBB. Interestingly, the rank order of apparent permeability (P (app)) values observed in these assays parallels that calculated by the computational approach. Brain microdialysis experiments in rat showed that intraperitoneal acute administration of some Dopimid compounds induced a dose-dependent increase

Infantile parkinsonism-dystonia: a dopamine "transportopathy".

PubMed

Blackstone, Craig

2009-06-01

The dopamine transporter (DAT) retrieves the neurotransmitter dopamine from the synaptic cleft at dopaminergic synapses. Variations in solute carrier family 6A, member 3 (SLC6A3/DAT1), the human gene encoding DAT, have been implicated in attention deficit hyperactivity and bipolar disorders, and DAT is a prominent site of action for drugs such as amphetamines and cocaine. In this issue of the JCI, Kurian et al. report that an autosomal recessive infantile parkinsonism-dystonia is caused by loss-of-function mutations in DAT that impair dopamine reuptake (see the related article beginning on page 1595). Though this might be predicted to result in dopamine excess in the synaptic cleft, it likely also causes depletion of presynaptic dopamine stores and possibly downregulation of postsynaptic dopamine receptor function, resulting in impairments in dopaminergic neurotransmission consistent with the clinical presentation. This is the first report of a genetic alteration in DAT function underlying a parkinsonian disorder.

The Role of the Dopamine Transporter (DAT) in the Development of PTSD in Preschool Children

PubMed Central

Drury, Stacy S.; Theall, Katherine P.; Keats, Bronya J.B.; Scheeringa, Michael

2015-01-01

Population-based association studies have supported the heritability of posttraumatic stress disorder (PTSD). This study explored the influence of genetic variation in the dopamine transporter (DAT) 3′ untranslated region variable number tandem repeat on the development of PTSD in preschool children exposed to Hurricane Katrina, diagnosed using a developmentally appropriate semistructured interview. A diagnosis according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV; American Psychiatric Association, 1994), total symptoms, and specifically Criterion D symptoms were significantly more likely to be found in children with the 9 allele. This study replicates a previous finding in adults with PTSD. The specificity of this finding to the increased arousal symptoms of Criterion D suggests that dopamine and the DAT allele may contribute to one heritable path in a multifinality model of the development of PTSD. PMID:19960520

Extended access to methamphetamine self-administration up-regulates dopamine transporter levels 72 hours after withdrawal in rats.

PubMed

D'Arcy, Christina; Luevano, Joe E; Miranda-Arango, Manuel; Pipkin, Joseph A; Jackson, Jonathan A; Castañeda, Eddie; Gosselink, Kristin L; O'Dell, Laura E

2016-01-01

Previous studies have demonstrated that there are persistent changes in dopamine systems following withdrawal from methamphetamine (METH). This study examined changes in striatal dopamine transporter (DAT), tyrosine hydroxylase (TH) and dopamine receptor 2 (D2) 72 h after withdrawal from METH intravenous self- administration (IVSA). Rats were given limited (1h) or extended (6h) access to METH IVSA (0.05 mg/kg/0.1 ml infusion) for 22 days. Controls did not receive METH IVSA. The rats given extended access to IVSA displayed higher METH intake during the first hour of drug access compared to rats given limited access. Extended access to METH also produced a concomitant increase in striatal DAT levels relative to drug-naïve controls. There were no changes in TH or D2 levels across groups. Previous studies have reported a decrease in striatal DAT levels during protracted periods (>7 days) of withdrawal from METH IVSA. This study extends previous work by showing an increase in striatal DAT protein expression during an earlier time point of withdrawal from this drug. These results are an important step toward understanding the dynamic changes in dopamine systems that occur during different time points of withdrawal from METH IVSA. Copyright © 2015 Elsevier B.V. All rights reserved.

Neuronal Depolarization Drives Increased Dopamine Synaptic Vesicle Loading via VGLUT.

PubMed

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

2017-08-30

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

X-ray structure of the dopamine transporter in complex with tricyclic antidepressant

PubMed Central

Penmatsa, Aravind; Wang, Kevin H.; Gouaux, Eric

2013-01-01

Antidepressants targeting Na+/Cl−-coupled neurotransmitter uptake define a major therapeutic strategy to treat clinical depression and neuropathic pain. However, identifying the molecular interactions that underlie the pharmacological activity of these transport inhibitors and thus the mechanism by which the inhibitors lead to increased synaptic neurotransmitter levels has proven elusive. Here we present the crystal structure of the Drosophila melanogaster dopamine transporter (dDAT) at 3.0 Å resolution bound to the tricyclic antidepressant nortriptyline. The transporter is locked in an outward-open conformation with nortriptyline wedged between TMs1/6 and 3/8, blocking the transporter from binding substrate and from isomerizing to an inward facing conformation. While the overall structure of dDAT is similar to that of its prokaryotic relative LeuT, there are multiple distinctions that include a kink in TM12 halfway across the membrane bilayer, a latch-like C-terminal helix that caps the cytoplasmic gate, and a cholesterol molecule wedged within a groove formed by TMs 1a, 5 and 7. Taken together, the dDAT structure reveals the molecular basis for antidepressant action on sodium-coupled neurotransmitter symporters and illuminates critical elements of eukaryotic transporter structure and modulation by lipids, thus expanding our understanding of mechanism and regulation of neurotransmitter uptake at chemical synapses. PMID:24037379

Dopamine transporter-dependent and -independent actions of trace amine beta-phenylethylamine.

PubMed

Sotnikova, Tatyana D; Budygin, Evgeny A; Jones, Sara R; Dykstra, Linda A; Caron, Marc G; Gainetdinov, Raul R

2004-10-01

Beta-phenylethylamine (beta-PEA) is an endogenous amine that is found in trace amounts in the brain. It is believed that the locomotor-stimulating action of beta-PEA, much like amphetamine, depends on its ability to increase extracellular dopamine (DA) concentrations owing to reversal of the direction of dopamine transporter (DAT)-mediated DA transport. beta-PEA can also bind directly to the recently identified G protein-coupled receptors, but the physiological significance of this interaction is unclear. To assess the mechanism by which beta-PEA mediates its effects, we compared the neurochemical and behavioral effects of this amine in wild type (WT), heterozygous and 'null' DAT mutant mice. In microdialysis studies, beta-PEA, administered either systemically or locally via intrastriatal infusion, produced a pronounced outflow of striatal DA in WT mice whereas no increase was detected in mice lacking the DAT (DAT-KO mice). Similarly, in fast-scan voltammetry studies beta-PEA did not alter DA release and clearance rate in striatal slices from DAT-KO mice. In behavioral studies beta-PEA produced a robust but transient increase in locomotor activity in WT and heterozygous mice. In DAT-KO mice, whose locomotor activity and stereotypy are increased in a novel environment, beta-PEA (10-100 mg/kg) exerted a potent inhibitory action. At high doses, beta-PEA induced stereotypies in WT and heterozygous mice; some manifestations of stereotypy were also observed in the DAT-KO mice. These data demonstrate that the DAT is required for the striatal DA-releasing and hyperlocomotor actions of beta-PEA. The inhibitory action on hyperactivity and certain stereotypies induced by beta-PEA in DAT-KO mice indicate that targets other than the DAT are responsible for these effects.

Small molecule induced oligomerization, clustering and clathrin-independent endocytosis of the dopamine transporter

PubMed Central

Sorkina, Tatiana; Ma, Shiqi; Larsen, Mads Breum; Watkins, Simon C

2018-01-01

Clathrin-independent endocytosis (CIE) mediates internalization of many transmembrane proteins but the mechanisms of cargo recruitment during CIE are poorly understood. We found that the cell-permeable furopyrimidine AIM-100 promotes dramatic oligomerization, clustering and CIE of human and mouse dopamine transporters (DAT), but not of their close homologues, norepinephrine and serotonin transporters. All effects of AIM-100 on DAT and the occupancy of substrate binding sites in the transporter were mutually exclusive, suggesting that AIM-100 may act by binding to DAT. Surprisingly, AIM-100-induced DAT endocytosis was independent of dynamin, cholesterol-rich microdomains and actin cytoskeleton, implying that a novel endocytic mechanism is involved. AIM-100 stimulated trafficking of internalized DAT was also unusual: DAT accumulated in early endosomes without significant recycling or degradation. We propose that AIM-100 augments DAT oligomerization through an allosteric mechanism associated with the DAT conformational state, and that oligomerization-triggered clustering leads to a coat-independent endocytosis and subsequent endosomal retention of DAT. PMID:29630493

Dopamine Gene Profiling to Predict Impulse Control and Effects of Dopamine Agonist Ropinirole.

PubMed

MacDonald, Hayley J; Stinear, Cathy M; Ren, April; Coxon, James P; Kao, Justin; Macdonald, Lorraine; Snow, Barry; Cramer, Steven C; Byblow, Winston D

2016-07-01

Dopamine agonists can impair inhibitory control and cause impulse control disorders for those with Parkinson disease (PD), although mechanistically this is not well understood. In this study, we hypothesized that the extent of such drug effects on impulse control is related to specific dopamine gene polymorphisms. This double-blind, placebo-controlled study aimed to examine the effect of single doses of 0.5 and 1.0 mg of the dopamine agonist ropinirole on impulse control in healthy adults of typical age for PD onset. Impulse control was measured by stop signal RT on a response inhibition task and by an index of impulsive decision-making on the Balloon Analogue Risk Task. A dopamine genetic risk score quantified basal dopamine neurotransmission from the influence of five genes: catechol-O-methyltransferase, dopamine transporter, and those encoding receptors D1, D2, and D3. With placebo, impulse control was better for the high versus low genetic risk score groups. Ropinirole modulated impulse control in a manner dependent on genetic risk score. For the lower score group, both doses improved response inhibition (decreased stop signal RT) whereas the lower dose reduced impulsiveness in decision-making. Conversely, the higher score group showed a trend for worsened response inhibition on the lower dose whereas both doses increased impulsiveness in decision-making. The implications of the present findings are that genotyping can be used to predict impulse control and whether it will improve or worsen with the administration of dopamine agonists.

The mechanistic basis for noncompetitive ibogaine inhibition of serotonin and dopamine transporters.

PubMed

Bulling, Simon; Schicker, Klaus; Zhang, Yuan-Wei; Steinkellner, Thomas; Stockner, Thomas; Gruber, Christian W; Boehm, Stefan; Freissmuth, Michael; Rudnick, Gary; Sitte, Harald H; Sandtner, Walter

2012-05-25

Ibogaine, a hallucinogenic alkaloid proposed as a treatment for opiate withdrawal, has been shown to inhibit serotonin transporter (SERT) noncompetitively, in contrast to all other known inhibitors, which are competitive with substrate. Ibogaine binding to SERT increases accessibility in the permeation pathway connecting the substrate-binding site with the cytoplasm. Because of the structural similarity between ibogaine and serotonin, it had been suggested that ibogaine binds to the substrate site of SERT. The results presented here show that ibogaine binds to a distinct site, accessible from the cell exterior, to inhibit both serotonin transport and serotonin-induced ionic currents. Ibogaine noncompetitively inhibited transport by both SERT and the homologous dopamine transporter (DAT). Ibogaine blocked substrate-induced currents also in DAT and increased accessibility of the DAT cytoplasmic permeation pathway. When present on the cell exterior, ibogaine inhibited SERT substrate-induced currents, but not when it was introduced into the cytoplasm through the patch electrode. Similar to noncompetitive transport inhibition, the current block was not reversed by increasing substrate concentration. The kinetics of inhibitor binding and dissociation, as determined by their effect on SERT currents, indicated that ibogaine does not inhibit by forming a long-lived complex with SERT, but rather binds directly to the transporter in an inward-open conformation. A kinetic model for transport describing the noncompetitive action of ibogaine and the competitive action of cocaine accounts well for the results of the present study.

The Mechanistic Basis for Noncompetitive Ibogaine Inhibition of Serotonin and Dopamine Transporters*

PubMed Central

Bulling, Simon; Schicker, Klaus; Zhang, Yuan-Wei; Steinkellner, Thomas; Stockner, Thomas; Gruber, Christian W.; Boehm, Stefan; Freissmuth, Michael; Rudnick, Gary; Sitte, Harald H.; Sandtner, Walter

2012-01-01

Ibogaine, a hallucinogenic alkaloid proposed as a treatment for opiate withdrawal, has been shown to inhibit serotonin transporter (SERT) noncompetitively, in contrast to all other known inhibitors, which are competitive with substrate. Ibogaine binding to SERT increases accessibility in the permeation pathway connecting the substrate-binding site with the cytoplasm. Because of the structural similarity between ibogaine and serotonin, it had been suggested that ibogaine binds to the substrate site of SERT. The results presented here show that ibogaine binds to a distinct site, accessible from the cell exterior, to inhibit both serotonin transport and serotonin-induced ionic currents. Ibogaine noncompetitively inhibited transport by both SERT and the homologous dopamine transporter (DAT). Ibogaine blocked substrate-induced currents also in DAT and increased accessibility of the DAT cytoplasmic permeation pathway. When present on the cell exterior, ibogaine inhibited SERT substrate-induced currents, but not when it was introduced into the cytoplasm through the patch electrode. Similar to noncompetitive transport inhibition, the current block was not reversed by increasing substrate concentration. The kinetics of inhibitor binding and dissociation, as determined by their effect on SERT currents, indicated that ibogaine does not inhibit by forming a long-lived complex with SERT, but rather binds directly to the transporter in an inward-open conformation. A kinetic model for transport describing the noncompetitive action of ibogaine and the competitive action of cocaine accounts well for the results of the present study. PMID:22451652

Dopamine alleviates nutrient deficiency-induced stress in Malus hupehensis.

PubMed

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

2017-10-01

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

Increased dopamine transporter function as a mechanism for dopamine hypoactivity in the adult infralimbic medial prefrontal cortex following adolescent social stress.

PubMed

Novick, Andrew M; Forster, Gina L; Hassell, James E; Davies, Daniel R; Scholl, Jamie L; Renner, Kenneth J; Watt, Michael J

2015-10-01

Being bullied during adolescence is associated with later mental illnesses characterized by deficits in cognitive tasks mediated by prefrontal cortex (PFC) dopamine (DA). Social defeat of adolescent male rats, as a model of teenage bullying victimization, results in medial PFC (mPFC) dopamine (DA) hypofunction in adulthood that is associated with increased drug seeking and working memory deficits. Increased expression of the DA transporter (DAT) is also seen in the adult infralimbic mPFC following adolescent defeat. We propose the functional consequence of this increased DAT expression is enhanced DA clearance and subsequently decreased infralimbic mPFC DA availability. To test this, in vivo chronoamperometry was used to measure changes in accumulation of the DA signal following DAT blockade, with increased DAT-mediated clearance being reflected by lower DA signal accumulation. Previously defeated rats and controls were pre-treated with the norepinephrine transporter (NET) inhibitor desipramine (20 mg/kg, ip.) to isolate infralimbic mPFC DA clearance to DAT, then administered the selective DAT inhibitor GBR-12909 (20 or 40 mg/kg, sc.). Sole NET inhibition with desipramine produced no differences in DA signal accumulation between defeated rats and controls. However, rats exposed to adolescent social defeat demonstrated decreased DA signal accumulation compared to controls in response to both doses of GBR-12909, indicating greater DAT-mediated clearance of infralimbic mPFC DA. These results suggest that protracted increases in infralimbic mPFC DAT function represent a mechanism by which adolescent social defeat stress produces deficits in adult mPFC DA activity and corresponding behavioral and cognitive dysfunction. Copyright © 2015 Elsevier Ltd. All rights reserved.

Atypical dopamine transporter inhibitors R-modafinil and JHW 007 differentially affect D2 autoreceptor neurotransmission and the firing rate of midbrain dopamine neurons.

PubMed

Avelar, Alicia J; Cao, Jianjing; Newman, Amy Hauck; Beckstead, Michael J

2017-09-01

Abuse of psychostimulants like cocaine that inhibit dopamine (DA) reuptake through the dopamine transporter (DAT) represents a major public health issue, however FDA-approved pharmacotherapies have yet to be developed. Recently a class of ligands termed "atypical DAT inhibitors" has gained attention due to their range of effectiveness in increasing extracellular DA levels without demonstrating significant abuse liability. These compounds not only hold promise as therapeutic agents to treat stimulant use disorders but also as experimental tools to improve our understanding of DAT function. Here we used patch clamp electrophysiology in mouse brain slices to explore the effects of two atypical DAT inhibitors (R-modafinil and JHW 007) on the physiology of single DA neurons in the substantia nigra and ventral tegmental area. Despite their commonalities of being DAT inhibitors that lack cocaine-like behavioral profiles, these compounds exhibited surprisingly divergent cellular effects. Similar to cocaine, R-modafinil slowed DA neuron firing in a D2 receptor-dependent manner and rapidly enhanced the amplitude and duration of D2 receptor-mediated currents in the midbrain. In contrast, JHW 007 exhibited little effect on firing, slow DAT blockade, and an unexpected inhibition of D2 receptor-mediated currents that may be due to direct D2 receptor antagonism. Furthermore, pretreatment with JHW 007 blunted the cellular effects of cocaine, suggesting that it may be valuable to investigate similar DAT inhibitors as potential therapeutic agents. Further exploration of these and other atypical DAT inhibitors may reveal important cellular effects of compounds that will have potential as pharmacotherapies for treating cocaine use disorders. Copyright © 2017 Elsevier Ltd. All rights reserved.

Interaction of Dopamine Transporter Gene and Observed Parenting Behaviors on Attention-Deficit/Hyperactivity Disorder: A Structural Equation Modeling Approach

ERIC Educational Resources Information Center

Li, James J.; Lee, Steve S.

2013-01-01

Emerging evidence suggests that some individuals may be simultaneously more responsive to the effects from environmental adversity "and" enrichment (i.e., differential susceptibility). Given that parenting behavior and a variable number tandem repeat polymorphism in the 3'untranslated region of the dopamine transporter (DAT1) gene are…

Infantile parkinsonism-dystonia: a dopamine “transportopathy”

PubMed Central

Blackstone, Craig

2009-01-01

The dopamine transporter (DAT) retrieves the neurotransmitter dopamine from the synaptic cleft at dopaminergic synapses. Variations in solute carrier family 6A, member 3 (SLC6A3/DAT1), the human gene encoding DAT, have been implicated in attention deficit hyperactivity and bipolar disorders, and DAT is a prominent site of action for drugs such as amphetamines and cocaine. In this issue of the JCI, Kurian et al. report that an autosomal recessive infantile parkinsonism-dystonia is caused by loss-of-function mutations in DAT that impair dopamine reuptake (see the related article beginning on page 1595). Though this might be predicted to result in dopamine excess in the synaptic cleft, it likely also causes depletion of presynaptic dopamine stores and possibly downregulation of postsynaptic dopamine receptor function, resulting in impairments in dopaminergic neurotransmission consistent with the clinical presentation. This is the first report of a genetic alteration in DAT function underlying a parkinsonian disorder. PMID:19504720

Bivalent phenethylamines as novel dopamine transporter inhibitors: evidence for multiple substrate-binding sites in a single transporter.

PubMed

Schmitt, Kyle C; Mamidyala, Sreeman; Biswas, Swati; Dutta, Aloke K; Reith, Maarten E A

2010-03-01

Bivalent ligands--compounds incorporating two receptor-interacting moieties linked by a flexible chain--often exhibit profoundly enhanced binding affinity compared with their monovalent components, implying concurrent binding to multiple sites on the target protein. It is generally assumed that neurotransmitter sodium symporter (NSS) proteins, such as the dopamine transporter (DAT), contain a single domain responsible for recognition of substrate molecules. In this report, we show that molecules possessing two substrate-like phenylalkylamine moieties linked by a progressively longer aliphatic spacer act as progressively more potent DAT inhibitors (rather than substrates). One compound bearing two dopamine (DA)-like pharmacophoric 'heads' separated by an 8-carbon linker achieved an 82-fold gain in inhibition of [(3)H] 2beta-carbomethoxy-3beta-(4-fluorophenyl)-tropane (CFT) binding compared with DA itself; bivalent compounds with a 6-carbon linker and heterologous combinations of DA-, amphetamine- and beta-phenethylamine-like heads all resulted in considerable and comparable gains in DAT affinity. A series of short-chain bivalent-like compounds with a single N-linkage was also identified, the most potent of which displayed a 74-fold gain in binding affinity. Computational modelling of the DAT protein and docking of the two most potent bivalent (-like) ligands suggested simultaneous occupancy of two discrete substrate-binding domains. Assays with the DAT mutants W84L and D313N--previously employed by our laboratory to probe conformation-specific binding of different structural classes of DAT inhibitors--indicated a bias of the bivalent ligands for inward-facing transporters. Our results strongly indicate the existence of multiple DAT substrate-interaction sites, implying that it is possible to design novel types of DAT inhibitors based upon the 'multivalent ligand' strategy.

Dopamine neurons in culture express VGLUT2 explaining their capacity to release glutamate at synapses in addition to dopamine.

PubMed

Dal Bo, Gregory; St-Gelais, Fannie; Danik, Marc; Williams, Sylvain; Cotton, Mathieu; Trudeau, Louis-Eric

2004-03-01

Dopamine neurons have been suggested to use glutamate as a cotransmitter. To identify the basis of such a phenotype, we have examined the expression of the three recently identified vesicular glutamate transporters (VGLUT1-3) in postnatal rat dopamine neurons in culture. We found that the majority of isolated dopamine neurons express VGLUT2, but not VGLUT1 or 3. In comparison, serotonin neurons express only VGLUT3. Single-cell RT-PCR experiments confirmed the presence of VGLUT2 mRNA in dopamine neurons. Arguing for phenotypic heterogeneity among axon terminals, we find that only a proportion of terminals established by dopamine neurons are VGLUT2-positive. Taken together, our results provide a basis for the ability of dopamine neurons to release glutamate as a cotransmitter. A detailed analysis of the conditions under which DA neurons gain or loose a glutamatergic phenotype may provide novel insight into pathophysiological processes that underlie diseases such as schizophrenia, Parkinson's disease and drug dependence.

ILLICIT DOPAMINE TRANSIENTS: RECONCILING ACTIONS OF ABUSED DRUGS

PubMed Central

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

2014-01-01

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

Regulation of the Dopamine and Vesicular Monoamine Transporters: Pharmacological Targets and Implications for Disease.

PubMed

German, Christopher L; Baladi, Michelle G; McFadden, Lisa M; Hanson, Glen R; Fleckenstein, Annette E

2015-10-01

Dopamine (DA) plays a well recognized role in a variety of physiologic functions such as movement, cognition, mood, and reward. Consequently, many human disorders are due, in part, to dysfunctional dopaminergic systems, including Parkinson's disease, attention deficit hyperactivity disorder, and substance abuse. Drugs that modify the DA system are clinically effective in treating symptoms of these diseases or are involved in their manifestation, implicating DA in their etiology. DA signaling and distribution are primarily modulated by the DA transporter (DAT) and by vesicular monoamine transporter (VMAT)-2, which transport DA into presynaptic terminals and synaptic vesicles, respectively. These transporters are regulated by complex processes such as phosphorylation, protein-protein interactions, and changes in intracellular localization. This review provides an overview of 1) the current understanding of DAT and VMAT2 neurobiology, including discussion of studies ranging from those conducted in vitro to those involving human subjects; 2) the role of these transporters in disease and how these transporters are affected by disease; and 3) and how selected drugs alter the function and expression of these transporters. Understanding the regulatory processes and the pathologic consequences of DAT and VMAT2 dysfunction underlies the evolution of therapeutic development for the treatment of DA-related disorders. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Regulation of the Dopamine and Vesicular Monoamine Transporters: Pharmacological Targets and Implications for Disease

PubMed Central

German, Christopher L.; Baladi, Michelle G.; McFadden, Lisa M.; Hanson, Glen R.

2015-01-01

Dopamine (DA) plays a well recognized role in a variety of physiologic functions such as movement, cognition, mood, and reward. Consequently, many human disorders are due, in part, to dysfunctional dopaminergic systems, including Parkinson’s disease, attention deficit hyperactivity disorder, and substance abuse. Drugs that modify the DA system are clinically effective in treating symptoms of these diseases or are involved in their manifestation, implicating DA in their etiology. DA signaling and distribution are primarily modulated by the DA transporter (DAT) and by vesicular monoamine transporter (VMAT)-2, which transport DA into presynaptic terminals and synaptic vesicles, respectively. These transporters are regulated by complex processes such as phosphorylation, protein–protein interactions, and changes in intracellular localization. This review provides an overview of 1) the current understanding of DAT and VMAT2 neurobiology, including discussion of studies ranging from those conducted in vitro to those involving human subjects; 2) the role of these transporters in disease and how these transporters are affected by disease; and 3) and how selected drugs alter the function and expression of these transporters. Understanding the regulatory processes and the pathologic consequences of DAT and VMAT2 dysfunction underlies the evolution of therapeutic development for the treatment of DA-related disorders. PMID:26408528

Effects of dopamine D2 receptor (DRD2) and transporter (SLC6A3) polymorphisms on smoking cue-induced cigarette craving among African-American smokers.

PubMed

Erblich, J; Lerman, C; Self, D W; Diaz, G A; Bovbjerg, D H

2005-04-01

Cue-induced craving for addictive substances has long been known to contribute to the problem of persistent addiction in humans. Research in animals over the past decade has solidly established the central role of dopamine in cue-induced craving for addictive substances, including nicotine. Analogous studies in humans, however, are lacking, especially among African-American smokers, who have lower quit rates than Caucasian smokers. Based on the animal literature, the study's objective was to test the hypothesis that smokers carrying specific variants in dopamine-related genes previously associated with risk for addictive behaviors would exhibit heightened levels of cigarette craving following laboratory exposure to cues. To this end, cigarette craving was induced in healthy African-American smokers (n=88) through laboratory exposure to smoking cues. Smokers carrying either the DRD2 (D2 dopamine receptor gene) TaqI A1 RFLP or the SLC6A3 (dopamine transporter gene) 9-repeat VNTR polymorphisms had stronger cue-induced cravings than noncarriers (Ps <0.05 and 0.01, respectively). Consistent with the separate biological pathways involved (receptor, transporter), carriers of both polymorphisms had markedly higher craving responses compared to those with neither (P<0.0006), reflecting additive effects. Findings provide support for the role of dopamine in cue-induced craving in humans, and suggest a possible genetic risk factor for persistent smoking behavior in African-American smokers.

Increased vesicular monoamine transporter binding during early abstinence in human methamphetamine users: Is VMAT2 a stable dopamine neuron biomarker?

PubMed

Boileau, Isabelle; Rusjan, Pablo; Houle, Sylvain; Wilkins, Diana; Tong, Junchao; Selby, Peter; Guttman, Mark; Saint-Cyr, Jean A; Wilson, Alan A; Kish, Stephen J

2008-09-24

Animal data indicate that methamphetamine can damage striatal dopamine terminals. Efforts to document dopamine neuron damage in living brain of methamphetamine users have focused on the binding of [(11)C]dihydrotetrabenazine (DTBZ), a vesicular monoamine transporter (VMAT2) positron emission tomography (PET) radioligand, as a stable dopamine neuron biomarker. Previous PET data report a slight decrease in striatal [(11)C]DTBZ binding in human methamphetamine users after prolonged (mean, 3 years) abstinence, suggesting that the reduction would likely be substantial in early abstinence. We measured striatal VMAT2 binding in 16 recently withdrawn (mean, 19 d; range, 1-90 d) methamphetamine users and in 14 healthy matched-control subjects during a PET scan with (+)[(11)C]DTBZ. Unexpectedly, striatal (+)[(11)C]DTBZ binding was increased in methamphetamine users relative to controls (+22%, caudate; +12%, putamen; +11%, ventral striatum). Increased (+)[(11)C]DTBZ binding in caudate was most marked in methamphetamine users abstinent for 1-3 d (+41%), relative to the 7-21 d (+15%) and >21 d (+9%) groups. Above-normal VMAT2 binding in some drug users suggests that any toxic effect of methamphetamine on dopamine neurons might be masked by an increased (+)[(11)C]DTBZ binding and that VMAT2 radioligand binding might not be, as is generally assumed, a "stable" index of dopamine neuron integrity in vivo. One potential explanation for increased (+)[(11)C]DTBZ binding is that VMAT2 binding is sensitive to changes in vesicular dopamine storage levels, presumably low in drug users. If correct, (+)[(11)C]DTBZ might be a useful imaging probe to correlate changes in brain dopamine stores and behavior in users of methamphetamine.

Dopamine transporter gene variation modulates activation of striatum in youth with ADHD

PubMed Central

Bédard, Anne-Claude; Schulz, Kurt P.; Cook, Edwin H.; Fan, Jin; Clerkin, Suzanne M.; Ivanov, Iliyan; Halperin, Jeffrey M.; Newcorn, Jeffrey H.

2009-01-01

Polymorphisms in the 3′ UTR variable number tandem repeat (VNTR) of exon 15 of the dopamine transporter gene (DAT1) have been linked to attention-deficit hyperactivity disorder (ADHD); moreover, variability in DAT1 3′UTR genotype may contribute to both heterogeneity of the ADHD phenotype and differences in response to stimulant medications. The impact of this VNTR on neuronal function in individuals with ADHD remains unclear despite evidence that the polymorphisms influence dopamine transporter expression. Thus, we used event-related functional magnetic resonance imaging to examine the impact of DAT1 3′UTR genotype on brain activation during response inhibition in unmedicated children and adolescents with ADHD. Twenty-one youth with ADHD who were homozygous for the 10-repeat (10R) allele of the DAT1 3′UTR and 12 youth who were carriers of the 9-repeat (9R) allele were scanned while they performed a Go/No-Go task. Response inhibition was modeled by contrasting activation during correct No-Go trials versus correct Go trials. Participants who were homozygous for the DAT1 3′UTR 10R allele and those who had a single 9R allele did not differ on percent of trials with successful inhibition, which was the primary measure of inhibitory control. Yet, youth with the DAT1 3′UTR 10R/10R genotype had significantly greater inhibitory control-related activation than those with one 9R allele in the left striatum, right dorsal premotor cortex, and bilaterally in the temporoparietal cortical junction. These findings provide preliminary evidence that neural activity related to inhibitory control may differ as a function of DAT1 3′UTR genotype in youth with ADHD. PMID:20026227

Dopamine transporter gene variation modulates activation of striatum in youth with ADHD.

PubMed

Bédard, Anne-Claude; Schulz, Kurt P; Cook, Edwin H; Fan, Jin; Clerkin, Suzanne M; Ivanov, Iliyan; Halperin, Jeffrey M; Newcorn, Jeffrey H

2010-11-15

Polymorphisms in the 3'UTR variable number tandem repeat (VNTR) of exon 15 of the dopamine transporter gene (DAT1) have been linked to attention-deficit hyperactivity disorder (ADHD); moreover, variability in DAT1 3'UTR genotype may contribute to both heterogeneity of the ADHD phenotype and differences in response to stimulant medications. The impact of this VNTR on neuronal function in individuals with ADHD remains unclear despite evidence that the polymorphisms influence dopamine transporter expression. Thus, we used event-related functional magnetic resonance imaging to examine the impact of DAT1 3'UTR genotype on brain activation during response inhibition in unmedicated children and adolescents with ADHD. Twenty-one youth with ADHD who were homozygous for the 10-repeat (10R) allele of the DAT1 3'UTR and 12 youth who were carriers of the 9-repeat (9R) allele were scanned while they performed a Go/No-Go task. Response inhibition was modeled by contrasting activation during correct No-Go trials versus correct Go trials. Participants who were homozygous for the DAT1 3'UTR 10R allele and those who had a single 9R allele did not differ on percent of trials with successful inhibition, which was the primary measure of inhibitory control. Yet, youth with the DAT1 3'UTR 10R/10R genotype had significantly greater inhibitory control-related activation than those with one 9R allele in the left striatum, right dorsal premotor cortex, and bilaterally in the temporoparietal cortical junction. These findings provide preliminary evidence that neural activity related to inhibitory control may differ as a function of DAT1 3'UTR genotype in youth with ADHD. Copyright 2009 Elsevier Inc. All rights reserved.

Phosphorylation of Dopamine Transporter Serine 7 Modulates Cocaine Analog Binding*

PubMed Central

Moritz, Amy E.; Foster, James D.; Gorentla, Balachandra K.; Mazei-Robison, Michelle S.; Yang, Jae-Won; Sitte, Harald H.; Blakely, Randy D.; Vaughan, Roxanne A.

2013-01-01

As an approach to elucidating dopamine transporter (DAT) phosphorylation characteristics, we examined in vitro phosphorylation of a recombinant rat DAT N-terminal peptide (NDAT) using purified protein kinases. We found that NDAT becomes phosphorylated at single distinct sites by protein kinase A (Ser-7) and calcium-calmodulin-dependent protein kinase II (Ser-13) and at multiple sites (Ser-4, Ser-7, and Ser-13) by protein kinase C (PKC), implicating these residues as potential sites of DAT phosphorylation by these kinases. Mapping of rat striatal DAT phosphopeptides by two-dimensional thin layer chromatography revealed basal and PKC-stimulated phosphorylation of the same peptide fragments and comigration of PKC-stimulated phosphopeptide fragments with NDAT Ser-7 phosphopeptide markers. We further confirmed by site-directed mutagenesis and mass spectrometry that Ser-7 is a site for PKC-stimulated phosphorylation in heterologously expressed rat and human DATs. Mutation of Ser-7 and nearby residues strongly reduced the affinity of rat DAT for the cocaine analog (−)-2β-carbomethoxy-3β-(4-fluorophenyl) tropane (CFT), whereas in rat striatal tissue, conditions that promote DAT phosphorylation caused increased CFT affinity. Ser-7 mutation also affected zinc modulation of CFT binding, with Ala and Asp substitutions inducing opposing effects. These results identify Ser-7 as a major site for basal and PKC-stimulated phosphorylation of native and expressed DAT and suggest that Ser-7 phosphorylation modulates transporter conformational equilibria, shifting the transporter between high and low affinity cocaine binding states. PMID:23161550

S(+)amphetamine induces a persistent leak in the human dopamine transporter: molecular stent hypothesis

PubMed Central

Rodriguez-Menchaca, Aldo A; Solis Jr, Ernesto; Cameron, Krasnodara; De Felice, Louis J

2012-01-01

BACKGROUND AND PURPOSE Wherever they are located, dopamine transporters (DATs) clear dopamine (DA) from the extracellular milieu to help regulate dopaminergic signalling. Exposure to amphetamine (AMPH) increases extracellular DA in the synaptic cleft, which has been ascribed to DAT reverse transport. Increased extracellular DA prolongs postsynaptic activity and reinforces abuse and hedonic behaviour. EXPERIMENTAL APPROACH Xenopus laevis oocytes expressing human (h) DAT were voltage-clamped and exposed to DA, R(-)AMPH, or S(+)AMPH. KEY RESULTS At -60mV, near neuronal resting potentials, S(+)AMPH induced a depolarizing current through hDAT, which after removing the drug, persisted for more than 30 min. This persistent leak in the absence of S(+)AMPH was in contrast to the currents induced by R(-)AMPH and DA, which returned to baseline immediately after their removal. Our data suggest that S(+)AMPH and Na+ carry the initial S(+)AMPH-induced current, whereas Na+ and Cl- carry the persistent leak current. We propose that the persistent current results from the internal action of S(+)AMPH on hDAT because the temporal effect was consistent with S(+)AMPH influx, and intracellular S(+)AMPH activated the effect. The persistent current was dependent on Na+ and was blocked by cocaine. Intracellular injection of S(+)AMPH also activated a DA-induced persistent leak current. CONCLUSIONS AND IMPLICATIONS We report a hitherto unknown action of S(+)AMPH on hDAT that potentially affects AMPH-induced DA release. We propose that internal S(+)AMPH acts as a molecular stent that holds the transporter open even after external S(+)AMPH is removed. Amphetamine-induced persistent leak currents are likely to influence dopaminergic signalling, DA release mechanisms, and amphetamine abuse. PMID:22014068

Dopamine transporter-dependent and -independent striatal binding of the benztropine analog JHW 007, a cocaine antagonist with low abuse liability

USDA-ARS?s Scientific Manuscript database

The benztropine analog JHW 007 displays high affinity for the dopamine transporter (DAT), but unlike typical DAT ligands, has relatively low abuse liability and blocks effects of cocaine,including its self-administration. To determine sites responsible for the cocaine-antagonist effects of JHW 007, ...

Illicit dopamine transients: reconciling actions of abused drugs.

PubMed

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

2014-04-01

Phasic increases in brain dopamine are required for cue-directed reward seeking. Although compelling within the framework of appetitive behavior, the view that illicit drugs hijack reward circuits by hyperactivating these dopamine transients is inconsistent with established psychostimulant pharmacology. However, recent work reclassifying amphetamine (AMPH), cocaine, and other addictive dopamine-transporter inhibitors (DAT-Is) supports transient hyperactivation as a unifying hypothesis of abused drugs. We argue here that reclassification also identifies generating burst firing by dopamine neurons as a keystone action. Unlike natural rewards, which are processed by sensory systems, drugs act directly on the brain. Consequently, to mimic natural rewards and exploit reward circuits, dopamine transients must be elicited de novo. Of available drug targets, only burst firing achieves this essential outcome. Copyright © 2014 Elsevier Ltd. All rights reserved.

Hybrid dopamine uptake blocker-serotonin releaser ligands: a new twist on transporter-focused therapeutics.

PubMed

Blough, Bruce E; Landavazo, Antonio; Partilla, John S; Baumann, Michael H; Decker, Ann M; Page, Kevin M; Rothman, Richard B

2014-06-12

As part of our program to study neurotransmitter releasers, we report herein a class of hybrid dopamine reuptake inhibitors that display serotonin releasing activity. Hybrid compounds are interesting since they increase the design potential of transporter related compounds and hence represent a novel and unexplored strategy for therapeutic drug discovery. A series of N-alkylpropiophenones was synthesized and assessed for uptake inhibition and release activity using rat brain synaptosomes. Substitution on the aromatic ring yielded compounds that maintained hybrid activity, with the two disubstituted analogues (PAL-787 and PAL-820) having the most potent hybrid activity.

Fungal-derived semiochemical 1-octen-3-ol disrupts dopamine packaging and causes neurodegeneration

PubMed Central

Inamdar, Arati A.; Hossain, Muhammad M.; Bernstein, Alison I.; Miller, Gary W.; Richardson, Jason R.; Bennett, Joan Wennstrom

2013-01-01

Parkinson disease (PD) is the most common movement disorder and, although the exact causes are unknown, recent epidemiological and experimental studies indicate that several environmental agents may be significant risk factors. To date, these suspected environmental risk factors have been man-made chemicals. In this report, we demonstrate via genetic, biochemical, and immunological studies that the common volatile fungal semiochemical 1-octen-3-ol reduces dopamine levels and causes dopamine neuron degeneration in Drosophila melanogaster. Overexpression of the vesicular monoamine transporter (VMAT) rescued the dopamine toxicity and neurodegeneration, whereas mutations decreasing VMAT and tyrosine hydroxylase exacerbated toxicity. Furthermore, 1-octen-3-ol also inhibited uptake of dopamine in human cell lines expressing the human plasma membrane dopamine transporter (DAT) and human VMAT ortholog, VMAT2. These data demonstrate that 1-octen-3-ol exerts toxicity via disruption of dopamine homeostasis and may represent a naturally occurring environmental agent involved in parkinsonism. PMID:24218591

A Markov State-based Quantitative Kinetic Model of Sodium Release from the Dopamine Transporter

NASA Astrophysics Data System (ADS)

Razavi, Asghar M.; Khelashvili, George; Weinstein, Harel

2017-01-01

The dopamine transporter (DAT) belongs to the neurotransmitter:sodium symporter (NSS) family of membrane proteins that are responsible for reuptake of neurotransmitters from the synaptic cleft to terminate a neuronal signal and enable subsequent neurotransmitter release from the presynaptic neuron. The release of one sodium ion from the crystallographically determined sodium binding site Na2 had been identified as an initial step in the transport cycle which prepares the transporter for substrate translocation by stabilizing an inward-open conformation. We have constructed Markov State Models (MSMs) from extensive molecular dynamics simulations of human DAT (hDAT) to explore the mechanism of this sodium release. Our results quantify the release process triggered by hydration of the Na2 site that occurs concomitantly with a conformational transition from an outward-facing to an inward-facing state of the transporter. The kinetics of the release process are computed from the MSM, and transition path theory is used to identify the most probable sodium release pathways. An intermediate state is discovered on the sodium release pathway, and the results reveal the importance of various modes of interaction of the N-terminus of hDAT in controlling the pathways of release.

Reduced Vesicular Acetylcholine Transporter favors antidepressant behaviors and modulates serotonin and dopamine in female mouse brain.

PubMed

Pádua-Reis, Marina; Aquino, Nayara S; Oliveira, Vinícius E M; Szawka, Raphael E; Prado, Marco A M; Prado, Vânia F; Pereira, Grace S

2017-07-14

Depression is extremely harmful to modern society. Despite its complex spectrum of symptoms, previous studies have mostly focused on the monaminergic system in search of pharmacological targets. However, other neurotransmitter systems have also been linked to the pathophysiology of depression. In this study, we provide evidence for a role of the cholinergic system in depressive-like behavior of female mice. We evaluated mice knockdown for the vesicular acetylcholine transporter (VAChT KD mice), which have been previously shown to exhibit reduced cholinergic transmission. Animals were subjected to the tail suspension and marble burying tests, classical paradigms to assess depressive-like behaviors and to screen for novel antidepressant drugs. In addition, brain levels of serotonin and dopamine were measured by high performance liquid chromatography. We found that female homozygous VAChT KD mice spent less time immobile during tail suspension and buried less marbles, indicating a less depressive phenotype. These differences in behavior were reverted by central, but not peripheral, acetylcholinesterase inhibition. Moreover, female homozygous VAChT KD mice exhibited higher levels of dopamine and serotonin in the striatum, and increased dopamine in the hippocampus. Our study thus shows a connection between depressive-like behaviors and the cholinergic system, and that the latter interacts with the monoaminergic system. Copyright © 2017 Elsevier B.V. All rights reserved.

Genetically determined interaction between the dopamine transporter and the D2 receptor on prefronto-striatal activity and volume in humans.

PubMed

Bertolino, Alessandro; Fazio, Leonardo; Di Giorgio, Annabella; Blasi, Giuseppe; Romano, Raffaella; Taurisano, Paolo; Caforio, Grazia; Sinibaldi, Lorenzo; Ursini, Gianluca; Popolizio, Teresa; Tirotta, Emanuele; Papp, Audrey; Dallapiccola, Bruno; Borrelli, Emiliana; Sadee, Wolfgang

2009-01-28

Dopamine modulation of neuronal activity during memory tasks identifies a nonlinear inverted-U shaped function. Both the dopamine transporter (DAT) and dopamine D(2) receptors (encoded by DRD(2)) critically regulate dopamine signaling in the striatum and in prefrontal cortex during memory. Moreover, in vitro studies have demonstrated that DAT and D(2) proteins reciprocally regulate each other presynaptically. Therefore, we have evaluated the genetic interaction between a DRD(2) polymorphism (rs1076560) causing reduced presynaptic D(2) receptor expression and the DAT 3'-VNTR variant (affecting DAT expression) in a large sample of healthy subjects undergoing blood oxygenation level-dependent (BOLD)-functional magnetic resonance imaging (MRI) during memory tasks and structural MRI. Results indicated a significant DRD(2)/DAT interaction in prefrontal cortex and striatum BOLD activity during both working memory and encoding of recognition memory. The differential effect on BOLD activity of the DAT variant was mostly manifest in the context of the DRD(2) allele associated with lower presynaptic expression. Similar results were also evident for gray matter volume in caudate. These interactions describe a nonlinear relationship between compound genotypes and brain activity or gray matter volume. Complementary data from striatal protein extracts from wild-type and D(2) knock-out animals (D2R(-/-)) indicate that DAT and D(2) proteins interact in vivo. Together, our results demonstrate that the interaction between genetic variants in DRD(2) and DAT critically modulates the nonlinear relationship between dopamine and neuronal activity during memory processing.

Striatal dopamine D1 and D2 receptors: widespread influences on methamphetamine-induced dopamine and serotonin neurotoxicity.

PubMed

Gross, Noah B; Duncker, Patrick C; Marshall, John F

2011-11-01

Methamphetamine (mAMPH) is an addictive psychostimulant drug that releases monoamines through nonexocytotic mechanisms. In animals, binge mAMPH dosing regimens deplete markers for monoamine nerve terminals, for example, dopamine and serotonin transporters (DAT and SERT), in striatum and cerebral cortex. Although the precise mechanism of mAMPH-induced damage to monoaminergic nerve terminals is uncertain, both dopamine D1 and D2 receptors are known to be important. Systemic administration of dopamine D1 or D2 receptor antagonists to rodents prevents mAMPH-induced damage to striatal dopamine nerve terminals. Because these studies employed systemic antagonist administration, the specific brain regions involved remain to be elucidated. The present study examined the contribution of dopamine D1 and D2 receptors in striatum to mAMPH-induced DAT and SERT neurotoxicities. In this experiment, either the dopamine D1 antagonist, SCH23390, or the dopamine D2 receptor antagonist, sulpiride, was intrastriatally infused during a binge mAMPH regimen. Striatal DAT and cortical, hippocampal, and amygdalar SERT were assessed as markers of mAMPH-induced neurotoxicity 1 week following binge mAMPH administration. Blockade of striatal dopamine D1 or D2 receptors during an otherwise neurotoxic binge mAMPH regimen produced widespread protection against mAMPH-induced striatal DAT loss and cortical, hippocampal, and amygdalar SERT loss. This study demonstrates that (1) dopamine D1 and D2 receptors in striatum, like nigral D1 receptors, are needed for mAMPH-induced striatal DAT reductions, (2) these same receptors are needed for mAMPH-induced SERT loss, and (3) these widespread influences of striatal dopamine receptor antagonists are likely attributable to circuits connecting basal ganglia to thalamus and cortex. Copyright © 2011 Wiley-Liss, Inc.

Amphetamine elevates nucleus accumbens dopamine via an action potential-dependent mechanism that is modulated by endocannabinoids

PubMed Central

Covey, Dan P.; Bunner, Kendra D.; Schuweiler, Douglas R.; Cheer, Joseph F.; Garris, Paul A.

2018-01-01

The reinforcing effects of abused drugs are mediated by their ability to elevate nucleus accumbens dopamine. Amphetamine (AMPH) was historically thought to increase dopamine by an action potential-independent, non-exocytotic type of release called efflux, involving reversal of dopamine transporter function and driven by vesicular dopamine depletion. Growing evidence suggests that AMPH also acts by an action potential-dependent mechanism. Indeed, fast-scan cyclic voltammetry demonstrates that AMPH activates dopamine transients, reward-related phasic signals generated by burst firing of dopamine neurons and dependent on intact vesicular dopamine. Not established for AMPH but indicating a shared mechanism, endocannabinoids facilitate this activation of dopamine transients by broad classes of abused drugs. Here, using fast-scan cyclic voltammetry coupled to pharmacological manipulations in awake rats, we investigated the action potential and endocannabinoid dependence of AMPH-induced elevations in nucleus accumbens dopamine. AMPH increased the frequency, amplitude and duration of transients, which were observed riding on top of slower dopamine increases. Surprisingly, silencing dopamine neuron firing abolished all AMPH-induced dopamine elevations, identifying an action potential-dependent origin. Blocking cannabinoid type 1 receptors prevented AMPH from increasing transient frequency, similar to reported effects on other abused drugs, but not from increasing transient duration and inhibiting dopamine uptake. Thus, AMPH elevates nucleus accumbens dopamine by eliciting transients via cannabinoid type 1 receptors and promoting the summation of temporally coincident transients, made more numerous, larger and wider by AMPH. Collectively, these findings are inconsistent with AMPH eliciting action potential-independent dopamine efflux and vesicular dopamine depletion, and support endocannabinoids facilitating phasic dopamine signalling as a common action in drug reinforcement

Amphetamine elevates nucleus accumbens dopamine via an action potential-dependent mechanism that is modulated by endocannabinoids.

PubMed

Covey, Dan P; Bunner, Kendra D; Schuweiler, Douglas R; Cheer, Joseph F; Garris, Paul A

2016-06-01

The reinforcing effects of abused drugs are mediated by their ability to elevate nucleus accumbens dopamine. Amphetamine (AMPH) was historically thought to increase dopamine by an action potential-independent, non-exocytotic type of release called efflux, involving reversal of dopamine transporter function and driven by vesicular dopamine depletion. Growing evidence suggests that AMPH also acts by an action potential-dependent mechanism. Indeed, fast-scan cyclic voltammetry demonstrates that AMPH activates dopamine transients, reward-related phasic signals generated by burst firing of dopamine neurons and dependent on intact vesicular dopamine. Not established for AMPH but indicating a shared mechanism, endocannabinoids facilitate this activation of dopamine transients by broad classes of abused drugs. Here, using fast-scan cyclic voltammetry coupled to pharmacological manipulations in awake rats, we investigated the action potential and endocannabinoid dependence of AMPH-induced elevations in nucleus accumbens dopamine. AMPH increased the frequency, amplitude and duration of transients, which were observed riding on top of slower dopamine increases. Surprisingly, silencing dopamine neuron firing abolished all AMPH-induced dopamine elevations, identifying an action potential-dependent origin. Blocking cannabinoid type 1 receptors prevented AMPH from increasing transient frequency, similar to reported effects on other abused drugs, but not from increasing transient duration and inhibiting dopamine uptake. Thus, AMPH elevates nucleus accumbens dopamine by eliciting transients via cannabinoid type 1 receptors and promoting the summation of temporally coincident transients, made more numerous, larger and wider by AMPH. Collectively, these findings are inconsistent with AMPH eliciting action potential-independent dopamine efflux and vesicular dopamine depletion, and support endocannabinoids facilitating phasic dopamine signalling as a common action in drug reinforcement

Mutations at Tyrosine 88, Lysine 92 and Tyrosine 470 of human dopamine transporter result in an attenuation of HIV-1 Tat-induced inhibition of dopamine transport

PubMed Central

Midde, Narasimha M.; Yuan, Yaxia; Quizon, Pamela M.; Sun, Wei-Lun; Huang, Xiaoqin; Zhan, Chang-Guo; Zhu, Jun

2015-01-01

HIV-1 transactivator of transcription (Tat) protein disrupts the dopamine (DA) neurotransmission by inhibiting DA transporter (DAT) function, leading to increased neurocognitive impairment in HIV-1 infected individuals. Through integrated computational modeling and pharmacological studies, we have demonstrated that mutation of tyrosine470 (Y470H) of human DAT (hDAT) attenuates Tat-induced inhibition of DA uptake by changing the transporter conformational transitions. The present study examined the functional influences of other substitutions at tyrosine470 (Y470F and Y470A) and tyrosine88 (Y88F) and lysine92 (K92M), two other relevant residues for Tat binding to hDAT, in Tat-induced inhibitory effects on DA transport. Y88F, K92M and Y470A attenuated Tat-induced inhibition of DA transport, implicating the functional relevance of these residues for Tat binding to hDAT. Compared to wild type hDAT, Y470A and K92M but not Y88F reduced the maximal velocity of [3H]DA uptake without changes in the Km. Y88F and K92M enhanced IC50 values for DA inhibition of [3H]DA uptake and [3H]WIN35,428 binding but decreased IC50 for cocaine and GBR12909 inhibition of [3H]DA uptake, suggesting that these residues are critical for substrate and these inhibitors. Y470F, Y470A, Y88F and K92M attenuated zinc-induced increase of [3H]WIN35,428 binding. Moreover, only Y470A and K92M enhanced DA efflux relative to wild type hDAT, suggesting mutations of these residues differentially modulate transporter conformational transitions. These results demonstrate Tyr88 and Lys92 along with Tyr470 as functional recognition residues in hDAT for Tat-induced inhibition of DA transport and provide mechanistic insights into identifying target residues on the DAT for Tat binding. PMID:25604666

Structure-activity relationships for serotonin transporter and dopamine receptor selectivity.

PubMed

Agatonovic-Kustrin, Snezana; Davies, Paul; Turner, Joseph V

2009-05-01

Antipsychotic medications have a diverse pharmacology with affinity for serotonergic, dopaminergic, adrenergic, histaminergic and cholinergic receptors. Their clinical use now also includes the treatment of mood disorders, thought to be mediated by serotonergic receptor activity. The aim of our study was to characterise the molecular properties of antipsychotic agents, and to develop a model that would indicate molecular specificity for the dopamine (D(2)) receptor and the serotonin (5-HT) transporter. Back-propagation artificial neural networks (ANNs) were trained on a dataset of 47 ligands categorically assigned antidepressant or antipsychotic utility. The structure of each compound was encoded with 63 calculated molecular descriptors. ANN parameters including hidden neurons and input descriptors were optimised based on sensitivity analyses, with optimum models containing between four and 14 descriptors. Predicted binding preferences were in excellent agreement with clinical antipsychotic or antidepressant utility. Validated models were further tested by use of an external prediction set of five drugs with unknown mechanism of action. The SAR models developed revealed the importance of simple molecular characteristics for differential binding to the D(2) receptor and the 5-HT transporter. These included molecular size and shape, solubility parameters, hydrogen donating potential, electrostatic parameters, stereochemistry and presence of nitrogen. The developed models and techniques employed are expected to be useful in the rational design of future therapeutic agents.

Enhanced dopamine D2 autoreceptor function in the adult prefrontal cortex contributes to dopamine hypoactivity following adolescent social stress.

PubMed

Weber, Matthew A; Graack, Eric T; Scholl, Jamie L; Renner, Kenneth J; Forster, Gina L; Watt, Michael J

2018-06-14

Adult psychiatric disorders characterized by cognitive deficits reliant on prefrontal cortex (PFC) dopamine are promoted by teenage bullying. Similarly, male Sprague-Dawley rats exposed to social defeat in mid-adolescence (P35-39) show impaired working memory in adulthood (P56-70), along with decreased medial PFC (mPFC) dopamine activity that results in part from increased dopamine transporter-mediated clearance. Here, we determined if dopamine synthesis and D2 autoreceptor-mediated inhibition of dopamine release in the adult mPFC are also enhanced by adolescent defeat to contribute to later dopamine hypofunction. Control and previously defeated rats did not differ in either DOPA accumulation following amino acid decarboxylase inhibition (NSD-1015 100 mg/kg ip.) or total/phosphorylated tyrosine hydroxylase protein expression, suggesting dopamine synthesis in the adult mPFC is not altered by adolescent defeat. However, exposure to adolescent defeat caused greater decreases in extracellular dopamine release (measured using in vivo chronoamperometry) in the adult mPFC upon local infusion of the D2 receptor agonist quinpirole (3 nM), implying greater D2 autoreceptor function. Equally enhanced D2 autoreceptor-mediated inhibition of dopamine release is seen in the adolescent (P40 or P49) mPFC, which declines in control rats by adulthood. However, this developmental decrease in autoreceptor function is absent following adolescent defeat, suggesting retention of an adolescent-like phenotype into adulthood. Current and previous findings indicate adolescent defeat decreases extracellular dopamine availability in the adult mPFC via both enhanced inhibition of dopamine release and increased dopamine clearance, which may be viable targets for improving treatment of cognitive deficits seen in neuropsychiatric disorders promoted by adolescent stress. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Dopamine receptor D2 (DRD2), dopamine transporter solute carrier family C6, member 4 (SLC6A3), and catechol-O-methyltransferase (COMT) genes as moderators of the relation between maternal history of maltreatment and infant emotion regulation.

PubMed

Villani, Vanessa; Ludmer, Jaclyn; Gonzalez, Andrea; Levitan, Robert; Kennedy, James; Masellis, Mario; Basile, Vincenzo S; Wekerle, Christine; Atkinson, Leslie

2018-05-01

Although infants less than 18 months old are capable of engaging in self-regulatory behavior (e.g., avoidance, withdrawal, and orienting to other aspects of their environment), the use of self-regulatory strategies at this age (as opposed to relying on caregivers) is associated with elevated behavioral and physiological distress. This study investigated infant dopamine-related genotypes (dopamine receptor D2 [DRD2], dopamine transporter solute carrier family C6, member 4 [SLC6A3], and catechol-O-methyltransferase [COMT]) as they interact with maternal self-reported history of maltreatment to predict observed infant independent emotion regulation behavior. A community sample (N = 193) of mother-infant dyads participated in a toy frustration challenge at infant age 15 months, and infant emotion regulation behavior was coded. Buccal cells were collected for genotyping. Maternal maltreatment history significantly interacted with infant SLC6A3 and COMT genotypes, such that infants with more 10-repeat and valine alleles of SLC6A3 and COMT, respectively, relative to infants with fewer or no 10-repeat and valine alleles, utilized more independent (i.e., maladaptive) regulatory behavior if mother reported a more extensive maltreatment history, as opposed to less. The findings indicate that child genetic factors moderate the intergenerational impact of maternal maltreatment history. The results are discussed in terms of potential mechanism of Gene × Environment interaction.

Putative presynaptic dopamine dysregulation in schizophrenia is supported by molecular evidence from post-mortem human midbrain

PubMed Central

Purves-Tyson, T D; Owens, S J; Rothmond, D A; Halliday, G M; Double, K L; Stevens, J; McCrossin, T; Shannon Weickert, C

2017-01-01

The dopamine hypothesis of schizophrenia posits that increased subcortical dopamine underpins psychosis. In vivo imaging studies indicate an increased presynaptic dopamine synthesis capacity in striatal terminals and cell bodies in the midbrain in schizophrenia; however, measures of the dopamine-synthesising enzyme, tyrosine hydroxylase (TH), have not identified consistent changes. We hypothesise that dopamine dysregulation in schizophrenia could result from changes in expression of dopamine synthesis enzymes, receptors, transporters or catabolic enzymes. Gene expression of 12 dopamine-related molecules was examined in post-mortem midbrain (28 antipsychotic-treated schizophrenia cases/29 controls) using quantitative PCR. TH and the synaptic dopamine transporter (DAT) proteins were examined in post-mortem midbrain (26 antipsychotic-treated schizophrenia cases per 27 controls) using immunoblotting. TH and aromatic acid decarboxylase (AADC) mRNA and TH protein were unchanged in the midbrain in schizophrenia compared with controls. Dopamine receptor D2 short, vesicular monoamine transporter (VMAT2) and DAT mRNAs were significantly decreased in schizophrenia, with no change in DRD3 mRNA, DRD3nf mRNA and DAT protein between diagnostic groups. However, DAT protein was significantly increased in putatively treatment-resistant cases of schizophrenia compared to putatively treatment-responsive cases. Midbrain monoamine oxidase A (MAOA) mRNA was increased, whereas MAOB and catechol-O-methyl transferase mRNAs were unchanged in schizophrenia. We conclude that, whereas some mRNA changes are consistent with increased dopamine action (decreased DAT mRNA), others suggest reduced dopamine action (increased MAOA mRNA) in the midbrain in schizophrenia. Here, we identify a molecular signature of dopamine dysregulation in the midbrain in schizophrenia that mainly includes gene expression changes of molecules involved in dopamine synthesis and in regulating the time course of dopamine

Dopamine receptors – IUPHAR Review 13

PubMed Central

Beaulieu, Jean-Martin; Espinoza, Stefano; Gainetdinov, Raul R

2015-01-01

The variety of physiological functions controlled by dopamine in the brain and periphery is mediated by the D1, D2, D3, D4 and D5 dopamine GPCRs. Drugs acting on dopamine receptors are significant tools for the management of several neuropsychiatric disorders including schizophrenia, bipolar disorder, depression and Parkinson's disease. Recent investigations of dopamine receptor signalling have shown that dopamine receptors, apart from their canonical action on cAMP-mediated signalling, can regulate a myriad of cellular responses to fine-tune the expression of dopamine-associated behaviours and functions. Such signalling mechanisms may involve alternate G protein coupling or non-G protein mechanisms involving ion channels, receptor tyrosine kinases or proteins such as β-arrestins that are classically involved in GPCR desensitization. Another level of complexity is the growing appreciation of the physiological roles played by dopamine receptor heteromers. Applications of new in vivo techniques have significantly furthered the understanding of the physiological functions played by dopamine receptors. Here we provide an update of the current knowledge regarding the complex biology, signalling, physiology and pharmacology of dopamine receptors. PMID:25671228

Dopamine dysregulation in the prefrontal cortex relates to cognitive deficits in the sub-chronic PCP-model for schizophrenia: A preliminary investigation.

PubMed

McLean, Samantha L; Harte, Michael K; Neill, Joanna C; Young, Andrew Mj

2017-06-01

Dopamine dysregulation in the prefrontal cortex (PFC) plays an important role in cognitive dysfunction in schizophrenia. Sub-chronic phencyclidine (scPCP) treatment produces cognitive impairments in rodents and is a thoroughly validated animal model for cognitive deficits in schizophrenia. The aim of our study was to investigate the role of PFC dopamine in scPCP-induced deficits in a cognitive task of relevance to the disorder, novel object recognition (NOR). Twelve adult female Lister Hooded rats received scPCP (2 mg/kg) or vehicle via the intraperitoneal route twice daily for 7 days, followed by 7 days washout. In vivo microdialysis was carried out prior to, during and following the NOR task. Vehicle rats successfully discriminated between novel and familiar objects and this was accompanied by a significant increase in dopamine in the PFC during the retention trial ( p < 0.01). scPCP produced a significant deficit in NOR ( p < 0.05 vs. control) and no PFC dopamine increase was observed. These data demonstrate an increase in dopamine during the retention trial in vehicle rats that was not observed in scPCP-treated rats accompanied by cognitive disruption in the scPCP group. This novel finding suggests a mechanism by which cognitive deficits are produced in this animal model and support its use for investigating disorders in which PFC dopamine is central to the pathophysiology.

Dopamine synapse is a neuroligin-2–mediated contact between dopaminergic presynaptic and GABAergic postsynaptic structures

PubMed Central

Uchigashima, Motokazu; Ohtsuka, Toshihisa; Kobayashi, Kazuto; Watanabe, Masahiko

2016-01-01

Midbrain dopamine neurons project densely to the striatum and form so-called dopamine synapses on medium spiny neurons (MSNs), principal neurons in the striatum. Because dopamine receptors are widely expressed away from dopamine synapses, it remains unclear how dopamine synapses are involved in dopaminergic transmission. Here we demonstrate that dopamine synapses are contacts formed between dopaminergic presynaptic and GABAergic postsynaptic structures. The presynaptic structure expressed tyrosine hydroxylase, vesicular monoamine transporter-2, and plasmalemmal dopamine transporter, which are essential for dopamine synthesis, vesicular filling, and recycling, but was below the detection threshold for molecules involving GABA synthesis and vesicular filling or for GABA itself. In contrast, the postsynaptic structure of dopamine synapses expressed GABAergic molecules, including postsynaptic adhesion molecule neuroligin-2, postsynaptic scaffolding molecule gephyrin, and GABAA receptor α1, without any specific clustering of dopamine receptors. Of these, neuroligin-2 promoted presynaptic differentiation in axons of midbrain dopamine neurons and striatal GABAergic neurons in culture. After neuroligin-2 knockdown in the striatum, a significant decrease of dopamine synapses coupled with a reciprocal increase of GABAergic synapses was observed on MSN dendrites. This finding suggests that neuroligin-2 controls striatal synapse formation by giving competitive advantage to heterologous dopamine synapses over conventional GABAergic synapses. Considering that MSN dendrites are preferential targets of dopamine synapses and express high levels of dopamine receptors, dopamine synapse formation may serve to increase the specificity and potency of dopaminergic modulation of striatal outputs by anchoring dopamine release sites to dopamine-sensing targets. PMID:27035941

Dopamine transporter and vesicular monoamine transporter knockout mice : implications for Parkinson's disease.

PubMed

Miller, G W; Wang, Y M; Gainetdinov, R R; Caron, M G

2001-01-01

One of the most valuable methods for understanding the function of a particular protein is the generation of animals that have had the gene encoding for the protein of interest disrupted, commonly known as a "quo;knockout"quo; or null mutant. By incorporating a sequence of DNA (typically encoding antibiotic resistance to aid in the selection of the mutant gene) into embryonic stem cells by homologous recombination, the normal transcription of the gene is effectively blocked (Fig. 1). Since a particular protein is encoded by two copies of a gene, it is necessary to have the gene on both alleles "quo;knocked out."quo; This is performed by cross-breeding animals with one affected allele (heterozygote) to generate offspring that have inherited two mutant alleles (homozygote). This procedure has been used to generate animals lacking either the plasma membrane dopamine transporter (DAT; Fig. 2) or the vesicular monoamine transporter (VMAT2; Fig. 3). Both DAT and VMAT2 are essential for dopamine homeostasis and are thought to participate in the pathogenesis of Parkinson's disease (1-5). Fig. 1. Maps of the targeting vector and the mock construct. The mouse genomic fragment (clone 11) was isolated from a Stratagene 129 SvJ library by standard colony hybridization using a PCR probe from the 5' end of rat cDNA. The restriction site abbreviations are as follows: H, HindIII; N, NotI; Sc, SacI; Sn, SnaI; X, XbaI; and Xh, XhoI. The region between HindIII and SnaI on clone 11 containing the coding sequence from transmembrane domains 3 and 4 of VMAT2 was deleted and replaced with PGK-neo. The 3' fragment of clone 11 was reserved as an external probe for Southern analysis. To facilitate PCR screening of embryonic stem cell clones, a mock construct containing the SnaI/XbaI fragment and part of the Neo cassette was generated as a positive control. pPNT and pGEM4Z were used to construct knockout and mock vectors, respectively. (Reproduced with permission from ref. 1). Fig. 2. DAT and

Vesicular Monoamine Transporter 2 (VMAT2) Level Regulates MPTP Vulnerability and Clearance of Excess Dopamine in Mouse Striatal Terminals.

PubMed

Lohr, Kelly M; Chen, Merry; Hoffman, Carlie A; McDaniel, Miranda J; Stout, Kristen A; Dunn, Amy R; Wang, Minzheng; Bernstein, Alison I; Miller, Gary W

2016-09-01

The vesicular monoamine transporter 2 (VMAT2) packages neurotransmitters for release during neurotransmission and sequesters toxicants into vesicles to prevent neuronal damage. In mice, low VMAT2 levels causes catecholaminergic cell loss and behaviors resembling Parkinson's disease, while high levels of VMAT2 increase dopamine release and protect against dopaminergic toxicants. However, comparisons across these VMAT2 mouse genotypes were impossible due to the differing genetic background strains of the animals. Following back-crossing to a C57BL/6 line, we confirmed that mice with approximately 95% lower VMAT2 levels compared with wild-type (VMAT2-LO) display significantly reduced vesicular uptake, progressive dopaminergic terminal loss with aging, and exacerbated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity. Conversely, VMAT2-overexpressing mice (VMAT2-HI) are protected from the loss of striatal terminals following MPTP treatment. We also provide evidence that enhanced vesicular filling in the VMAT2-HI mice modifies the handling of newly synthesized dopamine, indicated by changes in indirect measures of extracellular dopamine clearance. These results confirm the role of VMAT2 in the protection of vulnerable nigrostriatal dopamine neurons and may also provide new insight into the side effects of L-DOPA treatments in Parkinson's disease. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

The dopamine transporter gene may not contribute to susceptibility and the specific personality traits of amphetamine dependence.

PubMed

Tzeng, Nian-Sheng; Lu, Ru-Band; Yeh, Hui-Wen; Yeh, Yi-Wei; Huang, Chang-Chih; Yen, Che-Hung; Kuo, Shin-Chang; Chen, Chun-Yen; Chang, Hsin-An; Ho, Pei-Shen; Cheng, Serena; Shih, Mei-Chen; Huang, San-Yuan

2015-04-01

A substantial amount of evidence suggests that dysfunction of the dopamine transporter may be involved in the pathophysiology of amphetamine dependence (AD). The aim of this study was to examine whether the dopamine transporter gene (DAT1, SLC6A3) is associated with development of AD and whether this gene influences personality traits in patients with AD. Eighteen polymorphisms of the DAT1 gene were analyzed in a case-control study that included 909 Han Chinese men (568 patients with AD and 341 control subjects). The patients fulfilled the DSM-IV-TR criteria for AD. The Tridimensional Personality Questionnaire (TPQ) was used to assess personality traits and to examine the association between these traits and DAT1 gene variants. A weak association was found between the rs27072 polymorphism and development of AD, but these borderline associations were unconfirmed by logistic regression and haplotype analysis. Although harm avoidance and novelty seeking scores were significantly higher in patients than in controls, DAT1 polymorphisms did not influence these scores. This study suggests that high harm avoidance and novelty seeking personality traits may be a risk factor for the development of AD. However, the DAT1 gene may not contribute to AD susceptibility and specific personality traits observed in AD among Han Chinese men. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Obesity is associated with genetic variants that alter dopamine availability.

PubMed

Need, A C; Ahmadi, K R; Spector, T D; Goldstein, D B

2006-05-01

Human and animal studies have implicated dopamine in appetite regulation, and family studies have shown that BMI has a strong genetic component. Dopamine availability is controlled largely by three enzymes: COMT, MAOA and MAOB, and by the dopamine transporter SLC6A3, and each gene has a well-characterized functional variant. Here we look at these four functional polymorphisms together, to investigate how heritable variation in dopamine levels influences the risk of obesity in a cohort of 1150, including 240 defined as obese (BMI > or = 30). The COMT and SLC6A3 polymorphisms showed no association with either weight, BMI or obesity risk. We found, however, that both MAOA and MAOB show an excess of the low-activity genotypes in obese individuals (MAOA:chi2= 15.45, p = 0.004; MAOB:chi2= 8.05, p = 0.018). Additionally, the MAOA genotype was significantly associated with both weight (p = 0.0005) and BMI (p = 0.001). When considered together, the 'at risk genotype'--low activity genotypes at both the MAOA and MAOB loci--shows a relative risk for obesity of 5.01. These results have not been replicated and, given the experience of complex trait genetics, warrant caution in interpretation. In implicating both the MAOA and MOAB variants, however, this study provides the first indication that dopamine availability (as opposed to other effects of MAOA) is involved in human obesity. It is therefore a priority to assess the associations in replication datasets.

Investigation of the enzymology and pharmacology of novel substrates and inhibitors of dopamine beta-monooxygenase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Roberts, S.F.

1987-01-01

Dopamine beta-monooxygenase (DBM) was shown to catalyze the selenoxidation of 2-(phenylseleno)ethylamines, selenium-containing analogues of dopamine, by the normal monooxygenase pathway. The compounds 2-(phenylseleno)-ethylamine (PAESe), 2-(4'-hydroxyphenylseleno)ethylamine (pOH PAESe), and 1-(phenylseleno)-2-propylamine (Me PAESe) were synthesized and fully characterized as DBM substrates. Two other classes of compounds were investigated as potential alternate substrates for DBM. The possibility of stereoselective sulfonylation of 2-(phenylsulfenyl)- ethylamine (PAESO) was considered. A unique class of compounds, 2-(phenylthio)ethanols were designed and synthesized as DBM substrates but were found to be a novel class of potent competitive inhibitors of DBM with respect to tyramine. Preliminary experiments were also performed inmore » an effort to demonstrate that the potent antihypertensive and indirect-acting sympathomimetic activity of 2-(phenylthio)ethylamine (PAES) was a result of DBM-oxygenation of this compound in vivo. The specific reserpine-sensitive uptake of (/sup 3/H)-norepinephrine into rat brain synaptosomes was demonstrated as was the synaptosomal conversion of (/sup 3/H)-dopamine to (/sup 3/H)-norepinephrine.« less

Initial elevations in glutamate and dopamine neurotransmission decline with age, as does exploratory behavior, in LRRK2 G2019S knock-in mice

PubMed Central

Kuhlmann, Naila; Kadgien, Chelsie A; Tatarnikov, Igor; Fox, Jesse; Khinda, Jaskaran; Mitchell, Emma; Bergeron, Sabrina; Melrose, Heather

2017-01-01

LRRK2 mutations produce end-stage Parkinson’s disease (PD) with reduced nigrostriatal dopamine, whereas, asymptomatic carriers have increased dopamine turnover and altered brain connectivity. LRRK2 pathophysiology remains unclear, but reduced dopamine and mitochondrial abnormalities occur in aged G2019S mutant knock-in (GKI) mice. Conversely, cultured GKI neurons exhibit increased synaptic transmission. We assessed behavior and synaptic glutamate and dopamine function across a range of ages. Young GKI mice exhibit more vertical exploration, elevated glutamate and dopamine transmission, and aberrant D2-receptor responses. These phenomena decline with age, but are stable in littermates. In young GKI mice, dopamine transients are slower, independent of dopamine transporter (DAT), increasing the lifetime of extracellular dopamine. Slowing of dopamine transients is observed with age in littermates, suggesting premature ageing of dopamine synapses in GKI mice. Thus, GKI mice exhibit early, but declining, synaptic and behavioral phenotypes, making them amenable to investigation of early pathophysiological, and later parkinsonian-like, alterations. This model will prove valuable in efforts to develop neuroprotection for PD. PMID:28930069

Initial elevations in glutamate and dopamine neurotransmission decline with age, as does exploratory behavior, in LRRK2 G2019S knock-in mice.

PubMed

Volta, Mattia; Beccano-Kelly, Dayne A; Paschall, Sarah A; Cataldi, Stefano; MacIsaac, Sarah E; Kuhlmann, Naila; Kadgien, Chelsie A; Tatarnikov, Igor; Fox, Jesse; Khinda, Jaskaran; Mitchell, Emma; Bergeron, Sabrina; Melrose, Heather; Farrer, Matthew J; Milnerwood, Austen J

2017-09-20

LRRK2 mutations produce end-stage Parkinson's disease (PD) with reduced nigrostriatal dopamine, whereas, asymptomatic carriers have increased dopamine turnover and altered brain connectivity. LRRK2 pathophysiology remains unclear, but reduced dopamine and mitochondrial abnormalities occur in aged G2019S mutant knock-in (GKI) mice. Conversely, cultured GKI neurons exhibit increased synaptic transmission. We assessed behavior and synaptic glutamate and dopamine function across a range of ages. Young GKI mice exhibit more vertical exploration, elevated glutamate and dopamine transmission, and aberrant D2-receptor responses. These phenomena decline with age, but are stable in littermates. In young GKI mice, dopamine transients are slower, independent of dopamine transporter (DAT), increasing the lifetime of extracellular dopamine. Slowing of dopamine transients is observed with age in littermates, suggesting premature ageing of dopamine synapses in GKI mice. Thus, GKI mice exhibit early, but declining, synaptic and behavioral phenotypes, making them amenable to investigation of early pathophysiological, and later parkinsonian-like, alterations. This model will prove valuable in efforts to develop neuroprotection for PD.

Exposure to the Polybrominated Diphenyl Ether Mixture DE-71 Damages the Nigrostriatal Dopamine System: Role of Dopamine Handling in Neurotoxicity

PubMed Central

Bradner, Joshua M.; Suragh, Tiffany A.; Wilson, W. Wyatt; Lazo, Carlos R.; Stout, Kristen A.; Kim, Hye Mi; Wang, Min Z.; Walker, Douglas I.; Pennell, Kurt D.; Richardson, Jason R.; Miller, Gary W.; Caudle, W. Michael

2013-01-01

In the last several decades polybrominated diphenyl ethers (PBDEs) have replaced the previously banned polychlorinated biphenyls (PCBs) in multiple flame retardant utilities. As epidemiological and laboratory studies have suggested PCBs as a risk factor for Parkinson’s disease (PD), the similarities between PBDEs and PCBs suggest that PBDEs have the potential to be neurotoxic to the dopamine system. The purpose of this study was to evaluate the neurotoxic effects of the PBDE mixture, DE-71, on the nigrostriatal dopamine system and address the role of altered dopamine handling in mediating this neurotoxicity. Using an in vitro model system we found DE-71 effectively caused cell death in a dopaminergic cell line as well as reducing the number of TH+ neurons isolated from VMAT2 WT and LO animals. Assessment of DE-71 neurotoxicity in vivo demonstrated significant deposition of PBDE congeners in the brains of mice, leading to reductions in striatal dopamine and dopamine handling, as well as reductions in the striatal dopamine transporter (DAT) and VMAT2. Additionally, DE-71 elicited a significant locomotor deficit in the VMAT2 WT and LO mice. However, no change was seen in TH expression in dopamine terminal or in the number of dopamine neurons in the substantia nigra pars compacta (SNpc). To date, these are the first data to demonstrate that exposure to PBDEs disrupts the nigrostriatal dopamine system. Given their similarities to PCBs, additional laboratory and epidemiological research should be considered to assess PBDEs as a potential risk factor for PD and other neurological disorders. PMID:23287494

The dopamine-related polymorphisms BDNF, COMT, DRD2, DRD3, and DRD4 are not linked with changes in CSF dopamine levels and frequency of HIV infection.

PubMed

Horn, Anne; Scheller, C; du Plessis, S; Burger, R; Arendt, G; Joska, J; Sopper, S; Maschke, C M; Obermann, M; Husstedt, I W; Hain, J; Riederer, P; Koutsilieri, E

2017-04-01

We showed previously that higher levels in CSF dopamine in HIV patients are associated with the presence of the dopamine transporter (DAT) 10/10-repeat allele which was also detected more frequently in HIV-infected individuals compared to uninfected subjects. In the current study, we investigated further whether other genetic dopamine (DA)-related polymorphisms may be related with changes in CSF DA levels and frequency of HIV infection in HIV-infected subjects. Specifically, we studied genetic polymorphisms of brain-derived neurotrophic factor, catechol-O-methyltransferase, and dopamine receptors DRD2, DRD3, and DRD4 genetic polymorphisms in uninfected and HIV-infected people in two different ethnical groups, a German cohort (Caucasian, 72 individuals with HIV infection and 22 individuals without HIV infection) and a South African cohort (Xhosan, 54 individuals with HIV infection and 19 individuals without HIV infection). We correlated the polymorphisms with CSF DA levels, HIV dementia score, CD4 + T cell counts, and HIV viral load. None of the investigated DA-related polymorphisms was associated with altered CSF DA levels, CD4 + T cell count, viral load, and HIV dementia score. The respective allele frequencies were equally distributed between HIV-infected patients and controls. Our findings do not show any influence of the studied genetic polymorphisms on CSF DA levels and HIV infection. This is in contrast to what we found previously for the DAT 3'UTR VNTR and highlights the specific role of the DAT VNTR in HIV infection and disease.

Brain dopamine neurone 'damage': methamphetamine users vs. Parkinson's disease - a critical assessment of the evidence.

PubMed

Kish, Stephen J; Boileau, Isabelle; Callaghan, Russell C; Tong, Junchao

2017-01-01

The objective of this review is to evaluate the evidence that recreational methamphetamine exposure might damage dopamine neurones in human brain, as predicted by experimental animal findings. Brain dopamine marker data in methamphetamine users can now be compared with those in Parkinson's disease, for which the Oleh Hornykiewicz discovery in Vienna of a brain dopamine deficiency is established. Whereas all examined striatal (caudate and putamen) dopamine neuronal markers are decreased in Parkinson's disease, levels of only some (dopamine, dopamine transporter) but not others (dopamine metabolites, synthetic enzymes, vesicular monoamine transporter 2) are below normal in methamphetamine users. This suggests that loss of dopamine neurones might not be characteristic of methamphetamine exposure in at least some human drug users. In methamphetamine users, dopamine loss was more marked in caudate than in putamen, whereas in Parkinson's disease, the putamen is distinctly more affected. Substantia nigra loss of dopamine-containing cell bodies is characteristic of Parkinson's disease, but similar neuropathological studies have yet to be conducted in methamphetamine users. Similarly, it is uncertain whether brain gliosis, a common feature of brain damage, occurs after methamphetamine exposure in humans. Preliminary epidemiological findings suggest that methamphetamine use might increase risk of subsequent development of Parkinson's disease. We conclude that the available literature is insufficient to indicate that recreational methamphetamine exposure likely causes loss of dopamine neurones in humans but does suggest presence of a striatal dopamine deficiency that, in principle, could be corrected by dopamine substitution medication if safety and subject selection considerations can be resolved. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

The role of dopamine receptors in the neurotoxicity of methamphetamine.

PubMed

Ares-Santos, S; Granado, N; Moratalla, R

2013-05-01

Methamphetamine is a synthetic drug consumed by millions of users despite its neurotoxic effects in the brain, leading to loss of dopaminergic fibres and cell bodies. Moreover, clinical reports suggest that methamphetamine abusers are predisposed to Parkinson's disease. Therefore, it is important to elucidate the mechanisms involved in methamphetamine-induced neurotoxicity. Dopamine receptors may be a plausible target to prevent this neurotoxicity. Genetic inactivation of dopamine D1 or D2 receptors protects against the loss of dopaminergic fibres in the striatum and loss of dopaminergic neurons in the substantia nigra. Protection by D1 receptor inactivation is due to blockade of hypothermia, reduced dopamine content and turnover and increased stored vesicular dopamine in D1R(-/-) mice. However, the neuroprotective impact of D2 receptor inactivation is partially dependent on an effect on body temperature, as well as on the blockade of dopamine reuptake by decreased dopamine transporter activity, which results in reduced intracytosolic dopamine levels in D2R(-/-) mice. © 2013 The Association for the Publication of the Journal of Internal Medicine.

[Effects of dopamine and adenosine on regulation of water-electrolyte exchange in Amoeba proteus].

PubMed

Bagrov, Ia Iu; Manusova, N B

2014-01-01

Dopamine and adenosine both regulate transport of sodium chloride in the renal tubules in mammals. We have studied the effect of dopamine and adenosine on spontaneous activity of contractile vacuole of Amoeba proteous. Both substances stimulated contractile vacuole. The effect of dopamine was suppressed by D2 receptor antagonist, haloperidol, but not by D1 antagonist, SCH 39166. Adenylate cyclase inhibitor, 2.5-dideoxyadenosine, suppressed the effect of dopamine, but not of adenosine. Inhibitor of protein kinase C, staurosporine, in contrast, blocked the effect of adenosine, but not dopamine. Notably, dopamine opposed effect of adenosine and vice versa. These results suggest that similar effects of dopamine and adenosine could be mediated by different intracellulare mechanisms.

Dopamine neuron dependent behaviors mediated by glutamate cotransmission

PubMed Central

Mingote, Susana; Chuhma, Nao; Kalmbach, Abigail; Thomsen, Gretchen M; Wang, Yvonne; Mihali, Andra; Sferrazza, Caroline; Zucker-Scharff, Ilana; Siena, Anna-Claire; Welch, Martha G; Lizardi-Ortiz, José; Sulzer, David; Moore, Holly; Gaisler-Salomon, Inna; Rayport, Stephen

2017-01-01

Dopamine neurons in the ventral tegmental area use glutamate as a cotransmitter. To elucidate the behavioral role of the cotransmission, we targeted the glutamate-recycling enzyme glutaminase (gene Gls1). In mice with a dopamine transporter (Slc6a3)-driven conditional heterozygous (cHET) reduction of Gls1 in their dopamine neurons, dopamine neuron survival and transmission were unaffected, while glutamate cotransmission at phasic firing frequencies was reduced, enabling a selective focus on the cotransmission. The mice showed normal emotional and motor behaviors, and an unaffected response to acute amphetamine. Strikingly, amphetamine sensitization was reduced and latent inhibition potentiated. These behavioral effects, also seen in global GLS1 HETs with a schizophrenia resilience phenotype, were not seen in mice with an Emx1-driven forebrain reduction affecting most brain glutamatergic neurons. Thus, a reduction in dopamine neuron glutamate cotransmission appears to mediate significant components of the GLS1 HET schizophrenia resilience phenotype, and glutamate cotransmission appears to be important in attribution of motivational salience. DOI: http://dx.doi.org/10.7554/eLife.27566.001 PMID:28703706

Cholinergic Interneurons Underlie Spontaneous Dopamine Release in Nucleus Accumbens

PubMed Central

2017-01-01

The release of dopamine from terminals in the NAc is regulated by a number of factors, including voltage-gated ion channels, D2-autoreceptors, and nAChRs. Cholinergic interneurons (CINs) drive dopamine release through activation of nAChRs on dopamine terminals. Using cyclic voltammetry in mouse brain slices, nAChR-dependent spontaneous dopamine transients and the mechanisms underlying the origin were examined in the NAc. Spontaneous events were infrequent (0.3 per minute), but the rate and amplitude were increased after blocking Kv channels with 4-aminopyridine. Although the firing frequency of CINs was increased by blocking glutamate reuptake with TBOA and the Sk blocker apamin, only 4-aminopyridine increased the frequency of dopamine transients. In contrast, inhibition of CIN firing with the μ/δ selective opioid [Met5]enkephalin (1 μm) decreased spontaneous dopamine transients. Cocaine increased the rate and amplitude of dopamine transients, suggesting that the activity of the dopamine transporter limits the detection of these events. In the presence of cocaine, the rate of spontaneous dopamine transients was further increased after blocking D2-autoreceptors. Blockade of muscarinic receptors had no effect on evoked dopamine release, suggesting that feedback inhibition of acetylcholine release was not involved. Thus, although spontaneous dopamine transients are reliant on nAChRs, the frequency was not strictly governed by the activity of CINs. The increase in frequency of spontaneous dopamine transients induced by cocaine was not due to an increase in cholinergic tone and is likely a product of an increase in detection resulting from decreased dopamine reuptake. SIGNIFICANCE STATEMENT The actions of dopamine in the NAc are thought to be responsible for endogenous reward and the reinforcing properties of drugs of abuse, such as psychostimulants. The present work examines the mechanisms underlying nAChR-induced spontaneous dopamine release. This study

Dopamine and Caffeine Encapsulation within Boron Nitride (14,0) Nanotubes: Classical Molecular Dynamics and First Principles Calculations.

PubMed

García-Toral, Dolores; González-Melchor, Minerva; Rivas-Silva, Juan F; Meneses-Juárez, Efraín; Cano-Ordaz, José; H Cocoletzi, Gregorio

2018-06-07

Classical molecular dynamics (MD) and density functional theory (DFT) calculations are developed to investigate the dopamine and caffeine encapsulation within boron nitride (BN) nanotubes (NT) with (14,0) chirality. Classical MD studies are done at canonical and isobaric-isothermal conditions at 298 K and 1 bar in explicit water. Results reveal that both molecules are attracted by the nanotube; however, only dopamine is able to enter the nanotube, whereas caffeine moves in its vicinity, suggesting that both species can be transported: the first by encapsulation and the second by drag. Findings are analyzed using the dielectric behavior, pair correlation functions, diffusion of the species, and energy contributions. The DFT calculations are performed according to the BLYP approach and applying the atomic base of the divided valence 6-31g(d) orbitals. The geometry optimization uses the minimum-energy criterion, accounting for the total charge neutrality and multiplicity of 1. Adsorption energies in the dopamine encapsulation indicate physisorption, which induces the highly occupied molecular orbital-lower unoccupied molecular orbital gap reduction yielding a semiconductor behavior. The charge redistribution polarizes the BNNT/dopamine and BNNT/caffeine structures. The work function decrease and the chemical potential values suggest the proper transport properties in these systems, which may allow their use in nanobiomedicine.

A variable number of tandem repeats in the 3'-untranslated region of the dopamine transporter modulates striatal function during working memory updating across the adult age span.

PubMed

Sambataro, Fabio; Podell, Jamie E; Murty, Vishnu P; Das, Saumitra; Kolachana, Bhaskar; Goldberg, Terry E; Weinberger, Daniel R; Mattay, Venkata S

2015-08-01

Dopamine modulation of striatal function is critical for executive functions such as working memory (WM) updating. The dopamine transporter (DAT) regulates striatal dopamine signaling via synaptic reuptake. A variable number of tandem repeats in the 3'-untranslated region of SLC6A3 (DAT1-3'-UTR-VNTR) is associated with DAT expression, such that 9-repeat allele carriers tend to express lower levels (associated with higher extracellular dopamine concentrations) than 10-repeat homozygotes. Aging is also associated with decline of the dopamine system. The goal of the present study was to investigate the effects of aging and DAT1-3'-UTR-VNTR on the neural activity and functional connectivity of the striatum during WM updating. Our results showed both an age-related decrease in striatal activity and an effect of DAT1-3'-UTR-VNTR. Ten-repeat homozygotes showed reduced striatal activity and increased striatal-hippocampal connectivity during WM updating relative to the 9-repeat carriers. There was no age by DAT1-3'-UTR-VNTR interaction. These results suggest that, whereas striatal function during WM updating is modulated by both age and genetically determined DAT levels, the rate of the age-related decline in striatal function is similar across both DAT1-3'-UTR-VNTR genotype groups. They further suggest that, because of the baseline difference in striatal function based on DAT1-3'-UTR-VNTR polymorphism, 10-repeat homozygotes, who have lower levels of striatal function throughout the adult life span, may reach a threshold of decreased striatal function and manifest impairments in cognitive processes mediated by the striatum earlier in life than the 9-repeat carriers. Our data suggest that age and DAT1-3'-UTR-VNTR polymorphism independently modulate striatal function. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.

The dopamine precursor L-dihydroxyphenylalanine is transported by the amino acid transporters rBAT and LAT2 in renal cortex.

PubMed

Quiñones, Henry; Collazo, Roberto; Moe, Orson W

2004-07-01

The intrarenal autocrine-paracrine dopamine (DA) system is critical for Na(+) homeostasis. l-Dihydroxyphenylalanine (l-DOPA) uptake from the glomerular filtrate and plasma provides the substrate for DA generation by the renal proximal tubule. The transporter(s) responsible for proximal tubule l-DOPA uptake has not been characterized. Renal cortical poly-A(+) RNA injected into Xenopus laevis oocytes induced l-DOPA uptake in a time- and dose-dependent fashion with biphasic K(m)s in the millimolar and micromolar range and independent of inward Na(+), K(+), or H(+) gradients, suggesting the presence of low- and high-affinity l-DOPA carriers. Complementary RNA from two amino acid transporters yielded l-DOPA uptake significantly above water-injected controls the rBAT/b(0,+)AT dimer (rBAT) and the LAT2/4F2 dimer (LAT2). In contradistinction to renal cortical poly-A(+), l-DOPA kinetics of rBAT and LAT2 showed classic Michaelis-Menton kinetics with K(m)s in the micromolar and millimolar range, respectively. Sequence-specific antisense oligonucleotides to rBAT or LAT2 (AS) caused inhibition of rBAT and LAT2 cRNA-induced l-DOPA transport and cortical poly-A(+)-induced arginine and phenylalanine transport. However, the same ASs only partially blocked poly-A(+)-induced l-DOPA transport. In cultured kidney cells, silencing inhibitory RNA (siRNA) to rBAT significantly inhibited l-DOPA uptake. We conclude that rBAT and LAT2 can mediate apical and basolateral l-DOPA uptake into the proximal tubule, respectively. Additional l-DOPA transport mechanisms exist in the renal cortex that remain to be identified.

[Scans without Evidence of Dopamine Deficit (SWEDDs)].

PubMed

Mukai, Yohei; Murata, Miho

2016-01-01

Dopamine transporter (DaT) single-photon emission computed tomography (SPECT) and [18F]fluoro-L-DOPA ([18F]DOPA) positron emission tomography (PET) facilitate the investigation of dopaminergic hypofunction in neurodegenerative diseases. DaT SPECT and [18F]DOPA PET have been adopted as survey tools in clinical trials. In a large study on Parkinson's disease, 4-15% of subjects clinically diagnosed with early-stage Parkinson's disease had normal dopaminergic functional imaging scans. These are called Scans without Evidence of Dopamine Deficit (SWEDDs), and are considered to represent a state different from Parkinson's disease. Neurological diseases that exhibit parkinsonism and have normal dopaminergic cells in the nigrostriatal system (e.g., essential tremor, psychogenic parkinsonism, DOPA-responsive dystonia, vascular parkinsonism, drug-induced parkinsonism, manganism, brain tumor, myoclonus-dystonia (DYT11), and fragile X syndrome) might be diagnosed with SWEDDs. True bradykinesia with fatigue or decrement may be useful for distinguishing between Parkinson's disease and SWEDDs. However, because SWEDDs encompass many diseases, their properties may not be uniform. In this review, we discuss DaT SPECT, the concept of SWEDDs, and differential diagnosis.

Changes in dopamine transporter expression in the midbrain following traumatic brain injury: an immunohistochemical and in situ hybridization study in a mouse model.

PubMed

Shimada, Ryo; Abe, Keiichi; Furutani, Rui; Kibayashi, Kazuhiko

2014-03-01

An association has been suggested between trauma and neurological degenerative diseases. Magnetic resonance imaging has revealed that traumatic brain injury (TBI) can cause primary lesions in the midbrain including the substantia nigra (SN). Dopamine transporter (DAT) is mainly expressed in the SN, ventral tegmental area (VTA), and retrorubral field (RRF) of the ventral midbrain. Previous western blot studies have examined DAT levels in the rat frontal cortex and striatum after a controlled cortical impact (CCI); however, no study has comprehensively examined DAT expression in the midbrain following TBI in an animal model. We used immunohistochemistry and in situ hybridization to examine the time-dependent changes in the expression of DAT in the midbrain during the first 14 days after TBI in a mouse CCI model. The expression of DAT protein in the RRF on the side ipsilateral to the site of injury decreased in 14 days after injury. Dopamine transporter mRNA expression in the RRF on the ipsilateral side decreased in 1, 7, and 14 days and increased in 4 days after injury. These findings indicated that TBI induced changes in DAT expression in the RRF. Because the DAT pumps dopamine (DA) out of the synapse back into the cytosol and maintains DA homeostasis, the decreased expression of DAT after TBI may result in decreased DA neurotransmission in the brain.

Methamphetamine-induced alterations in monoamine transport: implications for neurotoxicity, neuroprotection and treatment.

PubMed

Volz, Trent J; Fleckenstein, Annette E; Hanson, Glen R

2007-04-01

To review studies delineating the neurotoxic effects of methamphetamine on monoamine transport in dopaminergic neurons of the striatum and nucleus accumbens. The scope of this review includes the English language dopamine transporter and vesicular monoamine transporter-2 primary literature to April 2006 identified by Pubmed, Science Citation Index and SciFinder Scholar literature searches. Changes in the function of the plasmalemmal dopamine transporter and the vesicular monoamine transporter-2 are key components of methamphetamine-induced persistent dopaminergic deficits. These deficits include persistent reductions in dopamine content, dopamine transporter density and tyrosine hydroxylase activity. The striatum is susceptible to these effects of methamphetamine while the nucleus accumbens is resistant. Differences in dopamine transporter density and activity, extracellular dopamine levels and antioxidant levels in these two brain regions may, in part, account for the resistance of the nucleus accumbens. These findings concerning the nature of methamphetamine-induced changes in plasmalemmal and vesicular dopamine transport have very important implications for drug targets and for understanding the etiology of dopaminergic neurodegenerative processes, such as those associated with methamphetamine addiction and Parkinson's disease.

Fluoroethoxy-1,4-diphenethylpiperidine and piperazine derivatives: Potent and selective inhibitors of [3H]dopamine uptake at the vesicular monoamine transporter-2.

PubMed

Hankosky, Emily R; Joolakanti, Shyam R; Nickell, Justin R; Janganati, Venumadhav; Dwoskin, Linda P; Crooks, Peter A

2017-12-15

A small library of fluoroethoxy-1,4-diphenethyl piperidine and fluoroethoxy-1,4-diphenethyl piperazine derivatives were designed, synthesized and evaluated for their ability to inhibit [ 3 H]dopamine (DA) uptake at the vesicular monoamine transporter-2 (VMAT2) and dopamine transporter (DAT), [ 3 H]serotonin (5-HT) uptake at the serotonin transporter (SERT), and [ 3 H]dofetilide binding at the human-ether-a-go-go-related gene (hERG) channel. The majority of the compounds exhibited potent inhibition of [ 3 H]DA uptake at VMAT2, Ki changes in the nanomolar range (K i  = 0.014-0.073 µM). Compound 15d exhibited the highest affinity (K i  = 0.014 µM) at VMAT2, and had 160-, 5-, and 60-fold greater selectivity for VMAT2 vs. DAT, SERT and hERG, respectively. Compound 15b exhibited the greatest selectivity (>60-fold) for VMAT2 relative to all the other targets evaluated, and 15b had high affinity for VMAT2 (K i  = 0.073 µM). Compound 15b was considered the lead compound from this analog series due to its high affinity and selectivity for VMAT2. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effects of Ketamine and Ketamine Metabolites on Evoked Striatal Dopamine Release, Dopamine Receptors, and Monoamine Transporters

PubMed Central

Can, Adem; Zanos, Panos; Moaddel, Ruin; Kang, Hye Jin; Dossou, Katinia S. S.; Wainer, Irving W.; Cheer, Joseph F.; Frost, Douglas O.; Huang, Xi-Ping

2016-01-01

Following administration at subanesthetic doses, (R,S)-ketamine (ketamine) induces rapid and robust relief from symptoms of depression in treatment-refractory depressed patients. Previous studies suggest that ketamine’s antidepressant properties involve enhancement of dopamine (DA) neurotransmission. Ketamine is rapidly metabolized to (2S,6S)- and (2R,6R)-hydroxynorketamine (HNK), which have antidepressant actions independent of N-methyl-d-aspartate glutamate receptor inhibition. These antidepressant actions of (2S,6S;2R,6R)-HNK, or other metabolites, as well as ketamine’s side effects, including abuse potential, may be related to direct effects on components of the dopaminergic (DAergic) system. Here, brain and blood distribution/clearance and pharmacodynamic analyses at DA receptors (D1–D5) and the DA, norepinephrine, and serotonin transporters were assessed for ketamine and its major metabolites (norketamine, dehydronorketamine, and HNKs). Additionally, we measured electrically evoked mesolimbic DA release and decay using fast-scan cyclic voltammetry following acute administration of subanesthetic doses of ketamine (2, 10, and 50 mg/kg, i.p.). Following ketamine injection, ketamine, norketamine, and multiple hydroxynorketamines were detected in the plasma and brain of mice. Dehydronorketamine was detectable in plasma, but concentrations were below detectable limits in the brain. Ketamine did not alter the magnitude or kinetics of evoked DA release in the nucleus accumbens in anesthetized mice. Neither ketamine’s enantiomers nor its metabolites had affinity for DA receptors or the DA, noradrenaline, and serotonin transporters (up to 10 μM). These results suggest that neither the side effects nor antidepressant actions of ketamine or ketamine metabolites are associated with direct effects on mesolimbic DAergic neurotransmission. Previously observed in vivo changes in DAergic neurotransmission following ketamine administration are likely indirect. PMID

Enhanced Striatal Dopamine Release During Food Stimulation in Binge Eating Disorder

PubMed Central

Wang, Gene-Jack; Geliebter, Allan; Volkow, Nora D.; Telang, Frank W.; Logan, Jean; Jayne, Millard C.; Galanti, Kochavi; Selig, Peter A.; Han, Hao; Zhu, Wei; Wong, Christopher T.; Fowler, Joanna S.

2011-01-01

Subjects with binge eating disorder (BED) regularly consume large amounts of food in short time periods. The neurobiology of BED is poorly understood. Brain dopamine, which regulates motivation for food intake, is likely to be involved. We assessed the involvement of brain dopamine in the motivation for food consumption in binge eaters. Positron emission tomography (PET) scans with [11C]raclopride were done in 10 obese BED and 8 obese subjects without BED. Changes in extracellular dopamine in the striatum in response to food stimulation in food-deprived subjects were evaluated after placebo and after oral methylphenidate (MPH), a drug that blocks the dopamine reuptake transporter and thus amplifies dopamine signals. Neither the neutral stimuli (with or without MPH) nor the food stimuli when given with placebo increased extracellular dopamine. The food stimuli when given with MPH significantly increased dopamine in the caudate and putamen in the binge eaters but not in the nonbinge eaters. Dopamine increases in the caudate were significantly correlated with the binge eating scores but not with BMI. These results identify dopamine neurotransmission in the caudate as being of relevance to the neurobiology of BED. The lack of correlation between BMI and dopamine changes suggests that dopamine release per se does not predict BMI within a group of obese individuals but that it predicts binge eating. PMID:21350434

Epistasis between dopamine regulating genes identifies a nonlinear response of the human hippocampus during memory tasks.

PubMed

Bertolino, Alessandro; Di Giorgio, Annabella; Blasi, Giuseppe; Sambataro, Fabio; Caforio, Grazia; Sinibaldi, Lorenzo; Latorre, Valeria; Rampino, Antonio; Taurisano, Paolo; Fazio, Leonardo; Romano, Raffaella; Douzgou, Sofia; Popolizio, Teresa; Kolachana, Bhaskar; Nardini, Marcello; Weinberger, Daniel R; Dallapiccola, Bruno

2008-08-01

Dopamine modulation of neuronal activity in prefrontal cortex maps to an inverted U-curve. Dopamine is also an important factor in regulation of hippocampal mediated memory processing. Here, we investigated the effect of genetic variation of dopamine inactivation via catechol-O-methyltransferase (COMT) and the dopamine transporter (DAT) on hippocampal activity in healthy humans during different memory conditions. Using blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) in 82 subjects matched for a series of demographic and genetic variables, we studied the effect of the COMT valine (Val)(158)methionine (Met) and the DAT 3' variable number tandem repeat (VNTR) polymorphisms on function of the hippocampus during encoding of recognition memory and during working memory. Our results consistently demonstrated a double dissociation so that DAT 9-repeat carrier alleles modulated activity in the hippocampus in the exact opposite direction of DAT 10/10-repeat alleles based on COMT Val(158)Met genotype during different memory conditions. Similar results were evident in ventrolateral and dorsolateral prefrontal cortex. These findings suggest that genetically determined dopamine signaling during memory processing maps to a nonlinear relationship also in the hippocampus. Our data also demonstrate in human brain epistasis of two genes implicated in dopamine signaling on brain activity during different memory conditions.

Reduced striatal dopamine transporters in people with internet addiction disorder.

PubMed

Hou, Haifeng; Jia, Shaowe; Hu, Shu; Fan, Rong; Sun, Wen; Sun, Taotao; Zhang, Hong

2012-01-01

In recent years, internet addiction disorder (IAD) has become more prevalent worldwide and the recognition of its devastating impact on the users and society has rapidly increased. However, the neurobiological mechanism of IAD has not bee fully expressed. The present study was designed to determine if the striatal dopamine transporter (DAT) levels measured by (99m)Tc-TRODAT-1 single photon emission computed tomography (SPECT) brain scans were altered in individuals with IAD. SPECT brain scans were acquired on 5 male IAD subjects and 9 healthy age-matched controls. The volume (V) and weight (W) of bilateral corpus striatum as well as the (99m)Tc-TRODAT-1 uptake ratio of corpus striatum/the whole brain (Ra) were calculated using mathematical models. It was displayed that DAT expression level of striatum was significantly decreased and the V, W, and Ra were greatly reduced in the individuals with IAD compared to controls. Taken together, these results suggest that IAD may cause serious damages to the brain and the neuroimaging findings further illustrate IAD is associated with dysfunctions in the dopaminergic brain systems. Our findings also support the claim that IAD may share similar neurobiological abnormalities with other addictive disorders.

Functional Rescue of a Misfolded Drosophila melanogaster Dopamine Transporter Mutant Associated with a Sleepless Phenotype by Pharmacological Chaperones.

PubMed

Kasture, Ameya; El-Kasaby, Ali; Szöllősi, Daniel; Asjad, H M Mazhar; Grimm, Alexandra; Stockner, Thomas; Hummel, Thomas; Freissmuth, Michael; Sucic, Sonja

2016-09-30

Folding-defective mutants of the human dopamine transporter (DAT) cause a syndrome of infantile dystonia/parkinsonism. Here, we provide a proof-of-principle that the folding deficit is amenable to correction in vivo by two means, the cognate DAT ligand noribogaine and the HSP70 inhibitor, pifithrin-μ. We examined the Drosophila melanogaster (d) mutant dDAT-G108Q, which leads to a sleepless phenotype in flies harboring this mutation. Molecular dynamics simulations suggested an unstable structure of dDAT-G108Q consistent with a folding defect. This conjecture was verified; heterologously expressed dDAT-G108Q and the human (h) equivalent hDAT-G140Q were retained in the endoplasmic reticulum in a complex with endogenous folding sensors (calnexin and HSP70-1A). Incubation of the cells with noribogaine (a DAT ligand selective for the inward-facing state) and/or pifithrin-μ (an HSP70 inhibitor) restored folding of, and hence dopamine transport by, dDAT-G108Q and hDAT-G140Q. The mutated versions of DAT were confined to the cell bodies of the dopaminergic neurons in the fly brain and failed to reach the axonal compartments. Axonal delivery was restored, and sleep time was increased to normal length (from 300 to 1000 min/day) if the dDAT-G108Q-expressing flies were treated with noribogaine and/or pifithrin-μ. Rescuing misfolded versions of DAT by pharmacochaperoning is of therapeutic interest; it may provide opportunities to remedy disorders arising from folding-defective mutants of human DAT and of other related SLC6 transporters. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Computational and Biochemical Docking of the Irreversible Cocaine Analog RTI 82 Directly Demonstrates Ligand Positioning in the Dopamine Transporter Central Substrate-binding Site*

PubMed Central

Dahal, Rejwi Acharya; Pramod, Akula Bala; Sharma, Babita; Krout, Danielle; Foster, James D.; Cha, Joo Hwan; Cao, Jianjing; Newman, Amy Hauck; Lever, John R.; Vaughan, Roxanne A.; Henry, L. Keith

2014-01-01

The dopamine transporter (DAT) functions as a key regulator of dopaminergic neurotransmission via re-uptake of synaptic dopamine (DA). Cocaine binding to DAT blocks this activity and elevates extracellular DA, leading to psychomotor stimulation and addiction, but the mechanisms by which cocaine interacts with DAT and inhibits transport remain incompletely understood. Here, we addressed these questions using computational and biochemical methodologies to localize the binding and adduction sites of the photoactivatable irreversible cocaine analog 3β-(p-chlorophenyl)tropane-2β-carboxylic acid, 4′-azido-3′-iodophenylethyl ester ([125I]RTI 82). Comparative modeling and small molecule docking indicated that the tropane pharmacophore of RTI 82 was positioned in the central DA active site with an orientation that juxtaposed the aryliodoazide group for cross-linking to rat DAT Phe-319. This prediction was verified by focused methionine substitution of residues flanking this site followed by cyanogen bromide mapping of the [125I]RTI 82-labeled mutants and by the substituted cysteine accessibility method protection analyses. These findings provide positive functional evidence linking tropane pharmacophore interaction with the core substrate-binding site and support a competitive mechanism for transport inhibition. This synergistic application of computational and biochemical methodologies overcomes many uncertainties inherent in other approaches and furnishes a schematic framework for elucidating the ligand-protein interactions of other classes of DA transport inhibitors. PMID:25179220

Effect of Gingerol on Cisplatin-Induced Pica Analogous to Emesis Via Modulating Expressions of Dopamine 2 Receptor, Dopamine Transporter and Tyrosine Hydroxylase in the Vomiting Model of Rats.

PubMed

Qian, Weibin; Cai, Xinrui; Wang, Yingying; Zhang, Xinying; Zhao, Hongmin; Qian, Qiuhai; Yang, Zhihong; Liu, Zhantao; Hasegawa, Junichi

2016-06-01

Gingerol, the generic term for pungent constituents in ginger, has been used for treating vomiting in China. We are going to investigate the mechanisms of inhibitive effect of gingerol on cisplatin-induced pica behaviour by studying on both peripheral and central levels, and the effects of gingerol on homeostasis of dopamine (DA) transmission: dopamine D2 receptor (D2R), dopamine transporter (DAT) and tyrosine hydroxylase (TH). The antiemetic effect of gingerol was investigated on a vomiting model in rats induced by cisplatin 3 mg·kg(-1) intraperitoneal injection (i.p.). Rats were randomly divided into the normal control group (C), simple gingerol control group (CG), cisplatin control group (V), cisplatin + metoclopramide group (M), cisplatin + low-dose gingerol group (GL), cisplatin + middle-dose gingerol group (GM) and cisplatin + high-dose gingerol group (GH). In observation period, rats in Groups C and V were pretreated with sterile saline 3 mL i.g.; rats in Group CG were pretreated with gingerol 40 mg·kg(-1) i.g.; rats in Group M were pretreated with metoclopramide 2.5 mg·kg(-1) i.g.; rats in Groups GL, GM and GH were pretreated with gingerol 10, 20 and 40 mg·kg(-1) i.g. for 3 days, respectively. Cisplatin (3 mg·kg(-1), i.p.) was administered one time after each treatment with the antiemetic agent or its vehicle except the Groups C and CG. The distribution of D2R, DAT and TH in the area postrema and ileum were measured by immunohistochemistry and quantitated based on the image analysis, and the expression of DAT and TH in the area postrema and ileum were measured by RT-PCR. The weights of kaolin eaten of the remaining rats were observed in every 6 h continuously for 72 h. The weight of kaolin eaten in rats induced by cisplatin was significantly reduced by pretreatment with gingerol in a dose-dependent manner during the 0-24 h and 24-72 h periods (P < 0.05). Gingerol markedly improved gastric emptying induced by cisplatin in a dose-dependent manner (P < 0

Intermittent Cocaine Self-Administration Produces Sensitization of Stimulant Effects at the Dopamine Transporter

PubMed Central

Calipari, Erin S.; Ferris, Mark J.; Siciliano, Cody A.; Zimmer, Benjamin A.

2014-01-01

Previous literature investigating neurobiological adaptations following cocaine self-administration has shown that high, continuous levels of cocaine intake (long access; LgA) results in reduced potency of cocaine at the dopamine transporter (DAT), whereas an intermittent pattern of cocaine administration (intermittent access; IntA) results in sensitization of cocaine potency at the DAT. Here, we aimed to determine whether these changes are specific to cocaine or translate to other psychostimulants. Psychostimulant potency was assessed by fast-scan cyclic voltammetry in brain slices containing the nucleus accumbens following IntA, short access, and LgA cocaine self-administration, as well as in brain slices from naive animals. We assessed the potency of amphetamine (a releaser), and methylphenidate (a DAT blocker, MPH). MPH was selected because it is functionally similar to cocaine and structurally related to amphetamine. We found that MPH and amphetamine potencies were increased following IntA, whereas neither was changed following LgA or short access cocaine self-administration. Therefore, whereas LgA-induced tolerance at the DAT is specific to cocaine as shown in previous work, the sensitizing effects of IntA apply to cocaine, MPH, and amphetamine. This demonstrates that the pattern with which cocaine is administered is important in determining the neurochemical consequences of not only cocaine effects but potential cross-sensitization/cross-tolerance effects of other psychostimulants as well. PMID:24566123

Regulation of ethanol intake under chronic mild stress: roles of dopamine receptors and transporters.

PubMed

Delis, Foteini; Rombola, Christina; Bellezza, Robert; Rosko, Lauren; Grandy, David K; Volkow, Nora D; Thanos, Panayotis K

2015-01-01

Studies have shown that exposure to chronic mild stress decreases ethanol intake and preference in dopamine D2 receptor wild-type mice (Drd2 (+/+)), while it increases intake in heterozygous (Drd2 (+/-)) and knockout (Drd2 (-/-)) mice. Dopaminergic neurotransmission in the basal forebrain plays a major role in the reinforcing actions of ethanol as well as in brain responses to stress. In order to identify neurochemical changes associated with the regulation of ethanol intake, we used in vitro receptor autoradiography to measure the levels and distribution of dopamine D1 and D2 receptors and dopamine transporters (DAT). Receptor levels were measured in the basal forebrain of Drd2 (+/+), Drd2 (+/-), and Drd2 (-/-) mice belonging to one of four groups: control (C), ethanol intake (E), chronic mild stress exposure (S), and ethanol intake under chronic mild stress (ES). D2 receptor levels were higher in the lateral and medial striatum of Drd2 (+/+) ES mice, compared with Drd2 (+/+) E mice. Ethanol intake in Drd2 (+/+) mice was negatively correlated with striatal D2 receptor levels. D2 receptor levels in Drd2(+/-) mice were the same among the four treatment groups. DAT levels were lower in Drd2(+/-) C and Drd2 (-/-) C mice, compared with Drd2 (+/+) C mice. Among Drd2(+/-) mice, S and ES groups had higher DAT levels compared with C and E groups in most regions examined. In Drd2(-/-) mice, ethanol intake was positively correlated with DAT levels in all regions studied. D1 receptor levels were lower in Drd2(+/-) and Drd2(-/-) mice, compared with Drd2(+/+), in all regions examined and remained unaffected by all treatments. The results suggest that in normal mice, ethanol intake is associated with D2 receptor-mediated neurotransmission, which exerts a protective effect against ethanol overconsumption under stress. In mice with low Drd2 expression, where DRD2 levels are not further modulated, ethanol intake is associated with DAT function which is upregulated under stress

Dopamine transporter down-regulation following repeated cocaine: implications for 3,4-methylenedioxymethamphetamine-induced acute effects and long-term neurotoxicity in mice.

PubMed

Peraile, I; Torres, E; Mayado, A; Izco, M; Lopez-Jimenez, A; Lopez-Moreno, J A; Colado, M I; O'Shea, E

2010-01-01

3,4-Methylenedioxymethamphetamine (MDMA) and cocaine are two widely abused psychostimulant drugs targeting the dopamine transporter (DAT). DAT availability regulates dopamine neurotransmission and uptake of MDMA-derived neurotoxic metabolites. We aimed to determine the effect of cocaine pre-exposure on the acute and long-term effects of MDMA in mice. Mice received a course of cocaine (20 mg*kg(-1), x2 for 3 days) followed by MDMA (20 mg*kg(-1), x2, 3 h apart). Locomotor activity, extracellular dopamine levels and dopaminergic neurotoxicity were determined. Furthermore, following the course of cocaine, DAT density in striatal plasma membrane and endosome fractions was measured. Four days after the course of cocaine, challenge with MDMA attenuated the MDMA-induced striatal dopaminergic neurotoxicity. Co-administration of the protein kinase C (PKC) inhibitor NPC 15437 prevented cocaine protection. At the same time, after the course of cocaine, DAT density was reduced in the plasma membrane and increased in the endosome fraction, and this effect was prevented by NPC 15437. The course of cocaine potentiated the MDMA-induced increase in extracellular dopamine and locomotor activity, following challenge 4 days later, compared with those pretreated with saline. Repeated cocaine treatment followed by withdrawal protected against MDMA-induced dopaminergic neurotoxicity by internalizing DAT via a mechanism which may involve PKC. Furthermore, repeated cocaine followed by withdrawal induced behavioural and neurochemical sensitization to MDMA, measures which could be indicative of increased rewarding effects of MDMA.

Prefrontal and Striatal Glutamate Differently Relate to Striatal Dopamine: Potential Regulatory Mechanisms of Striatal Presynaptic Dopamine Function?

PubMed

Gleich, Tobias; Deserno, Lorenz; Lorenz, Robert Christian; Boehme, Rebecca; Pankow, Anne; Buchert, Ralph; Kühn, Simone; Heinz, Andreas; Schlagenhauf, Florian; Gallinat, Jürgen

2015-07-01

Theoretical and animal work has proposed that prefrontal cortex (PFC) glutamate inhibits dopaminergic inputs to the ventral striatum (VS) indirectly, whereas direct VS glutamatergic afferents have been suggested to enhance dopaminergic inputs to the VS. In the present study, we aimed to investigate relationships of glutamate and dopamine measures in prefrontostriatal circuitries of healthy humans. We hypothesized that PFC and VS glutamate, as well as their balance, are differently associated with VS dopamine. Glutamate concentrations in the left lateral PFC and left striatum were assessed using 3-Tesla proton magnetic resonance spectroscopy. Striatal presynaptic dopamine synthesis capacity was measured by fluorine-18-l-dihydroxyphenylalanine (F-18-FDOPA) positron emission tomography. First, a negative relationship was observed between glutamate concentrations in lateral PFC and VS dopamine synthesis capacity (n = 28). Second, a positive relationship was revealed between striatal glutamate and VS dopamine synthesis capacity (n = 26). Additionally, the intraindividual difference between PFC and striatal glutamate concentrations correlated negatively with VS dopamine synthesis capacity (n = 24). The present results indicate an involvement of a balance in PFC and striatal glutamate in the regulation of VS dopamine synthesis capacity. This notion points toward a potential mechanism how VS presynaptic dopamine levels are kept in a fine-tuned range. A disruption of this mechanism may account for alterations in striatal dopamine turnover as observed in mental diseases (e.g., in schizophrenia). The present work demonstrates complementary relationships between prefrontal and striatal glutamate and ventral striatal presynaptic dopamine using human imaging measures: a negative correlation between prefrontal glutamate and presynaptic dopamine and a positive relationship between striatal glutamate and presynaptic dopamine are revealed. The results may reflect a regulatory role

Molecular dynamics study of a heteroditopic-calix[4]diquinone-assisted transfer of KCl and dopamine through a water-chloroform liquid-liquid interface.

PubMed

Santos, Sérgio M; Costa, Paulo J; Lankshear, Michael D; Beer, Paul D; Félix, Vítor

2010-09-02

The ability of two heteroditopic calix[4]diquinone receptors to transport a KCl ion-pair and a dopamine zwitterion through a water-chloroform interface was investigated via molecular dynamics (MD) simulations. Gas-phase conformational analysis has been carried on KCl and dopamine receptor binding associations and the lowest energy structures found in both cases show that the recognition of KCl and dopamine zwitterion occurs through multiple and cooperative N-H...anion and O...cation bonding interactions, with the receptor adopting equivalent folded conformations stabilized by pi-stacking interactions. The unconstrained MD simulations performed on KCl and dopamine complexes inserted in either the chloroform or water phase revealed that receptors are preferentially located at the interface with the hydrophobic tert-butyl groups of the calix[4]diquinone moiety immersed in the chloroform bulk while the polar anion binding cavity is directed toward the water phase. When the KCl complex is placed in chloroform, the release of the ion-pair occurs only after the first contact with the water interface, being a nonsimultaneous event, with the chloride anion leaving the receptor before the potassium cation. The dopamine, via the -NH(3)(+) binding entity, remains bound to the receptor during the entire time of the MD simulation (10 ns). In contrast, when both complexes were inserted in the water bulk, the full release of KCl and dopamine are fast events. The potentials of mean force (PMFs), associated with the migration of the complexes from chloroform to water through the interface, were calculated from steered molecular dynamics (SMD) simulations. The PMFs for the free KCl and zwitterionic dopamine migrations were also obtained for comparison purposes. The transport of KCl from water to chloroform (the reverse path) mediated by the receptor has a free energy barrier estimated in 6.50 kcal mol(-1), which is 3.0 kcal mol(-1) smaller than that found for the free KCl. The

Incident impulse control disorder symptoms and dopamine transporter imaging in Parkinson disease.

PubMed

Smith, Kara M; Xie, Sharon X; Weintraub, Daniel

2016-08-01

To describe the incidence of, and clinical and neurobiological risk factors for, new-onset impulse control disorder (ICD) symptoms and related behaviours in early Parkinson disease (PD). The Parkinson's Progression Markers Initiative is an international, multicenter, prospective study of de novo patients with PD untreated at baseline and assessed annually, including serial dopamine transporter imaging (DAT-SPECT) and ICD assessment (Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease short form, QUIP). Participants were included if they screened negative on the QUIP at baseline. Kaplan-Meier curves and generalised estimating equations examined frequency and predictors of incident ICD symptoms. Participants were seen at baseline (n=320), year 1 (n=284), year 2 (n=217) and year 3 (n=96). Estimated cumulative incident rates of ICD symptoms and related behaviours were 8% (year 1), 18% (year 2) and 25% (year 3) and increased each year in those on dopamine replacement therapy (DRT) and decreased in those not on DRT. In participants on DRT, risk factors for incident ICD symptoms were younger age (OR=0.97, p=0.05), a greater decrease in right caudate (OR=4.03, p=0.01) and mean striatal (OR=6.90, p=0.04) DAT availability over the first year, and lower right putamen (OR=0.06, p=0.01) and mean total striatal (OR=0.25, p=0.04) DAT availability at any post-baseline visit. The rate of incident ICD symptoms increases with time and initiation of DRT in early PD. In this preliminary study, a greater decrease or lower DAT binding over time increases risk of incident ICD symptoms, conferring additional risk to those taking DRT. NCT01141023. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

A Japanese Encephalitis Patient Presenting with Parkinsonism with Corresponding Laterality of Magnetic Resonance and Dopamine Transporter Imaging Findings.

PubMed

Tadokoro, Koh; Ohta, Yasuyuki; Sato, Kota; Maeki, Takahiro; Sasaki, Ryo; Takahashi, Yoshiaki; Shang, Jingwei; Takemoto, Mami; Hishikawa, Nozomi; Yamashita, Toru; Lim, Chang Kweng; Tajima, Shigeru; Abe, Koji

2018-03-09

Japanese encephalitis (JE) survivors often present with nigrostriatal aftereffects with parkinsonian features. A 67-year-old woman with JE showed right-dominant clinical parkinsonism and left-dominant substantia nigra lesions after magnetic resonance imaging (MRI). Dopamine transporter (DAT) imaging using 123 I-labeled 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane ( 123 I-FP-CIT) revealed a corresponding left-dominant decrease. The present case is the first to reveal a clear match of laterality between clinical parkinsonism, MRI-based substantia nigra lesions, and impaired DAT in presynaptic dopaminergic neurons in JE.

Adolescent binge-like alcohol alters sensitivity to acute alcohol effects on dopamine release in the nucleus accumbens of adult rats

PubMed Central

Shnitko, Tatiana A.; Spear, Linda P.; Robinson, Donita L.

2015-01-01

Rationale Early onset of alcohol drinking has been associated with alcohol abuse in adulthood. The neurobiology of this phenomenon is unclear, but mesolimbic dopamine pathways, which are dynamic during adolescence, may play a role. Objectives We investigated the impact of adolescent binge-like alcohol on phasic dopaminergic neurotransmission during adulthood. Methods Rats received intermittent intragastric ethanol, water or nothing during adolescence. In adulthood, electrically-evoked dopamine release and subsequent uptake were measured in the nucleus accumbens core at baseline and after acute challenge of ethanol or saline. Results Adolescent ethanol exposure did not alter basal measures of evoked dopamine release or uptake. Ethanol challenge dose-dependently decreased the amplitude of evoked dopamine release in rats by 30–50% in control groups, as previously reported, but did not alter evoked release in ethanol-exposed animals. To address the mechanism by which ethanol altered dopamine signaling, the evoked signals were modeled to estimate dopamine efflux per impulse and the velocity of the dopamine transporter. Dopamine uptake was slower in all exposure groups after ethanol challenge compared to saline, while dopamine efflux per pulse of electrical stimulation was reduced by ethanol only in ethanol-naive rats. Conclusions The results demonstrate that exposure to binge levels of ethanol during adolescence blunts the effect of ethanol challenge to reduce the amplitude of phasic dopamine release in adulthood. Large dopamine transients may result in more extracellular dopamine after alcohol challenge in adolescent-exposed rats, and may be one mechanism by which alcohol is more reinforcing in people who initiated drinking at an early age. PMID:26487039

Functional Rescue of a Misfolded Drosophila melanogaster Dopamine Transporter Mutant Associated with a Sleepless Phenotype by Pharmacological Chaperones*♦

PubMed Central

Kasture, Ameya; El-Kasaby, Ali; Szöllősi, Daniel; Asjad, H. M. Mazhar; Grimm, Alexandra; Stockner, Thomas; Hummel, Thomas; Freissmuth, Michael; Sucic, Sonja

2016-01-01

Folding-defective mutants of the human dopamine transporter (DAT) cause a syndrome of infantile dystonia/parkinsonism. Here, we provide a proof-of-principle that the folding deficit is amenable to correction in vivo by two means, the cognate DAT ligand noribogaine and the HSP70 inhibitor, pifithrin-μ. We examined the Drosophila melanogaster (d) mutant dDAT-G108Q, which leads to a sleepless phenotype in flies harboring this mutation. Molecular dynamics simulations suggested an unstable structure of dDAT-G108Q consistent with a folding defect. This conjecture was verified; heterologously expressed dDAT-G108Q and the human (h) equivalent hDAT-G140Q were retained in the endoplasmic reticulum in a complex with endogenous folding sensors (calnexin and HSP70-1A). Incubation of the cells with noribogaine (a DAT ligand selective for the inward-facing state) and/or pifithrin-μ (an HSP70 inhibitor) restored folding of, and hence dopamine transport by, dDAT-G108Q and hDAT-G140Q. The mutated versions of DAT were confined to the cell bodies of the dopaminergic neurons in the fly brain and failed to reach the axonal compartments. Axonal delivery was restored, and sleep time was increased to normal length (from 300 to 1000 min/day) if the dDAT-G108Q-expressing flies were treated with noribogaine and/or pifithrin-μ. Rescuing misfolded versions of DAT by pharmacochaperoning is of therapeutic interest; it may provide opportunities to remedy disorders arising from folding-defective mutants of human DAT and of other related SLC6 transporters. PMID:27481941

Dopamine D3 receptors contribute to methamphetamine-induced alterations in dopaminergic neuronal function: Role of hyperthermia

PubMed Central

Baladi, Michelle G.; Newman, Amy H.; Nielsen, Shannon M.; Hanson, Glen R.; Fleckenstein, Annette E.

2014-01-01

Methamphetamine administration causes long-term deficits to dopaminergic systems that, in humans, are thought to be associated with motor slowing and memory impairment. Methamphetamine interacts with the dopamine transporter (DAT) and increases extracellular concentrations of dopamine that, in turn, binds to a number of dopamine receptor subtypes. Although the relative contribution of each receptor subtype to the effects of methamphetamine is not fully known, non-selective dopamine D2/D3 receptor antagonists can attenuate methamphetamine-induced changes to dopamine systems. The present study extended these findings by testing the role of the dopamine D3 receptor subtype in mediating the long-term dopaminergic, and for comparison serotonergic, deficits caused by methamphetamine. Results indicate that the dopamine D3 receptor selective antagonist, PG01037, attenuated methamphetamine-induced decreases in striatal DAT, but not hippocampal serotonin (5HT) transporter (SERT), function, as assessed 7 days after treatment. However, PG01037 also attenuated methamphetamine-induced hyperthermia. When methamphetamine-induced hyperthermia was maintained by treating rats in a warm ambient environment, PG01037 failed to attenuate the effects of methamphetamine on DAT uptake. Furthermore, PG01037 did not attenuate methamphetamine-induced decreases in dopamine and 5HT content. Taken together, the present study demonstrates that dopamine D3 receptors mediate, in part, the long-term deficits in DAT function caused by methamphetamine, and that this effect likely involves an attenuation of methamphetamine-induced hyperthermia. PMID:24685638

Dopamine D(3) receptors contribute to methamphetamine-induced alterations in dopaminergic neuronal function: role of hyperthermia.

PubMed

Baladi, Michelle G; Newman, Amy H; Nielsen, Shannon M; Hanson, Glen R; Fleckenstein, Annette E

2014-06-05

Methamphetamine administration causes long-term deficits to dopaminergic systems that, in humans, are thought to be associated with motor slowing and memory impairment. Methamphetamine interacts with the dopamine transporter (DAT) and increases extracellular concentrations of dopamine that, in turn, binds to a number of dopamine receptor subtypes. Although the relative contribution of each receptor subtype to the effects of methamphetamine is not fully known, non-selective dopamine D2/D3 receptor antagonists can attenuate methamphetamine-induced changes to dopamine systems. The present study extended these findings by testing the role of the dopamine D3 receptor subtype in mediating the long-term dopaminergic, and for comparison serotonergic, deficits caused by methamphetamine. Results indicate that the dopamine D3 receptor selective antagonist, PG01037, attenuated methamphetamine-induced decreases in striatal DAT, but not hippocampal serotonin (5HT) transporter (SERT), function, as assessed 7 days after treatment. However, PG01037 also attenuated methamphetamine-induced hyperthermia. When methamphetamine-induced hyperthermia was maintained by treating rats in a warm ambient environment, PG01037 failed to attenuate the effects of methamphetamine on DAT uptake. Furthermore, PG01037 did not attenuate methamphetamine-induced decreases in dopamine and 5HT content. Taken together, the present study demonstrates that dopamine D3 receptors mediate, in part, the long-term deficits in DAT function caused by methamphetamine, and that this effect likely involves an attenuation of methamphetamine-induced hyperthermia. Copyright © 2014 Elsevier B.V. All rights reserved.

Self-esteem in remitted patients with mood disorders is not associated with the dopamine receptor D4 and the serotonin transporter genes.

PubMed

Serretti, A; Macciardi, F; Di Bella, D; Catalano, M; Smeraldi, E

1998-08-17

Disturbances of the dopaminergic and serotoninergic neurotransmitter systems have been implicated in the pathogenesis of depressive symptoms. Associations have been reported between markers of the two neurotransmitter systems and the presence of illness or severity of depressive episodes, but no attention has been focused on the periods of remission. The present report focuses on a possible association of self-esteem in remitted mood disorder patients with the functional polymorphism located in the upstream regulatory region of the serotonin transporter gene (5-HTTLPR) and the dopamine receptor D4 (DRD4). Inpatients (N=162) affected by bipolar (n=103) and unipolar (n=59) disorder (DSM III-R) were assessed by the Self-Esteem Scale (SES, Rosenberg, 1965) and were typed for DRD4 and 5-HTTLPR (n=58 subjects) variants at the third exon using polymerase chain reaction (PCR) techniques. Neither DRD4 nor 5-HTTLPR variants were associated with SES scores, and consideration of possible stratification effects such as sex and psychiatric diagnosis did not reveal any association either. The serotonin transporter and dopamine receptor D4 genes do not, therefore, influence self-esteem in remitted mood disorder subjects.

Dopamine transporter down-regulation following repeated cocaine: implications for 3,4-methylenedioxymethamphetamine-induced acute effects and long-term neurotoxicity in mice

PubMed Central

Peraile, I; Torres, E; Mayado, A; Izco, M; Lopez-Jimenez, A; Lopez-Moreno, JA; Colado, MI; O'Shea, E

2010-01-01

Background and purpose: 3,4-Methylenedioxymethamphetamine (MDMA) and cocaine are two widely abused psychostimulant drugs targeting the dopamine transporter (DAT). DAT availability regulates dopamine neurotransmission and uptake of MDMA-derived neurotoxic metabolites. We aimed to determine the effect of cocaine pre-exposure on the acute and long-term effects of MDMA in mice. Experimental approach: Mice received a course of cocaine (20 mg·kg−1, ×2 for 3 days) followed by MDMA (20 mg·kg−1, ×2, 3 h apart). Locomotor activity, extracellular dopamine levels and dopaminergic neurotoxicity were determined. Furthermore, following the course of cocaine, DAT density in striatal plasma membrane and endosome fractions was measured. Key results: Four days after the course of cocaine, challenge with MDMA attenuated the MDMA-induced striatal dopaminergic neurotoxicity. Co-administration of the protein kinase C (PKC) inhibitor NPC 15437 prevented cocaine protection. At the same time, after the course of cocaine, DAT density was reduced in the plasma membrane and increased in the endosome fraction, and this effect was prevented by NPC 15437. The course of cocaine potentiated the MDMA-induced increase in extracellular dopamine and locomotor activity, following challenge 4 days later, compared with those pretreated with saline. Conclusions and implications: Repeated cocaine treatment followed by withdrawal protected against MDMA-induced dopaminergic neurotoxicity by internalizing DAT via a mechanism which may involve PKC. Furthermore, repeated cocaine followed by withdrawal induced behavioural and neurochemical sensitization to MDMA, measures which could be indicative of increased rewarding effects of MDMA. PMID:20015297

Rare autism-associated variants implicate syntaxin 1 (STX1 R26Q) phosphorylation and the dopamine transporter (hDAT R51W) in dopamine neurotransmission and behaviors.

PubMed

Cartier, Etienne; Hamilton, Peter J; Belovich, Andrea N; Shekar, Aparna; Campbell, Nicholas G; Saunders, Christine; Andreassen, Thorvald F; Gether, Ulrik; Veenstra-Vanderweele, Jeremy; Sutcliffe, James S; Ulery-Reynolds, Paula G; Erreger, Kevin; Matthies, Heinrich J G; Galli, Aurelio

2015-02-01

Syntaxin 1 (STX1) is a presynaptic plasma membrane protein that coordinates synaptic vesicle fusion. STX1 also regulates the function of neurotransmitter transporters, including the dopamine (DA) transporter (DAT). The DAT is a membrane protein that controls DA homeostasis through the high-affinity re-uptake of synaptically released DA. We adopt newly developed animal models and state-of-the-art biophysical techniques to determine the contribution of the identified gene variants to impairments in DA neurotransmission observed in autism spectrum disorder (ASD). Here, we characterize two independent autism-associated variants in the genes that encode STX1 and the DAT. We demonstrate that each variant dramatically alters DAT function. We identify molecular mechanisms that converge to inhibit reverse transport of DA and DA-associated behaviors. These mechanisms involve decreased phosphorylation of STX1 at Ser14 mediated by casein kinase 2 as well as a reduction in STX1/DAT interaction. These findings point to STX1/DAT interactions and STX1 phosphorylation as key regulators of DA homeostasis. We determine the molecular identity and the impact of these variants with the intent of defining DA dysfunction and associated behaviors as possible complications of ASD.

Reduced dopamine receptors and transporters but not synthesis capacity in normal aging adults: a meta-analysis.

PubMed

Karrer, Teresa M; Josef, Anika K; Mata, Rui; Morris, Evan D; Samanez-Larkin, Gregory R

2017-09-01

Many theories of cognitive aging are based on evidence that dopamine (DA) declines with age. Here, we performed a systematic meta-analysis of cross-sectional positron emission tomography and single-photon emission-computed tomography studies on the average effects of age on distinct DA targets (receptors, transporters, or relevant enzymes) in healthy adults (N = 95 studies including 2611 participants). Results revealed significant moderate to large, negative effects of age on DA transporters and receptors. Age had a significantly larger effect on D1- than D2-like receptors. In contrast, there was no significant effect of age on DA synthesis capacity. The average age reductions across the DA system were 3.7%-14.0% per decade. A meta-regression found only DA target as a significant moderator of the age effect. This study precisely quantifies prior claims of reduced DA functionality with age. It also identifies presynaptic mechanisms (spared synthesis capacity and reduced DA transporters) that may partially account for previously unexplained phenomena whereby older adults appear to use dopaminergic resources effectively. Recommendations for future studies including minimum required samples sizes are provided. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Serine 129 phosphorylation of membrane-associated α-synuclein modulates dopamine transporter function in a G protein–coupled receptor kinase–dependent manner

PubMed Central

Hara, Susumu; Arawaka, Shigeki; Sato, Hiroyasu; Machiya, Youhei; Cui, Can; Sasaki, Asuka; Koyama, Shingo; Kato, Takeo

2013-01-01

Most α-synuclein (α-syn) deposited in Lewy bodies, the pathological hallmark of Parkinson disease (PD), is phosphorylated at Ser-129. However, the physiological and pathological roles of this modification are unclear. Here we investigate the effects of Ser-129 phosphorylation on dopamine (DA) uptake in dopaminergic SH-SY5Y cells expressing α-syn. Subcellular fractionation of small interfering RNA (siRNA)–treated cells shows that G protein–coupled receptor kinase 3 (GRK3), GRK5, GRK6, and casein kinase 2 (CK2) contribute to Ser-129 phosphorylation of membrane-associated α-syn, whereas cytosolic α-syn is phosphorylated exclusively by CK2. Expression of wild-type α-syn increases DA uptake, and this effect is diminished by introducing the S129A mutation into α-syn. However, wild-type and S129A α-syn equally increase the cell surface expression of dopamine transporter (DAT) in SH-SY5Y cells and nonneuronal HEK293 cells. In addition, siRNA-mediated knockdown of GRK5 or GRK6 significantly attenuates DA uptake without altering DAT cell surface expression, whereas knockdown of CK2 has no effect on uptake. Taken together, our results demonstrate that membrane-associated α-syn enhances DA uptake capacity of DAT by GRKs-mediated Ser-129 phosphorylation, suggesting that α-syn modulates intracellular DA levels with no functional redundancy in Ser-129 phosphorylation between GRKs and CK2. PMID:23576548

Dieldrin exposure induces oxidative damage in the mouse nigrostriatal dopamine system

PubMed Central

Hatcher, Jaime M.; Richardson, Jason R.; Guillot, Thomas S.; McCormack, Alison L.; Di Monte, Donato A.; Jones, Dean P.; Pennell, Kurt D.; Miller, Gary W.

2007-01-01

Numerous epidemiological studies have shown an association between pesticide exposure and an increased risk of developing Parkinson’s disease (PD). Here, we provide evidence that the insecticide dieldrin causes specific oxidative damage in the nigrostriatal dopamine (DA) system. We report that exposure of mice to low levels of dieldrin for 30 days resulted in alterations in dopamine-handling as evidenced by a decrease in dopamine metabolites, DOPAC (31.7% decrease) and HVA (29.2% decrease) and significantly increased cysteinyl-catechol levels in the striatum. Furthermore, dieldrin resulted in a 53% decrease in total glutathione, an increase in the redox potential of glutathione, and a 90% increase in protein carbonyls. α-Synuclein protein expression was also significantly increased in the striatum (25% increase). Finally, dieldrin caused a significant decrease in striatal expression of the dopamine transporter as measured by 3H-WIN 35,428 binding and 3H-dopamine uptake. These alterations occurred in the absence of dopamine neuron loss in the substantia nigra pars compacta. These effects represent the ability of low doses of dieldrin to increase the vulnerability of nigrostriatal dopamine neurons by inducing oxidative stress and suggest that pesticide exposure may act as a promoter of PD. PMID:17291500

Child Dopamine Transporter Genotype and Parenting: Evidence for Evocative Gene-Environment Correlations

PubMed Central

Hayden, Elizabeth P.; Hanna, Brigitte; Sheikh, Haroon I.; Laptook, Rebecca S.; Kim, Jiyon; Singh, Shiva M.; Klein, Daniel N.

2017-01-01

The dopamine transporter (DAT1) gene is implicated in psychopathology risk. While the processes by which this gene exerts its effects on risk are poorly understood, a small body of research suggests that DAT1 influences early emerging negative emotionality (NE), a marker of children’s psychopathology risk. As child NE evokes negative parenting practices, the DAT1 may also play a role in gene-environment correlations. To test this model, children (N = 365) were genotyped for DAT1 and participated in standardized parent-child interaction tasks with their primary caregiver. The DAT1 9-repeat variant was associated with child negative affect expressed toward the parent during parent-child interactions, and parents of children with a 9-repeat allele exhibited more hostility and lower guidance/engagement than parents of children without a 9-repeat allele. These gene-environment associations were partially mediated by child negative affect toward the parent. Findings implicate a specific polymorphism in eliciting negative parenting, suggesting that evocative associations play a role in elevating children’s risk for emotional trajectories toward psychopathology risk. PMID:23398760

Effect of Dopamine Transporter Gene (SLC6A3) Variation on Dorsal Anterior Cingulate Function in Attention-Deficit/Hyperactivity Disorder

PubMed Central

Brown, Ariel B.; Biederman, Joseph; Valera, Eve M.; Doyle, Alysa E.; Bush, George; Spencer, Thomas; Monuteaux, Michael C.; Mick, Eric; Whitfield-Gabrieli, Susan; Makris, Nikos; LaViolette, Peter S.; Oscar-Berman, Marlene; Faraone, Stephen V.; Seidman, Larry J.

2010-01-01

Objective - Although Attention-Deficit/Hyperactivity Disorder (ADHD) is associated both with brain alterations in attention and executive function (EF) circuitry and with genetic variations within the dopamine system (including the dopamine transporter gene [SLC6A3]), few studies have directly investigated how genetic variations are linked to brain alterations. We sought to examine how a polymorphism in the 3’ untranslated region (UTR) of SLC6A3, associated with ADHD in meta-analysis, might contribute to variation in dorsal anterior cingulate cortex (dACC) function in subjects with ADHD. Method - We collected fMRI scans of 42 individuals with ADHD, all of European descent and over the age of 17, while they performed the Multi-Source Interference Task (MSIT), a cognitive task shown to activate dACC. SLC6A3 3’ UTR variable number tandem repeat (VNTR) polymorphisms were genotyped and brain activity was compared for groups based on allele status. Results - ADHD individuals homozygous for the 10R allele showed significant hypoactivation in the left dACC compared to 9R-carriers. Exploratory analysis also showed trends toward hypoactivation in the 10R homozygotes in left cerebellar vermis and right lateral prefrontal cortex. Further breakdown of genotype groups showed similar activation in individuals heterozygous and homozygous for the 9R allele. Conclusions - Alterations in activation of attention and EF networks found previously to be involved in ADHD are likely influenced by SLC6A3 genotype. This genotype may contribute to heterogeneity of brain alterations found within ADHD samples. PMID:19676101

Modulation of motor behavior by dopamine and the D1-like dopamine receptor AmDOP2 in the honey bee

PubMed Central

Mustard, Julie A.; Pham, Priscilla M.; Smith, Brian H.

2009-01-01

Determining the specific molecular pathways through which dopamine affects behavior has been complicated by the presence of multiple dopamine receptor subtypes that couple to different second messenger pathways. The observation of freely moving adult bees in an arena was used to investigate the role of dopamine signaling in regulating the behavior of the honey bee. Dopamine or the dopamine receptor antagonist flupenthixol was injected into the hemolymph of worker honey bees. Significant differences between treated and control bees were seen for all behaviors (walking, stopped, upside down, grooming, flying and fanning), and behavioral shifts were dependent on drug dosage and time after injection. To examine the role of dopamine signaling through a specific dopamine receptor in the brain, RNA interference was used to reduce expression levels of a D1-like receptor, AmDOP2. Injection of Amdop2 dsRNA into the mushroom bodies reduced the levels of Amdop2 mRNA and produced significant changes in the amount of time honey bees spent performing specific behaviors with reductions in time spent walking offset by increases in grooming or time spent stopped. Taken together these results establish that dopamine plays an important role in regulating motor behavior of the honey bee. PMID:19945462

Modulation of motor behavior by dopamine and the D1-like dopamine receptor AmDOP2 in the honey bee.

PubMed

Mustard, Julie A; Pham, Priscilla M; Smith, Brian H

2010-04-01

Determining the specific molecular pathways through which dopamine affects behavior has been complicated by the presence of multiple dopamine receptor subtypes that couple to different second messenger pathways. The observation of freely moving adult bees in an arena was used to investigate the role of dopamine signaling in regulating the behavior of the honey bee. Dopamine or the dopamine receptor antagonist flupenthixol was injected into the hemolymph of worker honey bees. Significant differences between treated and control bees were seen for all behaviors (walking, stopped, upside down, grooming, flying and fanning), and behavioral shifts were dependent on drug dosage and time after injection. To examine the role of dopamine signaling through a specific dopamine receptor in the brain, RNA interference was used to reduce expression levels of a D1-like receptor, AmDOP2. Injection of Amdop2 dsRNA into the mushroom bodies reduced the levels of Amdop2 mRNA and produced significant changes in the amount of time honey bees spent performing specific behaviors with reductions in time spent walking offset by increases in grooming or time spent stopped. Taken together these results establish that dopamine plays an important role in regulating motor behavior of the honey bee. Copyright (c) 2009 Elsevier Ltd. All rights reserved.

Excessive D1 Dopamine Receptor Activation in the Dorsal Striatum Promotes Autistic-Like Behaviors.

PubMed

Lee, Yunjin; Kim, Hannah; Kim, Ji-Eun; Park, Jin-Young; Choi, Juli; Lee, Jung-Eun; Lee, Eun-Hwa; Han, Pyung-Lim

2018-07-01

The dopamine system has been characterized in motor function, goal-directed behaviors, and rewards. Recent studies recognize various dopamine system genes as being associated with autism spectrum disorder (ASD). However, how dopamine system dysfunction induces ASD pathophysiology remains unknown. In the present study, we demonstrated that mice with increased dopamine functions in the dorsal striatum via the suppression of dopamine transporter expression in substantia nigra neurons or the optogenetic stimulation of the nigro-striatal circuitry exhibited sociability deficits and repetitive behaviors relevant to ASD pathology in animal models, while these behavioral changes were blocked by a D1 receptor antagonist. Pharmacological activation of D1 dopamine receptors in normal mice or the genetic knockout (KO) of D2 dopamine receptors also produced typical autistic-like behaviors. Moreover, the siRNA-mediated inhibition of D2 dopamine receptors in the dorsal striatum was sufficient to replicate autistic-like phenotypes in D2 KO mice. Intervention of D1 dopamine receptor functions or the signaling pathways-related D1 receptors in D2 KO mice produced anti-autistic effects. Together, our results indicate that increased dopamine function in the dorsal striatum promotes autistic-like behaviors and that the dorsal striatum is the neural correlate of ASD core symptoms.

Effects of fluoxetine treatment on striatal dopamine transporter binding and cerebrospinal fluid insulin-like growth factor-1 in children with autism.

PubMed

Makkonen, I; Kokki, H; Kuikka, J; Turpeinen, U; Riikonen, R

2011-10-01

A positive effect of fluoxetine has been shown in some children with autism. The present study was undertaken to correlate striatal dopamine transporter (DAT) binding and cerebrospinal fluid insulin-like growth factor-1 (CSF-IGF-1) with clinical response in autistic children (n=13, age 5-16 years) after a 6-month fluoxetine treatment. Good clinical responders (n=6) had a decrease (p=0.031) in DAT binding as assessed using single-photon emission computed tomography with [123I]-nor-β-CIT, whereas poor responders had a trend to an increase. An increase in CSF-IGF-1 (p=0.003) was detected after the treatment period, but no correlation between the clinical response and CSF-IGF-1 was found. In conclusion, fluoxetine decreases DAT binding indicating alleviation of the hyperdopaminergic state and increases CSF-IGF-1 concentration, which may also have a neuroprotective effect against dopamine-induced neurotoxicity in autistic children. © Georg Thieme Verlag KG Stuttgart · New York.

Genetic variations in the dopamine system and facial expression recognition in healthy chinese college students.

PubMed

Zhu, Bi; Chen, Chuansheng; Moyzis, Robert K; Dong, Qi; Chen, Chunhui; He, Qinghua; Stern, Hal S; Li, He; Li, Jin; Li, Jun; Lessard, Jared; Lin, Chongde

2012-01-01

This study investigated the relation between genetic variations in the dopamine system and facial expression recognition. A sample of Chinese college students (n = 478) was given a facial expression recognition task. Subjects were genotyped for 98 loci [96 single-nucleotide polymorphisms (SNPs) and 2 variable number tandem repeats] in 16 genes involved in the dopamine neurotransmitter system, including its 4 subsystems: synthesis (TH, DDC, and DBH), degradation/transport (COMT,MAOA,MAOB, and SLC6A3), receptors (DRD1,DRD2,DRD3,DRD4, and DRD5), and modulation (NTS,NTSR1,NTSR2, and NLN). To quantify the total contributions of the dopamine system to emotion recognition, we used a series of multiple regression models. Permutation analyses were performed to assess the posterior probabilities of obtaining such results. Among the 78 loci that were included in the final analyses (after excluding 12 SNPs that were in high linkage disequilibrium and 8 that were not in Hardy-Weinberg equilibrium), 1 (for fear), 3 (for sadness), 5 (for anger), 13 (for surprise), and 15 (for disgust) loci exhibited main effects on the recognition of facial expressions. Genetic variations in the dopamine system accounted for 3% for fear, 6% for sadness, 7% for anger, 10% for surprise, and 18% for disgust, with the latter surviving a stringent permutation test. Genetic variations in the dopamine system (especially the dopamine synthesis and modulation subsystems) made significant contributions to individual differences in the recognition of disgust faces. Copyright © 2012 S. Karger AG, Basel.

The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment

PubMed Central

Ashok, A H; Marques, T R; Jauhar, S; Nour, M M; Goodwin, G M; Young, A H; Howes, O D

2017-01-01

Bipolar affective disorder is a common neuropsychiatric disorder. Although its neurobiological underpinnings are incompletely understood, the dopamine hypothesis has been a key theory of the pathophysiology of both manic and depressive phases of the illness for over four decades. The increased use of antidopaminergics in the treatment of this disorder and new in vivo neuroimaging and post-mortem studies makes it timely to review this theory. To do this, we conducted a systematic search for post-mortem, pharmacological, functional magnetic resonance and molecular imaging studies of dopamine function in bipolar disorder. Converging findings from pharmacological and imaging studies support the hypothesis that a state of hyperdopaminergia, specifically elevations in D2/3 receptor availability and a hyperactive reward processing network, underlies mania. In bipolar depression imaging studies show increased dopamine transporter levels, but changes in other aspects of dopaminergic function are inconsistent. Puzzlingly, pharmacological evidence shows that both dopamine agonists and antidopaminergics can improve bipolar depressive symptoms and perhaps actions at other receptors may reconcile these findings. Tentatively, this evidence suggests a model where an elevation in striatal D2/3 receptor availability would lead to increased dopaminergic neurotransmission and mania, whilst increased striatal dopamine transporter (DAT) levels would lead to reduced dopaminergic function and depression. Thus, it can be speculated that a failure of dopamine receptor and transporter homoeostasis might underlie the pathophysiology of this disorder. The limitations of this model include its reliance on pharmacological evidence, as these studies could potentially affect other monoamines, and the scarcity of imaging evidence on dopaminergic function. This model, if confirmed, has implications for developing new treatment strategies such as reducing the dopamine synthesis and/or release in

ADHD-Derived Coding Variation in the Dopamine Transporter Disrupts Microdomain Targeting and Trafficking Regulation

PubMed Central

Sakrikar, Dhananjay; Mazei-Robison, Michelle S.; Mergy, Marc A.; Richtand, Nathan W.; Han, Qiao; Hamilton, Peter J.; Bowton, Erica; Galli, Aurelio; Veenstra-VanderWeele, Jeremy; Gill, Michael; Blakely, Randy D.

2012-01-01

Attention-Deficit Hyperactivity Disorder (ADHD) is the most commonly diagnosed disorder of school-age children. Although genetic and brain imaging studies suggest a contribution of altered dopamine (DA) signaling in ADHD, evidence of signaling perturbations contributing to risk is largely circumstantial. The presynaptic, cocaine and amphetamine (AMPH)-sensitive DA transporter (DAT) constrains DA availability at pre- and post-synaptic receptors following vesicular release and is targeted by the most commonly prescribed ADHD therapeutics. Using polymorphism discovery approaches with an ADHD cohort, we identified a human DAT (hDAT) coding variant, R615C, located in the transporter’s distal C-terminus, a region previously implicated in constitutive and regulated transporter trafficking. Here we demonstrate that whereas wildtype DAT proteins traffic in a highly regulated manner, DAT 615C proteins recycle constitutively, and demonstrate insensitivity to the endocytic effects of AMPH and protein kinase C (PKC) activation. The disrupted regulation of DAT 615C parallels a redistribution of the transporter variant away from GM1 ganglioside- and flotillin1-enriched membranes, and is accompanied by altered calcium/calmodulin-dependent protein kinase II (CaMKII) and flotillin-1 interactions. Using C-terminal peptides derived from wildtype DAT and the R615C variant, we establish that the DAT 615C C-terminus can act dominantly to preclude AMPH regulation of wildtype DAT. Mutagenesis of DAT C-terminal sequences suggest that phosphorylation of T613 may be important in sorting DAT between constitutive and regulated pathways. Together, our studies support a coupling of DAT microdomain localization with transporter regulation and provide evidence of perturbed DAT activity and DA signaling as a risk determinant for ADHD. PMID:22514303

Comparison of phosphodiesterase 10A, dopamine receptors D1 and D2 and dopamine transporter ligand binding in the striatum of the R6/2 and BACHD mouse models of Huntington's disease.

PubMed

Miller, Silke; Hill Della Puppa, Geraldine; Reidling, Jack; Marcora, Edoardo; Thompson, Leslie M; Treanor, James

2014-01-01

Phosphodiesterase 10A (PDE10A) is expressed at high levels in the striatum and has been proposed both as a biomarker for Huntington's disease pathology and as a target for intervention. PDE10A radiotracers have been successfully used to measure changes in binding density in Huntington's disease patients, but little is known about PDE10A binding in mouse models that are used extensively to model pathology and test therapeutic interventions. Our study investigated changes in PDE10A binding using the selective tracer 3H-7980 at specific ages of two Huntington's disease transgenic mouse models: R6/2, a short-lived model carrying exon-1 of mutant HTT and BACHD, a longer-lived model carrying full-length mutant HTT. PDE10A binding was compared to binding of known markers of striatal atrophy in Huntington's disease, e.g. dopamine transporter (DAT) and dopamine receptors D1 and D2. We found that in the R6/2 model at 6 weeks of age, mice showed high variability of binding, however binding of all ligands was significantly decreased at 8 and 12 weeks of age. In contrast, no changes were detectable in the BACHD model at 8, 10 or 12 month of age. These findings suggest that radiotracer binding of PDE10A, DAT, D1 and D2 receptor in the R6/2 model may be a good indicator of striatal pathological changes that are observed in Huntington's disease patients, and that the first 12 months in the BACHD model may be more reflective of early stages of the disease.

Rare Autism-Associated Variants Implicate Syntaxin 1 (STX1 R26Q) Phosphorylation and the Dopamine Transporter (hDAT R51W) in Dopamine Neurotransmission and Behaviors

PubMed Central

Cartier, Etienne; Hamilton, Peter J.; Belovich, Andrea N.; Shekar, Aparna; Campbell, Nicholas G.; Saunders, Christine; Andreassen, Thorvald F.; Gether, Ulrik; Veenstra-Vanderweele, Jeremy; Sutcliffe, James S.; Ulery-Reynolds, Paula G.; Erreger, Kevin; Matthies, Heinrich J.G.; Galli, Aurelio

2015-01-01

Background Syntaxin 1 (STX1) is a presynaptic plasma membrane protein that coordinates synaptic vesicle fusion. STX1 also regulates the function of neurotransmitter transporters, including the dopamine (DA) transporter (DAT). The DAT is a membrane protein that controls DA homeostasis through the high-affinity re-uptake of synaptically released DA. Methods We adopt newly developed animal models and state-of-the-art biophysical techniques to determine the contribution of the identified gene variants to impairments in DA neurotransmission observed in autism spectrum disorder (ASD). Outcomes Here, we characterize two independent autism-associated variants in the genes that encode STX1 and the DAT. We demonstrate that each variant dramatically alters DAT function. We identify molecular mechanisms that converge to inhibit reverse transport of DA and DA-associated behaviors. These mechanisms involve decreased phosphorylation of STX1 at Ser14 mediated by casein kinase 2 as well as a reduction in STX1/DAT interaction. These findings point to STX1/DAT interactions and STX1 phosphorylation as key regulators of DA homeostasis. Interpretation We determine the molecular identity and the impact of these variants with the intent of defining DA dysfunction and associated behaviors as possible complications of ASD. PMID:25774383

Ventral tegmental ionotropic glutamate receptor stimulation of nucleus accumbens tonic dopamine efflux blunts hindbrain-evoked phasic neurotransmission: implications for dopamine dysregulation disorders.

PubMed

Tye, S J; Miller, A D; Blaha, C D

2013-11-12

Activation of glutamate receptors within the ventral tegmental area (VTA) stimulates extrasynaptic (basal) dopamine release in terminal regions, including the nucleus accumbens (NAc). Hindbrain inputs from the laterodorsal tegmental nucleus (LDT) are critical for elicitation of phasic VTA dopamine cell activity and consequent transient dopamine release. This study investigated the role of VTA ionotropic glutamate receptor (iGluR) stimulation on both basal and LDT electrical stimulation-evoked dopamine efflux in the NAc using in vivo chronoamperometry and fixed potential amperometry in combination with stearate-graphite paste and carbon fiber electrodes, respectively. Intra-VTA infusion of the iGluR agonists (±)-α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA; 1 μg/μl) or N-methyl-d-aspartic acid (NMDA; 2 μg/μl) enhanced basal NAc dopamine efflux. This iGluR-mediated potentiation of basal dopamine efflux was paralleled by an attenuation of LDT-evoked transient NAc dopamine efflux, suggesting that excitation of basal activity effectively inhibited the capacity of hindbrain afferents to elicit transient dopamine efflux. In line with this, post-NMDA infusion of the dopamine D2 autoreceptor (D2R) agonist quinpirole (1 μg/μl; intra-VTA) partially recovered NMDA-mediated attenuation of LDT-evoked NAc dopamine, while concurrently attenuating NMDA-mediated potentiation of basal dopamine efflux. Post-NMDA infusion of quinpirole (1 μg/μl) alone attenuated basal and LDT-evoked dopamine efflux. Taken together, these data reveal that hyperstimulation of basal dopamine transmission can stunt hindbrain burst-like stimulation-evoked dopamine efflux. Inhibitory autoreceptor mechanisms within the VTA help to partially recover the magnitude of phasic dopamine efflux, highlighting the importance of both iGluRs and D2 autoreceptors in maintaining the functional balance of tonic and phasic dopamine neurotransmission. Dysregulation of this balance may have important

Amphetamine Elicits Opposing Actions on Readily Releasable and Reserve Pools for Dopamine

PubMed Central

Covey, Dan P.; Juliano, Steven A.; Garris, Paul A.

2013-01-01

Amphetamine, a highly addictive drug with therapeutic efficacy, exerts paradoxical effects on the fundamental communication modes employed by dopamine neurons in modulating behavior. While amphetamine elevates tonic dopamine signaling by depleting vesicular stores and driving non-exocytotic release through reverse transport, this psychostimulant also activates phasic dopamine signaling by up-regulating vesicular dopamine release. We hypothesized that these seemingly incongruent effects arise from amphetamine depleting the reserve pool and enhancing the readily releasable pool. This novel hypothesis was tested using in vivo voltammetry and stimulus trains of varying duration to access different vesicular stores. We show that amphetamine actions are stimulus dependent in the dorsal striatum. Specifically, amphetamine up-regulated vesicular dopamine release elicited by a short-duration train, which interrogates the readily releasable pool, but depleted release elicited by a long-duration train, which interrogates the reserve pool. These opposing actions of vesicular dopamine release were associated with concurrent increases in tonic and phasic dopamine responses. A link between vesicular depletion and tonic signaling was supported by results obtained for amphetamine in the ventral striatum and cocaine in both striatal sub-regions, which demonstrated augmented vesicular release and phasic signals only. We submit that amphetamine differentially targeting dopamine stores reconciles the paradoxical activation of tonic and phasic dopamine signaling. Overall, these results further highlight the unique and region-distinct cellular mechanisms of amphetamine and may have important implications for its addictive and therapeutic properties. PMID:23671560

Putting desire on a budget: dopamine and energy expenditure, reconciling reward and resources

PubMed Central

Beeler, Jeff A.; Frazier, Cristianne R. M.; Zhuang, Xiaoxi

2012-01-01

Accumulating evidence indicates integration of dopamine function with metabolic signals, highlighting a potential role for dopamine in energy balance, frequently construed as modulating reward in response to homeostatic state. Though its precise role remains controversial, the reward perspective of dopamine has dominated investigation of motivational disorders, including obesity. In the hypothesis outlined here, we suggest instead that the primary role of dopamine in behavior is to modulate activity to adapt behavioral energy expenditure to the prevailing environmental energy conditions, with the role of dopamine in reward and motivated behaviors derived from its primary role in energy balance. Dopamine has long been known to modulate activity, exemplified by psychostimulants that act via dopamine. More recently, there has been nascent investigation into the role of dopamine in modulating voluntary activity, with some investigators suggesting that dopamine may serve as a final common pathway that couples energy sensing to regulated voluntary energy expenditure. We suggest that interposed between input from both the internal and external world, dopamine modulates behavioral energy expenditure along two axes: a conserve-expend axis that regulates generalized activity and an explore-exploit axes that regulates the degree to which reward value biases the distribution of activity. In this view, increased dopamine does not promote consumption of tasty food. Instead increased dopamine promotes energy expenditure and exploration while decreased dopamine favors energy conservation and exploitation. This hypothesis provides a mechanistic interpretation to an apparent paradox: the well-established role of dopamine in food seeking and the findings that low dopaminergic functions are associated with obesity. Our hypothesis provides an alternative perspective on the role of dopamine in obesity and reinterprets the “reward deficiency hypothesis” as a perceived energy deficit

Individual Variation in Incentive Salience Attribution and Accumbens Dopamine Transporter Expression and Function

PubMed Central

Singer, Bryan F.; Guptaroy, Bipasha; Austin, Curtis J.; Wohl, Isabella; Lovic, Vedran; Seiler, Jillian L; Vaughan, Roxanne A.; Gnegy, Margaret E.; Robinson, Terry E.; Aragona, Brandon J.

2015-01-01

Cues (conditioned stimuli; CSs) associated with rewards can come to motivate behavior, but there is considerable individual variation in their ability to do so. For example, a lever-CS that predicts food reward becomes attractive, wanted, and elicits reward-seeking behavior to a greater extent in some rats (“sign-trackers”; STs), than others (“goal-trackers”; GTs). Variation in dopamine (DA) neurotransmission in the nucleus accumbens (NAc) core is thought to contribute to such individual variation. Given that the DA transporter (DAT) exerts powerful regulation over DA signaling, we characterized the expression and function of the DAT in the accumbens of STs and GTs. STs showed greater DAT surface expression in ventral striatal synaptosomes than GTs, and ex vivo fast-scan cyclic voltammetry recordings of electrically-evoked DA release confirmed enhanced DAT function in STs, as indicated by faster DA uptake, specifically in the NAc core. Consistent with this, systemic amphetamine (AMPH) produced greater inhibition of DA uptake in STs than in GTs. Furthermore, injection of AMPH directly into the NAc core enhanced lever-directed approach in STs, presumably by amplifying the incentive value of the CS, but had no effect on goal tracking behavior. On the other hand, there were no differences between STs and GTs in electrically-evoked DA release in slices, or in total ventral striatal DA content. We conclude that greater DAT surface expression may facilitate the attribution of incentive salience to discrete reward cues. Investigating this variability in animal sub-populations may help explain why some people abuse drugs, while others do not. PMID:26613374

The metal transporter SMF-3/DMT-1 mediates aluminum-induced dopamine neuron degeneration.

PubMed

VanDuyn, Natalia; Settivari, Raja; LeVora, Jennifer; Zhou, Shaoyu; Unrine, Jason; Nass, Richard

2013-01-01

Aluminum (Al(3+)) is the most prevalent metal in the earth's crust and is a known human neurotoxicant. Al(3+) has been shown to accumulate in the substantia nigra of patients with Parkinson's disease (PD), and epidemiological studies suggest correlations between Al(3+) exposure and the propensity to develop both PD and the amyloid plaque-associated disorder Alzheimer's disease (AD). Although Al(3+) exposures have been associated with the development of the most common neurodegenerative disorders, the molecular mechanism involved in Al(3+) transport in neurons and subsequent cellular death has remained elusive. In this study, we show that a brief exposure to Al(3+) decreases mitochondrial membrane potential and cellular ATP levels, and confers dopamine (DA) neuron degeneration in the genetically tractable nematode Caenorhabditis elegans (C. elegans). Al(3+) exposure also exacerbates DA neuronal death conferred by the human PD-associated protein α-synuclein. DA neurodegeneration is dependent on SMF-3, a homologue to the human divalent metal transporter (DMT-1), as a functional null mutation partially inhibits the cell death. We also show that SMF-3 is expressed in DA neurons, Al(3+) exposure results in a significant decrease in protein levels, and the neurodegeneration is partially dependent on the PD-associated transcription factor Nrf2/SKN-1 and caspase Apaf1/CED-4. Furthermore, we provide evidence that the deletion of SMF-3 confers Al(3+) resistance due to sequestration of Al(3+) into an intracellular compartment. This study describes a novel model for Al(3+)-induced DA neurodegeneration and provides the first molecular evidence of an animal Al(3+) transporter. © 2012 International Society for Neurochemistry.

Functional Connectome Analysis of Dopamine Neuron Glutamatergic Connections in Forebrain Regions.

PubMed

Mingote, Susana; Chuhma, Nao; Kusnoor, Sheila V; Field, Bianca; Deutch, Ariel Y; Rayport, Stephen

2015-12-09

In the ventral tegmental area (VTA), a subpopulation of dopamine neurons express vesicular glutamate transporter 2 and make glutamatergic connections to nucleus accumbens (NAc) and olfactory tubercle (OT) neurons. However, their glutamatergic connections across the forebrain have not been explored systematically. To visualize dopamine neuron forebrain projections and to enable photostimulation of their axons independent of transmitter status, we virally transfected VTA neurons with channelrhodopsin-2 fused to enhanced yellow fluorescent protein (ChR2-EYFP) and used DAT(IREScre) mice to restrict expression to dopamine neurons. ChR2-EYFP-expressing neurons almost invariably stained for tyrosine hydroxylase, identifying them as dopaminergic. Dopamine neuron axons visualized by ChR2-EYFP fluorescence projected most densely to the striatum, moderately to the amygdala and entorhinal cortex (ERC), sparsely to prefrontal and cingulate cortices, and rarely to the hippocampus. Guided by ChR2-EYFP fluorescence, we recorded systematically from putative principal neurons in target areas and determined the incidence and strength of glutamatergic connections by activating all dopamine neuron terminals impinging on recorded neurons with wide-field photostimulation. This revealed strong glutamatergic connections in the NAc, OT, and ERC; moderate strength connections in the central amygdala; and weak connections in the cingulate cortex. No glutamatergic connections were found in the dorsal striatum, hippocampus, basolateral amygdala, or prefrontal cortex. These results indicate that VTA dopamine neurons elicit widespread, but regionally distinct, glutamatergic signals in the forebrain and begin to define the dopamine neuron excitatory functional connectome. Dopamine neurons are important for the control of motivated behavior and are involved in the pathophysiology of several major neuropsychiatric disorders. Recent studies have shown that some ventral midbrain dopamine neurons are

Molecular cloning and functional characterization of the dopamine transporter from Eloria noyesi, a caterpillar pest of cocaine-rich coca plants.

PubMed

Chen, Rong; Wu, Xiaohong; Wei, Hua; Han, Dawn D; Gu, Howard H

2006-01-17

Cocaine is produced by coca plants as a chemical defense to deter feeding by insects. It has been shown that cocaine sprayed on tomato leaves reduces insect feeding, causes abnormal behaviors at low doses and kills feeding insects at doses equivalent to that in coca leaves [Nathanson, J.A., Hunnicutt, E.J., Kantham, L., Scavone, C., 1993. Cocaine as a naturally occurring insecticide. Proc. Natl. Acad. Sci. U. S. A. 90, 9645-9648.]. Most insects avoid coca leaves except the larvae of Eloria noyesi, a caterpillar pest of coca plants, which feeds preferentially on coca leaves. In the current study, we cloned and characterized the dopamine transporters (DATs) from caterpillars of E. noyesi (enDAT) and the silkworm, Bombyx mori (B. mori, bmDAT). The two insect DATs shared 88% amino acid sequence homology and functional similarity. Although enDAT and bmDAT showed the highest affinity for dopamine among endogenous amines, they were more sensitive to mammalian NET-selective inhibitors than to mammalian DAT-selective inhibitors. Despite a high cocaine content in the food source for E. noyesi, cocaine sensitivity of enDAT was similar to that of bmDAT, suggesting that mechanisms other than DAT insensitivity to cocaine, such as cocaine sequestration, might be responsible for cocaine resistance in this species. Given the significant differences in pharmacological profile from mammalian DATs, invertebrate DATs provide excellent tools for identifying regions and residues in the transporters that contribute to high-affinity binding of psychostimulants and antidepressants.

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

PubMed Central

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

2009-01-01

Sleep deprivation can markedly impair human performance contributing to accidents and poor productivity. The mechanisms underlying this impairment are not well understood but brain dopamine systems have been implicated. Here we test whether one night of sleep deprivation changes dopamine brain activity. We studied fifteen healthy subjects using positron emission tomography and [11C]raclopride (dopamine D2/3 receptor radioligand) and [11C]cocaine (dopamine transporter radioligand). Subjects were tested twice; after one night of rested sleep and after on night of sleep deprivation. [11C]Raclopride’s specific binding in striatum and thalamus were significantly reduced after sleep deprivation and the magnitude of this reduction correlated with increases in fatigue (tiredness and sleepiness) and with deterioration in cognitive performance (visual attention and working memory). In contrast sleep deprivation did not affect the specific binding of [11C]cocaine in striatum. Since [11C]raclopride competes with endogenous dopamine for binding to D2/D3 receptors, we interpret the decreases in binding to reflect dopamine increases with sleep deprivation. However, we can not rule out the possibility that decreased [11C]raclopride binding reflects decreases in receptor levels or affinity. Sleep deprivation did not affect dopamine transporters (target for most wake-promoting medications) and thus dopamine increases are likely to reflect increases in dopamine cell firing and/or release rather than decreases in dopamine reuptake. Inasmuch as dopamine-enhancing drugs increase wakefulness we postulate that dopamine increases after sleep deprivation is a mechanism by which the brain maintains arousal as the drive to sleep increases but one that is insufficient to counteract behavioral and cognitive impairment. PMID:18716203

The Association of a Novel Haplotype in the Dopamine Transporter with Preschool Age Posttraumatic Stress Disorder

PubMed Central

Brett, Zoë H.; Henry, Caitlin; Scheeringa, Michael

2013-01-01

Abstract Objective Significant evidence supports a genetic contribution to the development of posttraumatic stress disorder (PTSD). Three previous studies have demonstrated an association between PTSD and the nine repeat allele of the 3′ untranslated region (3′UTR) variable number tandem repeat (VNTR) in the dopamine transporter (DAT, rs28363170). Recently a novel, functionally significant C/T single-nucleotide polymorphism (SNP) in the 3′UTR (rs27072) with putative interactions with the 3′VNTR, has been identified. To provide enhanced support for the role of DAT and striatal dopamine regulation in the development of PTSD, this study examined the impact of a haplotype defined by the C allele of rs27072 and the nine repeat allele of the 3′VNTR on PTSD diagnosis in young trauma-exposed children. Methods DAT haplotypes were determined in 150 trauma-exposed 3–6 year-old children. PTSD was assessed with a semistructured interview. After excluding double heterozygotes, analysis was performed on 143 total subjects. Haplotype was examined in relation to categorical and continuous measures of PTSD, controlling for trauma type and race. Additional analysis within the two largest race categories was performed, as other means of controlling for ethnic stratification were not available. Results The number of haplotypes (0, 1, or 2) defined by the presence of the nine repeat allele of rs28363170 (VNTR in the 3′UTR) and the C allele of rs27072 (SNP in the 3′UTR) was significantly associated with both the diagnosis of PTSD and total PTSD symptoms. Specifically, children with one or two copies of the haplotype had significantly more PTSD symptoms and were more likely to be diagnosed with PTSD than were children without this haplotype. Conclusions These findings extend previous findings associating genetic variation in the DAT with PTSD. The association of a haplotype in DAT with PTSD provides incremental traction for a model of genetic vulnerability to PTSD, a

Evaluation of the Dopamine Hypothesis of ADHD with PET Brain Imaging

ScienceCinema

Swanson, James

2018-01-24

The Dopamine (DA) Hypothesis of ADHD (Wender, 1971; Levy, 1990) suggests that abnormalities in the synaptic mechanisms of DA transmission may be disrupted, and specific abnormalities in DA receptors and DA transporters (DAT) have been proposed (see Swanson et al, 1998). Early studies with small samples (e.g., n = 6, Dougherty et al, 1999) used single photon emission tomography (SPECT) and the radioligand (123I Altropane) to test a theory that ADHD may be caused by an over expression of DAT and reported 'a 70% increase in age-corrected dopamine transporter density in patients with attention deficit hyperactivity disorder compared with healthy controls' and suggested that treatment with stimulant medication decreased DAT density in ADHD patients and corrected an underlying abnormality (Krause et al, 2000). The potential importance of these findings was noted by Swanson (1999): 'If true, this is a major finding and points the way for new investigations of the primary pharmacological treatment for ADHD (with the stimulant drugs - e.g., methylphenidate), for which the dopamine transporter is the primary site of action. The potential importance of this finding demands special scrutiny'. This has been provided over the past decade using Positron Emission Tomography (PET). Brain imaging studies were conducted at Brookhaven National Laboratory (BNL) in a relatively large sample of stimulant-naive adults assessed for DAT (11C cocaine) density and DA receptors (11C raclopride) availability. These studies (Volkow et al, 2007; Volkow et al, 2009) do not confirm the hypothesis of increased DAT density and suggest the opposite (i.e., decreased rather than increased DAT density), and follow-up after treatment (Wang et al, 2010) does not confirm the hypothesis that therapeutic doses of methylphenidate decrease DAT density and suggests the opposite (i.e., increased rather than decreased DAT density). The brain regions implicated by these PET imaging studies also suggest that a

Dopamine dynamics and cocaine sensitivity differ between striosome and matrix compartments of the striatum

PubMed Central

Salinas, Armando G.; Davis, Margaret I.; Lovinger, David M.; Mateo, Yolanda

2016-01-01

The striatum is typically classified according to its major output pathways, which consist of dopamine D1 and D2 receptor-expressing neurons. The striatum is also divided into striosome and matrix compartments, based on the differential expression of a number of proteins, including the mu opioid receptor, dopamine transporter (DAT), and Nr4a1 (nuclear receptor subfamily 4, group A, member 1). Numerous functional differences between the striosome and matrix compartments are implicated in dopamine-related neurological disorders including Parkinson’s disease and addiction. Using Nr4a1-eGFP mice, we provide evidence that electrically evoked dopamine release differs between the striosome and matrix compartments in a regionally-distinct manner. We further demonstrate that this difference is not due to differences in inhibition of dopamine release by dopamine autoreceptors or nicotinic acetylcholine receptors. Furthermore, cocaine enhanced extracellular dopamine in striosomes to a greater degree than in the matrix and concomitantly inhibited dopamine uptake in the matrix to a greater degree than in striosomes. Importantly, these compartment differences in cocaine sensitivity were limited to the dorsal striatum. These findings demonstrate a level of exquisite microanatomical regulation of dopamine by the DAT in striosomes relative to the matrix. PMID:27036891

Effect of acute millimeter wave exposure on dopamine metabolism of NGF-treated PC12 cells.

PubMed

Haas, Alexis J; Le Page, Yann; Zhadobov, Maxim; Sauleau, Ronan; Dréan, Yves Le; Saligaut, Christian

2017-07-01

Several forthcoming wireless telecommunication systems will use electromagnetic frequencies at millimeter waves (MMWs), and technologies developed around the 60-GHz band will soon know a widespread distribution. Free nerve endings within the skin have been suggested to be the targets of MMW therapy which has been used in the former Soviet Union. So far, no studies have assessed the impact of MMW exposure on neuronal metabolism. Here, we investigated the effects of a 24-h MMW exposure at 60.4 GHz, with an incident power density (IPD) of 5 mW/cm², on the dopaminergic turnover of NGF-treated PC12 cells. After MMW exposure, both intracellular and extracellular contents of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were studied using high performance liquid chromatography. Impact of exposure on the dopamine transporter (DAT) expression was also assessed by immunocytochemistry. We analyzed the dopamine turnover by assessing the ratio of DOPAC to DA, and measuring DOPAC accumulation in the medium. Neither dopamine turnover nor DAT protein expression level were impacted by MMW exposure. However, extracellular accumulation of DOPAC was found to be slightly increased, but not significantly. This result was related to the thermal effect, and overall, no evidence of non-thermal effects of MMW exposure were observed on dopamine metabolism. © The Author 2017. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

Rotigotine is a potent agonist at dopamine D1 receptors as well as at dopamine D2 and D3 receptors.

PubMed

Wood, Martyn; Dubois, Vanessa; Scheller, Dieter; Gillard, Michel

2015-02-01

Rotigotine acts as a dopamine receptor agonist with high affinity for the dopamine D2, D3, D4 and D5 receptors but with a low affinity for the dopamine D1 receptor. We have investigated this further in radioligand binding and functional studies and compared the profile of rotigotine with that of other drugs used in the treatment of Parkinson's disease (PD). The binding of rotigotine to human dopamine D1, D2, D3, D4 and D5 receptors was determined in radioligand binding studies using [(3)H]rotigotine and compared with that of standard antagonist radioligands. Functional interactions of rotigotine with human dopamine receptors was also determined. [(3)H]rotigotine can be used as an agonist radioligand to label all dopamine receptor subtypes and this can be important to derive agonist affinity estimates. Rotigotine maintains this high affinity in functional studies at all dopamine receptors especially D1, D2 and D3 receptors and, to a lesser extent, D4 and D5 receptors. Rotigotine, like apomorphine but unlike ropinirole and pramipexole, was a potent agonist at all dopamine receptors. Rotigotine is a high-potency agonist at human dopamine D1, D2 and D3 receptors with a lower potency at D4 and D5 receptors. These studies differentiate rotigotine from conventional dopamine D2 agonists, used in the treatment of PD, such as ropinirole and pramipexole which lack activity at the D1 and D5 receptors, but resembles that of apomorphine which has greater efficacy in PD than other dopamine agonists but has suboptimal pharmacokinetic properties. © 2014 The British Pharmacological Society.

Rotigotine is a potent agonist at dopamine D1 receptors as well as at dopamine D2 and D3 receptors

PubMed Central

Wood, Martyn; Dubois, Vanessa; Scheller, Dieter; Gillard, Michel

2015-01-01

Background and Purpose Rotigotine acts as a dopamine receptor agonist with high affinity for the dopamine D2, D3, D4 and D5 receptors but with a low affinity for the dopamine D1 receptor. We have investigated this further in radioligand binding and functional studies and compared the profile of rotigotine with that of other drugs used in the treatment of Parkinson's disease (PD). Experimental Approach The binding of rotigotine to human dopamine D1, D2, D3, D4 and D5 receptors was determined in radioligand binding studies using [3H]rotigotine and compared with that of standard antagonist radioligands. Functional interactions of rotigotine with human dopamine receptors was also determined. Key Results [3H]rotigotine can be used as an agonist radioligand to label all dopamine receptor subtypes and this can be important to derive agonist affinity estimates. Rotigotine maintains this high affinity in functional studies at all dopamine receptors especially D1, D2 and D3 receptors and, to a lesser extent, D4 and D5 receptors. Rotigotine, like apomorphine but unlike ropinirole and pramipexole, was a potent agonist at all dopamine receptors. Conclusions and Implications Rotigotine is a high-potency agonist at human dopamine D1, D2 and D3 receptors with a lower potency at D4 and D5 receptors. These studies differentiate rotigotine from conventional dopamine D2 agonists, used in the treatment of PD, such as ropinirole and pramipexole which lack activity at the D1 and D5 receptors, but resembles that of apomorphine which has greater efficacy in PD than other dopamine agonists but has suboptimal pharmacokinetic properties. PMID:25339241

Therapeutic doses of oral methylphenidate significantly increase extracellular dopamine in the human brain.

PubMed

Volkow, N D; Wang, G; Fowler, J S; Logan, J; Gerasimov, M; Maynard, L; Ding, Y; Gatley, S J; Gifford, A; Franceschi, D

2001-01-15

Methylphenidate (Ritalin) is the most commonly prescribed psychoactive drug in children for the treatment of attention deficit hyperactivity disorder (ADHD), yet the mechanisms responsible for its therapeutic effects are poorly understood. Whereas methylphenidate blocks the dopamine transporter (main mechanism for removal of extracellular dopamine), it is unclear whether at doses used therapeutically it significantly changes extracellular dopamine (DA) concentration. Here we used positron emission tomography and [(11)C]raclopride (D2 receptor radioligand that competes with endogenous DA for binding to the receptor) to evaluate whether oral methylphenidate changes extracellular DA in the human brain in 11 healthy controls. We showed that oral methylphenidate (average dose 0.8 +/- 0.11 mg/kg) significantly increased extracellular DA in brain, as evidenced by a significant reduction in B(max)/K(d) (measure of D2 receptor availability) in striatum (20 +/- 12%; p < 0.0005). These results provide direct evidence that oral methylphenidate at doses within the therapeutic range significantly increases extracellular DA in human brain. This result coupled with recent findings of increased dopamine transporters in ADHD patients (which is expected to result in reductions in extracellular DA) provides a mechanistic framework for the therapeutic efficacy of methylphenidate. The increase in DA caused by the blockade of dopamine transporters by methylphenidate predominantly reflects an amplification of spontaneously released DA, which in turn is responsive to environmental stimulation. Because DA decreases background firing rates and increases signal-to-noise in target neurons, we postulate that the amplification of weak DA signals in subjects with ADHD by methylphenidate would enhance task-specific signaling, improving attention and decreasing distractibility. Alternatively methylphenidate-induced increases in DA, a neurotransmitter involved with motivation and reward, could

Towards trans-diagnostic mechanisms in psychiatry: neurobehavioral profile of rats with a loss-of-function point mutation in the dopamine transporter gene

PubMed Central

Vengeliene, Valentina; Bespalov, Anton; Roßmanith, Martin; Horschitz, Sandra; Berger, Stefan; Relo, Ana L.; Noori, Hamid R.; Schneider, Peggy; Enkel, Thomas; Bartsch, Dusan; Schneider, Miriam; Behl, Berthold; Hansson, Anita C.; Schloss, Patrick

2017-01-01

ABSTRACT The research domain criteria (RDoC) matrix has been developed to reorient psychiatric research towards measurable behavioral dimensions and underlying mechanisms. Here, we used a new genetic rat model with a loss-of-function point mutation in the dopamine transporter (DAT) gene (Slc6a3_N157K) to systematically study the RDoC matrix. First, we examined the impact of the Slc6a3_N157K mutation on monoaminergic signaling. We then performed behavioral tests representing each of the five RDoC domains: negative and positive valence systems, cognitive, social and arousal/regulatory systems. The use of RDoC may be particularly helpful for drug development. We studied the effects of a novel pharmacological approach metabotropic glutamate receptor mGluR2/3 antagonism, in DAT mutants in a comparative way with standard medications. Loss of DAT functionality in mutant rats not only elevated subcortical extracellular dopamine concentration but also altered the balance of monoaminergic transmission. DAT mutant rats showed deficits in all five RDoC domains. Thus, mutant rats failed to show conditioned fear responses, were anhedonic, were unable to learn stimulus-reward associations, showed impaired cognition and social behavior, and were hyperactive. Hyperactivity in mutant rats was reduced by amphetamine and atomoxetine, which are well-established medications to reduce hyperactivity in humans. The mGluR2/3 antagonist LY341495 also normalized hyperactivity in DAT mutant rats without affecting extracellular dopamine levels. We systematically characterized an altered dopamine system within the context of the RDoC matrix and studied mGluR2/3 antagonism as a new pharmacological strategy to treat mental disorders with underlying subcortical dopaminergic hyperactivity. PMID:28167616

Poly(dopamine) coating to biodegradable polymers for bone tissue engineering.

PubMed

Tsai, Wei-Bor; Chen, Wen-Tung; Chien, Hsiu-Wen; Kuo, Wei-Hsuan; Wang, Meng-Jiy

2014-02-01

In this study, a technique based on poly(dopamine) deposition to promote cell adhesion was investigated for the application in bone tissue engineering. The adhesion and proliferation of rat osteoblasts were evaluated on poly(dopamine)-coated biodegradable polymer films, such as polycaprolactone, poly(l-lactide) and poly(lactic-co-glycolic acid), which are commonly used biodegradable polymers in tissue engineering. Cell adhesion was significantly increased to a plateau by merely 15 s of dopamine incubation, 2.2-4.0-folds of increase compared to the corresponding untreated substrates. Cell proliferation was also greatly enhanced by poly(dopamine) deposition, indicated by shortened cell doubling time. Mineralization was also increased on the poly(dopamine)-deposited surfaces. The potential of poly(dopamine) deposition in bone tissue engineering is demonstrated in this study.

In Vivo [11C]Dihydrotetrabenazine ([11C]DTBZ) Binding in Rat Striatum: Sensitivity to Dopamine Concentrations

PubMed Central

Kilbourn, Michael R.; Butch, Elizabeth R.; Desmond, Timothy; Sherman, Phillip; Harris, Paul E.; Frey, Kirk A.

2009-01-01

Introduction The sensitivity of the in vivo binding of [11C]dihydrotetrabenazine ([11C]DTBZ) and [11C]methylphenidate ([11C]MPH) to their respective targets, the vesicular monoamine transporter (VMAT2) and the neuronal membrane dopamine transporter (DAT), after alterations of endogenous levels of dopamine were examined in the rat brain. Methods In vivo binding of [11C]DTBZ and [11C]MPH were determined using a bolus+infusion protocol. In vitro numbers of VMAT2 binding sites were determined by autoradiography. Results Repeated dosing with α-methyl-p-tyrosine (AMPT) at doses that significantly (−75%) depleted brain tissue dopamine levels resulted in increased (+36%) in vivo [11C]DTBZ binding to VMAT2 in the striatum. The increase in binding could be completely reversed by treatment with L-DOPA/benserazide to restore dopamine levels. There were no changes in total numbers of VMAT2 binding sites as measured using in vitro autoradiography. No changes were observed for in vivo [11C]MPH binding to the DAT in the striatum following AMPT pretreatment. Conclusion These results indicate that large reductions of dopamine concentrations in the rat brain can produce modest but significant changes in binding of radioligands to the VMAT2, which can be reversed by repleneshment of dopamine using exogenous L-DOPA. PMID:20122661

The Atypical MAP Kinase SWIP-13/ERK8 Regulates Dopamine Transporters through a Rho-Dependent Mechanism

PubMed Central

Bermingham, Daniel P.; Snider, Sam L.; Miller, David M.

2017-01-01

The neurotransmitter dopamine (DA) regulates multiple behaviors across phylogeny, with disrupted DA signaling in humans associated with addiction, attention-deficit/ hyperactivity disorder, schizophrenia, and Parkinson's disease. The DA transporter (DAT) imposes spatial and temporal limits on DA action, and provides for presynaptic DA recycling to replenish neurotransmitter pools. Molecular mechanisms that regulate DAT expression, trafficking, and function, particularly in vivo, remain poorly understood, though recent studies have implicated rho-linked pathways in psychostimulant action. To identify genes that dictate the ability of DAT to sustain normal levels of DA clearance, we pursued a forward genetic screen in Caenorhabditis elegans based on the phenotype swimming-induced paralysis (Swip), a paralytic behavior observed in hermaphrodite worms with loss-of-function dat-1 mutations. Here, we report the identity of swip-13, which encodes a highly conserved ortholog of the human atypical MAP kinase ERK8. We present evidence that SWIP-13 acts presynaptically to insure adequate levels of surface DAT expression and DA clearance. Moreover, we provide in vitro and in vivo evidence supporting a conserved pathway involving SWIP-13/ERK8 activation of Rho GTPases that dictates DAT surface expression and function. SIGNIFICANCE STATEMENT Signaling by the neurotransmitter dopamine (DA) is tightly regulated by the DA transporter (DAT), insuring efficient DA clearance after release. Molecular networks that regulate DAT are poorly understood, particularly in vivo. Using a forward genetic screen in the nematode Caenorhabditis elegans, we implicate the atypical mitogen activated protein kinase, SWIP-13, in DAT regulation. Moreover, we provide in vitro and in vivo evidence that SWIP-13, as well as its human counterpart ERK8, regulate DAT surface availability via the activation of Rho proteins. Our findings implicate a novel pathway that regulates DA synaptic availability and that

Reinforcing Doses of Intravenous Cocaine Produce Only Modest Dopamine Uptake Inhibition.

PubMed

Brodnik, Zachary D; Ferris, Mark J; Jones, Sara R; España, Rodrigo A

2017-02-15

The reinforcing efficacy of cocaine is thought to stem from inhibition of the dopamine transporter (DAT) and subsequent increases in extracellular dopamine concentrations in the brain. In humans, this hypothesis has generally been supported by positron emission tomography imaging studies where the percent of DATs occupied by cocaine is used as a measure of cocaine activity in the brain. Interpretation of these studies, however, often relies on the assumption that measures of DAT occupancy directly correspond with functional DAT blockade. In the current studies, we used in vivo and in vitro fast scan cyclic voltammetry in mice to measure dopamine uptake inhibition following varying doses of cocaine as well as two high affinity DAT inhibitors. We then compared dopamine clearance rates following these drug treatments to dopamine clearance obtained from DAT knockout mice as a proxy for complete DAT blockade. We found that administration of abused doses of cocaine resulted in approximately 2% of maximal DAT blockade. Overall, our data indicate that abused doses of cocaine produce a relatively modest degree of DA uptake inhibition, and suggest that the relationship between DAT occupancy and functional blockade of the DAT is more complex than originally posited.

Distinct Effects of Nalmefene on Dopamine Uptake Rates and Kappa Opioid Receptor Activity in the Nucleus Accumbens Following Chronic Intermittent Ethanol Exposure

PubMed Central

Rose, Jamie H.; Karkhanis, Anushree N.; Steiniger-Brach, Björn; Jones, Sara R.

2016-01-01

The development of pharmacotherapeutics that reduce relapse to alcohol drinking in patients with alcohol dependence is of considerable research interest. Preclinical data support a role for nucleus accumbens (NAc) κ opioid receptors (KOR) in chronic intermittent ethanol (CIE) exposure-induced increases in ethanol intake. Nalmefene, a high-affinity KOR partial agonist, reduces drinking in at-risk patients and relapse drinking in rodents, potentially due to its effects on NAc KORs. However, the effects of nalmefene on accumbal dopamine transmission and KOR function are poorly understood. We investigated the effects of nalmefene on dopamine transmission and KORs using fast scan cyclic voltammetry in NAc brain slices from male C57BL/6J mice following five weeks of CIE or air exposure. Nalmefene concentration-dependently reduced dopamine release similarly in air and CIE groups, suggesting that dynorphin tone may not be present in brain slices. Further, nalmefene attenuated dopamine uptake rates to a greater extent in brain slices from CIE-exposed mice, suggesting that dopamine transporter-KOR interactions may be fundamentally altered following CIE. Additionally, nalmefene reversed the dopamine-decreasing effects of a maximal concentration of a KOR agonist selectively in brain slices of CIE-exposed mice. It is possible that nalmefene may attenuate withdrawal-induced increases in ethanol consumption by modulation of dopamine transmission through KORs. PMID:27472317

Accuracy of partial volume effect correction in clinical molecular imaging of dopamine transporter using SPECT

NASA Astrophysics Data System (ADS)

Soret, Marine; Alaoui, Jawad; Koulibaly, Pierre M.; Darcourt, Jacques; Buvat, Irène

2007-02-01

ObjectivesPartial volume effect (PVE) is a major source of bias in brain SPECT imaging of dopamine transporter. Various PVE corrections (PVC) making use of anatomical data have been developed and yield encouraging results. However, their accuracy in clinical data is difficult to demonstrate because the gold standard (GS) is usually unknown. The objective of this study was to assess the accuracy of PVC. MethodTwenty-three patients underwent MRI and 123I-FP-CIT SPECT. The binding potential (BP) values were measured in the striata segmented on the MR images after coregistration to SPECT images. These values were calculated without and with an original PVC. In addition, for each patient, a Monte Carlo simulation of the SPECT scan was performed. For these simulations where true simulated BP values were known, percent biases in BP estimates were calculated. For the real data, an evaluation method that simultaneously estimates the GS and a quadratic relationship between the observed and the GS values was used. It yields a surrogate mean square error (sMSE) between the estimated values and the estimated GS values. ResultsThe averaged percent difference between BP measured for real and for simulated patients was 0.7±9.7% without PVC and was -8.5±14.5% with PVC, suggesting that the simulated data reproduced the real data well enough. For the simulated patients, BP was underestimated by 66.6±9.3% on average without PVC and overestimated by 11.3±9.5% with PVC, demonstrating the greatest accuracy of BP estimates with PVC. For the simulated data, sMSE were 27.3 without PVC and 0.90 with PVC, confirming that our sMSE index properly captured the greatest accuracy of BP estimates with PVC. For the real patient data, sMSE was 50.8 without PVC and 3.5 with PVC. These results were consistent with those obtained on the simulated data, suggesting that for clinical data, and despite probable segmentation and registration errors, BP were more accurately estimated with PVC than without

Frequency-Dependent Modulation of Dopamine Release by Nicotine and Dopamine D1 Receptor Ligands: An In Vitro Fast Cyclic Voltammetry Study in Rat Striatum.

PubMed

Goutier, W; Lowry, J P; McCreary, A C; O'Connor, J J

2016-05-01

Nicotine is a highly addictive drug and exerts this effect partially through the modulation of dopamine release and increasing extracellular dopamine in regions such as the brain reward systems. Nicotine acts in these regions on nicotinic acetylcholine receptors. The effect of nicotine on the frequency dependent modulation of dopamine release is well established and the purpose of this study was to investigate whether dopamine D1 receptor (D1R) ligands have an influence on this. Using fast cyclic voltammetry and rat corticostriatal slices, we show that D1R ligands are able to modulate the effect of nicotine on dopamine release. Nicotine (500 nM) induced a decrease in dopamine efflux at low frequency (single pulse or five pulses at 10 Hz) and an increase at high frequency (100 Hz) electrical field stimulation. The D1R agonist SKF-38393, whilst having no effect on dopamine release on its own or on the effect of nicotine upon multiple pulse evoked dopamine release, did significantly prevent and reverse the effect of nicotine on single pulse dopamine release. Interestingly similar results were obtained with the D1R antagonist SCH-23390. In this study we have demonstrated that the modulation of dopamine release by nicotine can be altered by D1R ligands, but only when evoked by single pulse stimulation, and are likely working via cholinergic interneuron driven dopamine release.

Dopamine Signaling Regulates Fat Content through β-Oxidation in Caenorhabditis elegans

PubMed Central

Barros, Alexandre Guimarães de Almeida; Bridi, Jessika Cristina; de Souza, Bruno Rezende; de Castro Júnior, Célio; de Lima Torres, Karen Cecília; Malard, Leandro; Jorio, Ado; de Miranda, Débora Marques; Ashrafi, Kaveh; Romano-Silva, Marco Aurélio

2014-01-01

The regulation of energy balance involves an intricate interplay between neural mechanisms that respond to internal and external cues of energy demand and food availability. Compelling data have implicated the neurotransmitter dopamine as an important part of body weight regulation. However, the precise mechanisms through which dopamine regulates energy homeostasis remain poorly understood. Here, we investigate mechanisms through which dopamine modulates energy storage. We showed that dopamine signaling regulates fat reservoirs in Caenorhabditis elegans. We found that the fat reducing effects of dopamine were dependent on dopaminergic receptors and a set of fat oxidation enzymes. Our findings reveal an ancient role for dopaminergic regulation of fat and suggest that dopamine signaling elicits this outcome through cascades that ultimately mobilize peripheral fat depots. PMID:24465759

Individual variation in incentive salience attribution and accumbens dopamine transporter expression and function.

PubMed

Singer, Bryan F; Guptaroy, Bipasha; Austin, Curtis J; Wohl, Isabella; Lovic, Vedran; Seiler, Jillian L; Vaughan, Roxanne A; Gnegy, Margaret E; Robinson, Terry E; Aragona, Brandon J

2016-03-01

Cues (conditioned stimuli; CSs) associated with rewards can come to motivate behavior, but there is considerable individual variation in their ability to do so. For example, a lever-CS that predicts food reward becomes attractive and wanted, and elicits reward-seeking behavior, to a greater extent in some rats ('sign-trackers'; STs) than others ('goal-trackers'; GTs). Variation in dopamine (DA) neurotransmission in the nucleus accumbens (NAc) core is thought to contribute to such individual variation. Given that the DA transporter (DAT) exerts powerful regulation over DA signaling, we characterized the expression and function of the DAT in the accumbens of STs and GTs. STs showed greater DAT surface expression in ventral striatal synaptosomes than GTs, and ex vivo fast-scan cyclic voltammetry recordings of electrically evoked DA release confirmed enhanced DAT function in STs, as indicated by faster DA uptake, specifically in the NAc core. Consistent with this, systemic amphetamine (AMPH) produced greater inhibition of DA uptake in STs than in GTs. Furthermore, injection of AMPH directly into the NAc core enhanced lever-directed approach in STs, presumably by amplifying the incentive value of the CS, but had no effect on goal-tracking behavior. On the other hand, there were no differences between STs and GTs in electrically-evoked DA release in slices, or in total ventral striatal DA content. We conclude that greater DAT surface expression may facilitate the attribution of incentive salience to discrete reward cues. Investigating this variability in animal sub-populations may help explain why some people abuse drugs while others do not. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Towards trans-diagnostic mechanisms in psychiatry: neurobehavioral profile of rats with a loss-of-function point mutation in the dopamine transporter gene.

PubMed

Vengeliene, Valentina; Bespalov, Anton; Roßmanith, Martin; Horschitz, Sandra; Berger, Stefan; Relo, Ana L; Noori, Hamid R; Schneider, Peggy; Enkel, Thomas; Bartsch, Dusan; Schneider, Miriam; Behl, Berthold; Hansson, Anita C; Schloss, Patrick; Spanagel, Rainer

2017-04-01

The research domain criteria (RDoC) matrix has been developed to reorient psychiatric research towards measurable behavioral dimensions and underlying mechanisms. Here, we used a new genetic rat model with a loss-of-function point mutation in the dopamine transporter (DAT) gene ( Slc6a3 _N157K) to systematically study the RDoC matrix. First, we examined the impact of the Slc6a3 _N157K mutation on monoaminergic signaling. We then performed behavioral tests representing each of the five RDoC domains: negative and positive valence systems, cognitive, social and arousal/regulatory systems. The use of RDoC may be particularly helpful for drug development. We studied the effects of a novel pharmacological approach metabotropic glutamate receptor mGluR2/3 antagonism, in DAT mutants in a comparative way with standard medications. Loss of DAT functionality in mutant rats not only elevated subcortical extracellular dopamine concentration but also altered the balance of monoaminergic transmission. DAT mutant rats showed deficits in all five RDoC domains. Thus, mutant rats failed to show conditioned fear responses, were anhedonic, were unable to learn stimulus-reward associations, showed impaired cognition and social behavior, and were hyperactive. Hyperactivity in mutant rats was reduced by amphetamine and atomoxetine, which are well-established medications to reduce hyperactivity in humans. The mGluR2/3 antagonist LY341495 also normalized hyperactivity in DAT mutant rats without affecting extracellular dopamine levels. We systematically characterized an altered dopamine system within the context of the RDoC matrix and studied mGluR2/3 antagonism as a new pharmacological strategy to treat mental disorders with underlying subcortical dopaminergic hyperactivity. © 2017. Published by The Company of Biologists Ltd.

Changes in Expression of Dopamine, Its Receptor, and Transporter in Nucleus Accumbens of Heroin-Addicted Rats with Brain-Derived Neurotrophic Factor (BDNF) Overexpression.

PubMed

Li, Yixin; Xia, Baijuan; Li, Rongrong; Yin, Dan; Liang, Wenmei

2017-06-09

BACKGROUND The aim of this study was to explore how changes in the expression of BDNF in MLDS change the effect of BDNF on dopamine (DA) neurons, which may have therapeutic implications for heroin addiction. MATERIAL AND METHODS We established a rat model of heroin addiction and observed changes in the expression of BDNF, DA, dopamine receptor (DRD), dopamine transporter (DAT), and other relevant pathways in NAc. We also assessed the effect of BDNF overexpression in the NAc, behavioral changes of heroin-conditioned place preference (CPP), and naloxone withdrawal in rats with high levels of BDNF. We established 5 adult male rat groups: heroin addiction, lentivirus transfection, blank virus, sham operation, and control. The PCR gene chip was used to study gene expression changes. BDNF lentivirus transfection was used for BDNF overexpression. A heroin CPP model and a naloxone withdrawal model of rats were established. RESULTS Expression changes were found in 20 of the 84 DA-associated genes in the NAc of heroin-addicted rats. Weight loss and withdrawal symptoms in the lentivirus group for naloxone withdrawal was less than in the blank virus and the sham operation group. These 2 latter groups also showed significant behavioral changes, but such changes were not observed in the BDNF lentivirus group before or after training. DRD3 and DAT increased in the NAc of the lentivirus group. CONCLUSIONS BDNF and DA in the NAc are involved in heroin addiction. BDNF overexpression in NAc reduces withdrawal symptoms and craving behavior for medicine induced by environmental cues for heroin-addicted rats. BDNF participates in the regulation of the dopamine system by acting on DRD3 and DAT.

3,4-Methylenedioxypyrovalerone prevents while methylone enhances methamphetamine-induced damage to dopamine nerve endings: β-ketoamphetamine modulation of neurotoxicity by the dopamine transporter

PubMed Central

Anneken, John H.; Angoa-Pérez, Mariana; Kuhn, Donald M.

2016-01-01

Methylone, 3,4-methylenedioxypyrovalerone (MDPV), and mephedrone are psychoactive ingredients of ‘bath salts’ and their abuse represents a growing public health care concern. These drugs are cathinone derivatives and are classified chemically as β-ketoamphetamines. Because of their close structural similarity to the amphetamines, methylone, MDPV, and mephedrone share most of their pharmacological, neurochemical, and behavioral properties. One point of divergence in their actions is the ability to cause damage to the CNS. Unlike methamphetamine, the β-ketoamphetamines do not damage dopamine (DA) nerve endings. However, mephedrone has been shown to significantly accentuate methamphetamine neurotoxicity. Bath salt formulations contain numerous different psychoactive ingredients, and individuals who abuse bath salts also coabuse other illicit drugs. Therefore, we have evaluated the effects of methylone, MDPV, mephedrone, and methamphetamine on DA nerve endings. The β-ketoamphetamines alone or in all possible two-drug combinations do not result in damage to DA nerve endings but do cause hyperthermia. MDPV completely protects against the neurotoxic effects of methamphetamine while methylone accentuates it. Neither MDPV nor methylone attenuates the hyperthermic effects of methamphetamine. The potent neuroprotective effects of MDPV extend to amphetamine-, 3,4-methylenedioxymethamphetamine-, and MPTP-induced neurotoxicity. These results indicate that β-ketoamphetamine drugs that are non-substrate blockers of the DA transporter (i.e., MDPV) protect against methamphetamine neurotoxicity, whereas those that are substrates for uptake by the DA transporter and which cause DA release (i.e., methylone, mephedrone) accentuate neurotoxicity. PMID:25626880

Motivation deficit in ADHD is associated with dysfunction of the dopamine reward pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Volkow, N.D.; Wang, G.; Volkow, N.D.

Attention-deficit hyperactivity disorder (ADHD) is typically characterized as a disorder of inattention and hyperactivity/impulsivity but there is increasing evidence of deficits in motivation. Using positron emission tomography (PET), we showed decreased function in the brain dopamine reward pathway in adults with ADHD, which, we hypothesized, could underlie the motivation deficits in this disorder. To evaluate this hypothesis, we performed secondary analyses to assess the correlation between the PET measures of dopamine D2/D3 receptor and dopamine transporter availability (obtained with [{sup 11}C]raclopride and [{sup 11}C]cocaine, respectively) in the dopamine reward pathway (midbrain and nucleus accumbens) and a surrogate measure of traitmore » motivation (assessed using the Achievement scale on the Multidimensional Personality Questionnaire or MPQ) in 45 ADHD participants and 41 controls. The Achievement scale was lower in ADHD participants than in controls (11 {+-} 5 vs 14 {+-} 3, P < 0.001) and was significantly correlated with D2/D3 receptors (accumbens: r = 0.39, P < 0.008; midbrain: r = 0.41, P < 0.005) and transporters (accumbens: r = 0.35, P < 0.02) in ADHD participants, but not in controls. ADHD participants also had lower values in the Constraint factor and higher values in the Negative Emotionality factor of the MPQ but did not differ in the Positive Emotionality factor - and none of these were correlated with the dopamine measures. In ADHD participants, scores in the Achievement scale were also negatively correlated with symptoms of inattention (CAARS A, E and SWAN I). These findings provide evidence that disruption of the dopamine reward pathway is associated with motivation deficits in ADHD adults, which may contribute to attention deficits and supports the use of therapeutic interventions to enhance motivation in ADHD.« less

Striatal dopamine release codes uncertainty in pathological gambling.

PubMed

Linnet, Jakob; Mouridsen, Kim; Peterson, Ericka; Møller, Arne; Doudet, Doris Jeanne; Gjedde, Albert

2012-10-30

Two mechanisms of midbrain and striatal dopaminergic projections may be involved in pathological gambling: hypersensitivity to reward and sustained activation toward uncertainty. The midbrain-striatal dopamine system distinctly codes reward and uncertainty, where dopaminergic activation is a linear function of expected reward and an inverse U-shaped function of uncertainty. In this study, we investigated the dopaminergic coding of reward and uncertainty in 18 pathological gambling sufferers and 16 healthy controls. We used positron emission tomography (PET) with the tracer [(11)C]raclopride to measure dopamine release, and we used performance on the Iowa Gambling Task (IGT) to determine overall reward and uncertainty. We hypothesized that we would find a linear function between dopamine release and IGT performance, if dopamine release coded reward in pathological gambling. If, on the other hand, dopamine release coded uncertainty, we would find an inversely U-shaped function. The data supported an inverse U-shaped relation between striatal dopamine release and IGT performance if the pathological gambling group, but not in the healthy control group. These results are consistent with the hypothesis of dopaminergic sensitivity toward uncertainty, and suggest that dopaminergic sensitivity to uncertainty is pronounced in pathological gambling, but not among non-gambling healthy controls. The findings have implications for understanding dopamine dysfunctions in pathological gambling and addictive behaviors. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Nitrogen-based drugs are not essential for blockade of monoamine transporters.

PubMed

Madras, B K; Pristupa, Z B; Niznik, H B; Liang, A Y; Blundell, P; Gonzalez, M D; Meltzer, P C

1996-12-01

In brain, monoamine transporters are principal targets of widely used therapeutic drugs including antidepressants, methylphenidate (Ritalin), and the addictive drug cocaine. Without exception, these transport blocking agents contain an amine nitrogen. A prevalent view and untested premise is that an amine nitrogen is needed to bind to the same counterion on the transporter as does the amine nitrogen of the monoamine neurotransmitter. We report that several compounds without nitrogen (8-oxa-bicyclo-3-aryl-[3.2.1] octanes, or aryloxatropanes) are active at monoamine transporters. One of these, tropoxane (0-914), bound with high affinity to the dopamine (IC50: 3.35 +/- 0.39 nM), serotonin (IC50: 6.52 +/- 2.05 nM), and norepinephrine (IC50: 20.0 +/- 0.3 nM) transporters in monkey brain, the human striatal dopamine transporter (IC50: 5.01 +/- 1.74 nM), and blocked dopamine transport (IC50: 7.2 +/- 3.0 nM) in COS-7 cells transfected with the human dopamine transporter. These unique compounds require a revision of current concepts of the drug binding domains on monoamine transporters, open avenues for discovery of a new generation of drugs and raise the issue of whether mammalian transporters and receptors may respond to, as yet, undiscovered non-amine bearing neurotransmitters or drugs.

The dopamine beta-hydroxylase inhibitor nepicastat increases dopamine release and potentiates psychostimulant-induced dopamine release in the prefrontal cortex.

PubMed

Devoto, Paola; Flore, Giovanna; Saba, Pierluigi; Bini, Valentina; Gessa, Gian Luigi

2014-07-01

The dopamine-beta-hydroxylase inhibitor nepicastat has been shown to reproduce disulfiram ability to suppress the reinstatement of cocaine seeking after extinction in rats. To clarify its mechanism of action, we examined the effect of nepicastat, given alone or in association with cocaine or amphetamine, on catecholamine release in the medial prefrontal cortex and the nucleus accumbens, two key regions involved in the reinforcing and motivational effects of cocaine and in the reinstatement of cocaine seeking. Nepicastat effect on catecholamines was evaluated by microdialysis in freely moving rats. Nepicastat reduced noradrenaline release both in the medial prefrontal cortex and in the nucleus accumbens, and increased dopamine release in the medial prefrontal cortex but not in the nucleus accumbens. Moreover, nepicastat markedly potentiated cocaine- and amphetamine-induced extracellular dopamine accumulation in the medial prefrontal cortex but not in the nucleus accumbens. Extracellular dopamine accumulation produced by nepicastat alone or by its combination with cocaine or amphetamine was suppressed by the α2 -adrenoceptor agonist clonidine. It is suggested that nepicastat, by suppressing noradrenaline synthesis and release, eliminated the α2 -adrenoceptor mediated inhibitory mechanism that constrains dopamine release and cocaine- and amphetamine-induced dopamine release from noradrenaline or dopamine terminals in the medial prefrontal cortex. © 2012 The Authors, Addiction Biology © 2012 Society for the Study of Addiction.

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

PubMed Central

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

2014-01-01

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

Increased dopamine receptor expression and anti-depressant response following deep brain stimulation of the medial forebrain bundle.

PubMed

Dandekar, Manoj P; Luse, Dustin; Hoffmann, Carson; Cotton, Patrick; Peery, Travis; Ruiz, Christian; Hussey, Caroline; Giridharan, Vijayasree V; Soares, Jair C; Quevedo, Joao; Fenoy, Albert J

2017-08-01

Among several potential neuroanatomical targets pursued for deep brain stimulation (DBS) for treating those with treatment-resistant depression (TRD), the superolateral-branch of the medial forebrain bundle (MFB) is emerging as a privileged location. We investigated the antidepressant-like phenotypic and chemical changes associated with reward-processing dopaminergic systems in rat brains after MFB-DBS. Male Wistar rats were divided into three groups: sham-operated, DBS-Off, and DBS-On. For DBS, a concentric bipolar electrode was stereotactically implanted into the right MFB. Exploratory activity and depression-like behavior were evaluated using the open-field and forced-swimming test (FST), respectively. MFB-DBS effects on the dopaminergic system were evaluated using immunoblotting for tyrosine hydroxylase (TH), dopamine transporter (DAT), and dopamine receptors (D1-D5), and high-performance liquid chromatography for quantifying dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in brain homogenates of prefrontal cortex (PFC), hippocampus, amygdala, and nucleus accumbens (NAc). Animals receiving MFB-DBS showed a significant increase in swimming time without alterations in locomotor activity, relative to the DBS-Off (p<0.039) and sham-operated groups (p<0.014), indicating an antidepressant-like response. MFB-DBS led to a striking increase in protein levels of dopamine D2 receptors and DAT in the PFC and hippocampus, respectively. However, we did not observe appreciable differences in the expression of other dopamine receptors, TH, or in the concentrations of dopamine, DOPAC, and HVA in PFC, hippocampus, amygdala, and NAc. This study was not performed on an animal model of TRD. MFB-DBS rescues the depression-like phenotypes and selectively activates expression of dopamine receptors in brain regions distant from the target area of stimulation. Copyright © 2017. Published by Elsevier B.V.

Candidate-gene approach in posttraumatic stress disorder after urban violence: association analysis of the genes encoding serotonin transporter, dopamine transporter, and BDNF.

PubMed

Valente, Nina Leão Marques; Vallada, Homero; Cordeiro, Quirino; Miguita, Karen; Bressan, Rodrigo Affonseca; Andreoli, Sergio Baxter; Mari, Jair Jesus; Mello, Marcelo Feijó

2011-05-01

Posttraumatic stress disorder (PTSD) is a prevalent, disabling anxiety disorder marked by behavioral and physiologic alterations which commonly follows a chronic course. Exposure to a traumatic event constitutes a necessary, but not sufficient, factor. There is evidence from twin studies supporting a significant genetic predisposition to PTSD. However, the precise genetic loci still remain unclear. The objective of the present study was to identify, in a case-control study, whether the brain-derived neurotrophic factor (BDNF) val66met polymorphism (rs6265), the dopamine transporter (DAT1) three prime untranslated region (3'UTR) variable number of tandem repeats (VNTR), and the serotonin transporter (5-HTTPRL) short/long variants are associated with the development of PTSD in a group of victims of urban violence. All polymorphisms were genotyped in 65 PTSD patients as well as in 34 victims of violence without PTSD and in a community control group (n = 335). We did not find a statistical significant difference between the BDNF val66met and 5-HTTPRL polymorphism and the traumatic phenotype. However, a statistical association was found between DAT1 3'UTR VNTR nine repeats and PTSD (OR = 1.82; 95% CI, 1.20-2.76). This preliminary result confirms previous reports supporting a susceptibility role for allele 9 and PTSD.

Cutaneous synergistic analgesia of bupivacaine in combination with dopamine in rats.

PubMed

Tzeng, Jann-Inn; Wang, Jieh-Neng; Wang, Jhi-Joung; Chen, Yu-Wen; Hung, Ching-Hsia

2016-05-04

The main goal of the study was to investigate the interaction between bupivacaine and dopamine on local analgesia. After the blockade of the cutaneous trunci muscle reflex (CTMR) responses, which occurred following the drugs were subcutaneously injected in rats, the cutaneous analgesic effect of dopamine in a dosage-dependent fashion was compared to that of bupivacaine. Drug-drug interactions were evaluated by isobolographic methods. We showed the dose-dependent effects of dopamine on infiltrative cutaneous analgesia. On the 50% effective dose (ED50) basis, the rank of drug potency was bupivacaine (1.99 [1.92-2.09] μmol/kg) greater than dopamine (190 [181-203] μmol/kg) (P<0.01). At the equianalgesic doses (ED25, ED50, and ED75), dopamine elicited a similar duration of cutaneous analgesia compared with bupivacaine. The addition of dopamine to the bupivacaine solution exhibited a synergistic effect. Our pre-clinical data showed that dopamine produced a dose-dependent effect in producing cutaneous analgesia. When compared with bupivacaine, dopamine produced a lesser potency with a similar duration of cutaneous analgesia. Dopamine added to the bupivacaine preparation resulted in a synergistic analgesic effect. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Amphetamine and Methamphetamine Differentially Affect Dopamine Transporters in Vitro and in Vivo*S⃞

PubMed Central

Goodwin, J. Shawn; Larson, Gaynor A.; Swant, Jarod; Sen, Namita; Javitch, Jonathan A.; Zahniser, Nancy R.; De Felice, Louis J.; Khoshbouei, Habibeh

2009-01-01

The psychostimulants d-amphetamine (AMPH) and methamphetamine (METH) release excess dopamine (DA) into the synaptic clefts of dopaminergic neurons. Abnormal DA release is thought to occur by reverse transport through the DA transporter (DAT), and it is believed to underlie the severe behavioral effects of these drugs. Here we compare structurally similar AMPH and METH on DAT function in a heterologous expression system and in an animal model. In the in vitro expression system, DAT-mediated whole-cell currents were greater for METH stimulation than for AMPH. At the same voltage and concentration, METH released five times more DA than AMPH and did so at physiological membrane potentials. At maximally effective concentrations, METH released twice as much [Ca2+]i from internal stores compared with AMPH. [Ca2+]i responses to both drugs were independent of membrane voltage but inhibited by DAT antagonists. Intact phosphorylation sites in the N-terminal domain of DAT were required for the AMPH- and METH-induced increase in [Ca2+]i and for the enhanced effects of METH on [Ca2+]i elevation. Calmodulin-dependent protein kinase II and protein kinase C inhibitors alone or in combination also blocked AMPH- or METH-induced Ca2+ responses. Finally, in the rat nucleus accumbens, in vivo voltammetry showed that systemic application of METH inhibited DAT-mediated DA clearance more efficiently than AMPH, resulting in excess external DA. Together these data demonstrate that METH has a stronger effect on DAT-mediated cell physiology than AMPH, which may contribute to the euphoric and addictive properties of METH compared with AMPH. PMID:19047053

Dopamine agonist 3-PPP fails to protect against MPTP-induced toxicity.

PubMed

Muralikrishnan, Dhanasekaran; Ebadi, Manuchair; Brown-Borg, Holly M

2004-02-01

We investigated the neuroprotective effect of the dopamine agonist, 3-PPP [3-(3-hydroxyphenyl)-N-propylpiperidine] against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. MPTP (30 mg/kg, i.p., twice, 16 h apart) causes significant dopamine depletion in nucleus caudatus putamen (NCP) by 1 week. 3-PPP had no effect on the monoamine oxidase-B activity (MAO-B) activity in NCP. 3-PPP did not affect dopamine uptake, whereas mazindol significantly blocked the uptake of dopamine dose dependently. MPTP-induced behavioral changes in mice were not reduced by pretreatment with 3-PPP. This dopamine agonist did not prevent dopamine depletion caused by MPTP. MPP+ (20 microM) significantly inhibited the cell proliferation of SH-SY5Y dopaminergic neuronal cells. 3-PPP had no effect on the SH-SY5Y neuronal cell growth in culture and did not block the MPP(+)-induced cytotoxicity. This study shows that the dopamine agonist 3-PPP failed to protect against MPTP-induced dopaminergic neurotoxicity.

Dopamine dependency for acquisition and performance of Pavlovian conditioned response

PubMed Central

Darvas, Martin; Wunsch, Amanda M.; Gibbs, Jeffrey T.; Palmiter, Richard D.

2014-01-01

During Pavlovian conditioning, pairing of a neutral conditioned stimulus (CS) with a reward leads to conditioned reward-approach responses (CRs) that are elicited by presentation of the CS. CR behaviors can be sign tracking, in which animals engage the CS, or goal tracking, in which animals go to the reward location. We investigated CR behaviors in mice with only ∼5% of normal dopamine in the striatum using a Pavlovian conditioning paradigm. These mice had severely impaired acquisition of the CR, which was ameliorated by pharmacological restoration of dopamine synthesis with l-dopa. Surprisingly, after they had learned the CR, its expression decayed only gradually in following sessions that were conducted without l-dopa treatment. To assess specific contributions of dopamine signaling in the dorsal or ventral striatum, we performed virus-mediated restoration of dopamine synthesis in completely dopamine-deficient (DD) mice. Mice with dopamine signaling only in the dorsal striatum did not acquire a CR, whereas mice with dopamine signaling only in in the ventral striatum acquired a CR. The CR in mice with dopamine signaling only in the dorsal striatum was restored by subjecting the mice to instrumental training in which they had to interact with the CS to obtain rewards. We conclude that dopamine is essential for learning and performance of CR behavior that is predominantly goal tracking. Furthermore, although dopamine signaling in the ventral striatum is sufficient to support a CR, dopamine signaling only in the dorsal striatum can also support a CR under certain circumstances. PMID:24550305

Novel and High Affinity 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues as Atypical Dopamine Transporter Inhibitors

PubMed Central

Cao, Jianjing; Slack, Rachel D.; Bakare, Oluyomi M.; Burzynski, Caitlin; Rais, Rana; Slusher, Barbara S.; Kopajtic, Theresa; Bonifazi, Alessandro; Ellenberger, Michael P.; Yano, Hideaki; He, Yi; Bi, Guo-Hua; Xi, Zheng-Xiong; Loland, Claus J.; Newman, Amy Hauck

2016-01-01

The development of pharmacotherapeutic treatments of psychostimulant abuse has remained a challenge, despite significant efforts made towards relevant mechanistic targets, such as the dopamine transporter (DAT). The atypical DAT inhibitors have received attention due to their promising pharmacological profiles in animal models of cocaine and methamphetamine abuse. Herein we report a series of modafinil analogues that have an atypical DAT inhibitor profile. We extended SAR by chemically manipulating the oxidation states of the sulfoxide and the amide functional groups, halogenating the phenyl rings, and/or functionalizing the terminal nitrogen with substituted piperazines, resulting in several novel leads such as 11b, which demonstrated high DAT affinity (Ki=2.5 nM) and selectivity without producing concomitant locomotor stimulation in mice, as compared to cocaine. These results are consistent with an atypical DAT inhibitor profile and suggest that 11b may be a potential lead for development as a psychostimulant abuse medication. PMID:27933960

Effect of beta-phenylethylamine on extracellular concentrations of dopamine in the nucleus accumbens and prefrontal cortex.

PubMed

Murata, Mikio; Katagiri, Nobuyuki; Ishida, Kota; Abe, Kenji; Ishikawa, Masago; Utsunomiya, Iku; Hoshi, Keiko; Miyamoto, Ken-ichi; Taguchi, Kyoji

2009-05-07

It is known that psychostimulants stimulate dopamine transmission in the nucleus accumbens. In the present study, we examined the effects of systemically administered beta-phenylethylamine (beta-PEA), a psychomotor-stimulating trace amine, on dopamine concentrations in the nucleus accumbens and prefrontal cortex in freely moving rats, using an in vivo microdialysis technique. Intraperitoneal administration of beta-PEA (12.5 and 25 mg/kg) significantly increased extracellular dopamine levels in the nucleus accumbens shell. The observed increase in the dopamine concentration in nucleus accumbens shell dialysate after intraperitoneal administration of 25 mg/kg beta-PEA was inhibited by pre-treatment with a dopamine uptake inhibitor, GBR12909 (10 mg/kg, i.p.). In contrast, beta-PEA (25 mg/kg, i.p.) did not affect dopamine release in the nucleus accumbens core. Although a high dose of beta-PEA (50 mg/kg) significantly increased dopamine levels in the nucleus accumbens core, the dopamine increasing effect of beta-PEA was more potent in the nucleus accumbens shell. Systemic administration of 12.5 and 25 mg/kg beta-PEA also increased extracellular dopamine levels in the prefrontal cortex of rats. However, systemic 25 mg/kg beta-PEA-induced increases in extracellular dopamine levels were not blocked by GBR12909 within the prefrontal cortex. These results suggest that beta-PEA has a greater effect in the shell than in the core and low-dose beta-PEA stimulates dopamine release in the nucleus accumbens shell through uptake by a dopamine transporter. Similarly, beta-PEA increased extracellular dopamine levels in the prefrontal cortex. Thus, beta-PEA may increase extracellular dopamine concentrations in the mesocorticolimbic pathway.

Refining diagnosis of Parkinson's disease with deep learning-based interpretation of dopamine transporter imaging.

PubMed

Choi, Hongyoon; Ha, Seunggyun; Im, Hyung Jun; Paek, Sun Ha; Lee, Dong Soo

2017-01-01

Dopaminergic degeneration is a pathologic hallmark of Parkinson's disease (PD), which can be assessed by dopamine transporter imaging such as FP-CIT SPECT. Until now, imaging has been routinely interpreted by human though it can show interobserver variability and result in inconsistent diagnosis. In this study, we developed a deep learning-based FP-CIT SPECT interpretation system to refine the imaging diagnosis of Parkinson's disease. This system trained by SPECT images of PD patients and normal controls shows high classification accuracy comparable with the experts' evaluation referring quantification results. Its high accuracy was validated in an independent cohort composed of patients with PD and nonparkinsonian tremor. In addition, we showed that some patients clinically diagnosed as PD who have scans without evidence of dopaminergic deficit (SWEDD), an atypical subgroup of PD, could be reclassified by our automated system. Our results suggested that the deep learning-based model could accurately interpret FP-CIT SPECT and overcome variability of human evaluation. It could help imaging diagnosis of patients with uncertain Parkinsonism and provide objective patient group classification, particularly for SWEDD, in further clinical studies.

Investigation on the co-luminescence effect of europium (III)-lanthanum(III)-dopamine-sodium dodecylbenzene sulfonate system and its application.

PubMed

Si, Hailin; Zhao, Fang; Cai, Huan

2013-01-01

A novel luminescence, enhancement phenomenon in the europium(III)-dopamine-sodium dodecylbenzene sulfonate system was observed when lanthanum(III) was added. Based on this, a sensitive co-luminescence method was established for the determination of dopamine. The luminescence signal for the europium (III)-lanthanum(III)-dopamine-sodium dodecylbenzene sulfonate system was monitored at λ(ex) = 300 nm, λ(em) = 618 nm and pH 8.3. Under optimized conditions, the enhanced luminescence signal responded linearly to the concentration of dopamine in the range 1.0 × 10(-10)-5.0 × 10(-7) mol/L with a correlation coefficient of 0.9993 (n = 11). The detection limit (3σ) was 2.7 × 10(-11) mol/L and the relative standard deviation for 11 parallel measurements of 3.0 × 10(-8) mol/L dopamine was 1.9%. The presented method was successfully applied for the estimation of dopamine in samples of pharmaceutical preparations, human serum and urine. The possible luminescence enhancement mechanism of the system is discussed briefly. Copyright © 2013 John Wiley & Sons, Ltd.

Direct involvement of sigma-1 receptors in the dopamine D1 receptor-mediated effects of cocaine.

PubMed

Navarro, Gemma; Moreno, Estefanía; Aymerich, Marisol; Marcellino, Daniel; McCormick, Peter J; Mallol, Josefa; Cortés, Antoni; Casadó, Vicent; Canela, Enric I; Ortiz, Jordi; Fuxe, Kjell; Lluís, Carmen; Ferré, Sergi; Franco, Rafael

2010-10-26

It is well known that cocaine blocks the dopamine transporter. This mechanism should lead to a general increase in dopaminergic neurotransmission, and yet dopamine D(1) receptors (D(1)Rs) play a more significant role in the behavioral effects of cocaine than the other dopamine receptor subtypes. Cocaine also binds to σ-1 receptors, the physiological role of which is largely unknown. In the present study, D(1)R and σ(1)R were found to heteromerize in transfected cells, where cocaine robustly potentiated D(1)R-mediated adenylyl cyclase activation, induced MAPK activation per se and counteracted MAPK activation induced by D(1)R stimulation in a dopamine transporter-independent and σ(1)R-dependent manner. Some of these effects were also demonstrated in murine striatal slices and were absent in σ(1)R KO mice, providing evidence for the existence of σ(1)R-D(1)R heteromers in the brain. Therefore, these results provide a molecular explanation for which D(1)R plays a more significant role in the behavioral effects of cocaine, through σ(1)R-D(1)R heteromerization, and provide a unique perspective toward understanding the molecular basis of cocaine addiction.

Rapid Recovery of Vesicular Dopamine Levels in Methamphetamine Users in Early Abstinence

PubMed Central

Boileau, Isabelle; McCluskey, Tina; Tong, Junchao; Furukawa, Yoshiaki; Houle, Sylvain; Kish, Stephen J

2016-01-01

We previously reported very low levels of dopamine in post-mortem striatum of chronic methamphetamine users, raising the possibility that restoration of normal dopamine levels could help in this addiction and perhaps prevent early relapse. To establish relevance of this finding to the living brain, we tested whether striatal [11C]-(+)-dihydrotetrabenazine binding, a vesicular monoamine transporter probe sensitive to changes in (stored) vesicular dopamine, is elevated in methamphetamine users. Chronic methamphetamine users underwent [11C]-(+)-dihydrotetrabenazine positron emission tomography scans during early (mean 2.6 days) and later (~10 days) abstinence. Striatal [11C]-(+)-dihydrotetrabenazine binding was elevated (suggesting low stored dopamine) in methamphetamine users (n=28; 2.6 days after last use) relative to controls (n=22) (+28%, p<0.0001) and correlated with severity and recency of drug use and with cognitive impairment and withdrawal symptoms. Mean [11C]-(+)-dihydrotetrabenazine binding levels in the subgroup of methamphetamine users who could remain abstinent ~10 days following last use (n=17) were normal at the follow-up scan. Our imaging data support post-mortem findings and suggest that chronic methamphetamine users have low brain levels of stored dopamine during very early abstinence from MA, which could contribute to behavioral and cognitive deficits. Findings also suggest a rapid recovery of stored dopamine in some methamphetamine users who become abstinent and who therefore might not benefit from dopamine replacement medication (eg, levodopa). Further study is necessary to establish whether those users who could not maintain abstinence for the second scan might have a more severe and persistent dopamine deficiency and who could benefit from this medication. PMID:26321315

Rapid Recovery of Vesicular Dopamine Levels in Methamphetamine Users in Early Abstinence.

PubMed

Boileau, Isabelle; McCluskey, Tina; Tong, Junchao; Furukawa, Yoshiaki; Houle, Sylvain; Kish, Stephen J

2016-03-01

We previously reported very low levels of dopamine in post-mortem striatum of chronic methamphetamine users, raising the possibility that restoration of normal dopamine levels could help in this addiction and perhaps prevent early relapse. To establish relevance of this finding to the living brain, we tested whether striatal [(11)C]-(+)-dihydrotetrabenazine binding, a vesicular monoamine transporter probe sensitive to changes in (stored) vesicular dopamine, is elevated in methamphetamine users. Chronic methamphetamine users underwent [(11)C]-(+)-dihydrotetrabenazine positron emission tomography scans during early (mean 2.6 days) and later (~10 days) abstinence. Striatal [(11)C]-(+)-dihydrotetrabenazine binding was elevated (suggesting low stored dopamine) in methamphetamine users (n=28; 2.6 days after last use) relative to controls (n=22) (+28%, p<0.0001) and correlated with severity and recency of drug use and with cognitive impairment and withdrawal symptoms. Mean [(11)C]-(+)-dihydrotetrabenazine binding levels in the subgroup of methamphetamine users who could remain abstinent ~10 days following last use (n=17) were normal at the follow-up scan. Our imaging data support post-mortem findings and suggest that chronic methamphetamine users have low brain levels of stored dopamine during very early abstinence from MA, which could contribute to behavioral and cognitive deficits. Findings also suggest a rapid recovery of stored dopamine in some methamphetamine users who become abstinent and who therefore might not benefit from dopamine replacement medication (eg, levodopa). Further study is necessary to establish whether those users who could not maintain abstinence for the second scan might have a more severe and persistent dopamine deficiency and who could benefit from this medication.

Striatal and extrastriatal dopamine transporter in cannabis and tobacco addiction: a high-resolution PET study.

PubMed

Leroy, Claire; Karila, Laurent; Martinot, Jean-Luc; Lukasiewicz, Michaël; Duchesnay, Edouard; Comtat, Claude; Dollé, Frédéric; Benyamina, Amine; Artiges, Eric; Ribeiro, Maria-Joao; Reynaud, Michel; Trichard, Christian

2012-11-01

The dopamine (DA) system is known to be involved in the reward and dependence mechanisms of addiction. However, modifications in dopaminergic neurotransmission associated with long-term tobacco and cannabis use have been poorly documented in vivo. In order to assess striatal and extrastriatal dopamine transporter (DAT) availability in tobacco and cannabis addiction, three groups of male age-matched subjects were compared: 11 healthy non-smoker subjects, 14 tobacco-dependent smokers (17.6 ± 5.3 cigarettes/day for 12.1 ± 8.5 years) and 13 cannabis and tobacco smokers (CTS) (4.8 ± 5.3 cannabis joints/day for 8.7 ± 3.9 years). DAT availability was examined in positron emission tomography (HRRT) with a high resolution research tomograph after injection of [11C]PE2I, a selective DAT radioligand. Region of interest and voxel-by-voxel approaches using a simplified reference tissue model were performed for the between-group comparison of DAT availability. Measurements in the dorsal striatum from both analyses were concordant and showed a mean 20% lower DAT availability in drug users compared with controls. Whole-brain analysis also revealed lower DAT availability in the ventral striatum, the midbrain, the middle cingulate and the thalamus (ranging from -15 to -30%). The DAT availability was slightly lower in all regions in CTS than in subjects who smoke tobacco only, but the difference does not reach a significant level. These results support the existence of a decrease in DAT availability associated with tobacco and cannabis addictions involving all dopaminergic brain circuits. These findings are consistent with the idea of a global decrease in cerebral DA activity in dependent subjects. © 2011 The Authors, Addiction Biology © 2011 Society for the Study of Addiction.

Enhanced dopamine release by dopamine transport inhibitors described by a restricted diffusion model and fast scan cyclic voltammetry

PubMed Central

Hoffman, Alexander F.; Spivak, Charles E.; Lupica, Carl R.

2016-01-01

Fast-scan cyclic voltammetry (FSCV) using carbon fiber electrodes is widely used to rapidly monitor changes in dopamine (DA) levels in vitro and in vivo. Current analytical approaches utilize parameters such as peak oxidation current amplitude and decay times to estimate release and uptake processes, respectively. However, peak amplitude changes are often observed with uptake inhibitors, thereby confounding the interpretation of these parameters. To overcome this limitation, we demonstrate that a simple, 5 parameter, two compartment model mathematically describes DA signals as a balance of release (r/ke) and uptake (ku), summed with adsorption (kads and kdes) of DA to the carbon electrode surface. Using non-linear regression, we demonstrate that our model precisely describes measured DA signals obtained in brain slice recordings. The parameters extracted from these curves were then validated using pharmacological manipulations that selectively alter vesicular release or DA transporter (DAT)-mediated uptake. Manipulation of DA release through altered Ca2+/Mg2+ ratio or tetrodotoxin (TTX), reduced the release parameter with no effect on the uptake parameter. The DAT inhibitors methylenedioxypyrovalerone (MDPV), cocaine, and nomifensine significantly reduced uptake and increased vesicular DA release. In contrast, a low concentration of amphetamine reduced uptake but had no effect on DA release. Finally, the kappa-opioid receptor (KOR) agonist U50,488 significantly reduced vesicular DA release but had no effect on uptake. Together, these data demonstrate a novel analytical approach to distinguish the effects of manipulations on DA release or uptake that can be used to interpret FSCV data. PMID:27018734

Enhanced Dopamine Release by Dopamine Transport Inhibitors Described by a Restricted Diffusion Model and Fast-Scan Cyclic Voltammetry.

PubMed

Hoffman, Alexander F; Spivak, Charles E; Lupica, Carl R

2016-06-15

Fast-scan cyclic voltammetry (FSCV) using carbon fiber electrodes is widely used to rapidly monitor changes in dopamine (DA) levels in vitro and in vivo. Current analytical approaches utilize parameters such as peak oxidation current amplitude and decay times to estimate release and uptake processes, respectively. However, peak amplitude changes are often observed with uptake inhibitors, thereby confounding the interpretation of these parameters. To overcome this limitation, we demonstrate that a simple five-parameter, two-compartment model mathematically describes DA signals as a balance of release (r/ke) and uptake (ku), summed with adsorption (kads and kdes) of DA to the carbon electrode surface. Using nonlinear regression, we demonstrate that our model precisely describes measured DA signals obtained in brain slice recordings. The parameters extracted from these curves were then validated using pharmacological manipulations that selectively alter vesicular release or DA transporter (DAT)-mediated uptake. Manipulation of DA release through altering the Ca(2+)/Mg(2+) ratio or adding tetrodotoxin reduced the release parameter with no effect on the uptake parameter. DAT inhibitors methylenedioxypyrovalerone, cocaine, and nomifensine significantly reduced uptake and increased vesicular DA release. In contrast, a low concentration of amphetamine reduced uptake but had no effect on DA release. Finally, the kappa opioid receptor agonist U50,488 significantly reduced vesicular DA release but had no effect on uptake. Together, these data demonstrate a novel analytical approach to distinguish the effects of manipulations on DA release or uptake that can be used to interpret FSCV data.

Evaluating Dopamine Reward Pathway in ADHD

PubMed Central

Volkow, Nora D.; Wang, Gene-Jack; Kollins, Scott H.; Wigal, Tim L.; Newcorn, Jeffrey H.; Telang, Frank; Fowler, Joanna S.; Zhu, Wei; Logan, Jean; Ma, Yeming; Pradhan, Kith; Wong, Christopher; Swanson, James M.

2010-01-01

Context Attention-deficit/hyperactivity disorder (ADHD)—characterized by symptoms of inattention and hyperactivity-impulsivity—is the most prevalent childhood psychiatric disorder that frequently persists into adulthood, and there is increasing evidence of reward-motivation deficits in this disorder. Objective To evaluate biological bases that might underlie a reward/motivation deficit by imaging key components of the brain dopamine reward pathway (mesoaccumbens). Design, Setting, and Participants We used positron emission tomography to measure dopamine synaptic markers (transporters and D2/D3 receptors) in 53 nonmedicated adults with ADHD and 44 healthy controls between 2001–2009 at Brookhaven National Laboratory. Main Outcome Measures We measured specific binding of positron emission tomographic radioligands for dopamine transporters (DAT) using [11C]cocaine and for D2/D3 receptors using [11C]raclopride, quantified as binding potential (distribution volume ratio −1). Results For both ligands, statistical parametric mapping showed that specific binding was lower in ADHD than in controls (threshold for significance set at P<.005) in regions of the dopamine reward pathway in the left side of the brain. Region-of-interest analyses corroborated these findings. The mean (95% confidence interval [CI] of mean difference) for DAT in the nucleus accumbens for controls was 0.71 vs 0.63 for those with ADHD (95% CI, 0.03–0.13, P=.004) and in the midbrain for controls was 0.16 vs 0.09 for those with ADHD (95% CI, 0.03–0.12; P ≤ .001); for D2/D3 receptors, the mean accumbens for controls was 2.85 vs 2.68 for those with ADHD (95% CI, 0.06–0.30, P=.004); and in the midbrain, it was for controls 0.28 vs 0.18 for those with ADHD (95% CI, 0.02–0.17, P=.01). The analysis also corroborated differences in the left caudate: the mean DAT for controls was 0.66 vs 0.53 for those with ADHD (95% CI, 0.04–0.22; P=.003) and the mean D2/D3 for controls was 2.80 vs 2.47 for

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

PubMed

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 [ 11 C]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 [ 11 C]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

Psychostimulant Effect of the Synthetic Cannabinoid JWH-018 and AKB48: Behavioral, Neurochemical, and Dopamine Transporter Scan Imaging Studies in Mice

PubMed Central

Ossato, Andrea; Uccelli, Licia; Bilel, Sabrine; Canazza, Isabella; Di Domenico, Giovanni; Pasquali, Micol; Pupillo, Gaia; De Luca, Maria Antonietta; Boschi, Alessandra; Vincenzi, Fabrizio; Rimondo, Claudia; Beggiato, Sarah; Ferraro, Luca; Varani, Katia; Borea, Pier Andrea; Serpelloni, Giovanni; De-Giorgio, Fabio; Marti, Matteo

2017-01-01

JWH-018 and AKB48 are two synthetic cannabinoids (SCBs) belonging to different structural classes and illegally marketed as incense, herbal preparations, or chemical supply for theirs psychoactive cannabis-like effects. Clinical reports from emergency room reported psychomotor agitation as one of the most frequent effects in people assuming SCBs. This study aimed to investigate the psychostimulant properties of JWH-018 and AKB48 in male CD-1 mice and to compare their behavioral and biochemical effects with those caused by cocaine and amphetamine. In vivo studies showed that JWH-018 and AKB48, as cocaine and amphetamine, facilitated spontaneous locomotion in mice. These effects were prevented by CB1 receptor blockade and dopamine (DA) D1/5 and D2/3 receptors inhibition. SPECT-CT studies on dopamine transporter (DAT) revealed that, as cocaine and amphetamine, JWH-018 and AKB48 decreased the [123I]-FP-CIT binding in the mouse striatum. Conversely, in vitro competition binding studies revealed that, unlike cocaine and amphetamine, JWH-018 and AKB48 did not bind to mouse or human DAT. Moreover, microdialysis studies showed that the systemic administration of JWH-018, AKB48, cocaine, and amphetamine stimulated DA release in the nucleus accumbens (NAc) shell of freely moving mice. Finally, unlike amphetamine and cocaine, JWH-018 and AKB48 did not induce any changes on spontaneous [3H]-DA efflux from murine striatal synaptosomes. The present results suggest that SCBs facilitate striatal DA release possibly with different mechanisms than cocaine and amphetamine. Furthermore, they demonstrate, for the first time, that JWH-018 and AKB48 induce a psychostimulant effect in mice possibly by increasing NAc DA release. These data, according to clinical reports, outline the potential psychostimulant action of SCBs highlighting their possible danger to human health. PMID:28824464

Psychostimulant Effect of the Synthetic Cannabinoid JWH-018 and AKB48: Behavioral, Neurochemical, and Dopamine Transporter Scan Imaging Studies in Mice.

PubMed

Ossato, Andrea; Uccelli, Licia; Bilel, Sabrine; Canazza, Isabella; Di Domenico, Giovanni; Pasquali, Micol; Pupillo, Gaia; De Luca, Maria Antonietta; Boschi, Alessandra; Vincenzi, Fabrizio; Rimondo, Claudia; Beggiato, Sarah; Ferraro, Luca; Varani, Katia; Borea, Pier Andrea; Serpelloni, Giovanni; De-Giorgio, Fabio; Marti, Matteo

2017-01-01

JWH-018 and AKB48 are two synthetic cannabinoids (SCBs) belonging to different structural classes and illegally marketed as incense, herbal preparations, or chemical supply for theirs psychoactive cannabis-like effects. Clinical reports from emergency room reported psychomotor agitation as one of the most frequent effects in people assuming SCBs. This study aimed to investigate the psychostimulant properties of JWH-018 and AKB48 in male CD-1 mice and to compare their behavioral and biochemical effects with those caused by cocaine and amphetamine. In vivo studies showed that JWH-018 and AKB48, as cocaine and amphetamine, facilitated spontaneous locomotion in mice. These effects were prevented by CB 1 receptor blockade and dopamine (DA) D 1/5 and D 2/3 receptors inhibition. SPECT-CT studies on dopamine transporter (DAT) revealed that, as cocaine and amphetamine, JWH-018 and AKB48 decreased the [ 123 I]-FP-CIT binding in the mouse striatum. Conversely, in vitro competition binding studies revealed that, unlike cocaine and amphetamine, JWH-018 and AKB48 did not bind to mouse or human DAT. Moreover, microdialysis studies showed that the systemic administration of JWH-018, AKB48, cocaine, and amphetamine stimulated DA release in the nucleus accumbens (NAc) shell of freely moving mice. Finally, unlike amphetamine and cocaine, JWH-018 and AKB48 did not induce any changes on spontaneous [ 3 H]-DA efflux from murine striatal synaptosomes. The present results suggest that SCBs facilitate striatal DA release possibly with different mechanisms than cocaine and amphetamine. Furthermore, they demonstrate, for the first time, that JWH-018 and AKB48 induce a psychostimulant effect in mice possibly by increasing NAc DA release. These data, according to clinical reports, outline the potential psychostimulant action of SCBs highlighting their possible danger to human health.

Orbitofrontal Dopamine Depletion Upregulates Caudate Dopamine and Alters Behavior via Changes in Reinforcement Sensitivity

PubMed Central

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

Dopamine function and the efficiency of human movement.

PubMed

Gepshtein, Sergei; Li, Xiaoyan; Snider, Joseph; Plank, Markus; Lee, Dongpyo; Poizner, Howard

2014-03-01

To sustain successful behavior in dynamic environments, active organisms must be able to learn from the consequences of their actions and predict action outcomes. One of the most important discoveries in systems neuroscience over the last 15 years has been about the key role of the neurotransmitter dopamine in mediating such active behavior. Dopamine cell firing was found to encode differences between the expected and obtained outcomes of actions. Although activity of dopamine cells does not specify movements themselves, a recent study in humans has suggested that tonic levels of dopamine in the dorsal striatum may in part enable normal movement by encoding sensitivity to the energy cost of a movement, providing an implicit "motor motivational" signal for movement. We investigated the motivational hypothesis of dopamine by studying motor performance of patients with Parkinson disease who have marked dopamine depletion in the dorsal striatum and compared their performance with that of elderly healthy adults. All participants performed rapid sequential movements to visual targets associated with different risk and different energy costs, countered or assisted by gravity. In conditions of low energy cost, patients performed surprisingly well, similar to prescriptions of an ideal planner and healthy participants. As energy costs increased, however, performance of patients with Parkinson disease dropped markedly below the prescriptions for action by an ideal planner and below performance of healthy elderly participants. The results indicate that the ability for efficient planning depends on the energy cost of action and that the effect of energy cost on action is mediated by dopamine.

Dissociable roles of dopamine and serotonin transporter function in a rat model of negative urgency.

PubMed

Yates, Justin R; Darna, Mahesh; Gipson, Cassandra D; Dwoskin, Linda P; Bardo, Michael T

2015-09-15

Negative urgency is a facet of impulsivity that reflects mood-based rash action and is associated with various maladaptive behaviors in humans. However, the underlying neural mechanisms of negative urgency are not fully understood. Several brain regions within the mesocorticolimbic pathway, as well as the neurotransmitters dopamine (DA) and serotonin (5-HT), have been implicated in impulsivity. Extracellular DA and 5-HT concentrations are regulated by DA transporters (DAT) and 5-HT transporters (SERT); thus, these transporters may be important molecular mechanisms underlying individual differences in negative urgency. The current study employed a reward omission task to model negative urgency in rats. During reward trials, a cue light signaled the non-contingent delivery of one sucrose pellet; immediately following the non-contingent reward, rats responded on a lever to earn sucrose pellets (operant phase). Omission trials were similar to reward trials, except that non-contingent sucrose was omitted following the cue light prior to the operant phase. As expected, contingent responding was higher following omission of expected reward than following delivery of expected reward, thus reflecting negative urgency. Upon completion of behavioral training, Vmax and Km were obtained from kinetic analysis of [(3)H]DA and [(3)H]5-HT uptake using synaptosomes prepared from nucleus accumbens (NAc), dorsal striatum (Str), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC) isolated from individual rats. Vmax for DAT in NAc and for SERT in OFC were positively correlated with negative urgency scores. The current findings suggest that mood-based impulsivity (negative urgency) is associated with enhanced DAT function in NAc and SERT function in OFC. Copyright © 2015 Elsevier B.V. All rights reserved.

Valeriana officinalis does not alter the orofacial dyskinesia induced by haloperidol in rats: role of dopamine transporter.

PubMed

Fachinetto, Roselei; Villarinho, Jardel G; Wagner, Caroline; Pereira, Romaiana P; Avila, Daiana Silva; Burger, Marilise E; Calixto, João Batista; Rocha, João B T; Ferreira, Juliano

2007-10-01

Chronic treatment with classical neuroleptics in humans can produce a serious side effect, known as tardive dyskinesia (TD). Here, we examined the effects of V. officinalis, a medicinal herb widely used as calming and sleep-promoting, in an animal model of orofacial dyskinesia (OD) induced by long-term treatment with haloperidol. Adult male rats were treated during 12 weeks with haloperidol decanoate (38 mg/kg, i.m., each 28 days) and with V. officinalis (in the drinking water). Vacuous chewing movements (VCMs), locomotor activity and plus maze performance were evaluated. Haloperidol treatment produced VCM in 40% of the treated rats and the concomitant treatment with V. officinalis did not alter either prevalence or intensity of VCMs. The treatment with V. officinalis increased the percentage of the time spent on open arm and the number of entries into open arm in the plus maze test. Furthermore, the treatment with haloperidol and/or V. officinalis decreased the locomotor activity in the open field test. We did not find any difference among the groups when oxidative stress parameters were evaluated. Haloperidol treatment significantly decreased [(3)H]-dopamine uptake in striatal slices and V. officinalis was not able to prevent this effect. Taken together, our data suggest a mechanism involving the reduction of dopamine transport in the maintenance of chronic VCMs in rats. Furthermore, chronic treatment with V. officinalis seems not produce any oxidative damage to central nervous system (CNS), but it also seems to be devoid of action to prevent VCM, at least in the dose used in this study.

Determination of dopamine in pharmaceutical formulation using enhanced luminescence from europium complex

NASA Astrophysics Data System (ADS)

Wabaidur, Saikh Mohammad; ALOthman, Zeid Abdullah; Naushad, Mu.

Biologically important compound dopamine plays an important role in the central and peripheral nervous systems. Insufficient dopamine level due to the loss of dopamine producing cells may lead to disease called Schizophrenia and Parkinson's disease. Hence, a simple and fast detection of dopamine is necessary to study in the fields of neurophysiology and clinical medicine. An enhanced fluorimetric determination of dopamine in the presence of ascorbic acid is achieved using photoluminescence of europium complex, Eu(III)-dipicolinic acid. In order to obtain better responses, several operational parameters have been investigated. Under the optimum conditions, the method showed good stability and reproducibility. The application of this method for the determination of dopamine neurotransmitters was satisfactory. Linear response was found down to 3.0 × 10-7 M with limit of detection 1.0 × 10-8 M. The relative standard deviation was found to be 3.33% from 20 independent measurements for 1.0 × 10-5 M of dopamine.

Dynamic nigrostriatal dopamine biases action selection

PubMed Central

Howard, Christopher D.; Li, Hao; Geddes, Claire E.; Jin, Xin

2017-01-01

Summary Dopamine is thought to play a critical role in reinforcement learning and goal-directed behavior, but its function in action selection remains largely unknown. Here, we demonstrate that nigrostriatal dopamine biases ongoing action selection. When mice were trained to dynamically switch the action selected at different time points, changes in firing rate of nigrostriatal dopamine neurons, as well as dopamine signaling in the dorsal striatum, were found to be associated with action selection. This dopamine profile is specific to behavioral choice, scalable with interval duration, and doesn’t reflect reward prediction error, timing, or value as single factors alone. Genetic deletion of NMDA receptors on dopamine or striatal neurons, or optogenetic manipulation of dopamine concentration, alters dopamine signaling and biases action selection. These results unveil a crucial role of nigrostriatal dopamine in integrating diverse information for regulating upcoming actions and have important implications for neurological disorders including Parkinson’s disease and substance dependence. PMID:28285820

Dynamic Nigrostriatal Dopamine Biases Action Selection.

PubMed

Howard, Christopher D; Li, Hao; Geddes, Claire E; Jin, Xin

2017-03-22

Dopamine is thought to play a critical role in reinforcement learning and goal-directed behavior, but its function in action selection remains largely unknown. Here we demonstrate that nigrostriatal dopamine biases ongoing action selection. When mice were trained to dynamically switch the action selected at different time points, changes in firing rate of nigrostriatal dopamine neurons, as well as dopamine signaling in the dorsal striatum, were found to be associated with action selection. This dopamine profile is specific to behavioral choice, scalable with interval duration, and doesn't reflect reward prediction error, timing, or value as single factors alone. Genetic deletion of NMDA receptors on dopamine or striatal neurons or optogenetic manipulation of dopamine concentration alters dopamine signaling and biases action selection. These results unveil a crucial role of nigrostriatal dopamine in integrating diverse information for regulating upcoming actions, and they have important implications for neurological disorders, including Parkinson's disease and substance dependence. Copyright © 2017 Elsevier Inc. All rights reserved.

Structural and Functional Effect of an Oscillating Electric Field on the Dopamine-D3 Receptor: A Molecular Dynamics Simulation Study

PubMed Central

Fallah, Zohreh; Jamali, Yousef; Rafii-Tabar, Hashem

2016-01-01

Dopamine as a neurotransmitter plays a critical role in the functioning of the central nervous system. The structure of D3 receptor as a member of class A G-protein coupled receptors (GPCRs) has been reported. We used MD simulation to investigate the effect of an oscillating electric field, with frequencies in the range 0.6–800 GHz applied along the z-direction, on the dopamine-D3R complex. The simulations showed that at some frequencies, the application of an external oscillating electric field along the z-direction has a considerable effect on the dopamine-D3R. However, there is no enough evidence for prediction of changes in specific frequency, implying that there is no order in changes. Computing the correlation coefficient parameter showed that increasing the field frequency can weaken the interaction between dopamine and D3R and may decrease the Arg128{3.50}-Glu324{6.30} distance. Because of high stability of α helices along the z-direction, applying an oscillating electric field in this direction with an amplitude 10-time higher did not have a considerable effect. However, applying the oscillating field at the frequency of 0.6 GHz along other directions, such as X-Y and Y-Z planes, could change the energy between the dopamine and the D3R, and the number of internal hydrogen bonds of the protein. This can be due to the effect of the direction of the electric field vis-à-vis the ligands orientation and the interaction of the oscillating electric field with the dipole moment of the protein. PMID:27832207

Differential Internalization Rates and Postendocytic Sorting of the Norepinephrine and Dopamine Transporters Are Controlled by Structural Elements in the N Termini*

PubMed Central

Vuorenpää, Anne; Jørgensen, Trine N.; Newman, Amy H.; Madsen, Kenneth L.; Scheinin, Mika

2016-01-01

The norepinephrine transporter (NET) mediates reuptake of synaptically released norepinephrine in central and peripheral noradrenergic neurons. The molecular processes governing availability of NET in the plasma membrane are poorly understood. Here we use the fluorescent cocaine analogue JHC 1-64, as well as several other approaches, to investigate the trafficking itinerary of NET in live noradrenergic neurons. Confocal imaging revealed extensive constitutive internalization of JHC 1-64-labeled NET in the neuronal somata, proximal extensions and presynaptic boutons. Phorbol 12-myristate 13-acetate increased intracellular accumulation of JHC 1-64-labeled NET and caused a parallel reduction in uptake capacity. Internalized NET strongly colocalized with the “long loop” recycling marker Rab11, whereas less overlap was seen with the “short loop” recycling marker Rab4 and the late endosomal marker Rab7. Moreover, mitigating Rab11 function by overexpression of dominant negative Rab11 impaired NET function. Sorting of NET to the Rab11 recycling compartment was further supported by confocal imaging and reversible biotinylation experiments in transfected differentiated CATH.a cells. In contrast to NET, the dopamine transporter displayed markedly less constitutive internalization and limited sorting to the Rab11 recycling compartment in the differentiated CATH.a cells. Exchange of domains between the two homologous transporters revealed that this difference was determined by non-conserved structural elements in the intracellular N terminus. We conclude that NET displays a distinct trafficking itinerary characterized by continuous shuffling between the plasma membrane and the Rab11 recycling compartment and that the functional integrity of the Rab11 compartment is critical for maintaining proper presynaptic NET function. PMID:26786096

Pharmacological Characterization of a Dopamine Transporter Ligand That Functions as a Cocaine Antagonist

PubMed Central

Desai, Rajeev I.; Grandy, David K.; Lupica, Carl R.

2014-01-01

An N-butyl analog of benztropine, JHW007 [N-(n-butyl)-3α-[bis(4′-fluorophenyl)methoxy]-tropane], binds to dopamine transporters (DAT) but has reduced cocaine-like behavioral effects and antagonizes various effects of cocaine. The present study further examined mechanisms underlying these effects. Cocaine dose-dependently increased locomotion, whereas JHW007 was minimally effective but increased activity 24 hours after injection. JHW007 (3–10 mg/kg) dose-dependently and fully antagonized the locomotor-stimulant effects of cocaine (5–60 mg/kg), whereas N-methyl and N-allyl analogs and the dopamine (DA) uptake inhibitor GBR12909 [1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine dihydrochloride] stimulated activity and failed to antagonize effects of cocaine. JHW007 also blocked the locomotor-stimulant effects of the DAT inhibitor GBR12909 but not stimulation produced by the δ-opioid agonist SNC 80 [4-[(R)-[(2S,5R)-4-allyl-2,5-dimethylpiperazin-1-yl](3-methoxyphenyl)methyl]-N,N-diethylbenzamide], which increases activity through nondopaminergic mechanisms. JHW007 blocked locomotor-stimulant effects of cocaine in both DA D2- and CB1-receptor knockout and wild-type mice, indicating a lack of involvement of these targets. Furthermore, JHW007 blocked effects of cocaine on stereotyped rearing but enhanced stereotyped sniffing, suggesting that interference with locomotion by enhanced stereotypies is not responsible for the cocaine-antagonist effects of JHW007. Time-course data indicate that administration of JHW007 antagonized the locomotor-stimulant effects of cocaine within 10 minutes of injection, whereas occupancy at the DAT, as determined in vivo, did not reach a maximum until 4.5 hours after injection. The σ1-receptor antagonist BD 1008 [N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine dihydrobromide] blocked the locomotor-stimulant effects of cocaine. Overall, these findings suggest that JHW007 has cocaine

Hydroxide ion-mediated synthesis of monodisperse dopamine-melanin nanospheres.

PubMed

Cho, Soojeong; Kim, Shin-Hyun

2015-11-15

Dopamine-melanin nanospheres are promising materials for photoprotection, structural coloration, and thermoregulation due to their unusual optical and chemical properties. Here, we report the experimental parameters which influence size of dopamine-melanin nanospheres and uniformity. Dopamine precursors are oxidatively polymerized in basic aqueous medium. Therefore, concentration of hydroxide ions significantly influences reaction rate and size of nanospheres. To investigate the effect of hydroxide ions, we adjust three different parameters which affect pH of medium: concentration of sodium hydroxide and dopamine hydrochloride, and reaction temperature. At constant temperature, concentration of hydroxide ions is linearly proportional to initial reaction rates which determine the number of nuclei for nanosphere growth. Temperature alters not only initial reaction rate but also diffusivity of molecules, leading to deviation from the relation between the reaction rate and the number of nuclei. The diameter of dopamine-melanin nanospheres can be readily controlled in a range of 80-490nm through adjusting concentration of dopamine precursor, while maintaining uniform-size distribution and dispersion stability. The synthesized nanospheres are analyzed to confirm the chemical structure, which is composed of approximately 6 indole units. Moreover, surface and chemical properties of the nanospheres are characterized to provide valuable information for surface modification and application. Copyright © 2015 Elsevier Inc. All rights reserved.

Corticotropin-releasing hormone and dopamine release in healthy individuals.

PubMed

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 D 2/3 receptor radioligand [ 11 C]-(+)-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 D 2/3 PET probe [ 11 C]-(+)-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 [ 11 C]-(+)-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.

I-123 - FP-CIT pharmacokinetics and dosimetry show great potential for the evaluation of dopamine transporter system in clinical routine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Costa, D.C.; Walker, S.; Waddington, W.

1996-05-01

FP-CIT is a N-fluoropropyl analogue of the [2{beta}-carbomethoxy-3{beta}-(4-iodophenyl)tropane] which has been labelled with I-123 and developed as a new marker of the pre-synaptic dopamine transporter system. Its selective uptake in the striatum of non-human primates and human volunteers has been reported with advantageous faster brain kinetics than {beta}-CIT. In this pilot work we studied the whole body imaging kinetics of FP-CIT in one normal volunteer - NV (5, 60, 100, 360 minutes and 24 hours post-injection for 20 minutes each) and a drug-free patient with well established Parkinson`s disease - PD (100 minutes) after intravenous injection of 111 MBq. Bothmore » subjects had high resolution brain SPECT at 35 minutes and 3.5 hours post-injection. Percent of whole body uptake (geometric mean of anterior and posterior projections) in different organs, including total brain and basal ganglia shows rapid clearance from blood during the first hour with no significant change from 100 minutes to 24 hours. The basal ganglia uptake is approximately 0.4% of total body from 100 minutes onwards. Striatal uptake (ratio to frontal cortex) is different between subjects, mainly at 3.5 hours and more marked in the putamen: Calculated dosimetry (mSv/MBq) showed E.D.E.-0.034, and total doses to whole body - 0.01, total brain - 0.017, basal ganglia - 0.155, small intestine - 0.06, urinary bladder - 0.05 and liver - 0.03. These data confirm that FP-CIT has acceptable dosimetry with good pharmacokinetics enabling the study of pre-synaptic dopamine transport system in nigrostriatal degeneration with clinical SPECT at 3-4 hrs p.i.« less

Dopamine, reward learning, and active inference.

PubMed

FitzGerald, Thomas H B; Dolan, Raymond J; Friston, Karl

2015-01-01

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

Studies on striatal neurotoxicity caused by the 3,4-methylenedioxymethamphetamine/ malonate combination: implications for serotonin/dopamine interactions.

PubMed

Goñi-Allo, Beatriz; Ramos, Mar'a; Herv'as, Isabel; Lasheras, Berta; Aguirre, Norberto

2006-03-01

The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA) produces long-term toxicity to serotonin (5-HT) neurones in rats, which is exacerbated when combined with the mitochondrial inhibitor malonate. Moreover, MDMA, which does not produce dopamine depletion in the rat, potentiates malonate-induced striatal dopamine toxicity. Because the malonate/MDMA combination acutely causes a synergistic increase of 5-HT and dopamine release, in this study we sought to determine whether pharmacological blockade of MDMA- and/or malonate-induced dopamine release prevents neurotoxicity. Fluoxetine, given 30 min prior to the malonate/MDMA combination, afforded complete protection against 5-HT depletion and reversed MDMA-induced exacerbation of dopamine toxicity found in the malonate/MDMA treated rats. Protection afforded by fluoxetine was not related to changes in MDMA-induced hyperthermia. Similarly, potentiation of malonate-induced dopamine toxicity caused by MDMA was not observed in p-chlorophenylalanine-5-HT depleted rats. Finally, the dopamine transporter inhibitor GBR 12909 completely prevented dopamine neurotoxicity caused by the malonate/MDMA combination and reversed the exacerbating toxic effects of malonate on MDMA-induced 5-HT depletion without significantly altering the hyperthermic response. Overall, these results suggest that the synergic release of dopamine caused by the malonate/MDMA combination plays an important role in the long-term toxic effects. A possible mechanism of neurotoxicity and protection is proposed.

Edaravone Guards Dopamine Neurons in a Rotenone Model for Parkinson's Disease

PubMed Central

Chen, Chunnuan; Huang, Jinsha; Zhao, Ying; Zhang, Zhentao; Qiao, Xian; Feng, Yuan; Reesaul, Harrish; Zhang, Yongxue; Sun, Shenggang; Lin, Zhicheng; Wang, Tao

2011-01-01

3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone), an effective free radical scavenger, provides neuroprotection in stroke models and patients. In this study, we investigated its neuroprotective effects in a chronic rotenone rat model for Parkinson's disease. Here we showed that a five-week treatment with edaravone abolished rotenone's activity to induce catalepsy, damage mitochondria and degenerate dopamine neurons in the midbrain of rotenone-treated rats. This abolishment was attributable at least partly to edaravone's inhibition of rotenone-induced reactive oxygen species production or apoptotic promoter Bax expression and its up-regulation of the vesicular monoamine transporter 2 (VMAT2) expression. Collectively, edaravone may provide novel clinical therapeutics for PD. PMID:21677777

Reward modulation of cognitive function in adult attention-deficit/hyperactivity disorder: a pilot study on the role of striatal dopamine.

PubMed

Aarts, Esther; van Holstein, Mieke; Hoogman, Martine; Onnink, Marten; Kan, Cornelis; Franke, Barbara; Buitelaar, Jan; Cools, Roshan

2015-02-01

Attention-deficit/hyperactivity disorder (ADHD) is accompanied by impairments in cognitive control, such as task-switching deficits. We investigated whether such problems, and their remediation by medication, reflect abnormal reward motivation and associated striatal dopamine transmission in ADHD. We used functional genetic neuroimaging to assess the effects of dopaminergic medication and reward motivation on task-switching and striatal BOLD signal in 23 adults with ADHD, ON and OFF methylphenidate, and 26 healthy controls. Critically, we took into account interindividual variability in striatal dopamine by exploiting a common genetic polymorphism (3'-UTR VNTR) in the DAT1 gene coding for the dopamine transporter. The results showed a highly significant group by genotype interaction in the striatum. This was because a subgroup of patients with ADHD showed markedly exaggerated effects of reward on the striatal BOLD signal during task-switching when they were OFF their dopaminergic medication. Specifically, patients carrying the 9R allele showed a greater striatal signal than healthy controls carrying this allele, whereas no effect of diagnosis was observed in 10R homozygotes. Aberrant striatal responses were normalized when 9R-carrying patients with ADHD were ON medication. These pilot data indicate an important role for aberrant reward motivation, striatal dopamine and interindividual genetic differences in cognitive processes in adult ADHD.

Reward modulation of cognitive function in adult attention-deficit/hyperactivity disorder: a pilot study on the role of striatal dopamine

PubMed Central

Aarts, Esther; Hoogman, Martine; Onnink, Marten; Kan, Cornelis; Franke, Barbara; Buitelaar, Jan; Cools, Roshan

2015-01-01

Attention-deficit/hyperactivity disorder (ADHD) is accompanied by impairments in cognitive control, such as task-switching deficits. We investigated whether such problems, and their remediation by medication, reflect abnormal reward motivation and associated striatal dopamine transmission in ADHD. We used functional genetic neuroimaging to assess the effects of dopaminergic medication and reward motivation on task-switching and striatal BOLD signal in 23 adults with ADHD, ON and OFF methylphenidate, and 26 healthy controls. Critically, we took into account interindividual variability in striatal dopamine by exploiting a common genetic polymorphism (3′-UTR VNTR) in the DAT1 gene coding for the dopamine transporter. The results showed a highly significant group by genotype interaction in the striatum. This was because a subgroup of patients with ADHD showed markedly exaggerated effects of reward on the striatal BOLD signal during task-switching when they were OFF their dopaminergic medication. Specifically, patients carrying the 9R allele showed a greater striatal signal than healthy controls carrying this allele, whereas no effect of diagnosis was observed in 10R homozygotes. Aberrant striatal responses were normalized when 9R-carrying patients with ADHD were ON medication. These pilot data indicate an important role for aberrant reward motivation, striatal dopamine and interindividual genetic differences in cognitive processes in adult ADHD. PMID:25485641

Dopamine, reward learning, and active inference

PubMed Central

FitzGerald, Thomas H. B.; Dolan, Raymond J.; Friston, Karl

2015-01-01

Temporal difference learning models propose phasic dopamine signaling encodes reward prediction errors that drive learning. This is supported by studies where optogenetic stimulation of dopamine neurons can stand in lieu of actual reward. Nevertheless, a large body of data also shows that dopamine is not necessary for learning, and that dopamine depletion primarily affects task performance. We offer a resolution to this paradox based on an hypothesis that dopamine encodes the precision of beliefs about alternative actions, and thus controls the outcome-sensitivity of behavior. We extend an active inference scheme for solving Markov decision processes to include learning, and show that simulated dopamine dynamics strongly resemble those actually observed during instrumental conditioning. Furthermore, simulated dopamine depletion impairs performance but spares learning, while simulated excitation of dopamine neurons drives reward learning, through aberrant inference about outcome states. Our formal approach provides a novel and parsimonious reconciliation of apparently divergent experimental findings. PMID:26581305

Different roles of retinal dopamine in albino Guinea pig myopia.

PubMed

Mao, Junfeng; Liu, Shuangzhen

2017-02-03

To investigate whether the different role of ocular dopamine was involved in the myopic development between spontaneous myopia (SM) and form deprivation myopia (FDM) in albino guinea pigs. 55 myopic animals were randomly divided into SM, Levodapa (L-DOPA), L-DOPA+carbidopa and vehicle. 70 non-myopic animals were randomly divided into normal control, FDM, L-DOPA+FDM, L-DOPA+carbidopa+FDM and vehicle. Once per day, for 14days, L-DOPA (10mg/kg) was injected intraperitoneally, and carbidopa (1μg) was injected at the same time into the peribulbar space of the right eye. Refractive parameters and dopamine content in neural retina and RPE/choroid complex were measured. In SM animals, high myopia was formed at 5 week of ages. L-DOPA treatment could reduce its myopic degree, and inhibit the increase of axial length and vitreous chamber depth with the increase of retinal dopamine in both eyes. Administration of carbidopa could prevent the increase of retinal dopamine induced by L-DOPA, but no influenced on its refractive state in the injected eyes. In non-SM animals, intraperitoneal L-DOPA could inhibit FDM, accompanied by the increase of retinal dopamine. Carbidopa treatment diminished the inhibition of FDM and prevented the increase in retinal dopamine by L-Dopa. Retinal dopamine was highly correlated with ocular refraction in FDM, but not in SM. There was no significant difference in dopamine content of RPE/choroid complex among all groups. The role of retinal dopamine was different between SM and FDM in albino guinea pigs. Although systemic L-DOPA could inhibit the development of SM and FDM, retinal dopamine was only involved in the L-DOPA inhibition on FDM, but not on SM. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Heterogeneities in Axonal Structure and Transporter Distribution Lower Dopamine Reuptake Efficiency

PubMed Central

Block, Ethan R.; Bartol, Tom M.; Sorkin, Alexander

2018-01-01

Abstract Efficient clearance of dopamine (DA) from the synapse is key to regulating dopaminergic signaling. This role is fulfilled by DA transporters (DATs). Recent advances in the structural characterization of DAT from Drosophila (dDAT) and in high-resolution imaging of DA neurons and the distribution of DATs in living cells now permit us to gain a mechanistic understanding of DA reuptake events in silico. Using electron microscopy images and immunofluorescence of transgenic knock-in mouse brains that express hemagglutinin-tagged DAT in DA neurons, we reconstructed a realistic environment for MCell simulations of DA reuptake, wherein the identity, population and kinetics of homology-modeled human DAT (hDAT) substates were derived from molecular simulations. The complex morphology of axon terminals near active zones was observed to give rise to large variations in DA reuptake efficiency, and thereby in extracellular DA density. Comparison of the effect of different firing patterns showed that phasic firing would increase the probability of reaching local DA levels sufficiently high to activate low-affinity DA receptors, mainly owing to high DA levels transiently attained during the burst phase. The experimentally observed nonuniform surface distribution of DATs emerged as a major modulator of DA signaling: reuptake was slower, and the peaks/width of transient DA levels were sharper/wider under nonuniform distribution of DATs, compared with uniform. Overall, the study highlights the importance of accurate descriptions of extrasynaptic morphology, DAT distribution, and conformational kinetics for quantitative evaluation of dopaminergic transmission and for providing deeper understanding of the mechanisms that regulate DA transmission. PMID:29430519

Dopamine enhances duodenal epithelial permeability via the dopamine D5 receptor in rodent.

PubMed

Feng, X-Y; Zhang, D-N; Wang, Y-A; Fan, R-F; Hong, F; Zhang, Y; Li, Y; Zhu, J-X

2017-05-01

The intestinal barrier is made up of epithelial cells and intercellular junctional complexes to regulate epithelial ion transport and permeability. Dopamine (DA) is able to promote duodenal epithelial ion transport through D1-like receptors, which includes subtypes of D 1 (D 1 R) and D 5 (D 5 R), but whether D1-like receptors influence the duodenal permeability is unclear. FITC-dextran permeability, short-circuit current (I SC ), Western blot, immunohistochemistry and ELISA were used in human D 5 R transgenic mice and hyperendogenous enteric DA (HEnD) rats in this study. Dopamine induced a downward deflection in I SC and an increase in FITC-dextran permeability of control rat duodenum, which were inhibited by the D1-like receptor antagonist, SCH-23390. However, DA decreased duodenal transepithelial resistance (TER), an effect also reversed by SCH-23390. A strong immunofluorescence signal for D 5 R, but not D 1 R, was observed in the duodenum of control rat. In human D 5 R knock-in transgenic mice, duodenal mucosa displayed an increased basal I SC with high FITC-dextran permeability and decreased TER with a lowered expression of tight junction proteins, suggesting attenuated duodenal barrier function in these transgenic mice. D 5 R knock-down transgenic mice manifested a decreased basal I SC with lowered FITC-dextran permeability. Moreover, an increased FITC-dextran permeability combined with decreased TER and tight junction protein expression in duodenal mucosa were also observed in HEnD rats. This study demonstrates, for the first time, that DA enhances duodenal permeability of control rat via D 5 R, which provides new experimental and theoretical evidence for the influence of DA on duodenal epithelial barrier function. © 2016 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

Dopamine Innervation in the Thalamus: Monkey versus Rat

PubMed Central

García-Cabezas, Miguel Ángel; Martínez-Sánchez, Patricia; Sánchez-González, Miguel Ángel; Garzón, Miguel

2009-01-01

We recently identified the thalamic dopaminergic system in the human and macaque monkey brains, and, based on earlier reports on the paucity of dopamine in the rat thalamus, hypothesized that this dopaminergic system was particularly developed in primates. Here we test this hypothesis using immunohistochemistry against the dopamine transporter (DAT) in adult macaque and rat brains. The extent and density of DAT-immunoreactive (-ir) axons were remarkably greater in the macaque dorsal thalamus, where the mediodorsal association nucleus and the ventral motor nuclei held the densest immunolabeling. In contrast, sparse DAT immunolabeling was present in the rat dorsal thalamus; it was mainly located in the mediodorsal, paraventricular, ventral medial, and ventral lateral nuclei. The reticular nucleus, zona incerta, and lateral habenular nucleus held numerous DAT-ir axons in both species. Ultrastructural analysis in the macaque mediodorsal nucleus revealed that thalamic interneurons are a main postsynaptic target of DAT-ir axons; this suggests that the marked expansion of the dopamine innervation in the primate in comparison to the rodent thalamus may be related to the presence of a sizable interneuron population in primates. We remark that it is important to be aware of brain species differences when using animal models of human brain disease. PMID:18550594

An electrochemical dopamine sensor based on the ZnO/CuO nanohybrid structures.

PubMed

Khun, K; Ibupoto, Z H; Liu, X; Mansor, N A; Turner, A P F; Beni, V; Willander, M

2014-09-01

The selective detection of dopamine (DA) is of great importance in the modern medicine because dopamine is one of the main regulators in human behaviour. In this study, ZnO/CuO nanohybrid structures, grown on the gold coated glass substrate, have been investigated as a novel electrode material for the electrochemical detection of dopamine. Scanning electron microscopy (SEM), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS) techniques were used for the material characterization and the obtained results are in good agreement. The selective determination of dopamine was demonstrated by cyclic voltammetry (CV) and amperometric experiments. The amperometric response was linear for dopamine concentrations between 1.0 x 10(-3) and 8.0 mM with a sensitivity of 90.9 μA mM(-1) cm(-2). The proposed dopamine biosensor is very stable, selective over common interferents as glucose, uric acid and ascorbic acid, and also good reproducibility was observed for seven electrodes. Moreover, the dopamine sensor exhibited a fast response time of less than 10 s. The wide range and acceptable sensitivity of the presented dopamine sensor provide the possible application in analysing the dopamine from the real samples.

beta-Alanine elevates dopamine levels in the rat nucleus accumbens: antagonism by strychnine.

PubMed

Ericson, Mia; Clarke, Rhona B C; Chau, PeiPei; Adermark, Louise; Söderpalm, Bo

2010-04-01

Glycine receptors (GlyRs) in the nucleus accumbens (nAc) have recently been suggested to be involved in the reinforcing and dopamine-elevating properties of ethanol via a neuronal circuitry involving the VTA. Apart from ethanol, both glycine and taurine have the ability to modulate dopamine output via GlyRs in the same brain region. In the present study, we wanted to explore whether yet another endogenous ligand for the GlyR, beta-alanine, had similar effects. To this end, we monitored dopamine in the nAc by means of in vivo microdialysis and found that local perfusion of beta-alanine increased dopamine output. In line with previous observations investigating ethanol, glycine and taurine, the competitive GlyR antagonist strychnine completely blocked the dopamine elevation. The present results suggest that beta-alanine has the ability to modulate dopamine levels in the nAc via strychnine-sensitive GlyRs, and are consistent with previous studies suggesting the importance of this receptor for modulating dopamine output.

Amantadine Ameliorates Dopamine-Releasing Deficits and Behavioral Deficits in Rats after Fluid Percussion Injury

PubMed Central

Huang, Eagle Yi-Kung; Tsui, Pi-Fen; Kuo, Tung-Tai; Tsai, Jing-Jr.; Chou, Yu-Ching; Ma, Hsin-I; Chiang, Yung-Hsiao; Chen, Yuan-Hao

2014-01-01

Aims To investigate the role of dopamine in cognitive and motor learning skill deficits after a traumatic brain injury (TBI), we investigated dopamine release and behavioral changes at a series of time points after fluid percussion injury, and explored the potential of amantadine hydrochloride as a chronic treatment to provide behavioral recovery. Materials and Methods In this study, we sequentially investigated dopamine release at the striatum and behavioral changes at 1, 2, 4, 6, and 8 weeks after fluid percussion injury. Rats subjected to 6-Pa cerebral cortical fluid percussion injury were treated by using subcutaneous infusion pumps filled with either saline (sham group) or amantadine hydrochloride, with a releasing rate of 3.6mg/kg/hour for 8 weeks. The dopamine-releasing conditions and metabolism were analyzed sequentially by fast scan cyclic voltammetry (FSCV) and high-pressure liquid chromatography (HPLC). Novel object recognition (NOR) and fixed-speed rotarod (FSRR) behavioral tests were used to determine treatment effects on cognitive and motor deficits after injury. Results Sequential dopamine-release deficits were revealed in 6-Pa-fluid-percussion cerebral cortical injured animals. The reuptake rate (tau value) of dopamine in injured animals was prolonged, but the tau value became close to the value for the control group after amantadine therapy. Cognitive and motor learning impairments were shown evidenced by the NOR and FSRR behavioral tests after injury. Chronic amantadine therapy reversed dopamine-release deficits, and behavioral impairment after fluid percussion injuries were ameliorated in the rats treated by using amantadine-pumping infusion. Conclusion Chronic treatment with amantadine hydrochloride can ameliorate dopamine-release deficits as well as cognitive and motor deficits caused by cerebral fluid-percussion injury. PMID:24497943

Increased impulsive behavior and risk proneness following lentivirus-mediated dopamine transporter over-expression in rats' nucleus accumbens.

PubMed

Adriani, W; Boyer, F; Gioiosa, L; Macrì, S; Dreyer, J-L; Laviola, G

2009-03-03

Multiple theories have been proposed for sensation seeking and vulnerability to impulse-control disorders [Zuckerman M, Kuhlman DM (2000) Personality and risk-taking: Common biosocial factors. J Pers 68:999-1029], and many of these rely on a dopamine system deficit. Available animal models reproduce only some behavioral symptoms and seem devoid of construct validity. We used lentivirus tools for over-expressing or silencing the dopamine transporter (DAT) and we evaluated the resulting behavioral profiles in terms of motivation and self-control. Wistar adult rats received stereotaxic inoculation of a lentivirus that allowed localized intra-accumbens delivery of a DAT gene enhancer/silencer, or the green fluorescent protein, GFP. These animals were studied for intolerance to delay, risk proneness and novelty seeking. As expected, controls shifted their demanding from a large reward toward a small one when the delivery of the former was increasingly delayed (or uncertain). Interestingly, in the absence of general locomotor effects, DAT over-expressing rats showed increased impulsivity (i.e. a more marked shift of demanding from the large/delayed toward the small/soon reward), and increased risk proneness (i.e. a less marked shift from the large/uncertain toward the small/sure reward), compared with controls. Rats with enhanced or silenced DAT expression did not show any significant preference for a novel environment. In summary, consistent with literature on comorbidity between attention-deficit/hyperactivity disorder and pathological gambling, we demonstrate that DAT over-expression in rats' nucleus accumbens leads to impulsive and risk prone phenotype. Thus, a reduced dopaminergic tone following altered accumbal DAT function may subserve a sensation-seeker phenotype and the vulnerability to impulse-control disorders.

Striatal Dopamine Transporter Modulation After Rotigotine: Results From a Pilot Single-Photon Emission Computed Tomography Study in a Group of Early Stage Parkinson Disease Patients.

PubMed

Rossi, Carlo; Genovesi, Dario; Marzullo, Paolo; Giorgetti, Assuero; Filidei, Elena; Corsini, Giovanni Umberto; Bonuccelli, Ubaldo; Ceravolo, Roberto

Several in vitro data have reported negative interference by dopamine-agonists on the expression of dopamine transporter (DAT), whereas the majority of imaging studies have shown that neither L-dopa nor dopamine-agonists interfere with DAT availability. As yet, there are no in vivo studies on DAT expression after treatment with rotigotine. We evaluated presynaptic nigrostriatal function in 8 patients with de novo Parkinson disease (age, 59 ± 6.2 years; male/female sex, 5/3) using 123-I- N-ω-fluoropropyl-2-β-carbomethoxy-3-β-(4-iodophenyl)nortropane (FP-CIT) single-photon emission computed tomography before and after 3 months of treatment with rotigotine (mean dose, 7.75 ± 1.98 mg). For data analysis, specific (left and right caudate, left and right putamen) to nonspecific (occipital cortex) binding ratios, putamen-to-caudate ratios, and asymmetry indices were calculated. After rotigotine, motor symptoms improved in all patients (Unified Parkinson Disease Rating Scale III mean score, 11.88 ± 2.59 vs 7.63 ± 1.92 on therapy; P = 0.0022). Striatal FP-CIT levels showed a significant improvement in every patient at the follow-up scan. Comparisons between before and after treatment in the whole group revealed a significant improvement in FP-CIT uptake in both caudate and putamen (P < 0.001 in each nucleus). Putamen-to-caudate ratio and asymmetry indices did not show any significant difference before and after treatment. Although the study population was small, we found DAT overexpression after chronic treatment with rotigotine, presumably related to its pharmacological profile. The DAT upregulation by rotigotine in an opposite direction with respect to early Parkinson disease compensatory mechanisms might reduce the risk of dyskinesia, but it could imply less motor benefit because of less stimulation by the dopamine itself on dopaminergic receptors.

Dopamine Transporter Genetic Variants and Pesticides in Parkinson’s Disease

PubMed Central

Ritz, Beate R.; Manthripragada, Angelika D.; Costello, Sadie; Lincoln, Sarah J.; Farrer, Matthew J.; Cockburn, Myles; Bronstein, Jeff

2009-01-01

Background Research suggests that independent and joint effects of genetic variability in the dopamine transporter (DAT) locus and pesticides may influence Parkinson’s disease (PD) risk. Materials Methods: In 324 incident PD patients and 334 population controls from our rural California case–control study, we genotyped rs2652510, rs2550956 (for the DAT 5′ clades), and the 3′ variable number of tandem repeats (VNTR). Using geographic information system methods, we determined residential exposure to agricultural maneb and paraquat applications. We also collected occupational pesticide use data. Employing logistic regression, we calculated odds ratios (ORs) for clade diplotypes, VNTR genotype, and number of susceptibility (A clade and 9-repeat) alleles and assessed susceptibility allele–pesticide interactions. Results PD risk was increased separately in DAT A clade diplotype carriers [AA vs. BB: OR = 1.66; 95% confidence interval (CI), 1.08–2.57] and 3′ VNTR 9/9 carriers (9/9 vs. 10/10: OR = 1.8; 95% CI, 0.96–3.57), and our data suggest a gene dosing effect. Importantly, high exposure to paraquat and maneb in carriers of one susceptibility allele increased PD risk 3-fold (OR = 2.99; 95% CI, 0.88–10.2), and in carriers of two or more alleles more than 4-fold (OR = 4.53; 95% CI, 1.70–12.1). We obtained similar results for occupational pesticide measures. Discussion Using two independent pesticide measures, we a) replicated previously reported gene–environment interactions between DAT genetic variants and occupational pesticide exposure in men and b) overcame previous limitations of nonspecific pesticide measures and potential recall bias by employing state records and computer models to estimate residential pesticide exposure. Conclusion Our results suggest that DAT genetic variability and pesticide exposure interact to increase PD risk. PMID:19590691

Protective actions of the vesicular monoamine transporter 2 (VMAT2) in monoaminergic neurons.

PubMed

Guillot, Thomas S; Miller, Gary W

2009-04-01

Vesicular monoamine transporters (VMATs) are responsible for the packaging of neurotransmitters such as dopamine, serotonin, norepinephrine, and epinephrine into synaptic vesicles. These proteins evolved from precursors in the major facilitator superfamily of transporters and are among the members of the toxin extruding antiporter family. While the primary function of VMATs is to sequester neurotransmitters within vesicles, they can also translocate toxicants away from cytosolic sites of action. In the case of dopamine, this dual role of VMAT2 is combined-dopamine is more readily oxidized in the cytosol where it can cause oxidative stress so packaging into vesicles serves two purposes: neurotransmission and neuroprotection. Furthermore, the deleterious effects of exogenous toxicants on dopamine neurons, such as MPTP, can be attenuated by VMAT2 activity. The active metabolite of MPTP can be kept within vesicles and prevented from disrupting mitochondrial function thereby sparing the dopamine neuron. The highly addictive drug methamphetamine is also neurotoxic to dopamine neurons by using dopamine itself to destroy the axon terminals. Methamphetamine interferes with vesicular sequestration and increases the production of dopamine, escalating the amount in the cytosol and leading to oxidative damage of terminal components. Vesicular transport seems to resist this process by sequestering much of the excess dopamine, which is illustrated by the enhanced methamphetamine neurotoxicity in VMAT2-deficient mice. It is increasingly evident that VMAT2 provides neuroprotection from both endogenous and exogenous toxicants and that while VMAT2 has been adapted by eukaryotes for synaptic transmission, it is derived from phylogenetically ancient proteins that originally evolved for the purpose of cellular protection.

Blocking serotonin but not dopamine reuptake alters neural processing during perceptual decision making.

PubMed

Costa, Vincent D; Kakalios, Laura C; Averbeck, Bruno B

2016-10-01

Dopamine and serotonin have opponent interactions on aspects of impulsivity. Therefore we wanted to test the hypothesis that dopamine and serotonin would have opposing effects on speed-accuracy trade offs in a perceptual decision making task. Unlike other behavioral measures of impulsivity, perceptual decision making allows us to determine whether decreasing premature responses, often interpreted as decreased impulsivity, corresponds to increased behavioral performance. We administered GBR-12909 (a dopamine transporter blocker), escitalopram (a serotonin transporter blocker), or saline in separate sessions to 3 rhesus macaques. We found that animals had slower reaction times (RTs) on escitalopram than on GBR-12909 or saline. However, they were also least accurate on escitalopram. Animals were faster, although nonsignificantly, on GBR than saline and had equivalent accuracy. Administration of GBR-12909 did cause animals to be faster in error trials than correct trials. Therefore, from the point of view of RTs the animals were less impulsive on escitalopram. However, the decreased accuracy of the monkeys shows that they were not able to make use of their slower response times to make more accurate decisions. Therefore, impulsivity was reduced on escitalopram, but at the expense of a slower information-processing rate in the perceptual inference task. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Model-based predictions for dopamine.

PubMed

Langdon, Angela J; Sharpe, Melissa J; Schoenbaum, Geoffrey; Niv, Yael

2018-04-01

Phasic dopamine responses are thought to encode a prediction-error signal consistent with model-free reinforcement learning theories. However, a number of recent findings highlight the influence of model-based computations on dopamine responses, and suggest that dopamine prediction errors reflect more dimensions of an expected outcome than scalar reward value. Here, we review a selection of these recent results and discuss the implications and complications of model-based predictions for computational theories of dopamine and learning. Copyright © 2017. Published by Elsevier Ltd.

Central GLP-1 receptor activation modulates cocaine-evoked phasic dopamine signaling in the nucleus accumbens core.

PubMed

Fortin, Samantha M; Roitman, Mitchell F

2017-07-01

Drugs of abuse increase the frequency and magnitude of brief (1-3s), high concentration (phasic) dopamine release events in terminal regions. These are thought to be a critical part of drug reinforcement and ultimately the development of addiction. Recently, metabolic regulatory peptides, including the satiety signal glucagon-like peptide-1 (GLP-1), have been shown to modulate cocaine reward-driven behavior and sustained dopamine levels after cocaine administration. Here, we use fast-scan cyclic voltammetry (FSCV) to explore GLP-1 receptor (GLP-1R) modulation of dynamic dopamine release in the nucleus accumbens (NAc) during cocaine administration. We analyzed dopamine release events in both the NAc shell and core, as these two subregions are differentially affected by cocaine and uniquely contribute to motivated behavior. We found that central delivery of the GLP-1R agonist Exendin-4 suppressed the induction of phasic dopamine release events by intravenous cocaine. This effect was selective for dopamine signaling in the NAc core. Suppression of phasic signaling in the core by Exendin-4 could not be attributed to interference with cocaine binding to one of its major substrates, the dopamine transporter, as cocaine-induced increases in reuptake were unaffected. The results suggest that GLP-1R activation, instead, exerts its suppressive effects by altering dopamine release - possibly by suppressing the excitability of dopamine neurons. Given the role of NAc core dopamine in the generation of conditioned responses based on associative learning, suppression of cocaine-induced dopamine signaling in this subregion by GLP-1R agonism may decrease the reinforcing properties of cocaine. Thus, GLP-1Rs remain viable targets for the treatment and prevention of cocaine seeking, taking and relapse. Copyright © 2017 Elsevier Inc. All rights reserved.

Binding Interactions of Dopamine and Apomorphine in D2High and D2Low States of Human Dopamine D2 Receptor Using Computational and Experimental Techniques.

PubMed

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

2016-02-17

We have recently reported G-protein coupled receptor (GPCR) model structures for the active and inactive states of the human dopamine D2 receptor (D2R) using adrenergic crystal structures as templates. Since the therapeutic concentrations of dopamine agonists that suppress the release of prolactin are the same as those that act at the high-affinity state of the D2 receptor (D2High), D2High in the anterior pituitary gland is considered to be the functional state of the receptor. In addition, the therapeutic concentrations of anti-Parkinson drugs are also related to the dissociation constants in the D2High form of the receptor. The discrimination between the high- and low-affinity (D2Low) components of the D2R is not obvious and requires advanced computer-assisted structural biology investigations. Therefore, in this work, the derived D2High and D2Low receptor models (GPCR monomer and dimer three-dimensional structures) are used as drug-binding targets to investigate binding interactions of dopamine and apomorphine. The study reveals a match between the experimental dissociation constants of dopamine and apomorphine at their high- and low-affinity sites of the D2 receptor in monomer and dimer and their calculated dissociation constants. The allosteric receptor-receptor interaction for dopamine D2R dimer is associated with the accessibility of adjacent residues of transmembrane region 4. The measured negative cooperativity between agonist ligand at dopamine D2 receptor is also correctly predicted using the D2R homodimerization model.

Sampling phasic dopamine signaling with fast-scan cyclic voltammetry in awake behaving rats

PubMed Central

Fortin, SM; Cone, JJ; Ng-Evans, S; McCutcheon, JE; Roitman, MF

2015-01-01

Fast-scan cyclic voltammetry (FSCV) is an electrochemical technique which permits the in vivo measurement of extracellular fluctuations in multiple chemical species. The technique is frequently utilized to sample sub-second (phasic) concentration changes of the neurotransmitter dopamine in awake and behaving rats. Phasic dopamine signaling is implicated in reinforcement, goal-directed behavior, and locomotion and FSCV has been used to investigate how rapid changes in striatal dopamine concentration contribute to these and other behaviors. This unit describes the instrumentation and construction, implantation, and use of necessary components required to sample and analyze dopamine concentration changes in awake rats with FSCV. PMID:25559005

Dopamine function in cigarette smokers: an [¹⁸F]-DOPA PET study.

PubMed

Bloomfield, Michael A P; Pepper, Fiona; Egerton, Alice; Demjaha, Arsime; Tomasi, Gianpaolo; Mouchlianitis, Elias; Maximen, Levi; Veronese, Mattia; Turkheimer, Federico; Selvaraj, Sudhakar; Howes, Oliver D

2014-09-01

Tobacco addiction is a global public health problem. Addiction to tobacco is thought to involve the effects of nicotine on the dopaminergic system. Only one study has previously investigated dopamine synthesis capacity in cigarette smokers. This study, exclusively in male volunteers, reported increased dopamine synthesis capacity in heavy smokers compared with non-smokers. We sought to determine whether dopamine synthesis capacity was elevated in a larger sample of cigarette smokers that included females. Dopamine synthesis capacity was measured in 15 daily moderate smokers with 15 sex- and age-matched control subjects who had never smoked tobacco. Dopamine synthesis capacity (indexed as the influx rate constant K(i)(cer)) was measured with positron emission tomography and 3,4-dihydroxy-6-[(18)F]-fluoro-l-phenylalanine. There was no significant group difference in dopamine synthesis capacity between smokers and non-smoker controls in the whole striatum (t28=0.64, p=0.53) or any of its functional subdivisions. In smokers, there were no significant relationships between the number of cigarettes smoked per day and dopamine synthesis capacity in the whole striatum (r=-0.23, p=0.41) or any striatal subdivision. These findings indicate that moderate smoking is not associated with altered striatal dopamine synthesis capacity.

Transmembrane Segment Five Serines of the D4 Dopamine Receptor Uniquely Influence the Interactions of Dopamine, Norepinephrine, and Ro10-4548

PubMed Central

Cummings, David F.; Ericksen, Spencer S.; Goetz, Angela

2010-01-01

Conserved serines of transmembrane segment (TM) five (TM5) are critical for the interactions of endogenous catecholamines with α1- and α2-adrenergic, β2-adrenergic, and D1, D2, and D3 dopamine receptors. The unique high-affinity interaction of the D4 dopamine receptor subtype with both norepinephrine and dopamine, and the fact that TM5 serine interactions have never been studied for this receptor subtype, led us to investigate the interactions of ligands with D4 receptor TM5 serines. Serine-to-alanine mutations at positions 5.42 and 5.46 drastically decreased affinities of dopamine and norepinephrine for the D4 receptor. The D4-S5.43A receptor mutant had substantially reduced affinity for norepinephrine, but a modest loss of affinity for dopamine. In functional assays of cAMP accumulation, norephinephrine was unable to activate any of the mutant receptors, even though the agonist quinpirole displayed wild-type functional properties for all of them. Dopamine was unable to activate the S5.46A mutant and had reduced potency for the S5.43A mutant and reduced potency and efficacy for the S5.42A mutant. In contrast, Ro10-4548 [RAC-2′-2-hydroxy-3-4-(4-hydroxy-2-methoxyphenyl)-1-piperazinyl-propoxy-acetanilide], a catechol-like antagonist of the wild-type receptor unexpectedly functions as an agonist of the S5.43A mutant. Other noncatechol ligands had similar properties for mutant and wild-type receptors. This is the first example of a dopamine receptor point mutation selectively changing the receptor's interaction with a specific antagonist to that of an agonist, and together with other data, provides evidence, supported by molecular modeling, that catecholamine-type agonism is induced by different ligand-specific configurations of intermolecular H-bonds with the TM5 conserved serines. PMID:20215412

Axonal damage and loss of connectivity in nigrostriatal and mesolimbic dopamine pathways in early Parkinson's disease.

PubMed

Caminiti, Silvia Paola; Presotto, Luca; Baroncini, Damiano; Garibotto, Valentina; Moresco, Rosa Maria; Gianolli, Luigi; Volonté, Maria Antonietta; Antonini, Angelo; Perani, Daniela

2017-01-01

A progressive loss of dopamine neurons in the substantia nigra (SN) is considered the main feature of idiopathic Parkinson's disease (PD). Recent neuropathological evidence however suggests that the axons of the nigrostriatal dopaminergic system are the earliest target of α-synuclein accumulation in PD, thus the principal site for vulnerability. Whether this applies to in vivo PD, and also to the mesolimbic system has not been investigated yet. We used [ 11 C]FeCIT PET to measure presynaptic dopamine transporter (DAT) activity in both nigrostriatal and mesolimbic systems, in 36 early PD patients (mean disease duration in months ± SD 21.8 ± 10.7) and 14 healthy controls similar for age. We also performed anatomically-driven partial correlation analysis to evaluate possible changes in the connectivity within both the dopamine networks at an early clinical phase. In the nigrostriatal system, we found a severe DAT reduction in the afferents to the dorsal putamen (DPU) (η 2  = 0.84), whereas the SN was the less affected region (η 2  = 0.31). DAT activity in the ventral tegmental area (VTA) and the ventral striatum (VST) were also reduced in the patient group, but to a lesser degree (VST η 2  = 0.71 and VTA η 2  = 0.31). In the PD patients compared to the controls, there was a marked decrease in dopamine network connectivity between SN and DPU nodes, supporting the significant derangement in the nigrostriatal pathway. These results suggest that neurodegeneration in the dopamine pathways is initially more prominent in the afferent axons and more severe in the nigrostriatal system. Considering PD as a disconnection syndrome starting from the axons, it would justify neuroprotective interventions even if patients have already manifested clinical symptoms.

Mesolimbic Dopamine Signals the Value of Work

PubMed Central

Hamid, Arif A.; Pettibone, Jeffrey R.; Mabrouk, Omar S.; Hetrick, Vaughn L.; Schmidt, Robert; Vander Weele, Caitlin M.; Kennedy, Robert T.; Aragona, Brandon J.; Berke, Joshua D.

2015-01-01

Dopamine cell firing can encode errors in reward prediction, providing a learning signal to guide future behavior. Yet dopamine is also a key modulator of motivation, invigorating current behavior. Existing theories propose that fast (“phasic”) dopamine fluctuations support learning, while much slower (“tonic”) dopamine changes are involved in motivation. We examined dopamine release in the nucleus accumbens across multiple time scales, using complementary microdialysis and voltammetric methods during adaptive decision-making. We first show that minute-by-minute dopamine levels covary with reward rate and motivational vigor. We then show that second-by-second dopamine release encodes an estimate of temporally-discounted future reward (a value function). We demonstrate that changing dopamine immediately alters willingness to work, and reinforces preceding action choices by encoding temporal-difference reward prediction errors. Our results indicate that dopamine conveys a single, rapidly-evolving decision variable, the available reward for investment of effort, that is employed for both learning and motivational functions. PMID:26595651

Aberrant dopamine D2-like receptor function in a rodent model of schizophrenia.

PubMed

Perez, Stephanie M; Lodge, Daniel J

2012-11-01

Based on the observation that antipsychotic medications display antagonist properties at dopamine D2-like receptors, aberrant dopamine signaling has been proposed to underlie psychosis in patients with schizophrenia. Thus, it is not surprising that considerable research has been devoted to understanding the mechanisms involved in the antipsychotic action of these compounds. It is important to note that the majority of these studies have been performed in "normal" experimental animals. Given that these animals do not possess the aberrant neuronal information processing typically associated with schizophrenia, the aim of the current study was to examine the dopamine D2 receptor system in a rodent model of schizophrenia. Here, we demonstrate that methylazoxymethanol acetate (MAM)-treated rats display an enhanced effect of quinpirole on dopamine neuron activity and an aberrant locomotor response to D2-like receptor activation, suggesting changes in postsynaptic D2-like receptor function. To better understand the mechanisms underlying the enhanced response to D2-like ligands in MAM-treated rats, we examined the expression of D2, D3, and dopamine transporter mRNA in the nucleus accumbens and ventral tegmental area by quantitative reverse transcription-polymerase chain reaction. MAM-treated rats displayed a significant increase in dopamine D3 receptor mRNA expression in the nucleus accumbens with no significant changes in the expression of the D2 receptor. Taken together, these data demonstrate robust alterations in dopamine D2-like receptor function in a rodent model of schizophrenia and provide evidence that preclinical studies examining the mechanisms of antipsychotic drug action should be performed in animal models that mirror aspects of the abnormal neuronal transmission thought to underlie symptoms of schizophrenia.

Positive and negative feedback learning and associated dopamine and serotonin transporter binding after methamphetamine.

PubMed

Stolyarova, Alexandra; O'Dell, Steve J; Marshall, John F; Izquierdo, Alicia

2014-09-01

Learning from mistakes and prospectively adjusting behavior in response to reward feedback is an important facet of performance monitoring. Dopamine (DA) pathways play an important role in feedback learning and a growing literature has also emerged on the importance of serotonin (5HT) in reward learning, particularly during punishment or reward omission (negative feedback). Cognitive impairments resulting from psychostimulant exposure may arise from altered patterns in feedback learning, which in turn may be modulated by DA and 5HT transmission. We analyzed long-term, off-drug changes in learning from positive and negative feedback and associated striatal DA transporter (DAT) and frontocortical 5HT transporter (SERT) binding in rats pretreated with methamphetamine (mAMPH). Specifically, we assessed the reversal phase of pairwise visual discrimination learning in rats receiving single dose- (mAMPHsingle) vs. escalating-dose exposure (mAMPHescal). Using fine-grained trial-by-trial analyses, we found increased sensitivity to and reliance on positive feedback in mAMPH-pretreated animals, with the mAMPHsingle group showing more pronounced use of this type of feedback. In contrast, overall negative feedback sensitivity was not altered following any mAMPH treatment. In addition to validating the enduring effects of mAMPH on early reversal learning, we found more consecutive error commissions before the first correct response in mAMPH-pretreated rats. This behavioral rigidity was negatively correlated with subregional frontocortical SERT whereas positive feedback sensitivity negatively correlated with striatal DAT binding. These results provide new evidence for the overlapping, yet dissociable roles of DA and 5HT systems in overcoming perseveration and in learning new reward rules. Copyright © 2014 Elsevier B.V. All rights reserved.

Mutation of Drosophila dopamine receptor DopR leads to male-male courtship behavior.

PubMed

Chen, Bin; Liu, He; Ren, Jing; Guo, Aike

2012-07-06

In Drosophila, dopamine plays important roles in many biological processes as a neuromodulator. Previous studies showed that dopamine level could affect fly courtship behaviors. Disturbed dopamine level leads to abnormal courtship behavior in two different ways. Dopamine up-regulation induces male-male courtship behavior, while down-regulation of dopamine level results in increased sexual attractiveness of males towards other male flies. Until now, the identity of the dopamine receptor involved in this abnormal male-male courtship behavior remains unknown. Here we used genetic approaches to investigate the role of dopamine receptors in fly courtship behavior. We found that a dopamine D1-like receptor, DopR, was involved in fly courtship behavior. DopR mutant male flies display male-male courtship behavior. This behavior is mainly due to the male's increased propensity to court other males. Expression of functional DopR successfully rescued this mutant phenotype. Knock-down of D2-like receptor D2R and another D1-like receptor, DAMB, did not induce male-male courtship behavior, indicating the receptor-type specificity of this phenomenon. Our findings provide insight into a possible link between dopamine level disturbance and the induced male-male courtship behavior. Copyright © 2012 Elsevier Inc. All rights reserved.

The Role of Dopamine in Inflammation-Associated Depression: Mechanisms and Therapeutic Implications.

PubMed

Felger, Jennifer C

Studies investigating the impact of a variety of inflammatory stimuli on the brain and behavior have consistently reported evidence that inflammatory cytokines affect the basal ganglia and dopamine to mediate depressive symptoms related to motivation and motor activity. Findings have included inflammation-associated reductions in ventral striatal responses to hedonic reward, decreased dopamine and dopamine metabolites in cerebrospinal fluid, and decreased availability of striatal dopamine, all of which correlate with symptoms of anhedonia, fatigue, and psychomotor retardation. Similar relationships between alterations in dopamine-relevant corticostriatal reward circuitry and symptoms of anhedonia and psychomotor slowing have also been observed in patients with major depression who exhibit increased peripheral cytokines and other inflammatory markers, such as C-reactive protein. Of note, these inflammation-associated depressive symptoms are often difficult to treat in patients with medical illnesses or major depression. Furthermore, a wealth of literature suggests that inflammation can decrease dopamine synthesis, packaging, and release, thus sabotaging or circumventing the efficacy of standard antidepressant treatments. Herein, the mechanisms by which inflammation and cytokines affect dopamine neurotransmission are discussed, which may provide novel insights into treatment of inflammation-related behavioral symptoms that contribute to an inflammatory malaise.

Reduction of dopamine level enhances the attractiveness of male Drosophila to other males.

PubMed

Liu, Tong; Dartevelle, Laurence; Yuan, Chunyan; Wei, Hongping; Wang, Ying; Ferveur, Jean-François; Guo, Aike

2009-01-01

Dopamine is an important neuromodulator in animals and its roles in mammalian sexual behavior are extensively studied. Drosophila as a useful model system is widely used in many fields of biological studies. It has been reported that dopamine reduction can affect female receptivity in Drosophila and leave male-female courtship behavior unaffected. Here, we used genetic and pharmacological approaches to decrease the dopamine level in dopaminergic cells in Drosophila, and investigated the consequence of this manipulation on male homosexual courtship behavior. We find that reduction of dopamine level can induce Drosophila male-male courtship behavior, and that this behavior is mainly due to the increased male attractiveness or decreased aversiveness towards other males, but not to their enhanced propensity to court other males. Chemical signal input probably plays a crucial role in the male-male courtship induced by the courtees with reduction of dopamine. Our finding provides insight into the relationship between the dopamine reduction and male-male courtship behavior, and hints dopamine level is important for controlling Drosophila courtship behavior.

Reduction of Dopamine Level Enhances the Attractiveness of Male Drosophila to Other Males

PubMed Central

Liu, Tong; Dartevelle, Laurence; Yuan, Chunyan; Wei, Hongping; Wang, Ying; Ferveur, Jean-François; Guo, Aike

2009-01-01

Dopamine is an important neuromodulator in animals and its roles in mammalian sexual behavior are extensively studied. Drosophila as a useful model system is widely used in many fields of biological studies. It has been reported that dopamine reduction can affect female receptivity in Drosophila and leave male-female courtship behavior unaffected. Here, we used genetic and pharmacological approaches to decrease the dopamine level in dopaminergic cells in Drosophila, and investigated the consequence of this manipulation on male homosexual courtship behavior. We find that reduction of dopamine level can induce Drosophila male-male courtship behavior, and that this behavior is mainly due to the increased male attractiveness or decreased aversiveness towards other males, but not to their enhanced propensity to court other males. Chemical signal input probably plays a crucial role in the male-male courtship induced by the courtees with reduction of dopamine. Our finding provides insight into the relationship between the dopamine reduction and male-male courtship behavior, and hints dopamine level is important for controlling Drosophila courtship behavior. PMID:19238209

Electroconvulsive therapy (ECT) in Parkinson's disease: ECS and dopamine enhancement.

PubMed

Cumper, Samantha K; Ahle, Gabriella M; Liebman, Lauren S; Kellner, Charles H

2014-06-01

In addition to its effects in major psychiatric illness, electroconvulsive therapy (ECT) is known to have a beneficial effect on the core motor symptoms of Parkinson's disease (PD). This effect is believed to be mediated via dopamine in the striatum. Electroconvulsive shock (ECS), the animal analogue of ECT, is the model in which investigators have sought to elucidate the specific dopaminergic mechanisms by which ECT exerts its therapeutic effect in PD. Electroconvulsive shock has been given to intact animals as well as to animals with neurotoxic lesions that create parkinsonism. In this paper, we selectively review the electroconvulsive shock literature on dopamine in the striatum. Electroconvulsive shock, and by extension, ECT, is associated with increased dopamine release and modulation of dopamine receptors. Better understanding of how ECT works to enhance dopaminergic systems in the brain could help to make it a more accepted treatment for PD.

Dopamine Modulates Option Generation for Behavior.

PubMed

Ang, Yuen-Siang; Manohar, Sanjay; Plant, Olivia; Kienast, Annika; Le Heron, Campbell; Muhammed, Kinan; Hu, Michele; Husain, Masud

2018-05-21

Animals make innumerable decisions every day, each of which involves evaluating potential options for action. But how are options generated? Although much is now known about decision making when a fixed set of potential options is provided, surprisingly little progress has been made on self-generated options. Some researchers have proposed that such abilities might be modulated by dopamine. Here, we used a new measure of option generation that is quantitative, objective, and culture fair to investigate how humans generate different behavioral options. Participants were asked to draw as many different paths (options) as they could between two points within a fixed time. Healthy individuals (n = 96) exhibited a trade-off between uniqueness (how individually different their options were) and fluency (number of options), generating either many similar or few unique options. To assess influence of dopamine, we first examined patients with Parkinson's disease (n = 35) ON and OFF their dopaminergic medication and compared them to elderly healthy controls (n = 34). Then we conducted a double-blind, placebo-controlled crossover study of the D2 agonist cabergoline in healthy older people (n = 29). Across both studies, dopamine increased fluency but diminished overall uniqueness of options generated, due to the effect of fluency trading off with uniqueness. Crucially, however, when this trade-off was corrected for, dopamine was found to increase uniqueness for any given fluency. Three carefully designed control studies showed that performance on our option-generation task was not related to executing movements, planning actions, or selecting between generated options. These findings show that dopamine plays an important role in modulating option generation. Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Dopamine in the medial amygdala network mediates human bonding

PubMed Central

Touroutoglou, Alexandra; Rudy, Tali; Salcedo, Stephanie; Feldman, Ruth; Hooker, Jacob M.; Dickerson, Bradford C.; Catana, Ciprian; Barrett, Lisa Feldman

2017-01-01

Research in humans and nonhuman animals indicates that social affiliation, and particularly maternal bonding, depends on reward circuitry. Although numerous mechanistic studies in rodents demonstrated that maternal bonding depends on striatal dopamine transmission, the neurochemistry supporting maternal behavior in humans has not been described so far. In this study, we tested the role of central dopamine in human bonding. We applied a combined functional MRI-PET scanner to simultaneously probe mothers’ dopamine responses to their infants and the connectivity between the nucleus accumbens (NAcc), the amygdala, and the medial prefrontal cortex (mPFC), which form an intrinsic network (referred to as the “medial amygdala network”) that supports social functioning. We also measured the mothers’ behavioral synchrony with their infants and plasma oxytocin. The results of this study suggest that synchronous maternal behavior is associated with increased dopamine responses to the mother’s infant and stronger intrinsic connectivity within the medial amygdala network. Moreover, stronger network connectivity is associated with increased dopamine responses within the network and decreased plasma oxytocin. Together, these data indicate that dopamine is involved in human bonding. Compared with other mammals, humans have an unusually complex social life. The complexity of human bonding cannot be fully captured in nonhuman animal models, particularly in pathological bonding, such as that in autistic spectrum disorder or postpartum depression. Thus, investigations of the neurochemistry of social bonding in humans, for which this study provides initial evidence, are warranted. PMID:28193868

Dopamine in the medial amygdala network mediates human bonding.

PubMed

Atzil, Shir; Touroutoglou, Alexandra; Rudy, Tali; Salcedo, Stephanie; Feldman, Ruth; Hooker, Jacob M; Dickerson, Bradford C; Catana, Ciprian; Barrett, Lisa Feldman

2017-02-28

Research in humans and nonhuman animals indicates that social affiliation, and particularly maternal bonding, depends on reward circuitry. Although numerous mechanistic studies in rodents demonstrated that maternal bonding depends on striatal dopamine transmission, the neurochemistry supporting maternal behavior in humans has not been described so far. In this study, we tested the role of central dopamine in human bonding. We applied a combined functional MRI-PET scanner to simultaneously probe mothers' dopamine responses to their infants and the connectivity between the nucleus accumbens (NAcc), the amygdala, and the medial prefrontal cortex (mPFC), which form an intrinsic network (referred to as the "medial amygdala network") that supports social functioning. We also measured the mothers' behavioral synchrony with their infants and plasma oxytocin. The results of this study suggest that synchronous maternal behavior is associated with increased dopamine responses to the mother's infant and stronger intrinsic connectivity within the medial amygdala network. Moreover, stronger network connectivity is associated with increased dopamine responses within the network and decreased plasma oxytocin. Together, these data indicate that dopamine is involved in human bonding. Compared with other mammals, humans have an unusually complex social life. The complexity of human bonding cannot be fully captured in nonhuman animal models, particularly in pathological bonding, such as that in autistic spectrum disorder or postpartum depression. Thus, investigations of the neurochemistry of social bonding in humans, for which this study provides initial evidence, are warranted.

Individual differences in impulsive action and dopamine transporter function in rat orbitofrontal cortex.

PubMed

Yates, J R; Darna, M; Beckmann, J S; Dwoskin, L P; Bardo, M T

2016-01-28

Impulsivity, which can be subdivided into impulsive action and impulsive choice, is implicated as a factor underlying drug abuse vulnerability. Although previous research has shown that dopamine (DA) systems in prefrontal cortex are involved in impulsivity and substance abuse, it is not known if inherent variation in DA transporter (DAT) function contributes to impulsivity. The current study determined if individual differences in either impulsive action or impulsive choice are related to DAT function in orbitofrontal (OFC) and/or medial prefrontal cortex (mPFC). Rats were first tested both for impulsive action in a cued go/no-go task and for impulsive choice in a delay-discounting task. Following behavioral evaluation, in vitro [(3)H]DA uptake assays were performed in OFC and mPFC isolated from individual rats. Vmax in OFC, but not mPFC, was correlated with performance in the cued go/no-go task, with decreased OFC DAT function being associated with high impulsive action. In contrast, Vmax in OFC and mPFC was not correlated with performance in the delay-discounting task. The current results demonstrate that impulsive behavior in cued go/no-go performance is associated with decreased DAT function in OFC, suggesting that hyperdopaminergic tone in this prefrontal subregion mediates, at least in part, increased impulsive action. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Dopamine Synthesis and D3 Receptor Activation in Pancreatic β-Cells Regulates Insulin Secretion and Intracellular [Ca2+] Oscillations

PubMed Central

Ustione, Alessandro

2012-01-01

Pancreatic islets are critical for glucose homeostasis via the regulated secretion of insulin and other hormones. We propose a novel mechanism that regulates insulin secretion from β-cells within mouse pancreatic islets: a dopaminergic negative feedback acting on insulin secretion. We show that islets are a site of dopamine synthesis and accumulation outside the central nervous system. We show that both dopamine and its precursor l-dopa inhibit glucose-stimulated insulin secretion, and this inhibition correlates with a reduction in frequency of the intracellular [Ca2+] oscillations. We further show that the effects of dopamine are abolished by a specific antagonist of the dopamine receptor D3. Because the dopamine transporter and dopamine receptors are expressed in the islets, we propose that cosecretion of dopamine with insulin activates receptors on the β-cell surface. D3 receptor activation results in changes in intracellular [Ca2+] dynamics, which, in turn, lead to lowered insulin secretion. Because blocking dopaminergic negative feedback increases insulin secretion, expanding the knowledge of this pathway in β-cells might offer a potential new target for the treatment of type 2 diabetes. PMID:22918877

Cross-hemispheric dopamine projections have functional significance

PubMed Central

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

2016-01-01

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

A comparison of the effects of the dopamine partial agonists aripiprazole and (-)-3-PPP with quinpirole on stimulated dopamine release in the rat striatum: Studies using fast cyclic voltammetry in vitro.

PubMed

O'Connor, John J; Lowry, John P

2012-07-05

The effects of aripiprazole, (-)-(3-hydroxyphenyl)-N-n-propylpiperidine ((-)-3-PPP) and quinpirole on single and multiple pulse stimulated dopamine release were investigated using the technique of fast cyclic voltammetry (FCV) in isolated rat striatal slices. Aripiprazole and (-)-3-PPP had no significant effect on single pulse dopamine release at concentrations from 10nM to 10μM indicating low agonist activity. The compounds failed to potentiate 5 pulse stimulated release of dopamine although inhibitory effects were seen at 10μM for aripiprazole. Both compounds were tested against the concentration-response curve for quinpirole's inhibition of stimulated single pulse dopamine release. Aripiprazole and (-)-3-PPP shifted the concentration-response curve for quinpirole to the right. In each case this was greater than a 100-fold shift for the 10μM test compound. Whilst these results indicate that both compounds show little agonist activity on dopamine release and significant antagonism of the inhibitory effect of quinpirole on dopamine release, whether they are functionally selective dopamine D(2) ligands remains controversial. Copyright © 2012 Elsevier B.V. All rights reserved.

Sampling phasic dopamine signaling with fast-scan cyclic voltammetry in awake, behaving rats.

PubMed

Fortin, S M; Cone, J J; Ng-Evans, S; McCutcheon, J E; Roitman, M F

2015-01-05

Fast-scan cyclic voltammetry (FSCV) is an electrochemical technique that permits the in vivo measurement of extracellular fluctuations in multiple chemical species. The technique is frequently utilized to sample sub-second (phasic) concentration changes of the neurotransmitter dopamine in awake and behaving rats. Phasic dopamine signaling is implicated in reinforcement, goal-directed behavior, and locomotion, and FSCV has been used to investigate how rapid changes in striatal dopamine concentration contribute to these and other behaviors. This unit describes the instrumentation and construction, implantation, and use of components required to sample and analyze dopamine concentration changes in awake rats with FSCV. Copyright © 2015 John Wiley & Sons, Inc.

The Aversive Agent Lithium Chloride Suppresses Phasic Dopamine Release Through Central GLP-1 Receptors.

PubMed

Fortin, Samantha M; Chartoff, Elena H; Roitman, Mitchell F

2016-02-01

Unconditioned rewarding stimuli evoke phasic increases in dopamine concentration in the nucleus accumbens (NAc) while discrete aversive stimuli elicit pauses in dopamine neuron firing and reductions in NAc dopamine concentration. The unconditioned effects of more prolonged aversive states on dopamine release dynamics are not well understood and are investigated here using the malaise-inducing agent lithium chloride (LiCl). We used fast-scan cyclic voltammetry to measure phasic increases in NAc dopamine resulting from electrical stimulation of dopamine cell bodies in the ventral tegmental area (VTA). Systemic LiCl injection reduced electrically evoked dopamine release in the NAc of both anesthetized and awake rats. As some behavioral effects of LiCl appear to be mediated through glucagon-like peptide-1 receptor (GLP-1R) activation, we hypothesized that the suppression of phasic dopamine by LiCl is GLP-1R dependent. Indeed, peripheral pretreatment with the GLP-1R antagonist exendin-9 (Ex-9) potently attenuated the LiCl-induced suppression of dopamine. Pretreatment with Ex-9 did not, however, affect the suppression of phasic dopamine release by the kappa-opioid receptor agonist, salvinorin A, supporting a selective effect of GLP-1R stimulation in LiCl-induced dopamine suppression. By delivering Ex-9 to either the lateral or fourth ventricle, we highlight a population of central GLP-1 receptors rostral to the hindbrain that are involved in the LiCl-mediated suppression of NAc dopamine release.

Computational Systems Analysis of Dopamine Metabolism

PubMed Central

Qi, Zhen; Miller, Gary W.; Voit, Eberhard O.

2008-01-01

A prominent feature of Parkinson's disease (PD) is the loss of dopamine in the striatum, and many therapeutic interventions for the disease are aimed at restoring dopamine signaling. Dopamine signaling includes the synthesis, storage, release, and recycling of dopamine in the presynaptic terminal and activation of pre- and post-synaptic receptors and various downstream signaling cascades. As an aid that might facilitate our understanding of dopamine dynamics in the pathogenesis and treatment in PD, we have begun to merge currently available information and expert knowledge regarding presynaptic dopamine homeostasis into a computational model, following the guidelines of biochemical systems theory. After subjecting our model to mathematical diagnosis and analysis, we made direct comparisons between model predictions and experimental observations and found that the model exhibited a high degree of predictive capacity with respect to genetic and pharmacological changes in gene expression or function. Our results suggest potential approaches to restoring the dopamine imbalance and the associated generation of oxidative stress. While the proposed model of dopamine metabolism is preliminary, future extensions and refinements may eventually serve as an in silico platform for prescreening potential therapeutics, identifying immediate side effects, screening for biomarkers, and assessing the impact of risk factors of the disease. PMID:18568086

Evidence that Sleep Deprivation Downregulates Dopamine D2R in Ventral Striatum in the Human Brain

PubMed Central

Volkow, Nora D.; Tomasi, Dardo; Wang, Gene-Jack; Telang, Frank; Fowler, Joanna S.; Logan, Jean; Benveniste, Helene; Kim, Ron; Thanos, Panayotis K.; Ferré, Sergi

2012-01-01

Dopamine D2 receptors are involved with wakefulness but their role in the decreased alertness associated with sleep deprivation is unclear. We had shown that sleep deprivation reduced dopamine D2/D3 receptor availability (measured with PET and [11C]raclopride in controls) in striatum, but could not determine if this reflected dopamine increases ([11C]raclopride competes with dopamine for D2/D3 receptor binding) or receptor downregulation. To clarify this, we compared the dopamine increases induced by methylphenidate (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 [11C]raclopride after rested-sleep and after one 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 to 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 to 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 one 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. PMID:22573693

Dopamine-Secreting Paraganglioma in the Retroperitoneum.

PubMed

Matsuda, Yusuke; Kimura, Noriko; Yoshimoto, Takanobu; Sekiguchi, Yoshihiro; Tomoishi, Junzo; Kasahara, Ichiro; Hara, Yoshihito; Ogawa, Yoshihiro

2017-03-01

Pheochromocytomas and paragangliomas, which exclusively produce dopamine, are very rare. Herein, we report for the first time a Japanese case of an exclusively dopamine-producing paraganglioma accompanied by detailed immunohistochemical analyses. A 70-year-old Japanese woman was referred to our hospital for functional examination of her left retroperitoneal mass. Her adrenal functions were normal, except for excessive dopamine secretion. After the tumorectomy, her dopamine level normalized. The histopathological diagnosis of the tumor was paraganglioma; this was confirmed by positive immunostaining of chromogranin A (CgA), tyrosine hydroxylase (TH), dopamine β-hydroxylase (DBH), and succinate dehydrogenase gene subunit B (SDHB). However, the immunostaining of CgA in the tumor cells showed peculiar dot-like staining located corresponding to Golgi complex in the perinuclear area, rather than the diffuse cytoplasmic staining usually observed in epinephrine- or norepinephrine-producing functional pheochromocytomas and paragangliomas. The immunohistochemical results suggested that the tumor cells had sparse neuroendocrine granules in the cytoplasm, resulting in inhibition of catecholamine synthesis from dopamine to norepinephrine in neurosecretory granules. This may be the mechanism responsible for exclusive dopamine secretion in the present case.

Dopamine Release and Uptake Impairments and Behavioral Alterations Observed in Mice that Model Fragile X Mental Retardation Syndrome.

PubMed

Fulks, Jenny L; O'Bryhim, Bliss E; Wenzel, Sara K; Fowler, Stephen C; Vorontsova, Elena; Pinkston, Jonathan W; Ortiz, Andrea N; Johnson, Michael A

2010-10-20

In this study we evaluated the relationship between amphetamine-induced behavioral alterations and dopamine release and uptake characteristics in Fmr1 knockout (Fmr1 KO) mice, which model fragile X syndrome. The behavioral analyses, obtained at millisecond temporal resolution and 2 mm spatial resolution using a force-plate actometer, revealed that Fmr1 KO mice express a lower degree of focused stereotypy compared to wild type (WT) control mice after injection with 10 mg/kg (ip) amphetamine. To identify potentially related neurochemical mechanisms underlying this phenomenon, we measured electrically-evoked dopamine release and uptake using fast-scan cyclic voltammetry at carbon-fiber microelectrodes in striatal brain slices. At 10 weeks of age, dopamine release per pulse, which is dopamine release corrected for differences in uptake, was unchanged. However, at 15 (the age of behavioral testing) and 20 weeks of age, dopamine per pulse and the maximum rate of dopamine uptake was diminished in Fmr1 KO mice compared to WT mice. Dopamine uptake measurements, obtained at different amphetamine concentrations, indicated that dopamine transporters in both genotypes have equal affinities for amphetamine. Moreover, dopamine release measurements from slices treated with quinpirole, a D2-family receptor agonist, rule out enhanced D2 autoreceptor sensitivity as a mechanism of release inhibition. However, dopamine release, uncorrected for uptake and normalized against the corresponding pre-drug release peaks, increased in Fmr1 KO mice, but not in WT mice. Collectively, these data are consistent with a scenario in which a decrease in extracellular dopamine levels in the striatum result in diminished expression of focused stereotypy in Fmr1 KO mice.

Lack of dopamine supersensitivity in rats after chronic administration of blonanserin: Comparison with haloperidol.

PubMed

Hashimoto, Takashi; Baba, Satoko; Ikeda, Hiroko; Oda, Yasunori; Hashimoto, Kenji; Shimizu, Isao

2018-07-05

Long-term treatment with antipsychotic drugs in patients with schizophrenia can lead to dopamine supersensitivity psychosis. It is reported that repeated administration of haloperidol caused dopamine supersensitivity in rats. Blonanserin is an atypical antipsychotic drug with high affinity for dopamine D 2 , D 3 and serotonin 2A receptors. In this study, we investigated whether chronic administration of blonanserin leads to dopamine supersensitivity. Following oral treatment with blonanserin (0.78 mg/kg) or haloperidol (1.1 mg/kg) twice daily for 28 days, the dopamine D 2 agonist quinpirole-induced hyperlocomotion test and a dopamine D 2 receptor binding assay were conducted. We found that haloperidol significantly enhanced both quinpirole-induced hyperlocomotion and striatal dopamine D 2 receptor density in rats. On the other hand, repeated administration of blonanserin had no effect on either locomotor activity or striatal dopamine D 2 receptor density. Further, our results show that mRNA levels of dopamine D 2 and D 3 receptors in several brain regions were unaffected by repeated administration of both agents. In addition, we examined the effect of the dopamine D 3 receptor antagonist PG-01037 on development of dopamine supersensitivity induced by chronic haloperidol treatment and showed that PG-01037 prevents the development of supersensitivity to quinpirole in chronic haloperidol-treated rats. Given the higher affinity of blonanserin at dopamine D 3 receptors than haloperidol, antagonism of blonanserin at dopamine D 3 receptors may play a role in lack of dopamine supersensitivity after chronic administration. The present findings suggest long-term treatment with antipsychotic dose of blonanserin may be unlikely to lead to dopamine supersensitivity. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Imaging of striatal dopamine transporters in rat brain with single pinhole SPECT and co-aligned MRI is highly reproducible.

PubMed

Booij, Jan; de Bruin, Kora; de Win, Maartje M L; Lavini, Cristina; den Heeten, Gerard J; Habraken, Jan B A

2003-08-01

A recently developed pinhole high-resolution SPECT system was used to measure striatal to non-specific binding ratios in rats (n = 9), after injection of the dopamine transporter ligand (123)I-FP-CIT, and to assess its test/retest reproducibility. For co-alignment purposes, the rat brain was imaged on a 1.5 Tesla clinical MRI scanner using a specially developed surface coil. The SPECT images showed clear striatal uptake. On the MR images, cerebral and extra-cerebral structures could be easily delineated. The mean striatal to non-specific [(123)I]FP-CIT binding ratios of the test/retest studies were 1.7 +/- 0.2 and 1.6 +/- 0.2, respectively. The test/retest variability was approximately 9%. We conclude that the assessment of striatal [(123)I]FP-CIT binding ratios in rats is highly reproducible.

Estradiol, dopamine and motivation.

PubMed

Yoest, Katie E; Cummings, Jennifer A; Becker, Jill B

2014-01-01

The gonadal hormone estradiol modulates mesolimbic dopamine systems in the female rat. This modulatory effect is thought to be responsible for the observed effects of estradiol on motivated behaviors. Dopamine acting in the nucleus accumbens is thought to be important for the attribution of incentive motivational properties to cues that predict reward delivery, while dopamine in the striatum is associated with the expression of repetitive or stereotyped behaviors. Elevated concentrations of estradiol are associated with increased motivation for sex or cues associated with access to a mate, while simultaneously attenuating motivation for food. This shift in motivational salience is important for adaptive choice behavior in the natural environment. Additionally, estradiol's adaptive effects on motivation can be maladaptive when increasing motivation for non-natural reinforcers, such as drugs of abuse. Here we discuss the effect of estradiol on mesotelencephalic dopamine transmission and subsequent effects on motivated behaviors.

Isolated Flinders Sensitive Line rats have decreased dopamine D2 receptor mRNA.

PubMed

Bjørnebekk, Astrid; Mathé, Aleksander A; Brené, Stefan

2007-07-02

Social isolation has profound effects on animal behavior and dopamine systems. We investigated the effect of social isolation on the dopamine receptor and neuropeptide mRNAs in the brain reward system in an animal model of depression, the Flinders Sensitive Line rats and Sprague-Dawley controls. We demonstrate that socially isolated but not group housed Flinders sensitive line rats had lower dopamine D2 receptor mRNA levels compared with Sprague-Dawley rats. Isolated and group housed Flinders Sensitive Line rats had higher levels of dopamine D1 receptor and substance P and enkephalin but not dynorphin mRNAs when compared with Sprague-Dawley rats. Our findings of decreased dopamine D2 receptor levels in socially isolated Flinders Sensitive Line rats suggest that low D2 receptor expression may play a role in pathophysiology of depression.

Mapping Dopamine Function in Primates Using Pharmacologic Magnetic Resonance Imaging

PubMed Central

Sanchez-Pernaute, Rosario; Brownell, Anna-Liisa; Chen, Yin-Ching Iris; Isacson, Ole

2008-01-01

Dopamine (DA) receptors play a central role in such diverse pathologies as Parkinson's disease, schizophrenia, and drug abuse. We used an amphetamine challenge combined with pharmacologic magnetic resonance imaging (phMRI) to map DA-associated circuitry in nonhuman primates with high sensitivity and spatial resolution. Seven control cynomolgous monkeys and 10 MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-treated parkinsonian primates were studied longitudinally using both positron emission tomography (PET) and phMRI. Amphetamine challenge (2.5 mg/kg, i.v.) in control monkeys increased relative cerebral blood volume (rCBV) in a number of brain regions not described previously, such as parafascicular thalamus, precentral gyrus, and dentate nucleus of the cerebellum. With the high spatial resolution, we were also able to readily identify changes in rCBV in the anterior cingulate, substantia nigra, ventral tegmental area, caudate (tail and head), putamen, and nucleus accumbens. Amphetamine induced decreases in rCBV in occipital and posterior parietal cortices. Parkinsonian primates had a prominent loss of response to amphetamine, with relative sparing of the nucleus accumbens and parafascicular thalamus. There was a significant correlation between rCBV loss in the substantia nigra and both PET imaging of dopamine transporters and behavioral measures. Monkeys with partial lesions as defined by 2β-carbomethoxy-3β-(4-fluorophenyl) tropane binding to dopamine transporters showed recruitment of premotor and motor cortex after amphetamine stimulus similar to what has been noted in Parkinson's patients during motor tasks. These data indicate that phMRI is a powerful tool for assessment of dynamic changes associated with normal and dysfunctional DA brain circuitry in primates. PMID:15509742

α2A- and α2C-Adrenoceptors as Potential Targets for Dopamine and Dopamine Receptor Ligands.

PubMed

Sánchez-Soto, Marta; Casadó-Anguera, Verònica; Yano, Hideaki; Bender, Brian Joseph; Cai, Ning-Sheng; Moreno, Estefanía; Canela, Enric I; Cortés, Antoni; Meiler, Jens; Casadó, Vicent; Ferré, Sergi

2018-03-18

The poor norepinephrine innervation and high density of Gi/o-coupled α 2A - and α 2C -adrenoceptors in the striatum and the dense striatal dopamine innervation have prompted the possibility that dopamine could be an effective adrenoceptor ligand. Nevertheless, the reported adrenoceptor agonistic properties of dopamine are still inconclusive. In this study, we analyzed the binding of norepinephrine, dopamine, and several compounds reported as selective dopamine D 2 -like receptor ligands, such as the D 3 receptor agonist 7-OH-PIPAT and the D 4 receptor agonist RO-105824, to α 2 -adrenoceptors in cortical and striatal tissue, which express α 2A -adrenoceptors and both α 2A - and α 2C -adrenoceptors, respectively. The affinity of dopamine for α 2 -adrenoceptors was found to be similar to that for D 1 -like and D 2 -like receptors. Moreover, the exogenous dopamine receptor ligands also showed high affinity for α 2A - and α 2C -adrenoceptors. Their ability to activate Gi/o proteins through α 2A - and α 2C -adrenoceptors was also analyzed in transfected cells with bioluminescent resonance energy transfer techniques. The relative ligand potencies and efficacies were dependent on the Gi/o protein subtype. Furthermore, dopamine binding to α 2 -adrenoceptors was functional, inducing changes in dynamic mass redistribution, adenylyl cyclase activity, and ERK1/2 phosphorylation. Binding events were further studied with computer modeling of ligand docking. Docking of dopamine at α 2A - and α 2C -adrenoceptors was nearly identical to its binding to the crystallized D 3 receptor. Therefore, we provide conclusive evidence that α 2A - and α 2C -adrenoceptors are functional receptors for norepinephrine, dopamine, and other previously assumed selective D 2 -like receptor ligands, which calls for revisiting previous studies with those ligands.

Insights into the Modulation of Dopamine Transporter Function by Amphetamine, Orphenadrine, and Cocaine Binding

PubMed Central

Cheng, Mary Hongying; Block, Ethan; Hu, Feizhuo; Cobanoglu, Murat Can; Sorkin, Alexander; Bahar, Ivet

2015-01-01

Human dopamine (DA) transporter (hDAT) regulates dopaminergic signaling in the central nervous system by maintaining the synaptic concentration of DA at physiological levels, upon reuptake of DA into presynaptic terminals. DA translocation involves the co-transport of two sodium ions and the channeling of a chloride ion, and it is achieved via alternating access between outward-facing (OF) and inward-facing states of DAT. hDAT is a target for addictive drugs, such as cocaine, amphetamine (AMPH), and therapeutic antidepressants. Our recent quantitative systems pharmacology study suggested that orphenadrine (ORPH), an anticholinergic agent and anti-Parkinson drug, might be repurposable as a DAT drug. Previous studies have shown that DAT-substrates like AMPH or -blockers like cocaine modulate the function of DAT in different ways. However, the molecular mechanisms of modulation remained elusive due to the lack of structural data on DAT. The newly resolved DAT structure from Drosophila melanogaster opens the way to a deeper understanding of the mechanism and time evolution of DAT–drug/ligand interactions. Using a combination of homology modeling, docking analysis, molecular dynamics simulations, and molecular biology experiments, we performed a comparative study of the binding properties of DA, AMPH, ORPH, and cocaine and their modulation of hDAT function. Simulations demonstrate that binding DA or AMPH drives a structural transition toward a functional form predisposed to translocate the ligand. In contrast, ORPH appears to inhibit DAT function by arresting it in the OF open conformation. The analysis shows that cocaine and ORPH competitively bind DAT, with the binding pose and affinity dependent on the conformational state of DAT. Further assays show that the effect of ORPH on DAT uptake and endocytosis is comparable to that of cocaine. PMID:26106364

Dopamine Modulation of Avoidance Behavior in Caenorhabditis elegans Requires the NMDA Receptor NMR-1

PubMed Central

Baidya, Melvin; Genovez, Marx; Torres, Marissa; Chao, Michael Y.

2014-01-01

The nematode C. elegans utilizes a relatively simple neural circuit to mediate avoidance responses to noxious stimuli such as the volatile odorant octanol. This avoidance behavior is modulated by dopamine. cat-2 mutant animals that are deficient in dopamine biosynthesis have an increased response latency to octanol compared to wild type animals, and this defect can be fully restored with the application of exogenous dopamine. Because this avoidance behavior is mediated by glutamatergic signaling between sensory neurons and premotor interneurons, we investigated the genetic interactions between dopaminergic signaling and ionotropic glutamate receptors. cat-2 mutant animals lacking either the GLR-1 or GLR-2 AMPA/kainate receptors displayed an increased response latency to octanol, which could be restored via exogenous dopamine. However, whereas cat-2 mutant animals lacking the NMR-1 NMDA receptor had increased response latency to octanol they were insensitive to exogenous dopamine. Mutants that lacked both AMPA/kainate and NMDA receptors were also insensitive to exogenous dopamine. Our results indicate that dopamine modulation of octanol avoidance requires NMR-1, consistent with NMR-1 as a potential downstream signaling target for dopamine. PMID:25089710

Individual differences in the propensity to approach signals vs goals promote different adaptations in the dopamine system of rats.

PubMed

Flagel, Shelly B; Watson, Stanley J; Robinson, Terry E; Akil, Huda

2007-04-01

The way an individual responds to cues associated with rewards may be a key determinant of vulnerability to compulsive behavioral disorders. We studied individual differences in Pavlovian conditioned approach behavior and examined the expression of neurobiological markers associated with the dopaminergic system, the same neural system implicated in incentive motivational processes. Pavlovian autoshaping procedures consisted of the brief presentation of an illuminated retractable lever (conditioned stimulus) followed by the response-independent delivery of a food pellet (unconditioned stimulus), which lead to a Pavlovian conditioned response. In situ hybridization was performed on brains obtained either following the first or last (fifth) day of training. Two phenotypes emerged. Sign-trackers (ST) exhibited behavior that seemed to be largely controlled by the cue that signaled impending reward delivery; whereas goal-trackers (GT) preferentially approached the location where the reward was delivered. Following a single training session, ST showed greater expression of dopamine D1 receptor mRNA relative to GT. After 5 days of training, GT exhibited greater expression levels of tyrosine hydroxylase, dopamine transporter, and dopamine D2 receptor mRNA relative to ST. These findings suggest that the development of approach behavior towards signals vs goal leads to distinct adaptations in the dopamine system. The sign-tracker vs goal-tracker phenotype may prove to be a valuable animal model to investigate individual differences in the way incentive salience is attributed to environmental stimuli, which may contribute to the development of addiction and other compulsive behavioral disorders.

Dopamine Modulates Delta-Gamma Phase-Amplitude Coupling in the Prefrontal Cortex of Behaving Rats.

PubMed

Andino-Pavlovsky, Victoria; Souza, Annie C; Scheffer-Teixeira, Robson; Tort, Adriano B L; Etchenique, Roberto; Ribeiro, Sidarta

2017-01-01

Dopamine release and phase-amplitude cross-frequency coupling (CFC) have independently been implicated in prefrontal cortex (PFC) functioning. To causally investigate whether dopamine release affects phase-amplitude comodulation between different frequencies in local field potentials (LFP) recorded from the medial PFC (mPFC) of behaving rats, we used RuBiDopa, a light-sensitive caged compound that releases the neurotransmitter dopamine when irradiated with visible light. LFP power did not change in any frequency band after the application of light-uncaged dopamine, but significantly strengthened phase-amplitude comodulation between delta and gamma oscillations. Saline did not exert significant changes, while injections of dopamine and RuBiDopa produced a slow increase in comodulation for several minutes after the injection. The results show that dopamine release in the medial PFC shifts phase-amplitude comodulation from theta-gamma to delta-gamma. Although being preliminary results due to the limitation of the low number of animals present in this study, our findings suggest that dopamine-mediated modification of the frequencies involved in comodulation could be a mechanism by which this neurotransmitter regulates functioning in mPFC.

Linking unfounded beliefs to genetic dopamine availability

PubMed Central

Schmack, Katharina; Rössler, Hannes; Sekutowicz, Maria; Brandl, Eva J.; Müller, Daniel J.; Petrovic, Predrag; Sterzer, Philipp

2015-01-01

Unfounded convictions involving beliefs in the paranormal, grandiosity ideas or suspicious thoughts are endorsed at varying degrees among the general population. Here, we investigated the neurobiopsychological basis of the observed inter-individual variability in the propensity toward unfounded beliefs. One hundred two healthy individuals were genotyped for four polymorphisms in the COMT gene (rs6269, rs4633, rs4818, and rs4680, also known as val158met) that define common functional haplotypes with substantial impact on synaptic dopamine degradation, completed a questionnaire measuring unfounded beliefs, and took part in a behavioral experiment assessing perceptual inference. We found that greater dopamine availability was associated with a stronger propensity toward unfounded beliefs, and that this effect was statistically mediated by an enhanced influence of expectations on perceptual inference. Our results indicate that genetic differences in dopaminergic neurotransmission account for inter-individual differences in perceptual inference linked to the formation and maintenance of unfounded beliefs. Thus, dopamine might be critically involved in the processes underlying one's interpretation of the relationship between the self and the world. PMID:26483654

In vitro and in vivo evaluation of poly(3,4-ethylenedioxythiophene)/poly(styrene sulfonate)/dopamine-coated electrodes for dopamine delivery.

PubMed

Sui, L; Song, X J; Ren, J; Cai, W J; Ju, L H; Wang, Y; Wang, L Y; Chen, M

2014-06-01

Poly(3,4-ethylenedioxythiophene) (PEDOT) doped with poly(styrene sulfonate) (PSS) has a variety of chemical and biomedical applications. The application of PEDOT/PSS polymers in drug delivery has attracted attention. However, whether conducting polymers of PEDOT/PSS could be used for dopamine delivery has not clear. In the present study, the PEDOT/PSS coatings incorporated with dopamine were fabricated on 0.5 mm diameter platinum electrodes, electrochemical properties, and dopamine delivery capacities of these electrodes were evaluated in vitro and in vivo through implanting these electrodes into brain striatum area. The findings demonstrated that the PEDOT/PSS/dopamine coatings on platinum electrodes could reduce electrodes impedances, increase charge storage capacities, and release significant levels of dopamine upon electrical stimulation of these electrodes. These results indicated that polymers of PEDOT/PSS/dopamine could be used for dopamine delivery, implicating potential application of PEDOT/PSS/dopamine-coated implantable electrodes in the treatment of some diseases associated with dopamine deficits, such as, electrodes for the treatment of Parkinson's disease during deep brain stimulation. Copyright © 2013 Wiley Periodicals, Inc.

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

PubMed

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

2017-01-15

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

Engineering fluorescent poly(dopamine) capsules.

PubMed

Chen, Xi; Yan, Yan; Müllner, Markus; van Koeverden, Martin P; Noi, Ka Fung; Zhu, Wei; Caruso, Frank

2014-03-18

The recent development of poly(dopamine) (PDA) capsules provides new opportunities for their application in biology and medicine. To advance the biomedical application of PDA capsules, strategies that enable the preparation of fluorescently labeled PDA (F-PDA) capsules are required, as this will allow evaluation of their cellular interactions using a range of fluorescence-based techniques. Herein, we report a facile approach for the fabrication of F-PDA capsules via the polymerization of dopamine (DA) on sacrificial templates in the presence of hydrogen peroxide (H2O2). F-PDA capsules with well-defined sizes are prepared by templating different organic and inorganic particles. The resulting F-PDA capsules show negligible cytotoxicity in HeLa cells after incubation for 48 h. We also demonstrate visualization of the F-PDA capsules following internalization by HeLa cells using conventional fluorescence microscopy, en route toward detailed investigations on their biological interactions.

Does human presynaptic striatal dopamine function predict social conformity?

PubMed

Stokes, Paul R A; Benecke, Aaf; Puraite, Julita; Bloomfield, Michael A P; Shotbolt, Paul; Reeves, Suzanne J; Lingford-Hughes, Anne R; Howes, Oliver; Egerton, Alice

2014-03-01

Socially desirable responding (SDR) is a personality trait which reflects either a tendency to present oneself in an overly positive manner to others, consistent with social conformity (impression management (IM)), or the tendency to view one's own behaviour in an overly positive light (self-deceptive enhancement (SDE)). Neurochemical imaging studies report an inverse relationship between SDR and dorsal striatal dopamine D₂/₃ receptor availability. This may reflect an association between SDR and D₂/₃ receptor expression, synaptic dopamine levels or a combination of the two. In this study, we used a [¹⁸F]-DOPA positron emission tomography (PET) image database to investigate whether SDR is associated with presynaptic dopamine function. Striatal [¹⁸F]-DOPA uptake, (k(i)(cer), min⁻¹), was determined in two independent healthy participant cohorts (n=27 and 19), by Patlak analysis using a cerebellar reference region. SDR was assessed using the revised Eysenck Personality Questionnaire (EPQ-R) Lie scale, and IM and SDE were measured using the Paulhus Deception Scales. No significant associations were detected between Lie, SDE or IM scores and striatal [¹⁸F]-DOPA k(i)(cer). These results indicate that presynaptic striatal dopamine function is not associated with social conformity and suggests that social conformity may be associated with striatal D₂/₃ receptor expression rather than with synaptic dopamine levels.

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

PubMed

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

2017-10-25

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

Investigation of the reduction process of dopamine using paired pulse voltammetry

PubMed Central

Kim, Do Hyoung; Oh, Yoonbae; Shin, Hojin; Blaha, Charles D.; Bennet, Kevin E.; Lee, Kendall H.; Kim, In Young; Jang, Dong Pyo

2014-01-01

The oxidation of dopamine (DA) around +0.6V potential in anodic sweep and its reduction around −0.1V in cathodic sweep at a relatively fast scanning rate (300 V/s or greater) have been used for identification of DA oxidation in fast-scan cyclic voltammetry (FSCV). However, compared to the oxidation peak of DA, the reduction peak has not been fully examined in analytical studies, although it has been used as one of the representative features to identify DA. In this study, the reduction process of DA was investigated using paired pulse voltammetry (PPV), which consists of two identical triangle-shaped waveforms, separated by a short interval at the holding potential. Especially, the discrepancies between the magnitude of the oxidation and reduction peaks of DA were investigated based on three factors: (1) the instant desorption of the DA oxidation product (dopamine-o-quinone: DOQ) after production, (2) the effect of the holding potential on the reduction process, and (3) the rate-limited reduction process of DA. For the first test, the triangle waveform FSCV experiment was performed on DA with various scanrates (from 400 to 1000 V/s) and durations of switching potentials of the triangle waveform (from 0.0 to 6.0 ms) in order to vary the duration between the applied oxidation potential at +0.6V and the reduction potential at −0.2V. As a result, the ratio of reduction over oxidation peak current response decreased as the duration became longer. To evaluate the effect of holding potentials during the reduction process, FSCV experiments were conducted with holding potential from 0.0V to −0.8V. We found that more negative holding potentials lead to larger amount of reduction process. For evaluation of the rate-limited reduction process of DA, PPV with a 1Hz repetition rate and various delays (2, 8, 20, 40 and 80ms) between the paired scans were utilized to determine how much reduction process occurred during the holding potential (−0.4V). These tests showed that

Dysregulation of D₂-mediated dopamine transmission in monkeys after chronic escalating methamphetamine exposure.

PubMed

Groman, Stephanie M; Lee, Buyean; Seu, Emanuele; James, Alex S; Feiler, Karen; Mandelkern, Mark A; London, Edythe D; Jentsch, J David

2012-04-25

Compulsive drug-seeking and drug-taking are important substance-abuse behaviors that have been linked to alterations in dopaminergic neurotransmission and to impaired inhibitory control. Evidence supports the notions that abnormal D₂ receptor-mediated dopamine transmission and inhibitory control may be heritable risk factors for addictions, and that they also reflect drug-induced neuroadaptations. To provide a mechanistic explanation for the drug-induced emergence of inhibitory-control deficits, this study examined how a chronic, escalating-dose regimen of methamphetamine administration affected dopaminergic neurochemistry and cognition in monkeys. Dopamine D₂-like receptor and dopamine transporter (DAT) availability and reversal-learning performance were measured before and after exposure to methamphetamine (or saline), and brain dopamine levels were assayed at the conclusion of the study. Exposure to methamphetamine reduced dopamine D₂-like receptor and DAT availability and produced transient, selective impairments in the reversal of a stimulus-outcome association. Furthermore, individual differences in the change in D₂-like receptor availability in the striatum were related to the change in response to positive feedback. These data provide evidence that chronic, escalating-dose methamphetamine administration alters the dopamine system in a manner similar to that observed in methamphetamine-dependent humans. They also implicate alterations in positive-feedback sensitivity associated with D₂-like receptor dysfunction as the mechanism by which inhibitory control deficits emerge in stimulant-dependent individuals. Finally, a significant degree of neurochemical and behavioral variation in response to methamphetamine was detected, indicating that individual differences affect the degree to which drugs of abuse alter these processes. Identification of these factors ultimately may assist in the development of individualized treatments for substance dependence.

Single cocaine exposure does not alter striatal pre-synaptic dopamine function in mice: an [18 F]-FDOPA PET study.

PubMed

Bonsall, David R; Kokkinou, Michelle; Veronese, Mattia; Coello, Christopher; Wells, Lisa A; Howes, Oliver D

2017-12-01

Cocaine is a recreational drug of abuse that binds to the dopamine transporter, preventing reuptake of dopamine into pre-synaptic terminals. The increased presence of synaptic dopamine results in stimulation of both pre- and post-synaptic dopamine receptors, considered an important mechanism by which cocaine elicits its reinforcing properties. However, the effects of acute cocaine administration on pre-synaptic dopamine function remain unclear. Non-invasive imaging techniques such as positron emission tomography have revealed impaired pre-synaptic dopamine function in chronic cocaine users. Similar impairments have been seen in animal studies, with microdialysis experiments indicating decreased basal dopamine release. Here we use micro positron emission tomography imaging techniques in mice to measure dopamine synthesis capacity and determine the effect of acute cocaine administration of pre-synaptic dopamine function. We show that a dose of 20 mg/kg cocaine is sufficient to elicit hyperlocomotor activity, peaking 15-20 min post treatment (p < 0.001). However, dopamine synthesis capacity in the striatum was not significantly altered by acute cocaine treatment (KiCer: 0.0097 per min vs. 0.0112 per min in vehicle controls, p > 0.05). Furthermore, expression levels of two key enzymes related to dopamine synthesis, tyrosine hydroxylase and aromatic l-amino acid decarboxylase, within the striatum of scanned mice were not significantly affected by acute cocaine pre-treatment (p > 0.05). Our findings suggest that while the regulation of dopamine synthesis and release in the striatum have been shown to change with chronic cocaine use, leading to a reduced basal tone, these adaptations to pre-synaptic dopaminergic neurons are not initiated following a single exposure to the drug. © 2017 International Society for Neurochemistry.

Protective effects of minocycline on the reduction of dopamine transporters in the striatum after administration of methamphetamine: a positron emission tomography study in conscious monkeys.

PubMed

Hashimoto, Kenji; Tsukada, Hideo; Nishiyama, Shingo; Fukumoto, Dai; Kakiuchi, Takeharu; Iyo, Masaomi

2007-03-01

Positron emission tomography (PET) studies of methamphetamine (METH) abusers suggest that psychotic symptoms of METH abusers may be attributable to the reduction of dopamine transporters (DAT) in the human brain. However, there are currently no particular pharmacological treatments for the wide range of symptoms associated with METH abuse. Using a PET study in conscious monkeys, we investigated whether the second generation antibiotic minocycline could protect against the reduction of DAT in monkeys treated with METH (2 mg/kg x 3, 3-hour intervals). Pretreatment and subsequent administration of minocycline significantly attenuated the reduction of DAT in the striatum of monkeys treated with METH. Furthermore, posttreatment and subsequent administration of minocycline also significantly attenuated the reduction of DAT. In contrast, repeated administration of minocycline alone did not alter the density of DAT in the striatum of monkeys treated with METH. Our findings suggest that minocycline protects against METH-induced neurotoxicity in the monkey brain. Therefore, minocycline is likely to be a promising therapeutic agent for the treatment of several symptoms associated with METH use in humans.

Trans-synaptic (GABA-dopamine) modulation of cocaine induced dopamine release: A potential therapeutic strategy for cocaine abuse

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dewey, S.L.; Straughter-Moore, R.; Chen, R.

We recently developed a new experimental strategy for measuring interactions between functionally-linked neurotransmitter systems in the primate and human brain with PET. As part of this research, we demonstrated that increases in endogenous GABA concentrations significantly reduced striatal dopamine concentrations in the primate brain. We report here the application of the neurotransmitter interaction paradigm with PET and with microdialysis to the investigation of a novel therapeutic strategy for treating cocaine abuse based on the ability of GABA to inhibit cocaine induced increases in striatal dopamine. Using gamma-vinyl GABA (GVG, a suicide inhibitor of GABA transaminase), we performed a series ofmore » PET studies where animals received a baseline PET scan with labeled raclopride injection, animals received cocaine (2.0 mg/kg). Normally, a cocaine challenge significantly reduces the striatal binding of {sup 11}C-raclopride. However, in animals pretreated with GVG, {sup 11}C-raclopride binding was less affected by a cocaine challenge compared to control studies. Furthermore, microdialysis studies in freely moving rats demonstrate that GVG (300 mg/kg) significantly inhibited cocaine-induced increases in extracellular dopamine release. GVG also attenuated cocaine-induced increases in locomotor activity. However, at a dose of 100 mg/kg, GVG had no effect. Similar findings were obtained with alcohol. Alcohol pretreatment dose dependantly (1-4 g/kg) inhibited cocaine-induced increases in extracellular dopamine concentrations in freely moving rats. Taken together, these studies suggest that therapeutic strategies targeted at increasing central GABA concentrations may be beneficial for the treatment of cocaine abuse.« less

Dopamine-imprinted monolithic column for capillary electrochromatography.

PubMed

Aşır, Süleyman; Sarı, Duygu; Derazshamshir, Ali; Yılmaz, Fatma; Şarkaya, Koray; Denizli, Adil

2017-11-01

A dopamine-imprinted monolithic column was prepared and used in capillary electrochromatography as stationary phase for the first time. Dopamine was selectively separated from aqueous solution containing the competitor molecule norepinephrine, which is similar in size and shape to the template molecule. Morphology of the dopamine-imprinted column was observed by scanning electron microscopy. The influence of the organic solvent content of mobile phase, applied pressure and pH of the mobile phase on the recognition of dopamine by the imprinted monolithic column has been evaluated, and the imprinting effect in the dopamine-imprinted monolithic polymer was verified. Developed dopamine-imprinted monolithic column resulted in excellent separation of dopamine from structurally related competitor molecule, norepinephrine. Separation was achieved in a short period of 10 min, with the electrophoretic mobility of 5.81 × 10 -5  m 2 V -1 s -1 at pH 5.0 and 500 mbar pressure. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Antipsychotic treatment leading to dopamine supersensitivity persistently alters nucleus accumbens function.

PubMed

El Hage, Cynthia; Bédard, Anne-Marie; Samaha, Anne-Noël

2015-12-01

Chronic exposure to some antipsychotic medications can induce supersensitivity to dopamine receptor stimulation. This is linked to a worsening of clinical outcome and to antipsychotic treatment failure. Here we investigated the role of striatal subregions [nucleus accumbens (NAc) and caudate-putamen (CPu)] in the expression of antipsychotic-induced dopamine supersensitivity. We treated rats with haloperidol (HAL) or olanzapine (OLZ), using regimens that achieve clinically relevant kinetics of striatal D2 receptor occupancy. Under these conditions, HAL produces dopamine supersensitivity whereas OLZ does not. We then assessed behaviors evoked by the dopamine agonist amphetamine (AMPH). We either injected AMPH into the striatum or inhibited striatal function with microinjections of GABA receptor agonists prior to injecting AMPH systemically. HAL-treated rats were dopamine supersensitive, as indicated by sensitization to systemic AMPH-induced potentiation of both locomotor activity and operant responding for a conditioned reward (CR). Intra-CPu injections of AMPH had no effect on these behaviors, in any group. Intra-NAc injections of AMPH enhanced operant responding for CR in OLZ-treated and control rats, but not in HAL-treated rats. In HAL-treated rats, inhibition of the NAc also failed to disrupt systemic AMPH-induced potentiation of operant responding for CR. Furthermore, while intra-NAc AMPH enhanced locomotion in both HAL-treated and control animals, inhibition of the NAc disrupted systemic AMPH-induced locomotion only in control rats. Thus, antipsychotic-induced dopamine supersensitivity persistently disrupts NAc function, such that some behaviors that normally depend upon NAc dopamine no longer do so. This has implications for understanding dysfunctions in dopamine-mediated behaviors in patients undergoing chronic antipsychotic treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

PubMed

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.

[Dopamine receptor signaling regulates human osteoclastogenesis].

PubMed

Hanami, Kentaro; Nakano, Kazuhisa; Tanaka, Yoshiya

2013-01-01

Although the central nervous system and the neurotransmitters are known to control not only the immune system but also the homeostasis of bone mass, their pathological relevance to bone disorders remains unclear. Osteoclasts in the synovium of rheumatoid arthritis (RA) play an important role in bone destruction. It is known that increased sympathetic nervous activity increases both differentiation and function of osteoclasts, which leads to bone loss. Dopamine, a major neurotransmitter, transmits signals via five different seven-transmembrane G protein-coupled receptors termed D1 to D5. We previously reported that dopamine plays an important role in IL-6-IL-17 axis and subsequent joint destruction in RA. The major source of dopamine in the synovial tissue of RA was dendritic cells (DCs) that stored and secreted dopamine. Dopamine released by DCs bounded to D1-like dopamine receptors on T cells and induced activation of cAMP and differentiation to Th17 cells via IL-6 production We here overview the interplay among the immune system, bone metabolism and neurologic system shedding light upon dopaminergic signals upon osteoclastogenesis.

Dopamine, Affordance and Active Inference

PubMed Central

Friston, Karl J.; Shiner, Tamara; FitzGerald, Thomas; Galea, Joseph M.; Adams, Rick; Brown, Harriet; Dolan, Raymond J.; Moran, Rosalyn; Stephan, Klaas Enno; Bestmann, Sven

2012-01-01

The role of dopamine in behaviour and decision-making is often cast in terms of reinforcement learning and optimal decision theory. Here, we present an alternative view that frames the physiology of dopamine in terms of Bayes-optimal behaviour. In this account, dopamine controls the precision or salience of (external or internal) cues that engender action. In other words, dopamine balances bottom-up sensory information and top-down prior beliefs when making hierarchical inferences (predictions) about cues that have affordance. In this paper, we focus on the consequences of changing tonic levels of dopamine firing using simulations of cued sequential movements. Crucially, the predictions driving movements are based upon a hierarchical generative model that infers the context in which movements are made. This means that we can confuse agents by changing the context (order) in which cues are presented. These simulations provide a (Bayes-optimal) model of contextual uncertainty and set switching that can be quantified in terms of behavioural and electrophysiological responses. Furthermore, one can simulate dopaminergic lesions (by changing the precision of prediction errors) to produce pathological behaviours that are reminiscent of those seen in neurological disorders such as Parkinson's disease. We use these simulations to demonstrate how a single functional role for dopamine at the synaptic level can manifest in different ways at the behavioural level. PMID:22241972

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

PubMed

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

2017-01-01

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

Dopamine regulation of human speech and bird song: A critical review

PubMed Central

Simonyan, Kristina; Horwitz, Barry; Jarvis, Erich D.

2012-01-01

To understand the neural basis of human speech control, extensive research has been done using a variety of methodologies in a range of experimental models. Nevertheless, several critical questions about learned vocal motor control still remain open. One of them is the mechanism(s) by which neurotransmitters, such as dopamine, modulate speech and song production. In this review, we bring together the two fields of investigations of dopamine action on voice control in humans and songbirds, who share similar behavioral and neural mechanisms for speech and song production. While human studies investigating the role of dopamine in speech control are limited to reports in neurological patients, research on dopaminergic modulation of bird song control has recently expanded our views on how this system might be organized. We discuss the parallels between bird song and human speech from the perspective of dopaminergic control as well as outline important differences between these species. PMID:22284300

Dopamine and serotonin transporter genotypes moderate sensitivity to maternal expressed emotion: the case of conduct and emotional problems in attention deficit/hyperactivity disorder.

PubMed

Sonuga-Barke, Edmund J S; Oades, Robert D; Psychogiou, Lamprini; Chen, Wai; Franke, Barbara; Buitelaar, Jan; Banaschewski, Tobias; Ebstein, Richard P; Gil, Michael; Anney, Richard; Miranda, Ana; Roeyers, Herbert; Rothenberger, Aribert; Sergeant, Joseph; Steinhausen, Hans Christoph; Thompson, Margaret; Asherson, Philip; Faraone, Stephen V

2009-09-01

Mothers' positive emotions expressed about their children with attention deficit/hyperactivity disorder (ADHD) are associated with a reduced likelihood of comorbid conduct problems (CP). We examined whether this association with CP, and one with emotional problems (EMO), is moderated by variants within three genes, previously reported to be associated with ADHD and to moderate the impact of environmental risks on conduct and/or emotional problems; the dopamine transporter gene (SLC6A3/DAT1), the dopamine D4 receptor gene (DRD4) and the serotonin transporter gene (SLC6A4/5HTT). Seven hundred and twenty-eight males between the ages of 5 and 17 with a DSM-IV research diagnosis of combined type ADHD were included in these analyses. Parents and teachers rated children's conduct and emotional problems. Positive maternal expressed emotion (PMEE) was coded by independent observers on comments made during a clinical assessment with the mother based on current or recent medication-free periods. Sensitivity to the effects of PMEE on CP was moderated by variants of the DAT1 and 5HTT genes. Only children who did not carry the DAT1 10R/10R or the 5HTT l/l genotypes showed altered levels of CP when exposed to PMEE. The effect was most marked where the child with ADHD had both these genotypes. For EMO, sensitivity to PMEE was found only with those who carried the DAT1 9R/9R. There was no effect of DRD4 on CP or EMO. The gene-environment interactions observed suggested that genetic make-up can alter the degree of sensitivity an ADHD patients has to their family environment. Further research should focus on distinguishing general sensitivity genotypes from those conferring risk or protective qualities.

The Dopamine Imbalance Hypothesis of Fatigue in Multiple Sclerosis and Other Neurological Disorders

PubMed Central

Dobryakova, Ekaterina; Genova, Helen M.; DeLuca, John; Wylie, Glenn R.

2015-01-01

Fatigue is one of the most pervasive symptoms of multiple sclerosis (MS), and has engendered hundreds of investigations on the topic. While there is a growing literature using various methods to study fatigue, a unified theory of fatigue in MS is yet to emerge. In the current review, we synthesize findings from neuroimaging, pharmacological, neuropsychological, and immunological studies of fatigue in MS, which point to a specific hypothesis of fatigue in MS: the dopamine imbalance hypothesis. The communication between the striatum and prefrontal cortex is reliant on dopamine, a modulatory neurotransmitter. Neuroimaging findings suggest that fatigue results from the disruption of communication between these regions. Supporting the dopamine imbalance hypothesis, structural and functional neuroimaging studies show abnormalities in the frontal and striatal regions that are heavily innervated by dopamine neurons. Further, dopaminergic psychostimulant medication has been shown to alleviate fatigue in individuals with traumatic brain injury, chronic fatigue syndrome, and in cancer patients, also indicating that dopamine might play an important role in fatigue perception. This paper reviews the structural and functional neuroimaging evidence as well as pharmacological studies that suggest that dopamine plays a critical role in the phenomenon of fatigue. We conclude with how specific aspects of the dopamine imbalance hypothesis can be tested in future research. PMID:25814977

Insulin resistance impairs nigrostriatal dopamine function.

PubMed

Morris, J K; Bomhoff, G L; Gorres, B K; Davis, V A; Kim, J; Lee, P-P; Brooks, W M; Gerhardt, G A; Geiger, P C; Stanford, J A

2011-09-01

Clinical studies have indicated a link between Parkinson's disease (PD) and Type 2 Diabetes. Although preclinical studies have examined the effect of high-fat feeding on dopamine function in brain reward pathways, the effect of diet on neurotransmission in the nigrostriatal pathway, which is affected in PD and parkinsonism, is less clear. We hypothesized that a high-fat diet, which models early-stage Type 2 Diabetes, would disrupt nigrostriatal dopamine function in young adult Fischer 344 rats. Rats were fed a high fat diet (60% calories from fat) or a normal chow diet for 12 weeks. High fat-fed animals were insulin resistant compared to chow-fed controls. Potassium-evoked dopamine release and dopamine clearance were measured in the striatum using in vivo electrochemistry. Dopamine release was attenuated and dopamine clearance was diminished in the high-fat diet group compared to chow-fed rats. Magnetic resonance imaging indicated increased iron deposition in the substantia nigra of the high fat group. This finding was supported by alterations in the expression of several proteins involved in iron metabolism in the substantia nigra in this group compared to chow-fed animals. The diet-induced systemic and basal ganglia-specific changes may play a role in the observed impairment of nigrostriatal dopamine function. Copyright © 2011 Elsevier Inc. All rights reserved.

Adaptations of Presynaptic Dopamine Terminals Induced by Psychostimulant Self-Administration

PubMed Central

2015-01-01

A great deal of research has focused on investigating neurobiological alterations induced by chronic psychostimulant use in an effort to describe, understand, and treat the pathology of psychostimulant addiction. It has been known for several decades that dopamine neurotransmission in the nucleus accumbens is integrally involved in the selection and execution of motivated and goal-directed behaviors, and that psychostimulants act on this system to exert many of their effects. As such, a large body of work has focused on defining the consequences of psychostimulant use on dopamine signaling in the striatum as it relates to addictive behaviors. Here, we review presynaptic dopamine terminal alterations observed following self-administration of cocaine and amphetamine, as well as possible mechanisms by which these alterations occur and their impact on the progression of addiction. PMID:25491345

Dopamine and anorexia nervosa.

PubMed

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

2016-01-01

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

Interaction between effects of genes coding for dopamine and glutamate transmission on striatal and parahippocampal function.

PubMed

Pauli, Andreina; Prata, Diana P; Mechelli, Andrea; Picchioni, Marco; Fu, Cynthia H Y; Chaddock, Christopher A; Kane, Fergus; Kalidindi, Sridevi; McDonald, Colm; Kravariti, Eugenia; Toulopoulou, Timothea; Bramon, Elvira; Walshe, Muriel; Ehlert, Natascha; Georgiades, Anna; Murray, Robin; Collier, David A; McGuire, Philip

2013-09-01

The genes for the dopamine transporter (DAT) and the D-Amino acid oxidase activator (DAOA or G72) have been independently implicated in the risk for schizophrenia and in bipolar disorder and/or their related intermediate phenotypes. DAT and G72 respectively modulate central dopamine and glutamate transmission, the two systems most robustly implicated in these disorders. Contemporary studies have demonstrated that elevated dopamine function is associated with glutamatergic dysfunction in psychotic disorders. Using functional magnetic resonance imaging we examined whether there was an interaction between the effects of genes that influence dopamine and glutamate transmission (DAT and G72) on regional brain activation during verbal fluency, which is known to be abnormal in psychosis, in 80 healthy volunteers. Significant interactions between the effects of G72 and DAT polymorphisms on activation were evident in the striatum, parahippocampal gyrus, and supramarginal/angular gyri bilaterally, the right insula, in the right pre-/postcentral and the left posterior cingulate/retrosplenial gyri (P < 0.05, FDR-corrected across the whole brain). This provides evidence that interactions between the dopamine and the glutamate system, thought to be altered in psychosis, have an impact in executive processing which can be modulated by common genetic variation. Copyright © 2012 Wiley Periodicals, Inc., a Wiley company.

Dopamine Modulates Delta-Gamma Phase-Amplitude Coupling in the Prefrontal Cortex of Behaving Rats

PubMed Central

Andino-Pavlovsky, Victoria; Souza, Annie C.; Scheffer-Teixeira, Robson; Tort, Adriano B. L.; Etchenique, Roberto; Ribeiro, Sidarta

2017-01-01

Dopamine release and phase-amplitude cross-frequency coupling (CFC) have independently been implicated in prefrontal cortex (PFC) functioning. To causally investigate whether dopamine release affects phase-amplitude comodulation between different frequencies in local field potentials (LFP) recorded from the medial PFC (mPFC) of behaving rats, we used RuBiDopa, a light-sensitive caged compound that releases the neurotransmitter dopamine when irradiated with visible light. LFP power did not change in any frequency band after the application of light-uncaged dopamine, but significantly strengthened phase-amplitude comodulation between delta and gamma oscillations. Saline did not exert significant changes, while injections of dopamine and RuBiDopa produced a slow increase in comodulation for several minutes after the injection. The results show that dopamine release in the medial PFC shifts phase-amplitude comodulation from theta-gamma to delta-gamma. Although being preliminary results due to the limitation of the low number of animals present in this study, our findings suggest that dopamine-mediated modification of the frequencies involved in comodulation could be a mechanism by which this neurotransmitter regulates functioning in mPFC. PMID:28536507

Modafinil evokes striatal [(3)H]dopamine release and alters the subjective properties of stimulants.

PubMed

Dopheide, Marsha M; Morgan, Russell E; Rodvelt, Kelli R; Schachtman, Todd R; Miller, Dennis K

2007-07-30

Modafinil is a mild psychostimulant used for the treatment of sleep and arousal-related disorders, and has been considered a pharmacotherapy for cocaine and amphetamine dependence; however, modafinil's mechanism of action is largely unclear. The present study investigated modafinil using drug discrimination and slice superfusion techniques. Rats were trained to discriminate cocaine (1.6 or 5 mg/kg) or amphetamine (0.3 mg/kg) from saline injection for food reinforcement. Modafinil (64-128 mg/kg) substituted partially for both cocaine doses and amphetamine. Pretreatment with a lower modafinil dose (32 mg/kg) augmented the discriminative stimulus properties of cocaine (1.6 mg/kg dose group) and amphetamine. In neurochemical experiments, modafinil (100-300 microM) evoked [(3)H]overflow from rat striatal slices preloaded with [(3)H]dopamine in a concentration-dependent manner; however, modafinil was less potent and efficacious than amphetamine and nicotine. The dopamine transporter inhibitor nomifensine (10 microM) blocked modafinil-evoked [(3)H]overflow, and concentrations of modafinil (<100 microM) that did not have intrinsic activity attenuated amphetamine (1 and 3 microM)-evoked [(3)H]overflow. Modafinil-evoked [(3)H]overflow was not altered by the nicotinic acetylcholine receptor antagonist mecamylamine, and modafinil did not alter nicotine-evoked [(3)H]overflow, indicating that nicotinic acetylcholine receptors likely are not important for modafinil's mechanism of action. The present results indicate that modafinil evokes dopamine release from striatal neurons and is a psychostimulant that is pharmacologically similar to, but much less potent and efficacious than, amphetamine.

Direct and Systemic Administration of a CNS-Permeant Tamoxifen Analog Reduces Amphetamine-Induced Dopamine Release and Reinforcing Effects.

PubMed

Carpenter, Colleen; Zestos, Alexander G; Altshuler, Rachel; Sorenson, Roderick J; Guptaroy, Bipasha; Showalter, Hollis D; Kennedy, Robert T; Jutkiewicz, Emily; Gnegy, Margaret E

2017-09-01

Amphetamines (AMPHs) are globally abused. With no effective treatment for AMPH addiction to date, there is urgent need for the identification of druggable targets that mediate the reinforcing action of this stimulant class. AMPH-stimulated dopamine efflux is modulated by protein kinase C (PKC) activation. Inhibition of PKC reduces AMPH-stimulated dopamine efflux and locomotor activity. The only known CNS-permeant PKC inhibitor is the selective estrogen receptor modulator tamoxifen. In this study, we demonstrate that a tamoxifen analog, 6c, which more potently inhibits PKC than tamoxifen but lacks affinity for the estrogen receptor, reduces AMPH-stimulated increases in extracellular dopamine and reinforcement-related behavior. In rat striatal synaptosomes, 6c was almost fivefold more potent at inhibiting AMPH-stimulated dopamine efflux than [ 3 H]dopamine uptake through the dopamine transporter (DAT). The compound did not compete with [ 3 H]WIN 35,428 binding or affect surface DAT levels. Using microdialysis, direct accumbal administration of 1 μM 6c reduced dopamine overflow in freely moving rats. Using LC-MS, we demonstrate that 6c is CNS-permeant. Systemic treatment of rats with 6 mg/kg 6c either simultaneously or 18 h prior to systemic AMPH administration reduced both AMPH-stimulated dopamine overflow and AMPH-induced locomotor effects. Finally, 18 h pretreatment of rats with 6 mg/kg 6c s.c. reduces AMPH-self administration but not food self-administration. These results demonstrate the utility of tamoxifen analogs in reducing AMPH effects on dopamine and reinforcement-related behaviors and suggest a new avenue of development for therapeutics to reduce AMPH abuse.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Volkow N. D.; Fowler J.; Volkow, N.D.

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, dopaminemore » 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.« less

Striatal dopamine neurotransmission: regulation of release and uptake

PubMed Central

Sulzer, David; Cragg, Stephanie J.; Rice, Margaret E.

2016-01-01

Dopamine (DA) transmission is governed by processes that regulate release from axonal boutons in the forebrain and the somatodendritic compartment in midbrain, and by clearance by the DA transporter, diffusion, and extracellular metabolism. We review how axonal DA release is regulated by neuronal activity and by autoreceptors and heteroreceptors, and address how quantal release events are regulated in size and frequency. In brain regions densely innervated by DA axons, DA clearance is due predominantly to uptake by the DA transporter, whereas in cortex, midbrain, and other regions with relatively sparse DA inputs, the norepinephrine transporter and diffusion are involved. We discuss the role of DA uptake in restricting the sphere of influence of DA and in temporal accumulation of extracellular DA levels upon successive action potentials. The tonic discharge activity of DA neurons may be translated into a tonic extracellular DA level, whereas their bursting activity can generate discrete extracellular DA transients. PMID:27141430

Dopamine D1 and D2 Receptor Immunoreactivities in the Arcuate-Median Eminence Complex and their Link to the Tubero-Infundibular Dopamine Neurons

PubMed Central

Romero-Fernandez, W.; Borroto-Escuela, D.O.; Vargas-Barroso, V.; Narváez, M.; Di Palma, M.; Agnati, L.F.; Sahd, J. Larriva

2014-01-01

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 tuberoinfundibular 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 and differentially

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

PubMed

Romero-Fernandez, W; Borroto-Escuela, D O; Vargas-Barroso, V; Narváez, M; Di Palma, M; Agnati, L F; Larriva Sahd, J; Fuxe, K

2014-07-18

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 and differentially

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

ERIC Educational Resources Information Center

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…

Breathing is affected by dopamine D2-like receptors in the basolateral amygdala.

PubMed

Sugita, Toshihisa; Kanamaru, Mitsuko; Iizuka, Makito; Sato, Kanako; Tsukada, Setsuro; Kawamura, Mitsuru; Homma, Ikuo; Izumizaki, Masahiko

2015-04-01

The precise mechanisms underlying how emotions change breathing patterns remain unclear, but dopamine is a candidate neurotransmitter in the process of emotion-associated breathing. We investigated whether basal dopamine release occurs in the basolateral amygdala (BLA), where sensory-related inputs are received and lead to fear or anxiety responses, and whether D1- and D2-like receptor antagonists affect breathing patterns and dopamine release in the BLA. Adult male mice (C57BL/6N) were perfused with artificial cerebrospinal fluid, a D1-like receptor antagonist (SCH 23390), or a D2-like receptor antagonist ((S)-(-)-sulpiride) through a microdialysis probe in the BLA. Respiratory variables were measured using a double-chamber plethysmograph. Dopamine release was measured by an HPLC. Perfusion of (S)-(-)-sulpiride in the BLA, not SCH 23390, specifically decreased respiratory rate without changes in local release of dopamine. These results suggest that basal dopamine release in the BLA, at least partially, increases respiratory rates only through post-synaptic D2-like receptors, not autoreceptors, which might be associated with emotional responses. Copyright © 2014 Elsevier B.V. All rights reserved.

Pharmacochaperoning in a Drosophila model system rescues human dopamine transporter variants associated with infantile/juvenile parkinsonism

PubMed Central

Asjad, H. M. Mazhar; Kasture, Ameya; El-Kasaby, Ali; Sackel, Michael; Hummel, Thomas; Freissmuth, Michael; Sucic, Sonja

2017-01-01

Point mutations in the gene encoding the human dopamine transporter (hDAT, SLC6A3) cause a syndrome of infantile/juvenile dystonia and parkinsonism. To unravel the molecular mechanism underlying these disorders and investigate possible pharmacological therapies, here we examined 13 disease-causing DAT mutants that were retained in the endoplasmic reticulum when heterologously expressed in HEK293 cells. In three of these mutants, i.e. hDAT-V158F, hDAT-G327R, and hDAT-L368Q, the folding deficit was remedied with the pharmacochaperone noribogaine or the heat shock protein 70 (HSP70) inhibitor pifithrin-μ such that endoplasmic reticulum export of and radioligand binding and substrate uptake by these DAT mutants were restored. In Drosophila melanogaster, DAT deficiency results in reduced sleep. We therefore exploited the power of targeted transgene expression of mutant hDAT in Drosophila to explore whether these hDAT mutants could also be pharmacologically rescued in an intact organism. Noribogaine or pifithrin-μ treatment supported hDAT delivery to the presynaptic terminals of dopaminergic neurons and restored sleep to normal length in DAT-deficient (fumin) Drosophila lines expressing hDAT-V158F or hDAT-G327R. In contrast, expression of hDAT-L368Q in the Drosophila DAT mutant background caused developmental lethality, indicating a toxic action not remedied by pharmacochaperoning. Our observations identified those mutations most likely amenable to pharmacological rescue in the affected children. In addition, our findings also highlight the challenges of translating insights from pharmacochaperoning in cell culture to the clinical situation. Because of the evolutionary conservation in dopaminergic neurotransmission between Drosophila and people, pharmacochaperoning of DAT in D. melanogaster may allow us to bridge that gap. PMID:28972153

Running wheel exercise enhances recovery from nigrostriatal dopamine injury without inducing neuroprotection.

PubMed

O'Dell, S J; Gross, N B; Fricks, A N; Casiano, B D; Nguyen, T B; Marshall, J F

2007-02-09

Forced use of the forelimb contralateral to a unilateral injection of the dopaminergic neurotoxin 6-hydroxydopamine can promote recovery of motor function in that limb and can significantly decrease damage to dopamine terminals. The present study was conducted to determine (1) whether a form of voluntary exercise, wheel running, would improve motor performance in rats with such lesions, and (2) whether any beneficial effects of wheel running are attributable to ameliorating the dopaminergic damage. In experiment 1, rats were allowed to run in exercise wheels or kept in home cages for 2 1/2 weeks, then given stereotaxic infusions of 6-hydroxydopamine into the left striatum. The rats were replaced into their original environments (wheels or home cages) for four additional weeks, and asymmetries in forelimb use were quantified at 3, 10, 17, and 24 days postoperatively. After killing, dopaminergic damage was assessed by both quantifying 3 beta-(4-iodophenyl)tropan-2 beta-carboxylic acid methyl ester ([(125)I]RTI-55) binding to striatal dopamine transporters and counting tyrosine hydroxylase-positive cells in the substantia nigra. Exercised 6-hydroxydopamine-infused rats showed improved motor outcomes relative to sedentary lesioned controls, effects that were most apparent at postoperative days 17 and 24. Despite this behavioral improvement, 6-hydroxydopamine-induced loss of striatal dopamine transporters and tyrosine hydroxylase-positive nigral cells in exercised and sedentary groups did not differ. Since prior studies suggested that forced limb use improves motor performance by sparing nigrostriatal dopaminergic neurons from 6-hydroxydopamine damage, experiment 2 used a combined regimen of forced plus voluntary wheel running. Again, we found that the motor performance of exercised rats improved more rapidly than that of sedentary controls, but that there were no differences between these groups in the damage produced by 6-hydroxydopamine. It appears that voluntary

The human dopamine transporter forms a tetramer in the plasma membrane: cross-linking of a cysteine in the fourth transmembrane segment is sensitive to cocaine analogs.

PubMed

Hastrup, Hanne; Sen, Namita; Javitch, Jonathan A

2003-11-14

Using cysteine cross-linking, we demonstrated previously that the dopamine transporter (DAT) is at least a homodimer, with the extracellular end of transmembrane segment (TM) 6 at a symmetrical dimer interface. We have now explored the possibility that DAT exists as a higher order oligomer in the plasma membrane. Cysteine cross-linking of wild type DAT resulted in bands on SDS-PAGE consistent with dimer, trimer, and tetramer, suggesting that DAT forms a tetramer in the plasma membrane. A cysteine-depleted DAT (CD-DAT) into which only Cys243 or Cys306 was reintroduced was cross-linked to dimer, suggesting that these endogenous cysteines in TM4 and TM6, respectively, were cross-linked at a symmetrical dimer interface. Reintroduction of both Cys243 and Cys306 into CD-DAT led to a pattern of cross-linking indistinguishable from that of wild type, with dimer, trimer, and tetramer bands. This indicated that the TM4 interface and the TM6 interface are distinct and further suggested that DAT may exist in the plasma membrane as a dimer of dimers, with two symmetrical homodimer interfaces. The cocaine analog MFZ 2-12 and other DAT inhibitors, including benztropine and mazindol, protected Cys243 against cross-linking. In contrast, two substrates of DAT, dopamine and tyramine, did not significantly impact cross-linking. We propose that the impairment of cross-linking produced by the inhibitors results from a conformational change at the TM4 interface, further demonstrating that these compounds are not neutral blockers but by themselves have effects on the structure of the transporter.

Gastrin stimulates renal dopamine production by increasing the renal tubular uptake of l-DOPA.

PubMed

Jiang, Xiaoliang; Zhang, Yanrong; Yang, Yu; Yang, Jian; Asico, Laureano D; Chen, Wei; Felder, Robin A; Armando, Ines; Jose, Pedro A; Yang, Zhiwei

2017-01-01

Gastrin is a peptide hormone that is involved in the regulation of sodium balance and blood pressure. Dopamine, which is also involved in the regulation of sodium balance and blood pressure, directly or indirectly interacts with other blood pressure-regulating hormones, including gastrin. This study aimed to determine the mechanisms of the interaction between gastrin and dopamine and tested the hypothesis that gastrin produced in the kidney increases renal dopamine production to keep blood pressure within the normal range. We show that in human and mouse renal proximal tubule cells (hRPTCs and mRPTCs, respectively), gastrin stimulates renal dopamine production by increasing the cellular uptake of l-DOPA via the l-type amino acid transporter (LAT) at the plasma membrane. The uptake of l-DOPA in RPTCs from C57Bl/6J mice is lower than in RPTCs from normotensive humans. l-DOPA uptake in renal cortical slices is also lower in salt-sensitive C57Bl/6J than in salt-resistant BALB/c mice. The deficient renal cortical uptake of l-DOPA in C57Bl/6J mice may be due to decreased LAT-1 activity that is related to its decreased expression at the plasma membrane, relative to BALB/c mice. We also show that renal-selective silencing of Gast by the renal subcapsular injection of Gast siRNA in BALB/c mice decreases renal dopamine production and increases blood pressure. These results highlight the importance of renal gastrin in stimulating renal dopamine production, which may give a new perspective in the prevention and treatment of hypertension. Copyright © 2017 the American Physiological Society.

Dysregulation of D2-Mediated Dopamine Transmission in Monkeys after Chronic Escalating Methamphetamine Exposure

PubMed Central

Groman, S.M.; Lee, B.; Seu, E.; James, A.S.; Feiler, K.; Mandelkern, M.A.; London, E.D.; Jentsch, J.D.

2012-01-01

Compulsive drug-seeking and drug-taking are important substance-abuse behaviors that have been linked to alterations in dopaminergic neurotransmission and to impaired inhibitory control. Evidence supports the notions that abnormal D2 receptor-mediated dopamine transmission and inhibitory control may be heritable risk factors for addictions, and that they also reflect drug-induced neuroadaptations. To provide a mechanistic explanation for the drug-induced emergence of inhibitory-control deficits, this study examined how a chronic, escalating-dose regimen of methamphetamine administration affected dopaminergic neurochemistry and cognition in monkeys. Dopamine D2-like receptor and dopamine transporter (DAT) availability and reversal-learning performance were measured before and after exposure to methamphetamine (or saline), and brain dopamine levels were assayed at the conclusion of the study. Exposure to methamphetamine reduced dopamine D2-like receptor and DAT availability, and produced transient, selective impairments in the reversal of a stimulus-outcome association. Furthermore, individual differences in the change in D2-like receptor availability in the striatum were related to the change in response to positive feedback. These data provide evidence that chronic, escalating-dose methamphetamine administration alters the dopamine system in a manner similar to that observed in methamphetamine-dependent humans. They also implicate alterations in positive-feedback sensitivity associated with D2-like receptor dysfunction as the mechanism by which inhibitory control deficits emerge in stimulant-dependent individuals. Finally, a significant degree of neurochemical and behavioral variation in response to methamphetamine was detected, indicating that individual differences affect the degree to which drugs of abuse alter these processes. Identification of these factors ultimately may assist in the development of individualized treatments for substance dependence. PMID

Ctr9, a Protein in the Transcription Complex Paf1, Regulates Dopamine Transporter Activity at the Plasma Membrane.

PubMed

De Gois, Stéphanie; Slama, Patrick; Pietrancosta, Nicolas; Erdozain, Amaia M; Louis, Franck; Bouvrais-Veret, Caroline; Daviet, Laurent; Giros, Bruno

2015-07-17

Dopamine (DA) is a major regulator of sensorimotor and cognitive functions. The DA transporter (DAT) is the key protein that regulates the spatial and temporal activity of DA release into the synaptic cleft via the rapid reuptake of DA into presynaptic termini. Several lines of evidence have suggested that transporter-interacting proteins may play a role in DAT function and regulation. Here, we identified the tetratricopeptide repeat domain-containing protein Ctr9 as a novel DAT binding partner using a yeast two-hybrid system. We showed that Ctr9 is expressed in dopaminergic neurons and forms a stable complex with DAT in vivo via GST pulldown and co-immunoprecipitation assays. In mammalian cells co-expressing both proteins, Ctr9 partially colocalizes with DAT at the plasma membrane. This interaction between DAT and Ctr9 results in a dramatic enhancement of DAT-mediated DA uptake due to an increased number of DAT transporters at the plasma membrane. We determined that the binding of Ctr9 to DAT requires residues YKF in the first half of the DAT C terminus. In addition, we characterized Ctr9, providing new insight into this protein. Using three-dimensional modeling, we identified three novel tetratricopeptide repeat domains in the Ctr9 sequence, and based on deletion mutation experiments, we demonstrated the role of the SH2 domain of Ctr9 in nuclear localization. Our results demonstrate that Ctr9 localization is not restricted to the nucleus, as previously described for the transcription complex Paf1. Taken together, our data provide evidence that Ctr9 modulates DAT function by regulating its trafficking. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Reboxetine Enhances the Olanzapine-Induced Antipsychotic-Like Effect, Cortical Dopamine Outflow and NMDA Receptor-Mediated Transmission

PubMed Central

Marcus, Monica M; Jardemark, Kent; Malmerfelt, Anna; Björkholm, Carl; Svensson, Torgny H

2010-01-01

Preclinical data have shown that addition of the selective norepinephrine transporter (NET) inhibitor reboxetine increases the antipsychotic-like effect of the D2/3 antagonist raclopride and, in parallel, enhances cortical dopamine output. Subsequent clinical results suggested that adding reboxetine to stable treatments with various antipsychotic drugs (APDs) may improve positive, negative and depressive symptoms in schizophrenia. In this study, we investigated in rats the effects of adding reboxetine to the second-generation APD olanzapine on: (i) antipsychotic efficacy, using the conditioned avoidance response (CAR) test, (ii) extrapyramidal side effect (EPS) liability, using a catalepsy test, (iii) dopamine efflux in the medial prefrontal cortex and the nucleus accumbens, using in vivo microdialysis in freely moving animals and (iv) cortical N-methyl--aspartate (NMDA) receptor-mediated transmission, using intracellular electrophysiological recording in vitro. Reboxetine (6 mg/kg) enhanced the suppression of CAR induced by a suboptimal dose (1.25 mg/kg), but not an optimal (2.5 mg/kg) dose of olanzapine without any concomitant catalepsy. Addition of reboxetine to the low dose of olanzapine also markedly increased cortical dopamine outflow and facilitated prefrontal NMDA receptor-mediated transmission. Our data suggest that adjunctive treatment with a NET inhibitor may enhance the therapeutic effect of low-dose olanzapine in schizophrenia without increasing EPS liability and add an antidepressant action, thus in principle allowing for a dose reduction of olanzapine with a concomitant reduction of dose-related side effects, such as EPS and weight gain. PMID:20463659

Ethylenedioxy Homologs of N-Methyl-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) and its Corresponding Cathinone Analog Methylenedioxymethcathinone: Interactions with Transporters for Serotonin, Dopamine, and Norepinephrine

PubMed Central

Del Bello, Fabio; Sakloth, Farhana; Partilla, John S.; Baumann, Michael H.; Glennon, Richard A.

2015-01-01

N -Methyl-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA; ‘Ecstasy’; 1) and its β-keto analog methylone (MDMC; 2) are popular drugs of abuse. Little is known about their ring-expanded ethylenedioxy homologs. Here, we prepared N-methyl-(3,4-ethylenedioxyphenyl)-2-aminopropane (EDMA; 3), both of its optical isomers, and β-keto EDMA (i.e., EDMC; 4) to examine their effects at transporters for serotonin (SERT), dopamine (DAT), and norepinephrine (NET). In general, ring-expansion of the methylenedioxy group led to a several-fold reduction in potency at all three transporters. With respect to EDMA (3), S(+)3 was 6-fold, 50-fold, and 8-fold more potent than its R(−) enantiomer at SERT, DAT, and NET, respectively. Overall, in the absence of a β-carbonyl group, the ethylenedioxy (i.e., 1,4-dioxane) substituent seems better accommodated at SERT than at DAT and NET. PMID:26233799

Pharmacological Investigations of the Dissociative ‘Legal Highs’ Diphenidine, Methoxphenidine and Analogues

PubMed Central

Colestock, Tristan; Morris, Hamilton; Bortolotto, Zuner A.; Lodge, David; Halberstadt, Adam L.; Brandt, Simon D.

2016-01-01

1,2-Diarylethylamines including lanicemine, lefetamine, and remacemide have clinical relevance in a range of therapeutic areas including pain management, epilepsy, neurodegenerative disease and depression. More recently 1,2-diarylethylamines have been sold as ‘legal highs’ in a number of different forms including powders and tablets. These compounds are sold to circumvent governmental legislation regulating psychoactive drugs. Examples include the opioid MT-45 and the dissociative agents diphenidine (DPH) and 2-methoxy-diphenidine (2-MXP). A number of fatal and non-fatal overdoses have been linked to abuse of these compounds. As with many ‘legal highs’, little is known about their pharmacology. To obtain a better understanding, the effects of DPH, 2-MXP and its 3- and 4-MeO- isomers, and 2-Cl-diphenidine (2-Cl-DPH) were investigated using binding studies at 46 central nervous system receptors including the N-methyl-D-aspartate receptor (NMDAR), serotonin, dopamine, norepinephrine, histamine, and sigma receptors as well as the reuptake transporters for serotonin, dopamine and norepinephrine. Reuptake inhibition potencies were measured at serotonin, norepinephrine and dopamine transporters. NMDAR antagonism was established in vitro using NMDAR-induced field excitatory postsynaptic potential (fEPSP) experiments. Finally, DPH and 2-MXP were investigated using tests of pre-pulse inhibition of startle (PPI) in rats to determine whether they reduce sensorimotor gating, an effect observed with known dissociative drugs such as phencyclidine (PCP) and ketamine. The results suggest that these 1,2-diarylethylamines are relatively selective NMDAR antagonists with weak off-target inhibitory effects on dopamine and norepinephrine reuptake. DPH and 2-MXP significantly inhibited PPI. DPH showed greater potency than 2-MXP, acting with a median effective dose (ED50) of 9.5 mg/kg, which is less potent than values reported for other commonly abused dissociative drugs such as

Extrastriatal dopamine D2-receptor availability in social anxiety disorder.

PubMed

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.

Effects of Smoking Cessation on Presynaptic Dopamine Function of Addicted Male Smokers.

PubMed

Rademacher, Lena; Prinz, Susanne; Winz, Oliver; Henkel, Karsten; Dietrich, Claudia A; Schmaljohann, Jörn; Mohammadkhani Shali, Siamak; Schabram, Ina; Stoppe, Christian; Cumming, Paul; Hilgers, Ralf-Dieter; Kumakura, Yoshitaka; Coburn, Mark; Mottaghy, Felix M; Gründer, Gerhard; Vernaleken, Ingo

2016-08-01

There is evidence of abnormal cerebral dopamine transmission in nicotine-dependent smokers, but it is unclear whether dopaminergic abnormalities are due to acute nicotine abuse or whether they persist with abstinence. We addressed this question by conducting longitudinal positron emission tomography (PET) examination of smokers before and after 3 months of abstinence. We obtained baseline 6-[(18)F]fluoro-L-DOPA (FDOPA)-PET scans in 15 nonsmokers and 30 nicotine-dependent smokers, who either smoked as per their usual habit or were in acute withdrawal. All smokers then underwent cessation treatment, and successful abstainers were re-examined by FDOPA-PET after 3 months of abstinence (n = 15). Uptake of FDOPA was analyzed using a steady-state model yielding estimates of the dopamine synthesis capacity (K); the turnover of tracer dopamine formed in living brain (kloss); and the tracer distribution volume (Vd), which is an index of dopamine storage capacity. Compared with nonsmokers, K was 15% to 20% lower in the caudate nuclei of consuming smokers. Intraindividual comparisons of consumption and long-term abstinence revealed significant increases in K in the right dorsal and left ventral caudate nuclei. Relative to acute withdrawal, Vd significantly decreased in the right ventral and dorsal caudate after prolonged abstinence. Severity of nicotine dependence significantly correlated with dopamine synthesis capacity and dopamine turnover in the bilateral ventral putamen of consuming smokers. The results suggest a lower dopamine synthesis capacity in nicotine-dependent smokers that appears to normalize with abstinence. Further investigations are needed to clarify the role of dopamine in nicotine addiction to help develop smoking prevention and cessation treatments. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Dopamine reward prediction error coding.

PubMed

Schultz, Wolfram

2016-03-01

Reward prediction errors consist of the differences between received and predicted rewards. They are crucial for basic forms of learning about rewards and make us strive for more rewards-an evolutionary beneficial trait. Most dopamine neurons in the midbrain of humans, monkeys, and rodents signal a reward prediction error; they are activated by more reward than predicted (positive prediction error), remain at baseline activity for fully predicted rewards, and show depressed activity with less reward than predicted (negative prediction error). The dopamine signal increases nonlinearly with reward value and codes formal economic utility. Drugs of addiction generate, hijack, and amplify the dopamine reward signal and induce exaggerated, uncontrolled dopamine effects on neuronal plasticity. The striatum, amygdala, and frontal cortex also show reward prediction error coding, but only in subpopulations of neurons. Thus, the important concept of reward prediction errors is implemented in neuronal hardware.

Dopamine reward prediction error coding

PubMed Central

Schultz, Wolfram

2016-01-01

Reward prediction errors consist of the differences between received and predicted rewards. They are crucial for basic forms of learning about rewards and make us strive for more rewards—an evolutionary beneficial trait. Most dopamine neurons in the midbrain of humans, monkeys, and rodents signal a reward prediction error; they are activated by more reward than predicted (positive prediction error), remain at baseline activity for fully predicted rewards, and show depressed activity with less reward than predicted (negative prediction error). The dopamine signal increases nonlinearly with reward value and codes formal economic utility. Drugs of addiction generate, hijack, and amplify the dopamine reward signal and induce exaggerated, uncontrolled dopamine effects on neuronal plasticity. The striatum, amygdala, and frontal cortex also show reward prediction error coding, but only in subpopulations of neurons. Thus, the important concept of reward prediction errors is implemented in neuronal hardware. PMID:27069377

Control of extracellular dopamine at dendrite and axon terminals

PubMed Central

Ford, Christopher P.; Gantz, Stephanie C.; Phillips, Paul E. M.; Williams, John T.

2010-01-01

Midbrain dopamine neurons release dopamine from both axons and dendrites. The mechanism underlying release at these different sites has been proposed to differ. This study used electrochemical and electrophysiological methods to compare the time course and calcium-dependence of somatodendritc dopamine release in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) to that of axonal dopamine release in the dorsal striatum. The amount of dopamine released in the striatum was ~20 fold greater than in cell body regions of the VTA or SNc. However the calcium dependence and time to peak of the dopamine transients were similar. These results illustrate an unexpected overall similarity in the mechanisms of dopamine release in the striatum and cell body regions. To examine how diffusion regulates the time course of dopamine following release, dextran was added to the extracellular solution to slow diffusion. In the VTA, dextran slowed the rate of rise and fall of the extracellular dopamine transient as measured by fast-scan cyclic voltammetry (FSCV) yet did not alter the kinetics of the dopamine dependent inhibitory post-synaptic current (IPSC). Dextran failed to significantly alter the time course of the rise and fall of the dopamine transient in the striatum suggesting a more influential role for reuptake in the striatum. The conclusion is that the time course of dopamine within the extracellular space of the VTA is dependent on both diffusion and reuptake, whereas the activation of D2-receptors on dopamine neurons is primarily limited by reuptake. PMID:20484639

THE MYSTERIOUS MOTIVATIONAL FUNCTIONS OF MESOLIMBIC DOPAMINE

PubMed Central

Salamone, John D.; Correa, Mercè

2012-01-01

Summary Nucleus accumbens dopamine is known to play a role in motivational processes, and dysfunctions of mesolimbic dopamine may contribute to motivational symptoms of depression and other disorders, as well as features of substance abuse. Although it has become traditional to label dopamine neurons as “reward” neurons, this is an over-generalization, and it is important to distinguish between aspects of motivation that are differentially affected by dopaminergic manipulations. For example, accumbens dopamine does not mediate primary food motivation or appetite, but is involved in appetitive and aversive motivational processes including behavioral activation, exertion of effort, approach behavior, sustained task engagement, Pavlovian processes and instrumental learning. In this review, we discuss the complex roles of dopamine in behavioral functions related to motivation. PMID:23141060

Optimized in vivo detection of dopamine release using 18F-fallypride PET.

PubMed

Ceccarini, Jenny; Vrieze, Elske; Koole, Michel; Muylle, Tom; Bormans, Guy; Claes, Stephan; Van Laere, Koen

2012-10-01

The high-affinity D(2/3) PET radioligand (18)F-fallypride offers the possibility of measuring both striatal and extrastriatal dopamine release during activation paradigms. When a single (18)F-fallypride scanning protocol is used, task timing is critical to the ability to explore both striatal and extrastriatal dopamine release simultaneously. We evaluated the sensitivity and optimal timing of task administration for a single (18)F-fallypride PET protocol and the linearized simplified reference region kinetic model in detecting both striatal and extrastriatal reward-induced dopamine release, using human and simulation studies. Ten healthy volunteers underwent a single-bolus (18)F-fallypride PET protocol. A reward responsiveness learning task was initiated at 100 min after injection. PET data were analyzed using the linearized simplified reference region model, which accounts for time-dependent changes in (18)F-fallypride displacement. Voxel-based statistical maps, reflecting task-induced D(2/3) ligand displacement, and volume-of-interest-based analysis were performed to localize areas with increased ligand displacement after task initiation, thought to be proportional to changes in endogenous dopamine release (γ parameter). Simulated time-activity curves for baseline and hypothetical dopamine release functions (different peak heights of dopamine and task timings) were generated using the enhanced receptor-binding kinetic model to investigate γ as a function of these parameters. The reward task induced increased ligand displacement in extrastriatal regions of the reward circuit, including the medial orbitofrontal cortex, ventromedial prefrontal cortex, and dorsal anterior cingulate cortex. For task timing of 100 min, ligand displacement was found for the striatum only when peak height of dopamine was greater than 240 nM, whereas for frontal regions, γ was always positive for all task timings and peak heights of dopamine. Simulation results for a peak height of

CIN85 regulates dopamine receptor endocytosis and governs behaviour in mice

PubMed Central

Shimokawa, Noriaki; Haglund, Kaisa; Hölter, Sabine M; Grabbe, Caroline; Kirkin, Vladimir; Koibuchi, Noriyuki; Schultz, Christian; Rozman, Jan; Hoeller, Daniela; Qiu, Chun-Hong; Londoño, Marina B; Ikezawa, Jun; Jedlicka, Peter; Stein, Birgit; Schwarzacher, Stephan W; Wolfer, David P; Ehrhardt, Nicole; Heuchel, Rainer; Nezis, Ioannis; Brech, Andreas; Schmidt, Mirko H H; Fuchs, Helmut; Gailus-Durner, Valerie; Klingenspor, Martin; Bogler, Oliver; Wurst, Wolfgang; Deller, Thomas; de Angelis, Martin Hrabé; Dikic, Ivan

2010-01-01

Despite extensive investigations of Cbl-interacting protein of 85 kDa (CIN85) in receptor trafficking and cytoskeletal dynamics, little is known about its functions in vivo. Here, we report the study of a mouse deficient of the two CIN85 isoforms expressed in the central nervous system, exposing a function of CIN85 in dopamine receptor endocytosis. Mice lacking CIN85 exon 2 (CIN85Δex2) show hyperactivity phenotypes, characterized by increased physical activity and exploratory behaviour. Interestingly, CIN85Δex2 animals display abnormally high levels of dopamine and D2 dopamine receptors (D2DRs) in the striatum, an important centre for the coordination of animal behaviour. Importantly, CIN85 localizes to the post-synaptic compartment of striatal neurons in which it co-clusters with D2DRs. Moreover, it interacts with endocytic regulators such as dynamin and endophilins in the striatum. Absence of striatal CIN85 causes insufficient complex formation of endophilins with D2DRs in the striatum and ultimately decreased D2DR endocytosis in striatal neurons in response to dopamine stimulation. These findings indicate an important function of CIN85 in the regulation of dopamine receptor functions and provide a molecular explanation for the hyperactive behaviour of CIN85Δex2 mice. PMID:20551902

Glutamate neurons are intermixed with midbrain dopamine neurons in nonhuman primates and humans

PubMed Central

Root, David H.; Wang, Hui-Ling; Liu, Bing; Barker, David J.; Mód, László; Szocsics, Péter; Silva, Afonso C.; Maglóczky, Zsófia; Morales, Marisela

2016-01-01

The rodent ventral tegmental area (VTA) and substantia nigra pars compacta (SNC) contain dopamine neurons intermixed with glutamate neurons (expressing vesicular glutamate transporter 2; VGluT2), which play roles in reward and aversion. However, identifying the neuronal compositions of the VTA and SNC in higher mammals has remained challenging. Here, we revealed VGluT2 neurons within the VTA and SNC of nonhuman primates and humans by simultaneous detection of VGluT2 mRNA and tyrosine hydroxylase (TH; for identification of dopamine neurons). We found that several VTA subdivisions share similar cellular compositions in nonhuman primates and humans; their rostral linear nuclei have a high prevalence of VGluT2 neurons lacking TH; their paranigral and parabrachial pigmented nuclei have mostly TH neurons, and their parabrachial pigmented nuclei have dual VGluT2-TH neurons. Within nonhuman primates and humans SNC, the vast majority of neurons are TH neurons but VGluT2 neurons were detected in the pars lateralis subdivision. The demonstration that midbrain dopamine neurons are intermixed with glutamate or glutamate-dopamine neurons from rodents to humans offers new opportunities for translational studies towards analyzing the roles that each of these neurons play in human behavior and in midbrain-associated illnesses such as addiction, depression, schizophrenia, and Parkinson’s disease. PMID:27477243

The protective effect of dopamine on ventilator-induced lung injury via the inhibition of NLRP3 inflammasome.

PubMed

Yang, Xiaomei; Sun, Xiaotong; Chen, Hongli; Xi, Guangmin; Hou, Yonghao; Wu, Jianbo; Liu, Dejie; Wang, Huanliang; Hou, Yuedong; Yu, Jingui

2017-04-01

Dopamine (DA), a neurotransmitter, was previously shown to have anti-inflammatory effects. However, its role in ventilator-induced lung injury (VILI) has not been explicitly demonstrated. This study aimed to investigate the therapeutic efficacy and molecular mechanisms of dopamine in VILI. Rats were treated with dopamine during mechanical ventilation. Afterwards, the influence of dopamine on histological changes, pulmonary edema, the lung wet/dry (W/D) ratio, myeloperoxidase (MPO) activity, polymorphonuclear(PMN)counts, inflammatory cytokine levels, and NLRP3 inflammasome protein expression were examined. Our results showed that dopamine significantly attenuated lung tissue injury, the lung W/D ratio, MPO activity and neutrophil infiltration. Moreover, it inhibited inflammatory cytokine levels in the Bronchoalveolar lavage fluid (BAL). In addition, dopamine significantly inhibited ventilation-induced NLRP3 activation. Our experimental findings demonstrate that dopamine exerted protective effects in VILI by alleviating the inflammatory response through inhibition of NLRP3 signaling pathways. The present study indicated that dopamine could be a potential effective therapeutic strategy for the treatment of VILI. Copyright © 2017 Elsevier B.V. All rights reserved.

A Single Amphetamine Infusion Reverses Deficits in Dopamine Nerve-Terminal Function Caused by a History of Cocaine Self-Administration.

PubMed

Ferris, Mark J; Calipari, Erin S; Rose, Jamie H; Siciliano, Cody A; Sun, Haiguo; Chen, Rong; Jones, Sara R

2015-07-01

There are ∼ 1.6 million people who meet the criteria for cocaine addiction in the United States, and there are currently no FDA-approved pharmacotherapies. Amphetamine-based dopamine-releasing drugs have shown efficacy in reducing the motivation to self-administer cocaine and reducing intake in animals and humans. It is hypothesized that amphetamine acts as a replacement therapy for cocaine through elevation of extracellular dopamine levels. Using voltammetry in brain slices, we tested the ability of a single amphetamine infusion in vivo to modulate dopamine release, uptake kinetics, and cocaine potency in cocaine-naive animals and after a history of cocaine self-administration (1.5 mg/kg/infusion, fixed-ratio 1, 40 injections/day × 5 days). Dopamine kinetics were measured 1 and 24 h after amphetamine infusion (0.56 mg/kg, i.v.). Following cocaine self-administration, dopamine release, maximal rate of uptake (Vmax), and membrane-associated dopamine transporter (DAT) levels were reduced, and the DAT was less sensitive to cocaine. A single amphetamine infusion reduced Vmax and membrane DAT levels in cocaine-naive animals, but fully restored all aspects of dopamine terminal function in cocaine self-administering animals. Here, for the first time, we demonstrate pharmacologically induced, immediate rescue of deficits in dopamine nerve-terminal function in animals with a history of high-dose cocaine self-administration. This observation supports the notion that the DAT expression and function can be modulated on a rapid timescale and also suggests that the pharmacotherapeutic actions of amphetamine for cocaine addiction go beyond that of replacement therapy.

A Single Amphetamine Infusion Reverses Deficits in Dopamine Nerve-Terminal Function Caused by a History of Cocaine Self-Administration

PubMed Central

Ferris, Mark J; Calipari, Erin S; Rose, Jamie H; Siciliano, Cody A; Sun, Haiguo; Chen, Rong; Jones, Sara R

2015-01-01

There are ∼1.6 million people who meet the criteria for cocaine addiction in the United States, and there are currently no FDA-approved pharmacotherapies. Amphetamine-based dopamine-releasing drugs have shown efficacy in reducing the motivation to self-administer cocaine and reducing intake in animals and humans. It is hypothesized that amphetamine acts as a replacement therapy for cocaine through elevation of extracellular dopamine levels. Using voltammetry in brain slices, we tested the ability of a single amphetamine infusion in vivo to modulate dopamine release, uptake kinetics, and cocaine potency in cocaine-naive animals and after a history of cocaine self-administration (1.5 mg/kg/infusion, fixed-ratio 1, 40 injections/day × 5 days). Dopamine kinetics were measured 1 and 24 h after amphetamine infusion (0.56 mg/kg, i.v.). Following cocaine self-administration, dopamine release, maximal rate of uptake (Vmax), and membrane-associated dopamine transporter (DAT) levels were reduced, and the DAT was less sensitive to cocaine. A single amphetamine infusion reduced Vmax and membrane DAT levels in cocaine-naive animals, but fully restored all aspects of dopamine terminal function in cocaine self-administering animals. Here, for the first time, we demonstrate pharmacologically induced, immediate rescue of deficits in dopamine nerve-terminal function in animals with a history of high-dose cocaine self-administration. This observation supports the notion that the DAT expression and function can be modulated on a rapid timescale and also suggests that the pharmacotherapeutic actions of amphetamine for cocaine addiction go beyond that of replacement therapy. PMID:25689882

Renal dopamine containing nerves. What is their functional significance?

PubMed

DiBona, G F

1990-06-01

Biochemical and morphological studies indicate that there are nerves within the kidney that contain dopamine and that various structures within the kidney contain dopamine receptors. However, the functional significance of these renal dopamine containing nerves in relation to renal dopamine receptors is unknown. The functional significance could be defined by demonstrating that an alteration in one or more renal functions occurring in response to reflex or electrical activation of efferent renal nerves is dependent on release of dopamine as the neurotransmitter from the renal nerve terminals acting on renal dopamine receptors. Thus, the hypothesis becomes: reflex or electrical activation of efferent renal nerves causes alterations in renal function (eg, renal blood flow, water and solute handling) that are inhibited by specific and selective dopamine receptor antagonists. As reviewed herein, the published experimental data do not support the hypothesis. Therefore, the view that alterations in one or more renal functions occurring in response to reflex or electrical activation of efferent renal nerves are dependent on release of dopamine as the neurotransmitter from the renal nerve terminals acting on renal dopamine receptors remains unproven.

Eating High Fat Chow Decreases Dopamine Clearance in Adolescent and Adult Male Rats but Selectively Enhances the Locomotor Stimulating Effects of Cocaine in Adolescents

PubMed Central

Baladi, Michelle G.; Horton, Rebecca E.; Owens, William A.; Daws, Lynette C.

2015-01-01

Background: Feeding conditions can influence dopamine neurotransmission and impact behavioral and neurochemical effects of drugs acting on dopamine systems. This study examined whether eating high fat chow alters the locomotor effects of cocaine and dopamine transporter activity in adolescent (postnatal day 25) and adult (postnatal day 75) male Sprague-Dawley rats. Methods: Dose-response curves for cocaine-induced locomotor activity were generated in rats with free access to either standard or high fat chow or restricted access to high fat chow (body weight matched to rats eating standard chow). Results: Compared with eating standard chow, eating high fat chow increased the sensitivity of adolescent, but not adult, rats to the acute effects of cocaine. When tested once per week, sensitization to the locomotor effects of cocaine was enhanced in adolescent rats eating high fat chow compared with adolescent rats eating standard chow. Sensitization to cocaine was not different among feeding conditions in adults. When adolescent rats that previously ate high fat chow ate standard chow, sensitivity to cocaine returned to normal. As measured by chronoamperometry, dopamine clearance rate in striatum was decreased in both adolescent and adult rats eating high fat chow compared with age-matched rats eating standard chow. Conclusions: These results suggest that high fat diet-induced reductions in dopamine clearance rate do not always correspond to increased sensitivity to the locomotor effects of cocaine, suggesting that mechanisms other than dopamine transporter might play a role. Moreover, in adolescent but not adult rats, eating high fat chow increases sensitivity to cocaine and enhances the sensitization that develops to cocaine. PMID:25805560

Structural and Functional Characterization of the Interaction of Snapin with the Dopamine Transporter: Differential Modulation of Psychostimulant Actions.

PubMed

Erdozain, Amaia M; De Gois, Stéphanie; Bernard, Véronique; Gorgievski, Victor; Pietrancosta, Nicolas; Dumas, Sylvie; Macedo, Carlos E; Vanhoutte, Peter; Ortega, Jorge E; Meana, J Javier; Tzavara, Eleni T; Vialou, Vincent; Giros, Bruno

2018-04-01

The importance of dopamine (DA) neurotransmission is emphasized by its direct implication in several neurological and psychiatric disorders. The DA transporter (DAT), target of psychostimulant drugs, is the key protein that regulates spatial and temporal activity of DA in the synaptic cleft via the rapid reuptake of DA into the presynaptic terminal. There is strong evidence suggesting that DAT-interacting proteins may have a role in its function and regulation. Performing a two-hybrid screening, we identified snapin, a SNARE-associated protein implicated in synaptic transmission, as a new binding partner of the carboxyl terminal of DAT. Our data show that snapin is a direct partner and regulator of DAT. First, we determined the domains required for this interaction in both proteins and characterized the DAT-snapin interface by generating a 3D model. Using different approaches, we demonstrated that (i) snapin is expressed in vivo in dopaminergic neurons along with DAT; (ii) both proteins colocalize in cultured cells and brain and, (iii) DAT and snapin are present in the same protein complex. Moreover, by functional studies we showed that snapin produces a significant decrease in DAT uptake activity. Finally, snapin downregulation in mice produces an increase in DAT levels and transport activity, hence increasing DA concentration and locomotor response to amphetamine. In conclusion, snapin/DAT interaction represents a direct link between exocytotic and reuptake mechanisms and is a potential target for DA transmission modulation.

Stimulus-Dependent Dopamine Release in Attention-Deficit/Hyperactivity Disorder

ERIC Educational Resources Information Center

Sikstrom, Sverker; Soderlund, Goran

2007-01-01

Attention-deficit/hyperactivity disorder (ADHD) is related to an attenuated and dysfunctional dopamine system. Normally, a high extracellular dopamine level yields a tonic dopaminergic input that down-regulates stimuli-evoked phasic dopamine responses through autoreceptors. Abnormally low tonic extracellular dopamine in ADHD up-regulates the…

Dopamine depleters in the treatment of hyperkinetic movement disorders.

PubMed

Jankovic, Joseph

2016-12-01

Abnormal involuntary movements often improve in response to anti-dopaminergic drugs. In contrast to classic neuroleptics that block dopamine receptors, drugs that deplete presynaptic dopamine by blocking vesicular monoamine transporter type 2 (VMAT2) seem to be safer and have little or no risk of tardive dyskinesia. This is one reason why there has been a recent emergence of novel VMAT2 inhibitors. Areas covered: Since the approval of tetrabenazine, the classic VMAT2 inhibitor, in the treatment of chorea associated with Huntington disease (HD), other VMAT2 inhibitors (e.g. deutetrabenazine and valbenazine) have been studied in the treatment of HD-related chorea, tardive dyskinesia and tics associated with Tourette syndrome. This review, based largely on a detailed search of PubMed, will summarize the pharmacology and clinical experience with the various VMAT2 inhibitors. Expert commentary: Because of differences in pharmacology and pharmacokinetics these new VMAT2 inhibitors promise to be at least as effective as tetrabenazine but with a lower risk of adverse effects, such as sedation, insomnia, depression, parkinsonism, and akathisia.

Ih Current Is Necessary to Maintain Normal Dopamine Fluctuations and Sleep Consolidation in Drosophila

PubMed Central

Gonzalo-Gomez, Alicia; Turiegano, Enrique; León, Yolanda; Molina, Isabel; Torroja, Laura; Canal, Inmaculada

2012-01-01

HCN channels are becoming pharmacological targets mainly in cardiac diseases. But apart from their well-known role in heart pacemaking, these channels are widely expressed in the nervous system where they contribute to the neuron firing pattern. Consequently, abolishing Ih current might have detrimental consequences in a big repertoire of behavioral traits. Several studies in mammals have identified the Ih current as an important determinant of the firing activity of dopaminergic neurons, and recent evidences link alterations in this current to various dopamine-related disorders. We used the model organism Drosophila melanogaster to investigate how lack of Ih current affects dopamine levels and the behavioral consequences in the sleep∶activity pattern. Unlike mammals, in Drosophila there is only one gene encoding HCN channels. We generated a deficiency of the DmIh core gene region and measured, by HPLC, levels of dopamine. Our data demonstrate daily variations of dopamine in wild-type fly heads. Lack of Ih current dramatically alters dopamine pattern, but different mechanisms seem to operate during light and dark conditions. Behaviorally, DmIh mutant flies display alterations in the rest∶activity pattern, and altered circadian rhythms. Our data strongly suggest that Ih current is necessary to prevent dopamine overproduction at dark, while light input allows cycling of dopamine in an Ih current dependent manner. Moreover, lack of Ih current results in behavioral defects that are consistent with altered dopamine levels. PMID:22574167

Ih current is necessary to maintain normal dopamine fluctuations and sleep consolidation in Drosophila.

PubMed

Gonzalo-Gomez, Alicia; Turiegano, Enrique; León, Yolanda; Molina, Isabel; Torroja, Laura; Canal, Inmaculada

2012-01-01

HCN channels are becoming pharmacological targets mainly in cardiac diseases. But apart from their well-known role in heart pacemaking, these channels are widely expressed in the nervous system where they contribute to the neuron firing pattern. Consequently, abolishing Ih current might have detrimental consequences in a big repertoire of behavioral traits. Several studies in mammals have identified the Ih current as an important determinant of the firing activity of dopaminergic neurons, and recent evidences link alterations in this current to various dopamine-related disorders. We used the model organism Drosophila melanogaster to investigate how lack of Ih current affects dopamine levels and the behavioral consequences in the sleep:activity pattern. Unlike mammals, in Drosophila there is only one gene encoding HCN channels. We generated a deficiency of the DmIh core gene region and measured, by HPLC, levels of dopamine. Our data demonstrate daily variations of dopamine in wild-type fly heads. Lack of Ih current dramatically alters dopamine pattern, but different mechanisms seem to operate during light and dark conditions. Behaviorally, DmIh mutant flies display alterations in the rest:activity pattern, and altered circadian rhythms. Our data strongly suggest that Ih current is necessary to prevent dopamine overproduction at dark, while light input allows cycling of dopamine in an Ih current dependent manner. Moreover, lack of Ih current results in behavioral defects that are consistent with altered dopamine levels.

Enhanced Dopamine-Dependent Hippocampal Plasticity after Single MK-801 Application

PubMed Central

Bartsch, Julia C; Fidzinski, Pawel; Huck, Jojanneke HJ; Hörtnagl, Heide; Kovács, Richard; Liotta, Agustin; Priller, Josef; Wozny, Christian; Behr, Joachim

2015-01-01

Dopaminergic hyperfunction and N-methyl-D-aspartate receptor (NMDAR) hypofunction have both been implicated in psychosis. Dopamine-releasing drugs and NMDAR antagonists replicate symptoms associated with psychosis in healthy humans and exacerbate symptoms in patients with schizophrenia. Though hippocampal dysfunction contributes to psychosis, the impact of NMDAR hypofunction on hippocampal plasticity remains poorly understood. Here, we used an NMDAR antagonist rodent model of psychosis to investigate hippocampal long-term potentiation (LTP). We found that single systemic NMDAR antagonism results in a region-specific, presynaptic LTP at hippocampal CA1-subiculum synapses that is induced by activation of D1/D5 dopamine receptors and modulated by L-type voltage-gated Ca2+ channels. Thereby, our findings may provide a cellular mechanism how NMDAR antagonism can lead to an enhanced hippocampal output causing activation of the hippocampus-ventral tegmental area-loop and overdrive of the dopamine system. PMID:25315194

Absence of age-related dopamine transporter loss in current cocaine abusers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, G.J.; Volkow, N.D.; Fischman, M.

The brain dopamine (DA) system appears to play a crucial role in the reinforcing properties of cocaine. Using PET we had previously shown significant decreases in DA D2 receptors but no changes in DA transporters (DAT) in detoxified cocaine abusers (>1 month after last cocaine use). This study evaluates DAT availability in current cocaine abusers (15 male and 5 female; age = 36.2{+-}5.3 years old) using PET and [C-11]cocaine, as a DAT ligand, and compares it to that in 18 male and 2 female age matched normal controls. Cocaine abusers had a history of abusing 4.2{+-}2.8 gm /week of cocainemore » for an average of 11.0{+-}4.9 years and their last use of cocaine was 5.4{+-}8 days prior to PET study. DAT availability was obtained using the ratio of the distribution volume in the region of interest (caudate, pulamen) to that in cerebellum which is a function of Bmax./Kd.+1. DAT availability in cocaine abusers did not differ to that in normals (N) (C= 1.78{+-}0.14, N= 1.77{+-}0.13). In addition, there were no differences between the groups in the distribution volume or the Kl (plasma to brain transfer constant) measures for [C-11]cocaine. However, in the normals but not in the abusers striatal DAT availability decreased with age (C: r = -0.07, p = 0.76; N: r = -0.55, p < 0.01). Though this study fails to show group differences in DAT availability between normals and current cocaine abusers it indicates a blunting of the age-related decline in DAT availability in the cocaine abusers. Future studies in older cocaine abusers at different time after detoxification arc required in order to assess if cocaine slows the loss of DAT with age or whether these changes reflect compensation to increased DAT blockade and recover with detoxification.« less

[Dopamine neurotransmission of peripheral blood lymphocytes is a potential biomarker of psychiatric and neurological disorders].

PubMed

Taraskina, A E; Nasyrova, R F; Grunina, M N; Zabotina, A M; Ivashchenko, D V; Ershov, E E; Sosin, D N; Kirnichnaya, K A; Ivanov, M V; Krupitsky, E M

2015-01-01

Current literature on a role of dopamine in the development of mental and neurological disorders suggests that the discovery of endogenous dopamine in peripheral blood lymphocytes gave rise to a new line of research. Dopamine receptors are not only found on cells of the innate immune response (nonspecific), but also on cells of adaptive immune response (specific): T and B lymphocytes. These facts bring a new evidence of interrelationships between the peripheral immune system, neuroinflammation and neurodegeneration and suggest new ways for investigation of the pathogenesis of different mental and neurological disorders, in particular Parkinson's disease, Alzheimer's disease and schizophrenia. There is strong evidence that ligands of dopamine receptors can change the expression of coding genes both in central neurons and in peripheral cells. Thus, peripheral blood lymphocytes may prove a cellular tool to identify dopamine transmission disturbances in neuropsychiatric diseases, as well as to monitor the effects of pharmacological treatment.

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

PubMed Central

2016-01-01

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

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

PubMed

Rodeberg, Nathan T; Johnson, Justin A; Bucher, Elizabeth S; Wightman, R Mark

2016-11-16

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

Dopamine Depletion Reduces Food-Related Reward Activity Independent of BMI

PubMed Central

Frank, Sabine; Veit, Ralf; Sauer, Helene; Enck, Paul; Friederich, Hans-Christoph; Unholzer, Theresa; Bauer, Ute-Maria; Linder, Katarzyna; Heni, Martin; Fritsche, Andreas; Preissl, Hubert

2016-01-01

Reward sensitivity and possible alterations in the dopaminergic-reward system are associated with obesity. We therefore aimed to investigate the influence of dopamine depletion on food-reward processing. We investigated 34 female subjects in a randomized placebo-controlled, within-subject design (body mass index (BMI)=27.0 kg/m2 ±4.79 SD; age=28 years ±4.97 SD) using an acute phenylalanine/tyrosine depletion drink representing dopamine depletion and a balanced amino acid drink as the control condition. Brain activity was measured with functional magnetic resonance imaging during a ‘wanting' and ‘liking' rating of food items. Eating behavior-related traits and states were assessed on the basis of questionnaires. Dopamine depletion resulted in reduced activation in the striatum and higher activation in the superior frontal gyrus independent of BMI. Brain activity during the wanting task activated a more distributed network than during the liking task. This network included gustatory, memory, visual, reward, and frontal regions. An interaction effect of dopamine depletion and the wanting/liking task was observed in the hippocampus. The interaction with the covariate BMI was significant in motor and control regions but not in the striatum. Our results support the notion of altered brain activity in the reward and prefrontal network with blunted dopaminergic action during food-reward processing. This effect is, however, independent of BMI, which contradicts the reward-deficiency hypothesis. This hints to the hypothesis suggesting a different or more complex mechanism underlying the dopaminergic reward function in obesity. PMID:26450814

Dopamine controls the neural dynamics of memory signals and retrieval accuracy.

PubMed

Apitz, Thore; Bunzeck, Nico

2013-11-01

The human brain is capable of differentiating between new and already stored information rapidly to allow optimal behavior and decision-making. Although the neural mechanisms of novelty discrimination were often described as temporally constant (ie, with specific latencies), recent electrophysiological studies have demonstrated that the onset of neural novelty signals (ie, differences in event-related responses to new and old items) can be accelerated by reward motivation. While the precise physiological mechanisms underlying this acceleration remain unclear, the involvement of the neurotransmitter dopamine in both novelty and reward processing suggests that enhanced dopamine levels in the context of reward prospect may have a role. To investigate this hypothesis, we used magnetoencephalography (MEG) in combination with an old/new recognition memory task in which correct discrimination between old and new items was rewarded. Importantly, before the task, human subjects received either 150 mg of the dopamine precursor levodopa or placebo. For the placebo group, old/new signals peaked at ∼100 ms after stimulus onset over left temporal/occipital sensors. In contrast, after levodopa administration earliest old/new effects only emerged after ∼400 ms and retrieval accuracy was reduced as expressed in lower d' values. As such, our results point towards a previously unreported role of dopamine in controlling the chronometry of neural processes underlying the distinction between old and new information. They also suggest that this relationship follows a nonlinear function whereby slightly enhanced dopamine levels accelerate neural/cognitive processes and excessive dopamine levels impair them.

Dopamine and μ-opioid receptor dysregulation in the brains of binge-eating female rats - possible relevance in the psychopathology and treatment of binge-eating disorder.

PubMed

Heal, David J; Hallam, Michelle; Prow, Michael; Gosden, Jane; Cheetham, Sharon; Choi, Yong K; Tarazi, Frank; Hutson, Peter

2017-06-01