Dopaminergic Modulation of Risky Decision-Making

PubMed Central

Simon, Nicholas W.; Montgomery, Karienn S.; Beas, Blanca S.; Mitchell, Marci R.; LaSarge, Candi L.; Mendez, Ian A.; Bañuelos, Cristina; Vokes, Colin M.; Taylor, Aaron B.; Haberman, Rebecca P.; Bizon, Jennifer L.; Setlow, Barry

2012-01-01

Many psychiatric disorders are characterized by abnormal risky decision-making and dysregulated dopamine receptor expression. The current study was designed to determine how different dopamine receptor subtypes modulate risk-taking in young adult rats, using a “Risky Decision-making Task” that involves choices between small “safe” rewards and large “risky” rewards accompanied by adverse consequences. Rats showed considerable, stable individual differences in risk preference in the task, which were not related to multiple measures of reward motivation, anxiety, or pain sensitivity. Systemic activation of D2-like receptors robustly attenuated risk-taking, whereas drugs acting on D1-like receptors had no effect. Systemic amphetamine also reduced risk-taking, an effect which was attenuated by D2-like (but not D1-like) receptor blockade. Dopamine receptor mRNA expression was evaluated in a separate cohort of drug-naive rats characterized in the task. D1 mRNA expression in both nucleus accumbens shell and insular cortex was positively associated with risk-taking, while D2 mRNA expression in orbitofrontal and medial prefrontal cortex predicted risk preference in opposing nonlinear patterns. Additionally, lower levels of D2 mRNA in dorsal striatum were associated with greater risk-taking. These data strongly implicate dopamine signaling in prefrontal corticalstriatal circuitry in modulating decision-making processes involving integration of reward information with risks of adverse consequences. PMID:22131407

Serotoninergic and dopaminergic modulation of cortico-striatal circuit in executive and attention deficits induced by NMDA receptor hypofunction in the 5-choice serial reaction time task

PubMed Central

Carli, Mirjana; Invernizzi, Roberto W.

2014-01-01

Executive functions are an emerging propriety of neuronal processing in circuits encompassing frontal cortex and other cortical and subcortical brain regions such as basal ganglia and thalamus. Glutamate serves as the major neurotrasmitter in these circuits where glutamate receptors of NMDA type play key role. Serotonin and dopamine afferents are in position to modulate intrinsic glutamate neurotransmission along these circuits and in turn to optimize circuit performance for specific aspects of executive control over behavior. In this review, we focus on the 5-choice serial reaction time task which is able to provide various measures of attention and executive control over performance in rodents and the ability of prefrontocortical and striatal serotonin 5-HT1A, 5-HT2A, and 5-HT2C as well as dopamine D1- and D2-like receptors to modulate different aspects of executive and attention disturbances induced by NMDA receptor hypofunction in the prefrontal cortex. These behavioral studies are integrated with findings from microdialysis studies. These studies illustrate the control of attention selectivity by serotonin 5-HT1A, 5-HT2A, 5-HT2C, and dopamine D1- but not D2-like receptors and a distinct contribution of these cortical and striatal serotonin and dopamine receptors to the control of different aspects of executive control over performance such as impulsivity and compulsivity. An association between NMDA antagonist-induced increase in glutamate release in the prefrontal cortex and attention is suggested. Collectively, this review highlights the functional interaction of serotonin and dopamine with NMDA dependent glutamate neurotransmission in the cortico-striatal circuitry for specific cognitive demands and may shed some light on how dysregulation of neuronal processing in these circuits may be implicated in specific neuropsychiatric disorders. PMID:24966814

Medial prefrontal cortex dopamine controls the persistent storage of aversive memories

PubMed Central

Gonzalez, María C.; Kramar, Cecilia P.; Tomaiuolo, Micol; Katche, Cynthia; Weisstaub, Noelia; Cammarota, Martín; Medina, Jorge H.

2014-01-01

Medial prefrontal cortex (mPFC) is essential for initial memory processing and expression but its involvement in persistent memory storage has seldom been studied. Using the hippocampus dependent inhibitory avoidance learning task and the hippocampus-independent conditioned taste aversion paradigm together with specific dopamine receptor agonists and antagonists we found that persistence but not formation of long-term aversive memories requires dopamine D1/D5 receptors activation in mPFC immediately after training and, depending on the task, between 6 and 12 h later. Our results indicate that besides its well-known participation in retrieval and early consolidation, mPFC also modulates the endurance of long-lasting aversive memories regardless of whether formation of the aversive mnemonic trace requires the participation of the hippocampus. PMID:25506318

Dopamine-Modulated Recurrent Corticoefferent Feedback in Primary Sensory Cortex Promotes Detection of Behaviorally Relevant Stimuli

PubMed Central

Handschuh, Juliane

2014-01-01

Dopaminergic neurotransmission in primary auditory cortex (AI) has been shown to be involved in learning and memory functions. Moreover, dopaminergic projections and D1/D5 receptor distributions display a layer-dependent organization, suggesting specific functions in the cortical circuitry. However, the circuit effects of dopaminergic neurotransmission in sensory cortex and their possible roles in perception, learning, and memory are largely unknown. Here, we investigated layer-specific circuit effects of dopaminergic neuromodulation using current source density (CSD) analysis in AI of Mongolian gerbils. Pharmacological stimulation of D1/D5 receptors increased auditory-evoked synaptic currents in infragranular layers, prolonging local thalamocortical input via positive feedback between infragranular output and granular input. Subsequently, dopamine promoted sustained cortical activation by prolonged recruitment of long-range corticocortical networks. A detailed circuit analysis combining layer-specific intracortical microstimulation (ICMS), CSD analysis, and pharmacological cortical silencing revealed that cross-laminar feedback enhanced by dopamine relied on a positive, fast-acting recurrent corticoefferent loop, most likely relayed via local thalamic circuits. Behavioral signal detection analysis further showed that activation of corticoefferent output by infragranular ICMS, which mimicked auditory activation under dopaminergic influence, was most effective in eliciting a behaviorally detectable signal. Our results show that D1/D5-mediated dopaminergic modulation in sensory cortex regulates positive recurrent corticoefferent feedback, which enhances states of high, persistent activity in sensory cortex evoked by behaviorally relevant stimuli. In boosting horizontal network interactions, this potentially promotes the readout of task-related information from cortical synapses and improves behavioral stimulus detection. PMID:24453315

Memory Trace Reactivation and Behavioral Response during Retrieval Are Differentially Modulated by Amygdalar Glutamate Receptors Activity: Interaction between Amygdala and Insular Cortex

ERIC Educational Resources Information Center

Osorio-Gómez, Daniel; Guzmán-Ramos, Kioko; Bermúdez-Rattoni, Federico

2017-01-01

The insular cortex (IC) is required for conditioned taste aversion (CTA) retrieval. However, it remains unknown which cortical neurotransmitters levels are modified upon CTA retrieval. Using in vivo microdialysis, we observed that there were clear elevations in extracellular glutamate, norepinephrine, and dopamine in and around the center of the…

Dopamine D1 receptor stimulation modulates the formation and retrieval of novel object recognition memory: Role of the prelimbic cortex

PubMed Central

Pezze, Marie A.; Marshall, Hayley J.; Fone, Kevin C.F.; Cassaday, Helen J.

2015-01-01

Previous studies have shown that dopamine D1 receptor antagonists impair novel object recognition memory but the effects of dopamine D1 receptor stimulation remain to be determined. This study investigated the effects of the selective dopamine D1 receptor agonist SKF81297 on acquisition and retrieval in the novel object recognition task in male Wistar rats. SKF81297 (0.4 and 0.8 mg/kg s.c.) given 15 min before the sampling phase impaired novel object recognition evaluated 10 min or 24 h later. The same treatments also reduced novel object recognition memory tested 24 h after the sampling phase and when given 15 min before the choice session. These data indicate that D1 receptor stimulation modulates both the encoding and retrieval of object recognition memory. Microinfusion of SKF81297 (0.025 or 0.05 μg/side) into the prelimbic sub-region of the medial prefrontal cortex (mPFC) in this case 10 min before the sampling phase also impaired novel object recognition memory, suggesting that the mPFC is one important site mediating the effects of D1 receptor stimulation on visual recognition memory. PMID:26277743

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

Tomasi, D.; Fowler, J.; Tomasi, D.

Dopamine and dopamine transporters (DAT, which regulate extracellular dopamine in the brain) are implicated in the modulation of attention but their specific roles are not well understood. Here we hypothesized that dopamine modulates attention by facilitation of brain deactivation in the default mode network (DMN). Thus, higher striatal DAT levels, which would result in an enhanced clearance of dopamine and hence weaker dopamine signals, would be associated to lower deactivation in the DMN during an attention task. For this purpose we assessed the relationship between DAT in striatum (measured with positron emission tomography and [{sup 11}C]cocaine used as DAT radiotracer)more » and brain activation and deactivation during a parametric visual attention task (measured with blood oxygenation level dependent functional magnetic resonance imaging) in healthy controls. We show that DAT availability in caudate and putamen had a negative correlation with deactivation in ventral parietal regions of the DMN (precuneus, BA 7) and a positive correlation with deactivation in a small region in the ventral anterior cingulate gyrus (BA 24/32). With increasing attentional load, DAT in caudate showed a negative correlation with load-related deactivation increases in precuneus. These findings provide evidence that dopamine transporters modulate neural activity in the DMN and anterior cingulate gyrus during visuospatial attention. Our findings suggest that dopamine modulates attention in part by regulating neuronal activity in posterior parietal cortex including precuneus (region involved in alertness) and cingulate gyrus (region deactivated in proportion to emotional interference). These findings suggest that the beneficial effects of stimulant medications (increase dopamine by blocking DAT) in inattention reflect in part their ability to facilitate the deactivation of the DMN.« less

Cerebellar modulation of frontal cortex dopamine efflux in mice: relevance to autism and schizophrenia.

PubMed

Mittleman, Guy; Goldowitz, Daniel; Heck, Detlef H; Blaha, Charles D

2008-07-01

Cerebellar and frontal cortical pathologies have been commonly reported in schizophrenia, autism, and other developmental disorders. Whether there is a relationship between prefrontal and cerebellar pathologies is unknown. Using fixed potential amperometry, dopamine (DA) efflux evoked by cerebellar or, dentate nucleus electrical stimulation (50 Hz, 200 muA) was recorded in prefrontal cortex of urethane anesthetized lurcher (Lc/+) mice with 100% loss of cerebellar Purkinje cells and wildtype (+/+) control mice. Cerebellar stimulation with 25 and 100 pulses evoked prefrontal cortex DA efflux in +/+ mice that persisted for 12 and 25 s poststimulation, respectively. In contrast, 25 pulse cerebellar stimulation failed to evoke prefrontal cortex DA efflux in Lc/+ mice indicating a dependency on cerebellar Purkinje cell outputs. Dentate nucleus stimulation (25 pulses) evoked a comparable but briefer (baseline recovery within 7 s) increase in prefrontal cortex DA efflux compared to similar cerebellar stimulation in +/+ mice. However, in Lc/+ mice 25 pulse dentate nucleus evoked prefrontal cortex DA efflux was attenuated by 60% with baseline recovery within 4 s suggesting that dentate nucleus outputs to prefrontal cortex remain partially functional. DA reuptake blockade enhanced 100 pulse stimulation evoked prefrontal cortex responses, while serotonin or norepinephrine reuptake blockade were without effect indicating the specificity of the amperometric recordings to DA. Results provide neurochemical evidence that the cerebellum can modulate DA efflux in the prefrontal cortex. Together, these findings may explain why cerebellar and frontal cortical pathologies co-occur, and may provide a mechanism that accounts for the diversity of symptoms common to multiple developmental disorders.

Cerebellar Modulation of Frontal Cortex Dopamine Efflux in Mice: Relevance to Autism and Schizophrenia

PubMed Central

MITTLEMAN, GUY; GOLDOWITZ, DANIEL; HECK, DETLEF H.; BLAHA, CHARLES D.

2013-01-01

Cerebellar and frontal cortical pathologies have been commonly reported in schizophrenia, autism, and other developmental disorders. Whether there is a relationship between prefrontal and cerebellar pathologies is unknown. Using fixed potential amperometry, dopamine (DA) efflux evoked by cerebellar or, dentate nucleus electrical stimulation (50 Hz, 200 μA) was recorded in prefrontal cortex of urethane anesthetized lurcher (Lc/+) mice with 100% loss of cerebellar Purkinje cells and wildtype (+/+) control mice. Cerebellar stimulation with 25 and 100 pulses evoked prefrontal cortex DA efflux in +/+ mice that persisted for 12 and 25 s poststimulation, respectively. In contrast, 25 pulse cerebellar stimulation failed to evoke prefrontal cortex DA efflux in Lc/+ mice indicating a dependency on cerebellar Purkinje cell outputs. Dentate nucleus stimulation (25 pulses) evoked a comparable but briefer (baseline recovery within 7 s) increase in prefrontal cortex DA efflux compared to similar cerebellar stimulation in +/+ mice. However, in Lc/+ mice 25 pulse dentate nucleus evoked prefrontal cortex DA efflux was attenuated by 60% with baseline recovery within 4 s suggesting that dentate nucleus outputs to prefrontal cortex remain partially functional. DA reuptake blockade enhanced 100 pulse stimulation evoked pre-frontal cortex responses, while serotonin or norepinephrine reuptake blockade were without effect indicating the specificity of the amperometric recordings to DA. Results provide neurochemical evidence that the cerebellum can modulate DA efflux in the prefrontal cortex. Together, these findings may explain why cerebellar and frontal cortical pathologies co-occur, and may provide a mechanism that accounts for the diversity of symptoms common to multiple developmental disorders. PMID:18435424

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.

Toxoplasma gondii Infection in Mice Impairs Long-Term Fear Memory Consolidation through Dysfunction of the Cortex and Amygdala.

PubMed

Ihara, Fumiaki; Nishimura, Maki; Muroi, Yoshikage; Mahmoud, Motamed Elsayed; Yokoyama, Naoaki; Nagamune, Kisaburo; Nishikawa, Yoshifumi

2016-10-01

Chronic infection with Toxoplasma gondii becomes established in tissues of the central nervous system, where parasites may directly or indirectly modulate neuronal function. Epidemiological studies have revealed that chronic infection in humans is a risk factor for developing mental diseases. However, the mechanisms underlying parasite-induced neuronal dysfunction in the brain remain unclear. Here, we examined memory associated with conditioned fear in mice and found that T. gondii infection impairs consolidation of conditioned fear memory. To examine the brain pathology induced by T. gondii infection, we analyzed the parasite load and histopathological changes. T. gondii infects all brain areas, yet the cortex exhibits more severe tissue damage than other regions. We measured neurotransmitter levels in the cortex and amygdala because these regions are involved in fear memory expression. The levels of dopamine metabolites but not those of dopamine were increased in the cortex of infected mice compared with those in the cortex of uninfected mice. In contrast, serotonin levels were decreased in the amygdala and norepinephrine levels were decreased in the cortex and amygdala of infected mice. The levels of cortical dopamine metabolites were associated with the time spent freezing in the fear-conditioning test. These results suggest that T. gondii infection affects fear memory through dysfunction of the cortex and amygdala. Our findings provide insight into the mechanisms underlying the neurological changes seen during T. gondii infection. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Higher cortical and lower subcortical metabolism in detoxified methamphetamine abusers.

PubMed

Volkow, N D; Chang, L; Wang, G J; Fowler, J S; Franceschi, D; Sedler, M J; Gatley, S J; Hitzemann, R; Ding, Y S; Wong, C; Logan, J

2001-03-01

Methamphetamine has raised concerns because it may be neurotoxic to the human brain. Although prior work has focused primarily on the effects of methamphetamine on dopamine cells, there is evidence that other neuronal types are affected. The authors measured regional brain glucose metabolism, which serves as a marker of brain function, to assess if there is evidence of functional changes in methamphetamine abusers in regions other than those innervated by dopamine cells. Fifteen detoxified methamphetamine abusers and 21 comparison subjects underwent positron emission tomography following administration of [(18)F]fluorodeoxyglucose. Whole brain metabolism in the methamphetamine abusers was 14% higher than that of comparison subjects; the differences were most accentuated in the parietal cortex (20%). After normalization for whole brain metabolism, methamphetamine abusers exhibited significantly lower metabolism in the thalamus (17% difference) and striatum (where the differences were larger for the caudate [12%] than for the putamen [6%]). Statistical parametric mapping analyses corroborated these findings, revealing higher metabolism in the parietal cortex and lower metabolism in the thalamus and striatum of methamphetamine abusers. The fact that the parietal cortex is a region devoid of any significant dopaminergic innervation suggests that the higher metabolism seen in this region in the methamphetamine abusers is the result of methamphetamine effects in circuits other than those modulated by dopamine. In addition, the lower metabolism in the striatum and thalamus (major outputs of dopamine signals into the cortex) is likely to reflect the functional consequence of methamphetamine in dopaminergic circuits. These results provide evidence that, in humans, methamphetamine abuse results in changes in function of dopamine- and nondopamine-innervated brain regions.

Reorganization of circuits underlying cerebellar modulation of prefrontal cortical dopamine in mouse models of autism spectrum disorder

PubMed Central

Rogers, Tiffany D.; Dickson, Price E.; McKimm, Eric; Heck, Detlef H.; Goldowitz, Dan; Blaha, Charles D.; Mittleman, Guy

2013-01-01

Imaging, clinical and pre-clinical studies have provided ample evidence for a cerebellar involvement in cognitive brain function including cognitive brain disorders, such as autism and schizophrenia. We previously reported that cerebellar activity modulates dopamine release in the mouse medial prefrontal cortex (mPFC) via two distinct pathways: (1) cerebellum to mPFC via dopaminergic projections from the ventral tegmental area [VTA] and (2) cerebellum to mPFC via glutamatergic projections from the mediodorsal and ventrolateral thalamus (ThN md and vl). The present study compared functional adaptations of cerebello-cortical circuitry following developmental cerebellar pathology in a mouse model of developmental loss of Purkinje cells (Lurcher) and a mouse model of fragile X syndrome (Fmr1 KO mice). Fixed potential amperometry was used to measure mPFC dopamine release in response to cerebellar electrical stimulation. Mutant mice of both strains showed an attenuation in cerebellar-evoked mPFC dopamine release compared to respective wildtype mice. This was accompanied by a functional reorganization of the VTA and thalamic pathways mediating cerebellar modulation of mPFC dopamine release. Inactivation of the VTA pathway by intra-VTA lidocaine or kynurenate infusions decreased dopamine release by 50% in wildtype and 20-30% in mutant mice of both strains. Intra-ThN vl infusions of either drug decreased dopamine release by 15% in wildtype and 40% in mutant mice of both strains, while dopamine release remained relatively unchanged following intra-ThN md drug infusions. These results indicate a shift in strength towards the thalamic vl projection, away from the VTA. Thus, cerebellar neuropathologies associated with autism spectrum disorders may cause a reduction in cerebellar modulation of mPFC dopamine release that is related to a reorganization of the mediating neuronal pathways. PMID:23436049

Reorganization of circuits underlying cerebellar modulation of prefrontal cortical dopamine in mouse models of autism spectrum disorder.

PubMed

Rogers, Tiffany D; Dickson, Price E; McKimm, Eric; Heck, Detlef H; Goldowitz, Dan; Blaha, Charles D; Mittleman, Guy

2013-08-01

Imaging, clinical, and pre-clinical studies have provided ample evidence for a cerebellar involvement in cognitive brain function including cognitive brain disorders, such as autism and schizophrenia. We previously reported that cerebellar activity modulates dopamine release in the mouse medial prefrontal cortex (mPFC) via two distinct pathways: (1) cerebellum to mPFC via dopaminergic projections from the ventral tegmental area (VTA) and (2) cerebellum to mPFC via glutamatergic projections from the mediodorsal and ventrolateral thalamus (ThN md and vl). The present study compared functional adaptations of cerebello-cortical circuitry following developmental cerebellar pathology in a mouse model of developmental loss of Purkinje cells (Lurcher) and a mouse model of fragile X syndrome (Fmr1 KO mice). Fixed potential amperometry was used to measure mPFC dopamine release in response to cerebellar electrical stimulation. Mutant mice of both strains showed an attenuation in cerebellar-evoked mPFC dopamine release compared to respective wildtype mice. This was accompanied by a functional reorganization of the VTA and thalamic pathways mediating cerebellar modulation of mPFC dopamine release. Inactivation of the VTA pathway by intra-VTA lidocaine or kynurenate infusions decreased dopamine release by 50 % in wildtype and 20-30 % in mutant mice of both strains. Intra-ThN vl infusions of either drug decreased dopamine release by 15 % in wildtype and 40 % in mutant mice of both strains, while dopamine release remained relatively unchanged following intra-ThN md drug infusions. These results indicate a shift in strength towards the thalamic vl projection, away from the VTA. Thus, cerebellar neuropathologies associated with autism spectrum disorders may cause a reduction in cerebellar modulation of mPFC dopamine release that is related to a reorganization of the mediating neuronal pathways.

Dopamine D1 sensitivity in the prefrontal cortex predicts general cognitive abilities and is modulated by working memory training

PubMed Central

Wass, Christopher; Pizzo, Alessandro; Sauce, Bruno; Kawasumi, Yushi; Sturzoiu, Tudor; Ree, Fred; Otto, Tim; Matzel, Louis D.

2013-01-01

A common source of variance (i.e., “general intelligence”) underlies an individual's performance across diverse tests of cognitive ability, and evidence indicates that the processing efficacy of working memory may serve as one such source of common variance. One component of working memory, selective attention, has been reported to co-vary with general intelligence, and dopamine D1 signaling in prefrontal cortex can modulate attentional abilities. Based on their aggregate performance across five diverse tests of learning, here we characterized the general cognitive ability (GCA) of CD-1 outbred mice. In response to a D1 agonist (SKF82958, 1 mg/kg), we then assessed the relationship between GCA and activation of D1 receptor (D1R)-containing neurons in the prelimbic region of the medial prefrontal cortex, the agranular insular cortex, and the dorsomedial striatum. Increased activation of D1R-containing neurons in the prelimbic cortex (but not the agranular insular cortex or dorsomedial striatum) was observed in animals of high GCA relative to those of low GCA (quantified by c-Fos activation in response to the D1 agonist). However, a Western blot analysis revealed no differences in the density of D1Rs in the prelimbic cortex between animals of high and low GCA. Last, it was observed that working memory training promoted an increase in animals’ GCA and enhanced D1R-mediated neuronal activation in the prelimbic cortex. These results suggest that the sensitivity (but not density) of D1Rs in the prelimbic cortex may both regulate GCA and be a target for working memory training. PMID:24129098

Dopamine D1 sensitivity in the prefrontal cortex predicts general cognitive abilities and is modulated by working memory training.

PubMed

Wass, Christopher; Pizzo, Alessandro; Sauce, Bruno; Kawasumi, Yushi; Sturzoiu, Tudor; Ree, Fred; Otto, Tim; Matzel, Louis D

2013-10-15

A common source of variance (i.e., "general intelligence") underlies an individual's performance across diverse tests of cognitive ability, and evidence indicates that the processing efficacy of working memory may serve as one such source of common variance. One component of working memory, selective attention, has been reported to co-vary with general intelligence, and dopamine D1 signaling in prefrontal cortex can modulate attentional abilities. Based on their aggregate performance across five diverse tests of learning, here we characterized the general cognitive ability (GCA) of CD-1 outbred mice. In response to a D1 agonist (SKF82958, 1 mg/kg), we then assessed the relationship between GCA and activation of D1 receptor (D1R)-containing neurons in the prelimbic region of the medial prefrontal cortex, the agranular insular cortex, and the dorsomedial striatum. Increased activation of D1R-containing neurons in the prelimbic cortex (but not the agranular insular cortex or dorsomedial striatum) was observed in animals of high GCA relative to those of low GCA (quantified by c-Fos activation in response to the D1 agonist). However, a Western blot analysis revealed no differences in the density of D1Rs in the prelimbic cortex between animals of high and low GCA. Last, it was observed that working memory training promoted an increase in animals' GCA and enhanced D1R-mediated neuronal activation in the prelimbic cortex. These results suggest that the sensitivity (but not density) of D1Rs in the prelimbic cortex may both regulate GCA and be a target for working memory training.

On the Origin of Cortical Dopamine: Is it a Co-Transmitter in Noradrenergic Neurons?

PubMed Central

Devoto, Paola; Flore, Giovanna

2006-01-01

Dopamine (DA) and noradrenaline (NA) in the prefrontal cortex (PFC) modulate superior cognitive functions, and are involved in the aetiology of depressive and psychotic symptoms. Moreover, microdialysis studies in rats have shown how pharmacological treatments that induce modifications of extracellular NA in the medial PFC (mPFC), also produce parallel changes in extracellular DA. To explain the coupling of NA and DA changes, this article reviews the evidence supporting the hypothesis that extracellular DA in the cerebral cortex originates not only from dopaminergic terminals but also from noradrenergic ones, where it acts both as precursor for NA and as a co-transmitter. Accordingly, extracellular DA concentration in the occipital, parietal and cerebellar cortex was found to be much higher than expected in view of the scarce dopaminergic innervation in these areas. Systemic administration or intra-cortical perfusion of α2-adrenoceptor agonists and antagonists, consistent with their action on noradrenergic neuronal activity, produced concomitant changes not only in extracellular NA but also in DA in the mPFC, occipital and parietal cortex. Chemical modulation of the locus coeruleus by locally applied carbachol, kainate, NMDA or clonidine modified both NA and DA in the mPFC. Electrical stimulation of the locus coeruleus led to an increased efflux of both NA and DA in mPFC, parietal and occipital cortex, while in the striatum, NA efflux alone was enhanced. Atypical antipsychotics, such as clozapine and olanzapine, or antidepressants, including mirtazapine and mianserine, have been found to increase both NA and DA throughout the cerebral cortex, likely through blockade of α2-adrenoceptors. On the other hand, drugs selectively acting on dopaminergic transmission produced modest changes in extracellular DA in mPFC, and had no effect on the occipital or parietal cortex. Acute administration of morphine did not increase DA levels in the PFC (where NA is diminished), in contrast with augmented dopaminergic neuronal activity; moreover, during morphine withdrawal both DA and NA levels increased, in spite of a diminished dopaminergic activity, both increases being antagonised by clonidine but not quinpirole administration. Extensive 6-hydroxy dopamine lesion of the ventral tegmental area (VTA) decreases below 95% of control both intra- and extracellular DA and DOPAC in the nucleus accumbens, but only partially or not significantly in the mPFC and parietal cortex. The above evidence points to a common origin for NA and DA in the cerebral cortex and suggests the possible utility of noradrenergic system modulation as a target for drugs with potential clinical efficacy on cognitive functions. PMID:18615131

On the origin of cortical dopamine: is it a co-transmitter in noradrenergic neurons?

PubMed

Devoto, Paola; Flore, Giovanna

2006-04-01

Dopamine (DA) and noradrenaline (NA) in the prefrontal cortex (PFC) modulate superior cognitive functions, and are involved in the aetiology of depressive and psychotic symptoms. Moreover, microdialysis studies in rats have shown how pharmacological treatments that induce modifications of extracellular NA in the medial PFC (mPFC), also produce parallel changes in extracellular DA.To explain the coupling of NA and DA changes, this article reviews the evidence supporting the hypothesis that extracellular DA in the cerebral cortex originates not only from dopaminergic terminals but also from noradrenergic ones, where it acts both as precursor for NA and as a co-transmitter.Accordingly, extracellular DA concentration in the occipital, parietal and cerebellar cortex was found to be much higher than expected in view of the scarce dopaminergic innervation in these areas.Systemic administration or intra-cortical perfusion of alpha(2)-adrenoceptor agonists and antagonists, consistent with their action on noradrenergic neuronal activity, produced concomitant changes not only in extracellular NA but also in DA in the mPFC, occipital and parietal cortex.Chemical modulation of the locus coeruleus by locally applied carbachol, kainate, NMDA or clonidine modified both NA and DA in the mPFC.Electrical stimulation of the locus coeruleus led to an increased efflux of both NA and DA in mPFC, parietal and occipital cortex, while in the striatum, NA efflux alone was enhanced.Atypical antipsychotics, such as clozapine and olanzapine, or antidepressants, including mirtazapine and mianserine, have been found to increase both NA and DA throughout the cerebral cortex, likely through blockade of alpha(2)-adrenoceptors. On the other hand, drugs selectively acting on dopaminergic transmission produced modest changes in extracellular DA in mPFC, and had no effect on the occipital or parietal cortex.Acute administration of morphine did not increase DA levels in the PFC (where NA is diminished), in contrast with augmented dopaminergic neuronal activity; moreover, during morphine withdrawal both DA and NA levels increased, in spite of a diminished dopaminergic activity, both increases being antagonised by clonidine but not quinpirole administration.Extensive 6-hydroxy dopamine lesion of the ventral tegmental area (VTA) decreases below 95% of control both intra- and extracellular DA and DOPAC in the nucleus accumbens, but only partially or not significantly in the mPFC and parietal cortex.The above evidence points to a common origin for NA and DA in the cerebral cortex and suggests the possible utility of noradrenergic system modulation as a target for drugs with potential clinical efficacy on cognitive functions.

Dopamine-dependent effects on basal and glutamate stimulated network dynamics in cultured hippocampal neurons.

PubMed

Li, Yan; Chen, Xin; Dzakpasu, Rhonda; Conant, Katherine

2017-02-01

Oscillatory activity occurs in cortical and hippocampal networks with specific frequency ranges thought to be critical to working memory, attention, differentiation of neuronal precursors, and memory trace replay. Synchronized activity within relatively large neuronal populations is influenced by firing and bursting frequency within individual cells, and the latter is modulated by changes in intrinsic membrane excitability and synaptic transmission. Published work suggests that dopamine, a potent modulator of learning and memory, acts on dopamine receptor 1-like dopamine receptors to influence the phosphorylation and trafficking of glutamate receptor subunits, along with long-term potentiation of excitatory synaptic transmission in striatum and prefrontal cortex. Prior studies also suggest that dopamine can influence voltage gated ion channel function and membrane excitability in these regions. Fewer studies have examined dopamine's effect on related endpoints in hippocampus, or potential consequences in terms of network burst dynamics. In this study, we record action potential activity using a microelectrode array system to examine the ability of dopamine to modulate baseline and glutamate-stimulated bursting activity in an in vitro network of cultured murine hippocampal neurons. We show that dopamine stimulates a dopamine type-1 receptor-dependent increase in number of overall bursts within minutes of its application. Notably, however, at the concentration used herein, dopamine did not increase the overall synchrony of bursts between electrodes. Although the number of bursts normalizes by 40 min, bursting in response to a subsequent glutamate challenge is enhanced by dopamine pretreatment. Dopamine-dependent potentiation of glutamate-stimulated bursting was not observed when the two modulators were administered concurrently. In parallel, pretreatment of murine hippocampal cultures with dopamine stimulated lasting increases in the phosphorylation of the glutamate receptor subunit GluA1 at serine 845. This effect is consistent with the possibility that enhanced membrane insertion of GluAs may contribute to a more slowly evolving dopamine-dependent potentiation of glutamate-stimulated bursting. Together, these results are consistent with the possibility that dopamine can influence hippocampal bursting by at least two temporally distinct mechanisms, contributing to an emerging appreciation of dopamine-dependent effects on network activity in the hippocampus. © 2016 International Society for Neurochemistry.

Dopamine Modulates the Functional Organization of the Orbitofrontal Cortex.

PubMed

Kahnt, Thorsten; Tobler, Philippe N

2017-02-08

Neuromodulators such as dopamine can alter the intrinsic firing properties of neurons and may thereby change the configuration of larger functional circuits. The primate orbitofrontal cortex (OFC) receives dopaminergic input from midbrain nuclei, but the role of dopamine in the OFC is still unclear. Here we tested the idea that dopaminergic activity changes the pattern of connectivity between the OFC and the rest of the brain and thereby reconfigures functional networks in the OFC. To this end, we combined double-blind, placebo-controlled pharmacology [D 2 receptor (D2R) antagonist amisulpride] in humans with resting-state functional magnetic resonance imaging and clustering methods. In the placebo group, we replicated previously observed parcellations of the OFC into two and six subregions based on connectivity patterns with the rest of the brain. Most importantly, while the twofold clustering did not differ significantly between groups, blocking D2Rs significantly changed the composition of the sixfold parcellation, suggesting a dopamine-dependent reconfiguration of functional OFC subregions. Moreover, multivariate decoding analyses revealed that amisulpride changed the whole-brain connectivity patterns of individual OFC subregions. In particular, D2R blockade shifted the balance of OFC connectivity from associative areas in the temporal and parietal lobe toward functional connectivity with the frontal cortex. In summary, our results suggest that dopamine alters the composition of functional OFC circuits, possibly indicating a broader role for neuromodulators in the dynamic reconfiguration of functional brain networks. SIGNIFICANCE STATEMENT A key role of any neuromodulator may be the reconfiguration of functional brain circuits. Here we test this idea with regard to dopamine and the organization of functional networks in the orbitofrontal cortex (OFC). We show that blockade of dopamine D 2 receptors has profound effects on the functional connectivity patterns of the OFC, yielding altered connectivity-based subdivisions of this region. Our results suggest that dopamine changes the connectional configuration of the OFC, possibly leading to transitions between different operating modes that favor either sensory input or recurrent processing in the prefrontal cortex. More generally, our findings support a broader role for neuromodulators in the dynamic reconfiguration of functional brain networks and may have clinical implications for understanding the actions of antipsychotic agents. Copyright © 2017 the authors 0270-6474/17/371493-12$15.00/0.

Knockdown of mortalin within the medial prefrontal cortex impairs normal sensorimotor gating.

PubMed

Gabriele, Nicole; Pontoriero, Giuseppe F; Thomas, Nancy; Shethwala, Shazli K; Pristupa, Zdenek B; Gabriele, Joseph P

2010-11-01

The 70-kDa mitochondrial heat shock protein, mortalin, is a ubiquitously expressed, multifunctional protein that is capable of binding the neurotransmitter, dopamine, within the brain. Dopamine dysregulation has been implicated in many of the abnormal neurological behaviors. Although studies have indicated that mortalin is differentially regulated in response to dopaminergic modulation, research has yet to elucidate the role of mortalin in the regulation of dopaminergic activity. This study seeks to investigate the role of mortalin in the regulation of dopamine-dependent behavior, specifically as it pertains to schizophrenia (SCZ). Mortalin expression was knocked down through the infusion of antisense oligodeoxynucleotide molecules into the medial prefrontal cortex (mPFC). Rats infused with mortalin antisense oligodeoxynucleotide molecules exhibited significant prepulse inhibition deficits, suggestive of defects in normal sensorimotor gating. Furthermore, mortalin misexpression within the mPFC was coupled to a significant increase in mortalin protein expression within the nucleus accumbens at the molecular level. These findings demonstrate that mortalin plays an essential role in the regulation of dopamine-dependent behavior and plays an even greater role in the pathogenesis of SCZ.

Prefrontal cortex as a meta-reinforcement learning system.

PubMed

Wang, Jane X; Kurth-Nelson, Zeb; Kumaran, Dharshan; Tirumala, Dhruva; Soyer, Hubert; Leibo, Joel Z; Hassabis, Demis; Botvinick, Matthew

2018-06-01

Over the past 20 years, neuroscience research on reward-based learning has converged on a canonical model, under which the neurotransmitter dopamine 'stamps in' associations between situations, actions and rewards by modulating the strength of synaptic connections between neurons. However, a growing number of recent findings have placed this standard model under strain. We now draw on recent advances in artificial intelligence to introduce a new theory of reward-based learning. Here, the dopamine system trains another part of the brain, the prefrontal cortex, to operate as its own free-standing learning system. This new perspective accommodates the findings that motivated the standard model, but also deals gracefully with a wider range of observations, providing a fresh foundation for future research.

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

PubMed Central

Bath, Kevin G.; Daw, Nathaniel D.; Frank, Michael J.

2016-01-01

Considerable evidence suggests that multiple learning systems can drive behavior. Choice can proceed reflexively from previous actions and their associated outcomes, as captured by “model-free” learning algorithms, or flexibly from prospective consideration of outcomes that might occur, as captured by “model-based” learning algorithms. However, differential contributions of dopamine to these systems are poorly understood. Dopamine is widely thought to support model-free learning by modulating plasticity in striatum. Model-based learning may also be affected by these striatal effects, or by other dopaminergic effects elsewhere, notably on prefrontal working memory function. Indeed, prominent demonstrations linking striatal dopamine to putatively model-free learning did not rule out model-based effects, whereas other studies have reported dopaminergic modulation of verifiably model-based learning, but without distinguishing a prefrontal versus striatal locus. To clarify the relationships between dopamine, neural systems, and learning strategies, we combine a genetic association approach in humans with two well-studied reinforcement learning tasks: one isolating model-based from model-free behavior and the other sensitive to key aspects of striatal plasticity. Prefrontal function was indexed by a polymorphism in the COMT gene, differences of which reflect dopamine levels in the prefrontal cortex. This polymorphism has been associated with differences in prefrontal activity and working memory. Striatal function was indexed by a gene coding for DARPP-32, which is densely expressed in the striatum where it is necessary for synaptic plasticity. We found evidence for our hypothesis that variations in prefrontal dopamine relate to model-based learning, whereas variations in striatal dopamine function relate to model-free learning. SIGNIFICANCE STATEMENT Decisions can stem reflexively from their previously associated outcomes or flexibly from deliberative consideration of potential choice outcomes. Research implicates a dopamine-dependent striatal learning mechanism in the former type of choice. Although recent work has indicated that dopamine is also involved in flexible, goal-directed decision-making, it remains unclear whether it also contributes via striatum or via the dopamine-dependent working memory function of prefrontal cortex. We examined genetic indices of dopamine function in these regions and their relation to the two choice strategies. We found that striatal dopamine function related most clearly to the reflexive strategy, as previously shown, and that prefrontal dopamine related most clearly to the flexible strategy. These findings suggest that dissociable brain regions support dissociable choice strategies. PMID:26818509

Dopamine D2 receptors in the cerebral cortex: distribution and pharmacological characterization with [3H]raclopride.

PubMed Central

Lidow, M S; Goldman-Rakic, P S; Rakic, P; Innis, R B

1989-01-01

An apparent involvement of dopamine in the regulation of cognitive functions and the recognition of a widespread dopaminergic innervation of the cortex have focused attention on the identity of cortical dopamine receptors. However, only the presence and distribution of dopamine D1 receptors in the cortex have been well documented. Comparable information on cortical D2 sites is lacking. We report here the results of binding studies in the cortex and neostriatum of rat and monkey using the D2 selective antagonist [3H]raclopride. In both structures [3H]raclopride bound in a sodium-dependent and saturable manner to a single population of sites with pharmacological profiles of dopamine D2 receptors. D2 sites were present in all regions of the cortex, although their density was much lower than in the neostriatum. The density of these sites in both monkey and, to a lesser extent, rat cortex displayed a rostral-caudal gradient with highest concentrations in the prefrontal and lowest concentrations in the occipital cortex, corresponding to dopamine levels in these areas. Thus, the present study establishes the presence and widespread distribution of dopamine D2 receptors in the cortex. PMID:2548214

DRD2/CHRNA5 Interaction on Prefrontal Biology and Physiology during Working Memory

PubMed Central

Fazio, Leonardo; D'Ambrosio, Enrico; Gelao, Barbara; Tomasicchio, Aldo; Selvaggi, Pierluigi; Taurisano, Paolo; Quarto, Tiziana; Masellis, Rita; Rampino, Antonio; Caforio, Grazia; Popolizio, Teresa; Blasi, Giuseppe; Sadee, Wolfgang; Bertolino, Alessandro

2014-01-01

Background Prefrontal behavior and activity in humans are heritable. Studies in animals demonstrate an interaction between dopamine D2 receptors and nicotinic acetylcholine receptors on prefrontal behavior but evidence in humans is weak. Therefore, we hypothesize that genetic variation regulating dopamine D2 and nicotinic acetylcholine receptor signaling impact prefrontal cortex activity and related cognition. To test this hypothesis in humans, we explored the interaction between functional genetic variants in the D2 receptor gene (DRD2, rs1076560) and in the nicotinic receptor α5 gene (CHRNA5, rs16969968) on both dorsolateral prefrontal cortex mediated behavior and physiology during working memory and on prefrontal gray matter volume. Methods A large sample of healthy subjects was compared for genotypic differences for DRD2 rs1076560 (G>T) and CHNRA5 rs16969968 (G>A) on prefrontal phenotypes, including cognitive performance at the N-Back task, prefrontal physiology with BOLD fMRI during performance of the 2-Back working memory task, and prefrontal morphometry with structural MRI. Results We found that DRD2 rs1076560 and CHNRA5 rs16969968 interact to modulate cognitive function, prefrontal physiology during working memory, and prefrontal gray matter volume. More specifically, CHRNA5-AA/DRD2-GT subjects had greater behavioral performance, more efficient prefrontal cortex activity at 2Back working memory task, and greater prefrontal gray matter volume than the other genotype groups. Conclusions The present data extend previous studies in animals and enhance our understanding of dopamine and acetylcholine signaling in the human prefrontal cortex, demonstrating interactions elicited by working memory that are modulated by genetic variants in DRD2 and CHRNA5. PMID:24819610

DRD2/CHRNA5 interaction on prefrontal biology and physiology during working memory.

PubMed

Di Giorgio, Annabella; Smith, Ryan M; Fazio, Leonardo; D'Ambrosio, Enrico; Gelao, Barbara; Tomasicchio, Aldo; Selvaggi, Pierluigi; Taurisano, Paolo; Quarto, Tiziana; Masellis, Rita; Rampino, Antonio; Caforio, Grazia; Popolizio, Teresa; Blasi, Giuseppe; Sadee, Wolfgang; Bertolino, Alessandro

2014-01-01

Prefrontal behavior and activity in humans are heritable. Studies in animals demonstrate an interaction between dopamine D2 receptors and nicotinic acetylcholine receptors on prefrontal behavior but evidence in humans is weak. Therefore, we hypothesize that genetic variation regulating dopamine D2 and nicotinic acetylcholine receptor signaling impact prefrontal cortex activity and related cognition. To test this hypothesis in humans, we explored the interaction between functional genetic variants in the D2 receptor gene (DRD2, rs1076560) and in the nicotinic receptor α5 gene (CHRNA5, rs16969968) on both dorsolateral prefrontal cortex mediated behavior and physiology during working memory and on prefrontal gray matter volume. A large sample of healthy subjects was compared for genotypic differences for DRD2 rs1076560 (G>T) and CHNRA5 rs16969968 (G>A) on prefrontal phenotypes, including cognitive performance at the N-Back task, prefrontal physiology with BOLD fMRI during performance of the 2-Back working memory task, and prefrontal morphometry with structural MRI. We found that DRD2 rs1076560 and CHNRA5 rs16969968 interact to modulate cognitive function, prefrontal physiology during working memory, and prefrontal gray matter volume. More specifically, CHRNA5-AA/DRD2-GT subjects had greater behavioral performance, more efficient prefrontal cortex activity at 2Back working memory task, and greater prefrontal gray matter volume than the other genotype groups. The present data extend previous studies in animals and enhance our understanding of dopamine and acetylcholine signaling in the human prefrontal cortex, demonstrating interactions elicited by working memory that are modulated by genetic variants in DRD2 and CHRNA5.

Time Processing in Children with Tourette's Syndrome

ERIC Educational Resources Information Center

Vicario, Carmelo Mario; Martino, Davide; Spata, Felice; Defazio, Giovanni; Giacche, Roberta; Martino, Vito; Rappo, Gaetano; Pepi, Anna Maria; Silvestri, Paola Rosaria; Cardona, Francesco

2010-01-01

Background: Tourette syndrome (TS) is characterized by dysfunctional connectivity between prefrontal cortex and sub-cortical structures, and altered meso-cortical and/or meso-striatal dopamine release. Since time processing is also regulated by fronto-striatal circuits and modulated by dopaminergic transmission, we hypothesized that time…

Dopamine and serotonin interactions in the prefrontal cortex: insights on antipsychotic drugs and their mechanism of action.

PubMed

Di Pietro, N C; Seamans, J K

2007-12-01

Diminished activity within the prefrontal cortex (PFC) has been associated with many of the cognitive deficits that are observed in schizophrenia. It has been hypothesized that antipsychotic drugs (APDs) used to treat schizophrenia restore normal activity by antagonizing the dopamine (DA) D2 receptor, which is also known to modulate key ionic currents in the PFC. However, the hypothesis that an under-active cortical DA system is responsible for schizophrenic symptoms has been challenged by evidence that newer atypical APDs are weak antagonists at the D2 receptor but potent antagonists at the serotonin (5-HT) 2A receptor . This review examines how DA and 5-HT modulate cortical activity and how they may interact in ways that are relevant to schizophrenia. It is concluded that although D2 receptor antagonism remains a critical factor in restoring impaired cortical activity, effects on 5-HT receptors may act in a synergistic manner on NMDA and GABA currents to potentiate antipsychotic actions in the PFC.

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.

The neurobiology of social play and its rewarding value in rats

PubMed Central

Vanderschuren, Louk J.M.J.; Achterberg, E.J. Marijke; Trezza, Viviana

2016-01-01

In the young of many mammalian species, including humans, a vigorous and highly rewarding social activity is abundantly expressed, known as social play behaviour. Social play is thought to be important for the development of social, cognitive and emotional processes and their neural underpinnings, and it is disrupted in pediatric psychiatric disorders. Here, we summarize recent progress in our understanding of the brain mechanisms of social play behaviour, with a focus on its rewarding properties. Opioid, endocannabinoid, dopamine and noradrenaline systems play a prominent role in the modulation of social play. Of these, dopamine is particularly important for the motivational properties of social play. The nucleus accumbens has been identified as a key site for opioid and dopamine modulation of social play. Endocannabinoid influences on social play rely on the basolateral amygdala, whereas noradrenaline modulates social play through the basolateral amygdala, habenula and prefrontal cortex. In sum, social play behaviour is the result of coordinated activity in a network of corticolimbic structures, and its monoamine, opioid and endocannabinoid innervation. PMID:27587003

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. This may reflect altered dopamine function in these regions in schizophrenia.

A direct GABAergic output from the basal ganglia to frontal cortex

PubMed Central

Saunders, Arpiar; Oldenburg, Ian A.; Berezovskii, Vladimir K.; Johnson, Caroline A.; Kingery, Nathan D.; Elliott, Hunter L.; Xie, Tiao; Gerfen, Charles R.; Sabatini, Bernardo L.

2014-01-01

The basal ganglia (BG) are phylogenetically conserved subcortical nuclei necessary for coordinated motor action and reward learning1. Current models postulate that the BG modulate cerebral cortex indirectly via an inhibitory output to thalamus, bidirectionally controlled by the BG via direct (dSPNs) and indirect (iSPNs) pathway striatal projection neurons2–4. The BG thalamic output sculpts cortical activity by interacting with signals from sensory and motor systems5. Here we describe a direct projection from the globus pallidus externus (GP), a central nucleus of the BG, to frontal regions of the cerebral cortex (FC). Two cell types make up the GP-FC projection, distinguished by their electrophysiological properties, cortical projections and expression of choline acetyltransferase (ChAT), a synthetic enzyme for the neurotransmitter acetylcholine (ACh). Despite these differences, ChAT+ cells, which have been historically identified as an extension of the nucleus basalis (NB), as well as ChAT− cells, release the inhibitory neurotransmitter GABA (γ-aminobutyric acid) and are inhibited by iSPNs and dSPNs of dorsal striatum. Thus GP-FC cells comprise a direct GABAergic/cholinergic projection under the control of striatum that activates frontal cortex in vivo. Furthermore, iSPN inhibition of GP-FC cells is sensitive to dopamine 2 receptor signaling, revealing a pathway by which drugs that target dopamine receptors for the treatment of neuropsychiatric disorders can act in the BG to modulate frontal cortices. PMID:25739505

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.

Learning touch preferences with a tactile robot using dopamine modulated STDP in a model of insular cortex

PubMed Central

Chou, Ting-Shuo; Bucci, Liam D.; Krichmar, Jeffrey L.

2015-01-01

Neurorobots enable researchers to study how behaviors are produced by neural mechanisms in an uncertain, noisy, real-world environment. To investigate how the somatosensory system processes noisy, real-world touch inputs, we introduce a neurorobot called CARL-SJR, which has a full-body tactile sensory area. The design of CARL-SJR is such that it encourages people to communicate with it through gentle touch. CARL-SJR provides feedback to users by displaying bright colors on its surface. In the present study, we show that CARL-SJR is capable of learning associations between conditioned stimuli (CS; a color pattern on its surface) and unconditioned stimuli (US; a preferred touch pattern) by applying a spiking neural network (SNN) with neurobiologically inspired plasticity. Specifically, we modeled the primary somatosensory cortex, prefrontal cortex, striatum, and the insular cortex, which is important for hedonic touch, to process noisy data generated directly from CARL-SJR's tactile sensory area. To facilitate learning, we applied dopamine-modulated Spike Timing Dependent Plasticity (STDP) to our simulated prefrontal cortex, striatum, and insular cortex. To cope with noisy, varying inputs, the SNN was tuned to produce traveling waves of activity that carried spatiotemporal information. Despite the noisy tactile sensors, spike trains, and variations in subject hand swipes, the learning was quite robust. Further, insular cortex activities in the incremental pathway of dopaminergic reward system allowed us to control CARL-SJR's preference for touch direction without heavily pre-processed inputs. The emerged behaviors we found in this model match animal's behaviors wherein they prefer touch in particular areas and directions. Thus, the results in this paper could serve as an explanation on the underlying neural mechanisms for developing tactile preferences and hedonic touch. PMID:26257639

Carvacrol: from ancient flavoring to neuromodulatory agent.

PubMed

Zotti, Margherita; Colaianna, Marilena; Morgese, Maria Grazia; Tucci, Paolo; Schiavone, Stefania; Avato, Pinarosa; Trabace, Luigia

2013-05-24

Oregano and thyme essential oils are used for therapeutic, aromatic and gastronomic purposes due to their richness in active substances, like carvacrol; however, the effects of the latter on the central nervous system have been poorly investigated. The aim of our study was to define the effects of carvacrol on brain neurochemistry and behavioural outcome in rats. Biogenic amine content in the prefrontal cortex and hippocampus after chronic or acute oral carvacrol administration was measured. Animals were assessed by a forced swimming test. Carvacrol, administered for seven consecutive days (12.5 mg/kg p.o.), was able to increase dopamine and serotonin levels in the prefrontal cortex and hippocampus. When single doses were used (150 and 450 mg/kg p.o.), dopamine content was increased in the prefrontal cortex at both dose levels. On the contrary, a significant dopamine reduction in hippocampus of animals treated with 450 mg/kg of carvacrol was found. Acute carvacrol administration only significantly reduced serotonin content in either the prefrontal cortex or in the hippocampus at the highest dose. Moreover, acute carvacrol was ineffective in producing changes in the forced swimming test. Our data suggest that carvacrol is a brain-active molecule that clearly influences neuronal activity through modulation of neurotransmitters. If regularly ingested in low concentrations, it might determine feelings of well-being and could possibly have positive reinforcer effects.

Developmental origins of brain disorders: roles for dopamine

PubMed Central

Money, Kelli M.; Stanwood, Gregg D.

2013-01-01

Neurotransmitters and neuromodulators, such as dopamine, participate in a wide range of behavioral and cognitive functions in the adult brain, including movement, cognition, and reward. Dopamine-mediated signaling plays a fundamental neurodevelopmental role in forebrain differentiation and circuit formation. These developmental effects, such as modulation of neuronal migration and dendritic growth, occur before synaptogenesis and demonstrate novel roles for dopaminergic signaling beyond neuromodulation at the synapse. Pharmacologic and genetic disruptions demonstrate that these effects are brain region- and receptor subtype-specific. For example, the striatum and frontal cortex exhibit abnormal neuronal structure and function following prenatal disruption of dopamine receptor signaling. Alterations in these processes are implicated in the pathophysiology of neuropsychiatric disorders, and emerging studies of neurodevelopmental disruptions may shed light on the pathophysiology of abnormal neuronal circuitry in neuropsychiatric disorders. PMID:24391541

Functional variants of the dopamine receptor D2 gene modulate prefronto-striatal phenotypes in schizophrenia.

PubMed

Bertolino, Alessandro; Fazio, Leonardo; Caforio, Grazia; Blasi, Giuseppe; Rampino, Antonio; Romano, Raffaella; Di Giorgio, Annabella; Taurisano, Paolo; Papp, Audrey; Pinsonneault, Julia; Wang, Danxin; Nardini, Marcello; Popolizio, Teresa; Sadee, Wolfgang

2009-02-01

Dopamine D2 receptor signalling is strongly implicated in the aetiology of schizophrenia. We have recently characterized the function of three DRD2 SNPs: rs12364283 in the promoter affecting total D2 mRNA expression; rs2283265 and rs1076560, respectively in introns 5 and 6, shifting mRNA splicing to two functionally distinct isoforms, the short form of D2 (D2S) and the long form (D2L). These two isoforms differentially contribute to dopamine signalling in prefrontal cortex and in striatum. We performed a case-control study to determine association of these variants and of their main haplotypes with several schizophrenia-related phenotypes. We demonstrate that the minor allele in the intronic variants is associated with reduced expression of %D2S of total mRNA in post-mortem prefrontal cortex, and with impaired working memory behavioural performance, both in patients and controls. However, the fMRI results show opposite effects in patients compared with controls: enhanced engagement of prefronto-striatal pathways in controls and reduced activity in patients. Moreover, the promoter variant is also associated with working memory activity in prefrontal cortex and striatum of patients, and less robustly with negative symptoms scores. Main haplotypes formed by the three DRD2 variants showed significant associations with these phenotypes consistent with those of the individual SNPs. Our results indicate that the three functional DRD2 variants modulate schizophrenia phenotypes possibly by modifying D2S/D2L ratios in the context of different total D2 density.

Functional variants of the dopamine receptor D2 gene modulate prefronto-striatal phenotypes in schizophrenia

PubMed Central

Fazio, Leonardo; Caforio, Grazia; Blasi, Giuseppe; Rampino, Antonio; Romano, Raffaella; Di Giorgio, Annabella; Taurisano, Paolo; Papp, Audrey; Pinsonneault, Julia; Wang, Danxin; Nardini, Marcello; Popolizio, Teresa; Sadee, Wolfgang

2009-01-01

Dopamine D2 receptor signalling is strongly implicated in the aetiology of schizophrenia. We have recently characterized the function of three DRD2 SNPs: rs12364283 in the promoter affecting total D2 mRNA expression; rs2283265 and rs1076560, respectively in introns 5 and 6, shifting mRNA splicing to two functionally distinct isoforms, the short form of D2 (D2S) and the long form (D2L). These two isoforms differentially contribute to dopamine signalling in prefrontal cortex and in striatum. We performed a case–control study to determine association of these variants and of their main haplotypes with several schizophrenia-related phenotypes. We demonstrate that the minor allele in the intronic variants is associated with reduced expression of %D2S of total mRNA in post-mortem prefrontal cortex, and with impaired working memory behavioural performance, both in patients and controls. However, the fMRI results show opposite effects in patients compared with controls: enhanced engagement of prefronto-striatal pathways in controls and reduced activity in patients. Moreover, the promoter variant is also associated with working memory activity in prefrontal cortex and striatum of patients, and less robustly with negative symptoms scores. Main haplotypes formed by the three DRD2 variants showed significant associations with these phenotypes consistent with those of the individual SNPs. Our results indicate that the three functional DRD2 variants modulate schizophrenia phenotypes possibly by modifying D2S/D2L ratios in the context of different total D2 density. PMID:18829695

Adenosine A2A receptors modulate the dopamine D2 receptor-mediated inhibition of synaptic transmission in the mouse prefrontal cortex.

PubMed

Real, Joana I; Simões, Ana Patrícia; Cunha, Rodrigo A; Ferreira, Samira G; Rial, Daniel

2018-05-01

Prefrontal cortex (PFC) circuits are modulated by dopamine acting on D 1 - and D 2 -like receptors, which are pharmacologically exploited to manage neuropsychiatric conditions. Adenosine A 2A receptors (A 2 A R) also control PFC-related responses and A 2 A R antagonists are potential anti-psychotic drugs. As tight antagonistic A 2 A R-D 2 R and synergistic A 2 A R-D 1 R interactions occur in other brain regions, we now investigated the crosstalk between A 2 A R and D 1 /D 2 R controlling synaptic transmission between layers II/III and V in mouse PFC coronal slices. Dopamine decreased synaptic transmission, a presynaptic effect based on the parallel increase in paired-pulse responses. Dopamine inhibition was prevented by the D 2 R-like antagonist sulpiride but not by the D 1 R antagonist SCH23390 and was mimicked by the D 2 R agonist sumanirole, but not by the agonists of either D 4 R (A-412997) or D 3 R (PD128907). Dopamine inhibition was prevented by the A 2 A R antagonist, SCH58261, and attenuated in A 2 A R knockout mice. Accordingly, triple-labelling immunocytochemistry experiments revealed the co-localization of A 2 A R and D 2 R immunoreactivity in glutamatergic (vGluT1-positive) nerve terminals of the PFC. This reported positive A 2 A R-D 2 R interaction controlling PFC synaptic transmission provides a mechanistic justification for the anti-psychotic potential of A 2 A R antagonists. © 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Selective effects of buspirone and molindone on dopamine metabolism and function in the striatum and frontal cortex of the rat.

PubMed

McMillen, B A; McDonald, C C

1983-03-01

The hypothesis that the nerve endings of the dopamine projection of the frontal cortex lack autoreceptors for regulation of tyrosine hydroxylase was tested by using the preferential inhibitors of dopamine autoreceptors, molindole and buspirone. In contrast to haloperidol, which elevates dopamine metabolism in the striatum and frontal cortex, both molindone and buspirone elicited little change in dopamine metabolism in the frontal cortex at doses up to 3.0 mg/kg, which cause the same maximal response in the corpus striatum as does haloperidol. Thus, the lack of autoreceptors in the frontal cortex is of pharmacological importance. That preferential inhibition of striatal dopamine autoreceptors may reverse catalepsy by enhancing synthesis and release of dopamine was tested by first inducing catalepsy with different drugs and then administering molindone or buspirone. Only buspirone (1.0 mg/kg) reversed catalepsy. This effect does not require presynaptic dopamine as catalepsy was reversed by buspirone in the dopamine-depleted rat (with 2.0 mg/kg R04-1284) as well as after postsynaptic dopamine receptor blockade by haloperidol of cis-flupenthixol. Thus, the mechanism for the reversal of catalepsy appears to be located efferent from the dopamine neuron. Buspirone, a non-benzodiazepine anti-anxiety drug, may prove useful for treatment of extrapyramidal motor disorders of either iatrogenic or idiosyncratic origin.

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

PubMed

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

2016-01-27

Considerable evidence suggests that multiple learning systems can drive behavior. Choice can proceed reflexively from previous actions and their associated outcomes, as captured by "model-free" learning algorithms, or flexibly from prospective consideration of outcomes that might occur, as captured by "model-based" learning algorithms. However, differential contributions of dopamine to these systems are poorly understood. Dopamine is widely thought to support model-free learning by modulating plasticity in striatum. Model-based learning may also be affected by these striatal effects, or by other dopaminergic effects elsewhere, notably on prefrontal working memory function. Indeed, prominent demonstrations linking striatal dopamine to putatively model-free learning did not rule out model-based effects, whereas other studies have reported dopaminergic modulation of verifiably model-based learning, but without distinguishing a prefrontal versus striatal locus. To clarify the relationships between dopamine, neural systems, and learning strategies, we combine a genetic association approach in humans with two well-studied reinforcement learning tasks: one isolating model-based from model-free behavior and the other sensitive to key aspects of striatal plasticity. Prefrontal function was indexed by a polymorphism in the COMT gene, differences of which reflect dopamine levels in the prefrontal cortex. This polymorphism has been associated with differences in prefrontal activity and working memory. Striatal function was indexed by a gene coding for DARPP-32, which is densely expressed in the striatum where it is necessary for synaptic plasticity. We found evidence for our hypothesis that variations in prefrontal dopamine relate to model-based learning, whereas variations in striatal dopamine function relate to model-free learning. Decisions can stem reflexively from their previously associated outcomes or flexibly from deliberative consideration of potential choice outcomes. Research implicates a dopamine-dependent striatal learning mechanism in the former type of choice. Although recent work has indicated that dopamine is also involved in flexible, goal-directed decision-making, it remains unclear whether it also contributes via striatum or via the dopamine-dependent working memory function of prefrontal cortex. We examined genetic indices of dopamine function in these regions and their relation to the two choice strategies. We found that striatal dopamine function related most clearly to the reflexive strategy, as previously shown, and that prefrontal dopamine related most clearly to the flexible strategy. These findings suggest that dissociable brain regions support dissociable choice strategies. Copyright © 2016 the authors 0270-6474/16/361211-12$15.00/0.

D-amino acid oxidase is expressed in the ventral tegmental area and modulates cortical dopamine

PubMed Central

Betts, Jill F.; Schweimer, Judith V.; Burnham, Katherine E.; Burnet, Philip W. J.; Sharp, Trevor; Harrison, Paul J.

2014-01-01

D-amino acid oxidase (DAO, DAAO) degrades the NMDA receptor co-agonist D-serine, modulating D-serine levels and thence NMDA receptor function. DAO inhibitors are under development as a therapy for schizophrenia, a disorder involving both NMDA receptor and dopaminergic dysfunction. However, a direct role for DAO in dopamine regulation has not been demonstrated. Here, we address this question in two ways. First, using in situ hybridization and immunohistochemistry, we show that DAO mRNA and immunoreactivity are present in the ventral tegmental area (VTA) of the rat, in tyrosine hydroxylase (TH)-positive and -negative neurons, and in glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes. Second, we show that injection into the VTA of sodium benzoate, a DAO inhibitor, increases frontal cortex extracellular dopamine, as measured by in vivo microdialysis and high performance liquid chromatography. Combining sodium benzoate and D-serine did not enhance this effect, and injection of D-serine alone affected dopamine metabolites but not dopamine. These data show that DAO is expressed in the VTA, and suggest that it impacts on the mesocortical dopamine system. The mechanism by which the observed effects occur, and the implications of these findings for schizophrenia therapy, require further study. PMID:24822045

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.

Effects of dopamine D1 modulation of the anterior cingulate cortex in a fear conditioning procedure

PubMed Central

Pezze, M.A.; Marshall, H.J.; Domonkos, A.; Cassaday, H.J.

2016-01-01

The anterior cingulate cortex (AC) component of the medial prefrontal cortex (mPFC) has been implicated in attention and working memory as measured by trace conditioning. Since dopamine (DA) is a key modulator of mPFC function, the present study evaluated the role of DA receptor agents in rat AC, using trace fear conditioning. A conditioned stimulus (CS, noise) was followed by an unconditioned stimulus (US, shock) with or without a 10 s trace interval interposed between these events in a between-subjects design. Conditioned suppression of drinking was assessed in response to presentation of the CS or an experimental background stimulus (flashing lights, previously presented for the duration of the conditioning session). The selective D1 agonist SKF81297 (0.05 μg/side) or D1 antagonist SCH23390 (0.5 μg/side) was administered by intra-cerebral microinfusion directly into AC. It was predicted that either of these manipulations should be sufficient to impair trace (but not delay) conditioning. Counter to expectation, there was no effect of DA D1 modulation on trace conditioning as measured by suppression to the noise CS. However, rats infused with SKF81297 acquired stronger conditioned suppression to the experimental background stimulus than those infused with SCH23390 or saline. Thus, the DA D1 agonist SKF81297 increased conditioned suppression to the contextual background light stimulus but was otherwise without effect on fear conditioning. PMID:26343307

Impulsive behavior and nicotinic acetylcholine receptors.

PubMed

Ohmura, Yu; Tsutsui-Kimura, Iku; Yoshioka, Mitsuhiro

2012-01-01

Higher impulsivity is thought to be a risk factor for drug addiction, criminal involvement, and suicide. Excessive levels of impulsivity are often observed in several psychiatric disorders including attention-deficit/hyperactivity disorder and schizophrenia. Previous studies have demonstrated that nicotinic acetylcholine receptors (nAChRs) are involved in impulsive behavior. Here, we introduce recent advances in this field and describe the role of the following nAChR-related brain mechanisms in modulating impulsive behavior: dopamine release in the ventral striatum; α4β2 nAChRs in the infralimbic cortex, which is a ventral part of the medial prefrontal cortex (mPFC); and dopamine release in the mPFC. We also suggest several potential therapeutic drugs to address these mechanisms in impulsivity-related disorders and explore future directions to further elucidate the roles of central nAChRs in impulsive behavior.

Striatal dysfunction increases basal ganglia output during motor cortex activation in parkinsonian rats.

PubMed

Belluscio, Mariano A; Riquelme, Luis A; Murer, M Gustavo

2007-05-01

During movement, inhibitory neurons in the basal ganglia output nuclei show complex modulations of firing, which are presumptively driven by corticostriatal and corticosubthalamic input. Reductions in discharge should facilitate movement by disinhibiting thalamic and brain stem nuclei while increases would do the opposite. A proposal that nigrostriatal dopamine pathway degeneration disrupts trans-striatal pathways' balance resulting in sustained overactivity of basal ganglia output nuclei neurons and Parkinson's disease clinical signs is not fully supported by experimental evidence, which instead shows abnormal synchronous oscillatory activity in animal models and patients. Yet, the possibility that variation in motor cortex activity drives transient overactivity in output nuclei neurons in parkinsonism has not been explored. In Sprague-Dawley rats with 6-hydroxydopamine (6-OHDA)-induced nigrostriatal lesions, approximately 50% substantia nigra pars reticulata (SNpr) units show abnormal cortically driven slow oscillations of discharge. Moreover, these units selectively show abnormal responses to motor cortex stimulation consisting in augmented excitations of an odd latency, which overlapped that of inhibitory responses presumptively mediated by the trans-striatal direct pathway in control rats. Delivering D1 or D2 dopamine agonists into the striatum of parkinsonian rats by reverse microdialysis reduced these abnormal excitations but had no effect on pathological oscillations. The present study establishes that dopamine-deficiency related changes of striatal function contribute to producing abnormally augmented excitatory responses to motor cortex stimulation in the SNpr. If a similar transient overactivity of basal ganglia output were driven by motor cortex input during movement, it could contribute to impeding movement initiation or execution in Parkinson's disease.

Pharmacological Blockade of Serotonin 5-HT7 Receptor Reverses Working Memory Deficits in Rats by Normalizing Cortical Glutamate Neurotransmission

PubMed Central

Bonaventure, Pascal; Aluisio, Leah; Shoblock, James; Boggs, Jamin D.; Fraser, Ian C.; Lord, Brian; Lovenberg, Timothy W.; Galici, Ruggero

2011-01-01

The role of 5-HT7 receptor has been demonstrated in various animal models of mood disorders; however its function in cognition remains largely speculative. This study evaluates the effects of SB-269970, a selective 5-HT7 antagonist, in a translational model of working memory deficit and investigates whether it modulates cortical glutamate and/or dopamine neurotransmission in rats. The effect of SB-269970 was evaluated in the delayed non-matching to position task alone or in combination with MK-801, a non-competitive NMDA receptor antagonist, and, in separate experiments, with scopolamine, a non-selective muscarinic antagonist. SB-269970 (10 mg/kg) significantly reversed the deficits induced by MK-801 (0.1 mg/kg) but augmented the deficit induced by scopolamine (0.06 mg/kg). The ability of SB-269970 to modulate MK-801-induced glutamate and dopamine extracellular levels was separately evaluated using biosensor technology and microdialysis in the prefrontal cortex of freely moving rats. SB-269970 normalized MK-801 -induced glutamate but not dopamine extracellular levels in the prefrontal cortex. Rat plasma and brain concentrations of MK-801 were not affected by co-administration of SB-269970, arguing for a pharmacodynamic rather than a pharmacokinetic mechanism. These results indicate that 5-HT7 receptor antagonists might reverse cognitive deficits associated with NMDA receptor hypofunction by selectively normalizing glutamatergic neurotransmission. PMID:21701689

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

PubMed

Yang, Chen; Ge, Shun-Nan; Zhang, Jia-Rui; Chen, Lei; Yan, Zhi-Qiang; Heng, Li-Jun; Zhao, Tian-Zhi; Li, Wei-Xin; Jia, Dong; Zhu, Jun-Ling; Gao, Guo-Dong

2013-01-01

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

Norepinephrine versus Dopamine and their Interaction in Modulating Synaptic Function in the Prefrontal Cortex

PubMed Central

Xing, Bo; Li, Yan-Chun; Gao, Wen-Jun

2016-01-01

Among the neuromodulators that regulate prefrontal cortical circuit function, the catecholamine transmitters norepinephrine (NE) and dopamine (DA) stand out as powerful players in working memory and attention. Perturbation of either NE or DA signaling is implicated in the pathogenesis of several neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), schizophrenia, and drug addiction. Although the precise mechanisms employed by NE and DA to cooperatively control prefrontal functions are not fully understood, emerging research indicates that both transmitters regulate electrical and biochemical aspects of neuronal function by modulating convergent ionic and synaptic signaling in the prefrontal cortex (PFC). This review summarizes previous studies that investigated the effects of both NE and DA on excitatory and inhibitory transmissions in the prefrontal cortical circuitry. Specifically, we focus on the functional interaction between NE and DA in prefrontal cortical local circuitry, synaptic integration, signaling pathways, and receptor properties. Although it is clear that both NE and DA innervate the PFC extensively and modulate synaptic function by activating distinctly different receptor subtypes and signaling pathways, it remains unclear how these two systems coordinate their actions to optimize PFC function for appropriate behavior. Throughout this review, we provide perspectives and highlight several critical topics for future studies. PMID:26790349

Decreased prefrontal cortical dopamine transmission in alcoholism.

PubMed

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

2014-08-01

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

Tonic effects of the dopaminergic ventral midbrain on the auditory cortex of awake macaque monkeys.

PubMed

Huang, Ying; Mylius, Judith; Scheich, Henning; Brosch, Michael

2016-03-01

This study shows that ongoing electrical stimulation of the dopaminergic ventral midbrain can modify neuronal activity in the auditory cortex of awake primates for several seconds. This was reflected in a decrease of the spontaneous firing and in a bidirectional modification of the power of auditory evoked potentials. We consider that both effects are due to an increase in the dopamine tone in auditory cortex induced by the electrical stimulation. Thus, the dopaminergic ventral midbrain may contribute to the tonic activity in auditory cortex that has been proposed to be involved in associating events of auditory tasks (Brosch et al. Hear Res 271:66-73, 2011) and may modulate the signal-to-noise ratio of the responses to auditory stimuli.

Association of Catechol-O-Methyltransferase (COMT) Polymorphism and Academic Achievement in a Chinese Cohort

ERIC Educational Resources Information Center

Yeh, Ting-Kuang; Chang, Chun-Yen; Hu, Chung-Yi; Yeh, Ting-Chi; Lin, Ming-Yeh

2009-01-01

Catechol-O-methyltransferase (COMT) is a methylation enzyme that catalyzes the degradation pathway and inactivation of dopamine. It is accepted widely as being involved in the modulation of dopaminergic physiology and prefrontal cortex (PFC) function. The COMT Val158Met polymorphism is associated with variation in COMT activity. COMT 158Met allele…

Placebo neural systems: nitric oxide, morphine and the dopamine brain reward and motivation circuitries.

PubMed

Fricchione, Gregory; Stefano, George B

2005-05-01

Evidence suggests that the placebo response is related to the tonic effects of constitutive nitric oxide in neural, vascular and immune tissues. Constitutive nitric oxide levels play a role in the modulation of dopamine outflow in the nigrostriatal movement and the mesolimbic and mesocortical reward and motivation circuitries. Endogenous morphine, which stimulates constitutive nitric oxide, may be an important signal molecule working at mu receptors on gamma aminobutyric acid B interneurons to disinhibit nigral and tegmental dopamine output. We surmise that placebo induced belief will activate the prefrontal cortex with downstream stimulatory effects on these dopamine systems as well as on periaqueductal grey opioid output neurons. Placebo responses in Parkinson's disease, depression and pain disorder may result. In addition, mesolimbic/mesocortical control of the stress response systems may provide a way for the placebo response to benefit other medical conditions.

Behavioral activation system modulation on brain activation during appetitive and aversive stimulus processing.

PubMed

Barrós-Loscertales, Alfonso; Ventura-Campos, Noelia; Sanjuán-Tomás, Ana; Belloch, Vicente; Parcet, Maria-Antònia; Avila, César

2010-03-01

The reinforcement sensitivity theory (RST) proposed the behavioral activation system (BAS) as a neurobehavioral system that is dependent on dopamine-irrigated structures and that mediates the individual differences in sensitivity and reactivity to appetitive stimuli associated with BAS-related personality traits. Theoretical developments propose that high BAS sensitivity is associated with both enhanced appetitive stimuli processing and the diminished processing of aversive stimuli. The objective of this study was to analyze how individual differences in BAS functioning were associated with brain activation during erotic and aversive picture processing while subjects were involved in a simple goal-directed task. Forty-five male participants took part in this study. The task activation results confirm the activation of the reward and punishment brain-related structures while viewing erotic and aversive pictures, respectively. The SR scores show a positive correlation with activation of the left lateral prefrontal cortex, the mesial prefrontal cortex and the right occipital cortex while viewing erotic pictures, and a negative correlation with the right lateral prefrontal cortex and the left occipital cortex while viewing aversive pictures. In summary, the SR scores modulate the activity of the cortical areas in the prefrontal and the occipital cortices that are proposed to modulate the BAS and the BIS-FFFS.

Dampened dopamine-mediated neuromodulation in prefrontal cortex of fragile X mice

PubMed Central

Paul, Kush; Venkitaramani, Deepa V; Cox, Charles L

2013-01-01

Fragile X syndrome (FXS) is the most common form of inheritable mental retardation caused by transcriptional silencing of the Fmr1 gene resulting in the absence of fragile X mental retardation protein (FMRP). The role of this protein in neurons is complex and its absence gives rise to diverse alterations in neuronal function leading to neurological disorders including mental retardation, hyperactivity, cognitive impairment, obsessive-compulsive behaviour, seizure activity and autism. FMRP regulates mRNA translation at dendritic spines where synapses are formed, and thus the lack of FMRP can lead to disruptions in synaptic transmission and plasticity. Many of these neurological deficits in FXS probably involve the prefrontal cortex, and in this study, we have focused on modulatory actions of dopamine in the medial prefrontal cortex. Our data indicate that dopamine produces a long-lasting enhancement of evoked inhibitory postsynaptic currents (IPSCs) mediated by D1-type receptors seen in wild-type mice; however, such enhancement is absent in the Fmr1 knock-out (Fmr1 KO) mice. The facilitation of IPSCs produced by direct cAMP stimulation was unaffected in Fmr1 KO, but D1 receptor levels were reduced in these animals. Our results show significant disruption of dopaminergic modulation of synaptic transmission in the Fmr1 KO mice and this alteration in inhibitory activity may provide insight into potential targets for the rescue of deficits associated with FXS. PMID:23148316

Dampened dopamine-mediated neuromodulation in prefrontal cortex of fragile X mice.

PubMed

Paul, Kush; Venkitaramani, Deepa V; Cox, Charles L

2013-02-15

Fragile X syndrome (FXS) is the most common form of inheritable mental retardation caused by transcriptional silencing of the Fmr1 gene resulting in the absence of fragile X mental retardation protein (FMRP). The role of this protein in neurons is complex and its absence gives rise to diverse alterations in neuronal function leading to neurological disorders including mental retardation, hyperactivity, cognitive impairment, obsessive-compulsive behaviour, seizure activity and autism. FMRP regulates mRNA translation at dendritic spines where synapses are formed, and thus the lack of FMRP can lead to disruptions in synaptic transmission and plasticity. Many of these neurological deficits in FXS probably involve the prefrontal cortex, and in this study, we have focused on modulatory actions of dopamine in the medial prefrontal cortex. Our data indicate that dopamine produces a long-lasting enhancement of evoked inhibitory postsynaptic currents (IPSCs) mediated by D1-type receptors seen in wild-type mice; however, such enhancement is absent in the Fmr1 knock-out (Fmr1 KO) mice. The facilitation of IPSCs produced by direct cAMP stimulation was unaffected in Fmr1 KO, but D1 receptor levels were reduced in these animals. Our results show significant disruption of dopaminergic modulation of synaptic transmission in the Fmr1 KO mice and this alteration in inhibitory activity may provide insight into potential targets for the rescue of deficits associated with FXS.

Dopamine D1 Sensitivity in the Prefrontal Cortex Predicts General Cognitive Abilities and is Modulated by Working Memory Training

ERIC Educational Resources Information Center

Wass, Christopher; Pizzo, Alessandro; Sauce, Bruno; Kawasumi, Yushi; Sturzoiu, Tudor; Ree, Fred; Otto, Tim; Matzel, Louis D.

2013-01-01

A common source of variance (i.e., "general intelligence") underlies an individual's performance across diverse tests of cognitive ability, and evidence indicates that the processing efficacy of working memory may serve as one such source of common variance. One component of working memory, selective attention, has been reported to…

Dopaminergic modulation of the orbitofrontal cortex affects attention, motivation and impulsive responding in rats performing the five-choice serial reaction time task.

PubMed

Winstanley, Catharine A; Zeeb, Fiona D; Bedard, Amanda; Fu, Kent; Lai, Barbara; Steele, Christina; Wong, Adeline C

2010-07-11

Understanding the neurobiological factors underlying individual differences in impulsivity may provide valuable insight into vulnerability to impulse control disorders. Recent data implicate both the orbitofrontal cortex (OFC) and the dopaminergic system in psychiatric disorders associated with high levels of impulsivity, including substance abuse, mania and obsessive-compulsive disorder. However, the consequences of modulating dopaminergic activity within the OFC on impulsive behaviour are largely unknown. The effects of direct intra-OFC infusions of agonists and antagonists at the dopamine D(1) and D(2) receptors were therefore assessed in rats performing the five-choice serial reaction time test (5CSRT) of attention and motor impulsivity. Intra-OFC administration of SCH23390, a D(1) receptor antagonist, decreased impulsive responding in highly impulsive (HI) rats, but did not affect behaviour in less impulsive (LI) animals. Furthermore, the D(2) agonist quinpirole caused significant deficits in task performance, impairing accuracy, increasing omissions and decreasing the number of trials completed, which resembled the effects of systemic administration. In contrast, the D(1) agonist SKF 81297 had little effect on behaviour. Neither agonist increased impulsivity. These data provide partial support for the suggestion that high levels of impulsivity are associated with increased dopamine levels within the OFC, but further indicate that simulating dopamine's actions selectively at the D(1) or D(2) receptor cannot reproduce a highly impulsive phenotype. Dopaminergic activity within the OFC may therefore modulate impulsivity indirectly, perhaps in conjunction with other neurotransmitter systems. Furthermore, D(2)-mediated neurotransmission within the OFC could make a more fundamental contribution to cognitive behaviour. Copyright 2010 Elsevier B.V. All rights reserved.

The medial prefrontal and orbitofrontal cortices differentially regulate dopamine system function.

PubMed

Lodge, Daniel J

2011-05-01

The prefrontal cortex (PFC) is essential for top-down control over higher-order executive function. In this study we demonstrate that the medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC) differentially regulate VTA dopamine neuron activity, and furthermore, the pattern of activity in the PFC drastically alters the dopamine neuron response. Thus, although single-pulse activation of the mPFC either excites or inhibits equivalent numbers of dopamine neurons, activation of the OFC induces a primarily inhibitory response. Moreover, activation of the PFC with a pattern that mimics spontaneous burst firing of pyramidal neurons produces a strikingly different response. Specifically, burst-like activation of the mPFC induces a massive increase in dopamine neuron firing, whereas a similar pattern of OFC activation largely inhibits dopamine activity. Taken together, these data demonstrate that the mPFC and OFC differentially regulate dopamine neuron activity, and that the pattern of cortical activation is critical for determining dopamine system output.

Noradrenaline transporter blockade increases fronto-parietal functional connectivity relevant for working memory.

PubMed

Hernaus, Dennis; Casales Santa, Marta Ma; Offermann, Jan Stefan; Van Amelsvoort, Thérèse

2017-04-01

Experimental animal work has demonstrated that dopamine and noradrenaline play an essential role in modulating prefrontal cortex-mediated networks underlying working memory performance. Studies of functional connectivity have been instrumental in extending such notions to humans but, so far, have almost exclusively focussed on pharmacological agents with a predominant dopaminergic mechanism of action. Here, we investigate the effect of a single dose of atomoxetine 60mg, a noradrenaline transporter inhibitor, on working memory performance and associated functional connectivity during an n-back task in 19 healthy male volunteers. Atomoxetine increased functional connectivity between right anterior insula and dorsolateral prefrontal cortex, precentral gyrus, posterior parietal cortex and precuneus during the high-working memory load condition of the n-back task. Increased atomoxetine-induced insula-dorsolateral prefrontal cortex functional connectivity during this condition correlated with decreased reaction time variability and was furthermore predicted by working memory capacity. These results show for the first time that noradrenaline transporter blockade-induced increases in cortical catecholamines accentuate fronto-parietal working memory-related network integrity. The observation of significant inter-subject variability in response to atomoxetine has implications for inverted-U frameworks of dopamine and noradrenaline function, which could be useful to predict drug effects in clinical disorders with variable treatment response. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.

Norepinephrine versus dopamine and their interaction in modulating synaptic function in the prefrontal cortex.

PubMed

Xing, Bo; Li, Yan-Chun; Gao, Wen-Jun

2016-06-15

Among the neuromodulators that regulate prefrontal cortical circuit function, the catecholamine transmitters norepinephrine (NE) and dopamine (DA) stand out as powerful players in working memory and attention. Perturbation of either NE or DA signaling is implicated in the pathogenesis of several neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), schizophrenia, and drug addiction. Although the precise mechanisms employed by NE and DA to cooperatively control prefrontal functions are not fully understood, emerging research indicates that both transmitters regulate electrical and biochemical aspects of neuronal function by modulating convergent ionic and synaptic signaling in the prefrontal cortex (PFC). This review summarizes previous studies that investigated the effects of both NE and DA on excitatory and inhibitory transmissions in the prefrontal cortical circuitry. Specifically, we focus on the functional interaction between NE and DA in prefrontal cortical local circuitry, synaptic integration, signaling pathways, and receptor properties. Although it is clear that both NE and DA innervate the PFC extensively and modulate synaptic function by activating distinctly different receptor subtypes and signaling pathways, it remains unclear how these two systems coordinate their actions to optimize PFC function for appropriate behavior. Throughout this review, we provide perspectives and highlight several critical topics for future studies. This article is part of a Special Issue entitled SI: Noradrenergic System. Copyright © 2016 Elsevier B.V. All rights reserved.

Antagonism of dopamine D2 receptors alters phosphorylation of Fyn in the rat medial prefrontal cortex

PubMed Central

Mao, Li-Min; Wang, John Q.

2017-01-01

Several Src family kinase (SFK) members are expressed in the mammalian brain and serve as key kinases in the regulation of a variety of cellular and synaptic events. These SFKs may be subject to the modulation by dopamine, although this topic has been investigated incompletely. In this study, we explored whether dopamine D2 receptors (D2R) regulate SFKs in adult rat brains in vivo. We investigated the role of D2Rs in two forebrain areas, the medial prefrontal cortex (mPFC) and hippocampus, since dopamine plays a pivotal role in regulating activity of mPFC and hippocampal neurons and D2Rs are expressed in these regions. We found that a systemic injection of a D2R selective antagonist eticlopride elevated phosphorylation of SFKs at a conserved autophosphorylation site, an event correlated with activation of SFKs, in the mPFC. Similarly, antagonism of D2Rs by haloperidol increased SFK phosphorylation. In contrast, eticlopride and haloperidol did not alter SFK phosphorylation in the hippocampus. The effect of eticlopride was time-dependent and relatively delayed. Among two common SFK members enriched at synaptic sites, eticlopride selectively altered phosphorylation of Fyn but not Src. Our data suggest that D2Rs exert an inhibitory effect on the activity-related phosphorylation of Fyn in the mPFC under normal conditions. PMID:28176147

Frontal Transcranial Direct Current Stimulation Induces Dopamine Release in the Ventral Striatum in Human

PubMed Central

Fonteneau, Clara; Redoute, Jérome; Haesebaert, Frédéric; Le Bars, Didier; Costes, Nicolas; Suaud-Chagny, Marie-Françoise; Brunelin, Jérome

2018-01-01

Abstract A single transcranial direct current stimulation (tDCS) session applied over the dorsolateral prefrontal cortex (DLFPC) can be associated with procognitive effects. Furthermore, repeated DLPFC tDCS sessions are under investigation as a new therapeutic tool for a range of neuropsychiatric conditions. A possible mechanism explaining such beneficial effects is a modulation of meso-cortico-limbic dopamine transmission. We explored the spatial and temporal neurobiological effects of bifrontal tDCS on subcortical dopamine transmission during and immediately after the stimulation. In a double blind sham-controlled study, 32 healthy subjects randomly received a single session of either active (20 min, 2 mA; n = 14) or sham (n = 18) tDCS during a dynamic positron emission tomography scan using [11C]raclopride binding. During the stimulation period, no significant effect of tDCS was observed. After the stimulation period, compared with sham tDCS, active tDCS induced a significant decrease in [11C]raclopride binding potential ratio in the striatum, suggesting an increase in extracellular dopamine in a part of the striatum involved in the reward–motivation network. The present study provides the first evidence that bifrontal tDCS induces neurotransmitter release in polysynaptic connected subcortical areas. Therefore, levels of dopamine activity and reactivity should be a new element to consider for a general hypothesis of brain modulation by bifrontal tDCS. PMID:29688276

Frontal Transcranial Direct Current Stimulation Induces Dopamine Release in the Ventral Striatum in Human.

PubMed

Fonteneau, Clara; Redoute, Jérome; Haesebaert, Frédéric; Le Bars, Didier; Costes, Nicolas; Suaud-Chagny, Marie-Françoise; Brunelin, Jérome

2018-07-01

A single transcranial direct current stimulation (tDCS) session applied over the dorsolateral prefrontal cortex (DLFPC) can be associated with procognitive effects. Furthermore, repeated DLPFC tDCS sessions are under investigation as a new therapeutic tool for a range of neuropsychiatric conditions. A possible mechanism explaining such beneficial effects is a modulation of meso-cortico-limbic dopamine transmission. We explored the spatial and temporal neurobiological effects of bifrontal tDCS on subcortical dopamine transmission during and immediately after the stimulation. In a double blind sham-controlled study, 32 healthy subjects randomly received a single session of either active (20 min, 2 mA; n = 14) or sham (n = 18) tDCS during a dynamic positron emission tomography scan using [11C]raclopride binding. During the stimulation period, no significant effect of tDCS was observed. After the stimulation period, compared with sham tDCS, active tDCS induced a significant decrease in [11C]raclopride binding potential ratio in the striatum, suggesting an increase in extracellular dopamine in a part of the striatum involved in the reward-motivation network. The present study provides the first evidence that bifrontal tDCS induces neurotransmitter release in polysynaptic connected subcortical areas. Therefore, levels of dopamine activity and reactivity should be a new element to consider for a general hypothesis of brain modulation by bifrontal tDCS.

FMRP acts as a key messenger for dopamine modulation in the forebrain.

PubMed

Wang, Hansen; Wu, Long-Jun; Kim, Susan S; Lee, Frank J S; Gong, Bo; Toyoda, Hiroki; Ren, Ming; Shang, Yu-Ze; Xu, Hui; Liu, Fang; Zhao, Ming-Gao; Zhuo, Min

2008-08-28

The fragile X mental retardation protein (FMRP) is an RNA-binding protein that controls translational efficiency and regulates synaptic plasticity. Here, we report that FMRP is involved in dopamine (DA) modulation of synaptic potentiation. AMPA glutamate receptor subtype 1 (GluR1) surface expression and phosphorylation in response to D1 receptor stimulation were reduced in cultured Fmr1(-/-) prefrontal cortex (PFC) neurons. Furthermore, D1 receptor signaling was impaired, accompanied by D1 receptor hyperphosphorylation at serine sites and subcellular redistribution of G protein-coupled receptor kinase 2 (GRK2) in both PFC and striatum of Fmr1(-/-) mice. FMRP interacted with GRK2, and pharmacological inhibition of GRK2 rescued D1 receptor signaling in Fmr1(-/-) neurons. Finally, D1 receptor agonist partially rescued hyperactivity and enhanced the motor function of Fmr1(-/-) mice. Our study has identified FMRP as a key messenger for DA modulation in the forebrain and may provide insights into the cellular and molecular mechanisms underlying fragile X syndrome.

The effects of AMPA receptor blockade in the prelimbic cortex on systemic and ventral tegmental area opiate reward sensitivity.

PubMed

De Jaeger, Xavier; Bishop, Stephanie F; Ahmad, Tasha; Lyons, Danika; Ng, Garye Ami; Laviolette, Steven R

2013-02-01

The medial prefrontal cortex (mPFC) is a key neural region involved in opiate-related reward memory processing. AMPA receptor transmission in the mPFC modulates opiate-related reward memory processing, and chronic opiate exposure is associated with alterations in intra-mPFC AMPA receptor function. The objectives of this study were to examine how pharmacological blockade of AMPA receptor transmission in the prelimbic (PLC) division of the mPFC may modulate opiate reward memory acquisition and whether opiate exposure state may modulate the functional role of intra-PLC AMPA receptor transmission during opiate reward learning. Using an unbiased conditioned place preference (CPP) procedure in rats, we performed discrete, bilateral intra-PLC microinfusions of the AMPA receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione, prior to behavioral morphine CPP conditioning, using sub-reward threshold conditioning doses of either systemic (0.05 mg/kg; i.p.) or intra-ventral tegmental area (VTA) morphine (250 ng/0.5 μl). We show that, in both opiate-naïve and opiate-dependent states, intra-PLC blockade of AMPA receptor transmission, but not the infralimbic cortex, increases the behavioral reward magnitude of systemic or intra-VTA morphine. This effect is dependent on dopamine (DA)ergic signaling because pre-administration of cis-(Z)-flupenthixol-dihydrochloride (α-flu), a broad-spectrum dopamine receptor antagonist, blocked the morphine-reward potentiating effects of AMPA receptor blockade. These findings suggest a critical role for intra-PLC AMPA receptor transmission in the processing of opiate reward signaling. Furthermore, blockade of AMPA transmission specifically within the PLC is capable of switching opiate reward processing to a DA-dependent reward system, independently of previous opiate exposure history.

Dopaminergic modulation of the trade-off between probability and time in economic decision-making.

PubMed

Arrondo, Gonzalo; Aznárez-Sanado, Maite; Fernández-Seara, Maria A; Goñi, Joaquín; Loayza, Francis R; Salamon-Klobut, Ewa; Heukamp, Franz H; Pastor, Maria A

2015-06-01

Studies on animals and humans have demonstrated the importance of dopamine in modulating decision-making processes. In this work, we have tested dopaminergic modulation of economic decision-making and its neural correlates by administering either placebo or metoclopramide, a dopamine D2-receptor antagonist, to healthy subjects, during a functional MRI study. The decision-making task combined probability and time delay with a fixed monetary reward. For individual behavioral characterization, we used the Probability Time Trade-off (PTT) economic model, which integrates the traditional trade-offs of reward magnitude-time and reward magnitude-probability into a single measurement, thereby quantifying the subjective value of a delayed and probabilistic outcome. A regression analysis between BOLD signal and the PTT model index permitted to identify the neural substrate encoding the subjective reward-value. Behaviorally, medication reduced the rate of temporal discounting over probability, reflected in medicated subjects being more prone to postpone the reward in order to increase the outcome probability. In addition, medicated subjects showed less activity during the task in the postcentral gyrus as well as frontomedian areas, whereas there were no differences in the ventromedial orbitofrontal cortex (VMOFC) between groups when coding the subjective value. The present study demonstrates by means of behavior and imaging that dopamine modulation alters the probability-time trade-off in human economic decision-making. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

Dynamic Re-wiring of Neural Circuits in the Motor Cortex in Mouse Models of Parkinson's Disease

PubMed Central

Lalchandani, Rupa R.; Cui, Yuting; Shu, Yu; Xu, Tonghui; Ding, Jun B.

2015-01-01

SUMMARY Dynamic adaptations in synaptic plasticity are critical for learning new motor skills and maintaining memory throughout life, which rapidly decline with Parkinson's disease (PD). Plasticity in the motor cortex is important for acquisition and maintenance of novel motor skills, but how the loss of dopamine in PD leads to disrupted structural and functional plasticity in the motor cortex is not well understood. Here, we utilized mouse models of PD and 2-photon imaging to show that dopamine depletion resulted in structural changes in the motor cortex. We further discovered that dopamine D1 and D2 receptor signaling were linked to selectively and distinctly regulating these aberrant changes in structural and functional plasticity. Our findings suggest that both D1 and D2 receptor signaling regulate motor cortex plasticity, and loss of dopamine results in atypical synaptic adaptations that may contribute to the impairment of motor performance and motor memory observed in PD. PMID:26237365

Dissociated roles of the anterior cingulate cortex in reward and conflict processing as revealed by the feedback error-related negativity and N200.

PubMed

Baker, Travis E; Holroyd, Clay B

2011-04-01

The reinforcement learning theory of the error-related negativity (ERN) holds that the impact of reward signals carried by the midbrain dopamine system modulates activity of the anterior cingulate cortex (ACC), alternatively disinhibiting and inhibiting the ACC following unpredicted error and reward events, respectively. According to a recent formulation of the theory, activity that is intrinsic to the ACC produces a component of the event-related brain potential (ERP) called the N200, and following unpredicted rewards, the N200 is suppressed by extrinsically applied positive dopamine reward signals, resulting in an ERP component called the feedback-ERN (fERN). Here we demonstrate that, despite extensive spatial and temporal overlap between the two ERP components, the functional processes indexed by the N200 (conflict) and the fERN (reward) are dissociable. These results point toward avenues for future investigation. Copyright © 2011 Elsevier B.V. All rights reserved.

Altered brain activation in a reversal learning task unmasks adaptive changes in cognitive control in writer's cramp.

PubMed

Zeuner, Kirsten E; Knutzen, Arne; Granert, Oliver; Sablowsky, Simone; Götz, Julia; Wolff, Stephan; Jansen, Olav; Dressler, Dirk; Schneider, Susanne A; Klein, Christine; Deuschl, Günther; van Eimeren, Thilo; Witt, Karsten

2016-01-01

Previous receptor binding studies suggest dopamine function is altered in the basal ganglia circuitry in task-specific dystonia, a condition characterized by contraction of agonist and antagonist muscles while performing specific tasks. Dopamine plays a role in reward-based learning. Using fMRI, this study compared 31 right-handed writer's cramp patients to 35 controls in reward-based learning of a probabilistic reversal-learning task. All subjects chose between two stimuli and indicated their response with their left or right index finger. One stimulus response was rewarded 80%, the other 20%. After contingencies reversal, the second stimulus response was rewarded in 80%. We further linked the DRD2/ANKK1-TaqIa polymorphism, which is associated with 30% reduction of the striatal dopamine receptor density with reward-based learning and assumed impaired reversal learning in A + subjects. Feedback learning in patients was normal. Blood-oxygen level dependent (BOLD) signal in controls increased with negative feedback in the insula, rostral cingulate cortex, middle frontal gyrus and parietal cortex (pFWE < 0.05). In comparison to controls, patients showed greater increase in BOLD activity following negative feedback in the dorsal anterior cingulate cortex (BA32). The genetic status was not correlated with the BOLD activity. The Brodmann area 32 (BA32) is part of the dorsal anterior cingulate cortex (dACC) that plays an important role in coordinating and integrating information to guide behavior and in reward-based learning. The dACC is connected with the basal ganglia-thalamo-loop modulated by dopaminergic signaling. This finding suggests disturbed integration of reinforcement history in decision making and implicate that the reward system might contribute to the pathogenesis in writer's cramp.

Nardostachys jatamansi Targets BDNF-TrkB to Alleviate Ketamine-Induced Schizophrenia-Like Symptoms in Rats.

PubMed

Janardhanan, Anjali; Sadanand, Anjana; Vanisree, Arambakkam Janardhanam

2016-01-01

Schizophrenia, a common neurological disorder appearing in the late teens or early adulthood, is characterized by disorganized thinking, behaviour, and perception of emotions. Aberrant N-methyl-D-aspartate (NMDA) receptor-mediated synaptic plasticity is a major pathological event here due to dysfunction of dopamine and glutamate transmission at NMDA receptors. De-regulated brain-derived neurotrophic factor (BDNF), i.e., its signalling through the tropomyosin receptor kinase B (TrkB) receptor, is a major feature of schizophrenia. With recent global awareness of traditional plant medicines in reducing side effects, the aim of our study was to evaluate the efficacy of the ethanolic root extract of a herb belonging to the Valerianacea family, Nardostachys jatamansi, against ketamine-induced schizophrenia-like model in rats. The effect of the N. jatamansi drug (oral dosage of 500 mg/kg body weight for 14 days) in ketamine-administered male Wistar albino rats (30 mg/kg body weight for 5 days) on modulating behaviour and the level of neurotransmitters like dopamine and glutamate was studied in whole-brain homogenates, and its influence on BDNF and TrkB levels in 2 relevant brain regions, the hippocampus and prefrontal cortex, was assessed. We observed that N. jatamansi treatment exhibited encouraging results in the modulation of ketamine-induced schizophrenia-like behaviours, principally the positive symptoms. Our drug both significantly upregulated the glutamate level and downregulated the dopamine level in whole-brain homogenates and retained the normal levels of BDNF (in the hippocampus but not in the prefrontal cortex) and TrkB (in both hippocampus and prefrontal cortex) induced by ketamine in rats. These findings suggest a neuroprotective effect of the ethanolic root extract of N. jatamansi against ketamine-induced schizophrenia-like symptoms in rats; possibly, regarding its effect on TrkB signalling. Further research is warranted in the treatment of schizophrenic symptoms. © 2017 S. Karger AG, Basel.

Dopamine depletion increases the power and coherence of high-voltage spindles in the globus pallidus and motor cortex of freely moving rats.

PubMed

Ge, Shunnan; Yang, Chen; Li, Min; Li, Jiang; Chang, Xiaozan; Fu, Jian; Chen, Lei; Chang, Chongwang; Wang, Xuelian; Zhu, Junling; Gao, Guodong

2012-07-17

Studies on patients with Parkinson's disease and in animal models have observed enhanced synchronization of oscillations in several frequency bands within and between the cortical-basal ganglia (BG) structures. Recent research has also shown that synchronization of high-voltage spindles (HVSs) in the cortex, striatum and substantia nigra pars reticulate is increased by dopamine depletion. However, more evidence is needed to determine whether HVS activity in the whole cortex-BG network represents homologous alteration following dopamine depletion. As the globus pallidus (GP) is in a central position to propagate and synchronize oscillations in the cortical-BG circuits, we employed local-field potentials and electrocorticogram to simultaneously record oscillations in the GP and primary (M1) and secondary (M2) motor cortices on freely moving 6-hydroxydopamine (6-OHDA) lesioned and control rats. Results showed that HVS episodes recorded from GP, and M2 and M1 cortex areas were more numerous and longer in 6-OHDA lesioned rats compared to controls. Relative power associated with HVS activity in the GP, and M2 and M1 cortices of 6-OHDA lesioned rats was significantly greater than that for control rats. Coherence values for HVS activity between the GP, and M2 and M1 cortex areas were significantly increased by dopamine depletion. Time lag between the M1 cortex HVS and GP HVS was significantly shorter for dopamine depleted than normal rats. Findings indicate a crucial rule for dopamine in the regulation of HVS activity in the whole cortical-BG circuit, and suggest a close relationship between abnormally synchronized HVS oscillations in the cortex-BG network and Parkinson's disease. Copyright © 2012 Elsevier B.V. All rights reserved.

Dopamine D1 and D3 Receptors Modulate Heroin-Induced Cognitive Impairment through Opponent Actions in Mice

PubMed Central

Zhu, Yongsheng; Wang, Yunpeng; Wei, Shuguang; Zhang, Hongbo; Yan, Peng; Li, Yunxiao; Qiao, Xiaomeng; Yin, Fangyuan

2017-01-01

Abstract Background: Chronic abuse of heroin leads to long-lasting and complicated cognitive impairment. Dopamine receptors are critically involved in the impulsive drug-driven behavior and the altered attention, processing speed, and mental flexibility that are associated with higher relapse rates. However, the effects of the different dopamine receptors and their possible involvement in heroin-induced cognitive impairment remain unclear. Methods: The 5-choice serial reaction time task was used to investigate the profiles of heroin-induced cognitive impairment in mice. The expression levels of dopamine D1- and D2-like receptors in the prefrontal cortex, nucleus accumbens, and caudate-putamen were determined. The effects of dopamine receptors on heroin-induced impulsivity in the 5-choice serial reaction time task were examined by agonist/antagonist treatment on D1 or D3 receptor mutant mice. Results: Systemic heroin administration influences several variables in the 5-choice serial reaction time task, most notably premature responses, a measure of motor impulsivity. These behavioral impairments are associated with increased D1 receptor and decreased D3 receptor mRNA and protein levels in 3 observed brain areas. The heroin-evoked increase in premature responses is mimicked by a D1 agonist and prevented by a D1 antagonist or genetic ablation of the D1 receptor gene. In contrast, a D3 agonist decreases both basal and heroin-evoked premature responses, while genetic ablation of the D3 receptor gene results in increased basal and heroin-evoked premature responses. Conclusions: Heroin-induced impulsive behavior in the 5-choice serial reaction time task is oppositely modulated by D1 and D3 receptor activation. The D1 receptors in the cortical-mesolimbic region play an indispensable role in modulating such behaviors. PMID:27815417

Motor learning in animal models of Parkinson’s Disease: Aberrant synaptic plasticity in the motor cortex

PubMed Central

Xu, Tonghui; Wang, Shaofang; Lalchandani, Rupa R.; Ding, Jun B

2017-01-01

In Parkinson’s disease (PD), dopamine depletion causes dramatic changes in the brain resulting in debilitating cognitive and motor deficits. PD neuropathology has been restricted to postmortem examinations, which are limited to only a single time point of PD progression. Models of PD where dopamine tone in the brain are chemically or physically disrupted are valuable tools in understanding the mechanisms of the disease. The basal ganglia have been well studied in the context of PD, and circuit changes in response to dopamine loss have been linked to the motor dysfunctions in PD. However, the etiology of the cognitive dysfunctions that are comorbid in PD patients has remained unclear until now. In this paper, we review recent studies exploring how dopamine depletion affects the motor cortex at the synaptic level. In particular, we highlight our recent findings on abnormal spine dynamics in the motor cortex of PD mouse models through in vivo, time-lapse imaging and motor-skill behavior assays. In combination with previous studies, a role of the motor cortex in skill-learning, and the impairment of this ability with the loss of dopamine, is becoming more apparent. Taken together, we conclude with a discussion on the potential role for the motor cortex in the motor-skill learning and cognitive impairments of PD, with the possibility of targeting the motor cortex for future PD therapeutics. PMID:28343366

Dopamine D1 Receptors in the Anterior Cingulate Cortex Regulate Effort-Based Decision Making

ERIC Educational Resources Information Center

Schweimer, Judith; Hauber, Wolfgang

2006-01-01

The anterior cingulate cortex (ACC) has been implicated in encoding whether or not an action is worth performing in view of the expected benefit and the cost of performing the action. Dopamine input to the ACC may be critical for this form of effort-based decision making; however, the role of distinct ACC dopamine receptors is yet unknown.…

Involvement of the Cannabinoid CB1 Receptor in Modulation of Dopamine Output in the Prefrontal Cortex Associated with Food Restriction in Rats

PubMed Central

Biggio, Francesca; Utzeri, Cinzia; Lallai, Valeria; Licheri, Valentina; Lutzu, Stefano; Mostallino, Maria Cristina; Secci, Pietro Paolo; Biggio, Giovanni; Sanna, Enrico

2014-01-01

Increase in dopamine output on corticolimbic structures, such as medial prefrontal cortex (mPFC) and nucleus accumbens, has been related to reward effects associated with palatable food or food presentation after a fasting period. The endocannabinoid system regulates feeding behavior through a modulatory action on different neurotransmitter systems, including the dopaminergic system. To elucidate the involvement of type 1 cannabinoid receptors in the regulation of dopamine output in the mPFC associated with feeding in hungry rats, we restricted the food availability to a 2-h period daily for 3 weeks. In food-restricted rats the extracellular dopamine concentration in the mPFC increased starting 80 min before food presentation and returned to baseline after food removal. These changes were attenuated in animals treated with the CB1 receptor antagonist SR141716. To better understand how food restriction can change the response of mesocortical dopaminergic neurons, we studied several components of the neuronal circuit that regulates dopamine output in the mPFC. Patch-clamp experiments revealed that the inhibitory effect of the CB1 receptor agonist WIN 55,212-2 on GABAergic sIPSC frequency was diminished in mPFC neurons of FR compared to fed ad libitum rats. The basal sIPSC frequency resulted reduced in mPFC neurons of food-restricted rats, suggestive of an altered regulation of presynaptic GABA release; these changes were accompanied by an enhanced excitability of mPFC and ventral tegmental area neurons. Finally, type 1 cannabinoid receptor expression in the mPFC was reduced in food-restricted rats. Together, our data support an involvement of the endocannabinoid system in regulation of dopamine release in the mPFC through changes in GABA inhibitory synapses and suggest that the emphasized feeding-associated increase in dopamine output in the mPFC of food-restricted rats might be correlated with an altered expression and function of type 1 cannabinoid receptor in this brain region. PMID:24632810

Involvement of the cannabinoid CB1 receptor in modulation of dopamine output in the prefrontal cortex associated with food restriction in rats.

PubMed

Dazzi, Laura; Talani, Giuseppe; Biggio, Francesca; Utzeri, Cinzia; Lallai, Valeria; Licheri, Valentina; Lutzu, Stefano; Mostallino, Maria Cristina; Secci, Pietro Paolo; Biggio, Giovanni; Sanna, Enrico

2014-01-01

Increase in dopamine output on corticolimbic structures, such as medial prefrontal cortex (mPFC) and nucleus accumbens, has been related to reward effects associated with palatable food or food presentation after a fasting period. The endocannabinoid system regulates feeding behavior through a modulatory action on different neurotransmitter systems, including the dopaminergic system. To elucidate the involvement of type 1 cannabinoid receptors in the regulation of dopamine output in the mPFC associated with feeding in hungry rats, we restricted the food availability to a 2-h period daily for 3 weeks. In food-restricted rats the extracellular dopamine concentration in the mPFC increased starting 80 min before food presentation and returned to baseline after food removal. These changes were attenuated in animals treated with the CB1 receptor antagonist SR141716. To better understand how food restriction can change the response of mesocortical dopaminergic neurons, we studied several components of the neuronal circuit that regulates dopamine output in the mPFC. Patch-clamp experiments revealed that the inhibitory effect of the CB1 receptor agonist WIN 55,212-2 on GABAergic sIPSC frequency was diminished in mPFC neurons of FR compared to fed ad libitum rats. The basal sIPSC frequency resulted reduced in mPFC neurons of food-restricted rats, suggestive of an altered regulation of presynaptic GABA release; these changes were accompanied by an enhanced excitability of mPFC and ventral tegmental area neurons. Finally, type 1 cannabinoid receptor expression in the mPFC was reduced in food-restricted rats. Together, our data support an involvement of the endocannabinoid system in regulation of dopamine release in the mPFC through changes in GABA inhibitory synapses and suggest that the emphasized feeding-associated increase in dopamine output in the mPFC of food-restricted rats might be correlated with an altered expression and function of type 1 cannabinoid receptor in this brain region.

Chemical neuromodulation of frontal-executive functions in humans and other animals.

PubMed

Robbins, T W

2000-07-01

Neuromodulation of frontal-executive function is reviewed in the context of experiments on rats, monkeys and human subjects. The different functions of the chemically identified systems of the reticular core are analysed from the perspective of their possible different interactions with the prefrontal cortex. The role of dopamine in spatial working memory is reviewed, taking account of its deleterious as well as facilitatory effects. Baseline-dependent effects of dopaminergic manipulation are described in rats on an attentional task, including evidence of enhanced function following infusions of D1 receptor agonists into the prefrontal cortex. The precise nature of the cognitive task under study is shown to be a powerful determinant of the effects of mesofrontal dopamine depletion in monkeys. Parallels are identified in human subjects receiving drugs such as the indirect catecholamine agonists L-dopa, methylphenidate and the dopamine D2 receptor blocker sulpiride. The effects of these drugs on different types of cognitive function sensitive to frontal lobe dysfunction are contrasted with those of a manipulation of 5-HT function, dietary tryptophan depletion. Hypotheses are advanced that accord the ascending systems a greater deal of specificity in modulating prefrontal cortical function than has hitherto been entertained, and clinical and theoretical implications of this hypothesis are discussed.

Dopamine modulates striatal response to reward and punishment in patients with Parkinson's disease: a pharmacological challenge fMRI study.

PubMed

Argyelan, Miklos; Herzallah, Mohammad; Sako, Wataru; DeLucia, Ivana; Sarpal, Deepak; Vo, An; Fitzpatrick, Toni; Moustafa, Ahmed A; Eidelberg, David; Gluck, Mark

2018-05-02

It is well established that Parkinson's disease leads to impaired learning from reward and enhanced learning from punishment. The administration of dopaminergic medications reverses this learning pattern. However, few studies have investigated the neural underpinnings of these cognitive processes. In this study, using fMRI, we tested a group of Parkinson's disease patients on and off dopaminergic medications and matched healthy individuals. All individuals completed an fMRI cognitive task that dissociates feedback learning from reward versus punishment. The administration of dopaminergic medications attenuated blood oxygen level dependent (BOLD) responses to punishment in the bilateral putamen, in bilateral dorsolateral prefrontal cortex and the left premotor cortex. Further, the administration of dopaminergic medications resulted in a higher ratio of BOLD activity between reward and punishment trials in these brain areas. BOLD activity in these brain areas was significantly correlated with learning from punishment, but not from reward trials. Furthermore, the administration of dopaminergic medications altered BOLD activity in the right insula and ventromedial prefrontal cortex when Parkinson's disease patients were anticipating feedback. These findings are in agreement with a large body of literature indicating that Parkinson's disease is associated with enhanced learning from punishment. However, it was surprising that dopaminergic medications modulated punishment learning as opposed to reward learning, although reward learning has been directly linked to dopaminergic function. We argue that these results might be attributed to both a change in the balance between direct and indirect pathway activation in the basal ganglia as well as the differential activity of D1 versus D2 dopamine receptors.

Contrasting contribution of 5-hydroxytryptamine 1A receptor activation to neurochemical profile of novel antipsychotics: frontocortical dopamine and hippocampal serotonin release in rat brain.

PubMed

Assié, Marie-Bernadette; Ravailhe, Véronique; Faucillon, Valérie; Newman-Tancredi, Adrian

2005-10-01

Several novel antipsychotics, such as aripiprazole, bifeprunox, SSR181507 [(3-exo)-8-benzoyl-N-(((2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl)methyl)-8-azabicyclo(3.2.1)octane-3-methanamine], and SLV313 [1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-4-[5-(4-fluorophenyl)-pyridin-3-ylmethyl]-piperazine], activate serotonin 5-hydroxytryptamine (5-HT)1A receptors. Such activity is associated with enhanced treatment of negative symptoms and cognitive deficits, which may be mediated by modulation of cerebral dopamine and serotonin levels. We employed microdialysis coupled to high pressure liquid chromatography with electrochemical detection to examine 5-HT1A receptor activation in the modulation of extracellular dopamine in medial prefrontal cortex and serotonin in hippocampus of freely moving rats. The above compounds were compared with drugs that have less interaction with 5-HT1A receptors (clozapine, nemonapride, ziprasidone, olanzapine, risperidone, and haloperidol). Hippocampal 5-HT was decreased by bifeprunox, SSR181507, SLV313, sarizotan, and nemonapride, effects similar to those seen with the 5-HT1A agonist, (+)-8-hydroxy-2-(di-n-propylamino)tetralin [(+)8-OH-DPAT], consistent with activation of 5-HT1A autoreceptors. These decreases were reversed by the selective 5-HT1A antagonist, WAY100635 [N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide]. In contrast, haloperidol, risperidone, clozapine, olanzapine, ziprasidone, and aripiprazole did not significantly modify hippocampal serotonin levels. In medial prefrontal cortex, dopamine levels were increased by SSR181507, SLV313, sarizotan, and (+)8-OH-DPAT. These effects were reversed by WAY100635, indicating mediation by 5-HT1A receptors. In contrast, the increases in dopamine levels induced by clozapine, risperidone, olanzapine, and ziprasidone were not blocked by WAY100635, consistent with predominant influence of other mechanisms in the actions of these drugs. Haloperidol, nemonapride, and the D2 partial agonists, aripiprazole and bifeprunox, did not significantly alter dopamine release. Taken together, these data demonstrate the diverse contribution of 5-HT1A receptor activation to the profile of antipsychotics and suggest that novel drugs selectively targeting D2 and 5-HT1A receptors may present distinctive therapeutic properties.

Nonlinear modulation of interacting between COMT and depression on brain function.

PubMed

Gong, L; He, C; Yin, Y; Ye, Q; Bai, F; Yuan, Y; Zhang, H; Lv, L; Zhang, H; Zhang, Z; Xie, C

2017-09-01

The catechol-O-methyltransferase (COMT) gene is related to dopamine degradation and has been suggested to be involved in the pathogenesis of major depressive disorder (MDD). However, how this gene affects brain function properties in MDD is still unclear. Fifty patients with MDD and 35 cognitively normal participants underwent a resting-state functional magnetic resonance imaging scan. A voxelwise and data-drive global functional connectivity density (gFCD) analysis was used to investigate the main effects and the interactions of disease states and COMT rs4680 gene polymorphism on brain function. We found significant group differences of the gFCD in bilateral fusiform area (FFA), post-central and pre-central cortex, left superior temporal gyrus (STG), rectal and superior temporal gyrus and right ventrolateral prefrontal cortex (vlPFC); abnormal gFCDs in left STG were positively correlated with severity of depression in MDD group. Significant disease×COMT interaction effects were found in the bilateral calcarine gyrus, right vlPFC, hippocampus and thalamus, and left SFG and FFA. Further post-hoc tests showed a nonlinear modulation effect of COMT on gFCD in the development of MDD. Interestingly, an inverted U-shaped modulation was found in the prefrontal cortex (control system) but U-shaped modulations were found in the hippocampus, thalamus and occipital cortex (processing system). Our study demonstrated nonlinear modulation of the interaction between COMT and depression on brain function. These findings expand our understanding of the COMT effect underlying the pathophysiology of MDD. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

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

PubMed

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

2017-01-01

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

Gray-matter volume, midbrain dopamine D2/D3 receptors and drug craving in methamphetamine users.

PubMed

Morales, A M; Kohno, M; Robertson, C L; Dean, A C; Mandelkern, M A; London, E D

2015-06-01

Dysfunction of the mesocorticolimbic system has a critical role in clinical features of addiction. Despite evidence suggesting that midbrain dopamine receptors influence amphetamine-induced dopamine release and that dopamine is involved in methamphetamine-induced neurotoxicity, associations between dopamine receptors and gray-matter volume have been unexplored in methamphetamine users. Here we used magnetic resonance imaging and [(18)F]fallypride positron emission tomography, respectively, to measure gray-matter volume (in 58 methamphetamine users) and dopamine D2/D3 receptor availability (binding potential relative to nondisplaceable uptake of the radiotracer, BPnd) (in 31 methamphetamine users and 37 control participants). Relationships between these measures and self-reported drug craving were examined. Although no difference in midbrain D2/D3 BPnd was detected between methamphetamine and control groups, midbrain D2/D3 BPnd was positively correlated with gray-matter volume in the striatum, prefrontal cortex, insula, hippocampus and temporal cortex in methamphetamine users, but not in control participants (group-by-midbrain D2/D3 BPnd interaction, P<0.05 corrected for multiple comparisons). Craving for methamphetamine was negatively associated with gray-matter volume in the insula, prefrontal cortex, amygdala, temporal cortex, occipital cortex, cerebellum and thalamus (P<0.05 corrected for multiple comparisons). A relationship between midbrain D2/D3 BPnd and methamphetamine craving was not detected. Lower midbrain D2/D3 BPnd may increase vulnerability to deficits in gray-matter volume in mesocorticolimbic circuitry in methamphetamine users, possibly reflecting greater dopamine-induced toxicity. Identifying factors that influence prefrontal and limbic volume, such as midbrain BPnd, may be important for understanding the basis of drug craving, a key factor in the maintenance of substance-use disorders.

Gray-Matter Volume, Midbrain Dopamine D2/D3 Receptors and Drug Craving in Methamphetamine Users

PubMed Central

Morales, Angelica A.; Kohno, Milky; Robertson, Chelsea L.; Dean, Andy C.; Mandelkern, Mark A.; London, Edythe D.

2015-01-01

Dysfunction of the mesocorticolimbic system plays a critical role in clinical features of addiction. Despite evidence suggesting that midbrain dopamine receptors influence amphetamine-induced dopamine release and that dopamine is involved in methamphetamine-induced neurotoxicity, associations between dopamine receptors and gray-matter volume have been unexplored in methamphetamine users. Here we used magnetic resonance imaging and [18F]fallypride positron emission tomography, respectively, to measure gray-matter volume (in 58 methamphetamine users) and dopamine D2/D3 receptor availability (binding potential relative to nondisplaceable uptake of the radiotracer, BPnd) (in 31 methamphetamine users and 37 control participants). Relationships between these measures and self-reported drug craving were examined. Although no difference in midbrain D2/D3 BPnd was detected between methamphetamine and control groups, midbrain D2/D3 BPnd was positively correlated with gray-matter volume in the striatum, prefrontal cortex, insula, hippocampus and temporal cortex in methamphetamine users, but not in control participants (group-by-midbrain D2/D3 BPnd interaction, p<0.05 corrected for multiple comparisons). Craving for methamphetamine was negatively associated with gray-matter volume in the insula, prefrontal cortex, amygdala, temporal cortex, occipital cortex, cerebellum, and thalamus (p<0.05 corrected for multiple comparisons). A relationship between midbrain D2/D3 BPnd and methamphetamine craving was not detected. Lower midbrain D2/D3 BPnd may increase vulnerability to deficits in gray-matter volume in mesocorticolimbic circuitry in methamphetamine users, possibly reflecting greater dopamine-induced toxicity. Identifying factors that influence prefrontal and limbic volume, such as midbrain BPnd, may be important for understanding the basis of drug craving, a key factor in the maintenance of substance use disorders. PMID:25896164

Effect of perinatal asphyxia and carbamazepine treatment on cortical dopamine and DOPAC levels.

PubMed

López-Pérez, Silvia J; Morales-Villagrán, Alberto; Medina-Ceja, Laura

2015-02-13

One of the most important manifestations of perinatal asphyxia is the occurrence of seizures, which are treated with antiepileptic drugs, such as carbamazepine. These early seizures, combined with pharmacological treatments, may influence the development of dopaminergic neurotransmission in the frontal cortex. This study aimed to determine the extracellular levels of dopamine and its main metabolite DOPAC in 30-day-old rats that had been asphyxiated for 45 min in a low (8%) oxygen chamber at a perinatal age and treated with daily doses of carbamazepine. Quantifications were performed using microdialysis coupled to a high-performance liquid chromatography (HPLC) system in basal conditions and following the use of the chemical stimulus. Significant decreases in basal and stimulated extracellular dopamine and DOPAC content were observed in the frontal cortex of the asphyxiated group, and these decreases were partially recovered in the animals administered daily doses of carbamazepine. Greater basal dopamine concentrations were also observed as an independent effect of carbamazepine. Perinatal asphyxia plus carbamazepine affects extracellular levels of dopamine and DOPAC in the frontal cortex and stimulated the release of dopamine, which provides evidence for the altered availability of dopamine in cortical brain areas during brain development.

A Dopaminergic Gene Cluster in the Prefrontal Cortex Predicts Performance Indicative of General Intelligence in Genetically Heterogeneous Mice

PubMed Central

Kolata, Stefan; Light, Kenneth; Wass, Christopher D.; Colas-Zelin, Danielle; Roy, Debasri; Matzel, Louis D.

2010-01-01

Background Genetically heterogeneous mice express a trait that is qualitatively and psychometrically analogous to general intelligence in humans, and as in humans, this trait co-varies with the processing efficacy of working memory (including its dependence on selective attention). Dopamine signaling in the prefrontal cortex (PFC) has been established to play a critical role in animals' performance in both working memory and selective attention tasks. Owing to this role of the PFC in the regulation of working memory, here we compared PFC gene expression profiles of 60 genetically diverse CD-1 mice that exhibited a wide range of general learning abilities (i.e., aggregate performance across five diverse learning tasks). Methodology/Principal Findings Animals' general cognitive abilities were first determined based on their aggregate performance across a battery of five diverse learning tasks. With a procedure designed to minimize false positive identifications, analysis of gene expression microarrays (comprised of ≈25,000 genes) identified a small number (<20) of genes that were differentially expressed across animals that exhibited fast and slow aggregate learning abilities. Of these genes, one functional cluster was identified, and this cluster (Darpp-32, Drd1a, and Rgs9) is an established modulator of dopamine signaling. Subsequent quantitative PCR found that expression of these dopaminegic genes plus one vascular gene (Nudt6) were significantly correlated with individual animal's general cognitive performance. Conclusions/Significance These results indicate that D1-mediated dopamine signaling in the PFC, possibly through its modulation of working memory, is predictive of general cognitive abilities. Furthermore, these results provide the first direct evidence of specific molecular pathways that might potentially regulate general intelligence. PMID:21103339

Variation in the dopamine D2 receptor gene plays a key role in human pain and its modulation by transcranial magnetic stimulation.

PubMed

Jääskeläinen, Satu K; Lindholm, Pauliina; Valmunen, Tanja; Pesonen, Ullamari; Taiminen, Tero; Virtanen, Arja; Lamusuo, Salla; Forssell, Heli; Hagelberg, Nora; Hietala, Jarmo; Pertovaara, Antti

2014-10-01

We tested whether variation of the dopamine D2 receptor (DRD2) gene contributes to individual differences in thermal pain sensitivity and analgesic efficacy of repetitive transcranial magnetic stimulation (rTMS) in healthy subjects (n=29) or susceptibility to neuropathic pain in patients with neurophysiologically confirmed diagnosis (n=16). Thermal sensitivity of healthy subjects was assessed before and after navigated rTMS provided to the S1/M1 cortex. All subjects were genotyped for the DRD2 gene 957C>T and catechol-O-methyltransferase (COMT) protein Val158Met polymorphisms. In healthy subjects, 957C>T influenced both innocuous and noxious thermal detection thresholds that were lowest in 957TT homozygotes (P values from .0277 to .0462). rTMS to S1 cortex had analgesic effect only in 957TT homozygote genotype (P=.0086). In patients, prevalence of 957TT homozygote genotype was higher than in a healthy Finnish population (50% vs 27%; P=.0191). Patients with 957TT genotype reported more severe pain than patients with other genotypes (P=.0351). COMT Val158Met polymorphism was not independently associated with the studied variables. Genetic regulation of DRD2 function by 957C>T polymorphism thus seems to influence thermal and pain sensitivity, its modulation by rTMS, and susceptibility to neuropathic pain. This indicates a central role for the dopamine system and DRD2 in pain and analgesia. This may have clinical implications regarding individualized selection of patients for rTMS treatment and assessment of risks for neuropathic pain. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Midbrain dopamine neurons regulate preprotachykinin-A mRNA expression in the rat forebrain during development.

PubMed

Brené, S; Lindefors, N; Persson, H

1992-06-01

Intracerebroventricular 6-hydroxydopamine injections were performed at postnatal days 3 and 6 in animals pretreated with the norepinephrine uptakeblocker desimipramine in order to generate a selective lesion of dopamine neurons. In situ hybridization was then used to analyze preprotachykinin-A (PPT-A) mRNA expression in the lesioned as well as in saline-injected control animals. The midbrain dopaminergic lesion caused a 22-25% increase in the level of PPT-A mRNA in cingulate cortex and frontoparietal cortex when analysed at 2 weeks of age, compared to saline-injected control animals. In contrast, the lesion caused no change in PPT-A mRNA expression in the neonatal caudate-putamen. These results indicate that dopamine neurons downregulate the expression of PPT-A mRNA specifically in cingulate cortex and frontoparietal cortex during early postnatal brain development. In the adult rat forebrain, lesioned at P3 and P6, no change in the level of PPT-A mRNA was seen in cingulate cortex and frontoparietal cortex. However, a 29% decrease in PPT-A mRNA was seen in the lateral caudate-putamen with no significant change in neurons of medial caudate-putamen. Thus, dopamine neurons appears to exert a region specific influence on PPT-A mRNA expression during brain development.

NMDA receptor blockade in the prelimbic cortex activates the mesolimbic system and dopamine-dependent opiate reward signaling.

PubMed

Tan, Huibing; Rosen, Laura G; Ng, Garye A; Rushlow, Walter J; Laviolette, Steven R

2014-12-01

N-Methyl-D-aspartate (NMDA) receptors in the medial prefrontal cortex (mPFC) are involved in opiate reward processing and modulate sub-cortical dopamine (DA) activity. NMDA receptor blockade in the prelimbic (PLC) division of the mPFC strongly potentiates the rewarding behavioural properties of normally sub-reward threshold doses of opiates. However, the possible functional interactions between cortical NMDA and sub-cortical DAergic motivational neural pathways underlying these effects are not understood. This study examines how NMDA receptor modulation in the PLC influences opiate reward processing via interactions with sub-cortical DAergic transmission. We further examined whether direct intra-PLC NMDA receptor modulation may activate DA-dependent opiate reward signaling via interactions with the ventral tegmental area (VTA). Using an unbiased place conditioning procedure (CPP) in rats, we performed bilateral intra-PLC microinfusions of the competitive NMDA receptor antagonist, (2R)-amino-5-phosphonovaleric acid (AP-5), prior to behavioural morphine place conditioning and challenged the rewarding effects of morphine with DA receptor blockade. We next examined the effects of intra-PLC NMDA receptor blockade on the spontaneous activity patterns of presumptive VTA DA or GABAergic neurons, using single-unit, extracellular in vivo neuronal recordings. We show that intra-PLC NMDA receptor blockade strongly activates sub-cortical DA neurons within the VTA while inhibiting presumptive non-DA GABAergic neurons. Behaviourally, NMDA receptor blockade activates a DA-dependent opiate reward system, as pharmacological blockade of DA transmission blocked morphine reward only in the presence of intra-PLC NMDA receptor antagonism. These findings demonstrate a cortical NMDA-mediated mechanism controlling mesolimbic DAergic modulation of opiate reward processing.

The role of the mesolimbic dopamine system in the formation of blood-oxygen-level dependent responses in the medial prefrontal/anterior cingulate cortex during high-frequency stimulation of the rat perforant pathway.

PubMed

Helbing, Cornelia; Brocka, Marta; Scherf, Thomas; Lippert, Michael T; Angenstein, Frank

2016-12-01

Several human functional magnetic resonance imaging studies point to an activation of the mesolimbic dopamine system during reward, addiction and learning. We previously found activation of the mesolimbic system in response to continuous but not to discontinuous perforant pathway stimulation in an experimental model that we now used to investigate the role of dopamine release for the formation of functional magnetic resonance imaging responses. The two stimulation protocols elicited blood-oxygen-level dependent responses in the medial prefrontal/anterior cingulate cortex and nucleus accumbens. Inhibition of dopamine D 1/5 receptors abolished the formation of functional magnetic resonance imaging responses in the medial prefrontal/anterior cingulate cortex during continuous but not during discontinuous pulse stimulations, i.e. only when the mesolimbic system was activated. Direct electrical or optogenetic stimulation of the ventral tegmental area caused strong dopamine release but only electrical stimulation triggered significant blood-oxygen level-dependent responses in the medial prefrontal/anterior cingulate cortex and nucleus accumbens. These functional magnetic resonance imaging responses were not affected by the D 1/5 receptor antagonist SCH23390 but reduced by the N-methyl-D-aspartate receptor antagonist MK801. Therefore, glutamatergic ventral tegmental area neurons are already sufficient to trigger blood-oxygen-level dependent responses in the medial prefrontal/anterior cingulate cortex and nucleus accumbens. Although dopamine release alone does not affect blood-oxygen-level dependent responses it can act as a switch, permitting the formation of blood-oxygen-level dependent responses. © The Author(s) 2015.

Primate Phencyclidine Model of Schizophrenia: Sex-Specific Effects on Cognition, Brain Derived Neurotrophic Factor, Spine Synapses, and Dopamine Turnover in Prefrontal Cortex

PubMed Central

Groman, Stephanie M.; Jentsch, James D.; Leranth, Csaba; Redmond, D. Eugene; Kim, Jung D.; Diano, Sabrina; Roth, Robert H.

2015-01-01

Background: Cognitive deficits are a core symptom of schizophrenia, yet they remain particularly resistant to treatment. The model provided by repeatedly exposing adult nonhuman primates to phencyclidine has generated important insights into the neurobiology of these deficits, but it remains possible that administration of this psychotomimetic agent during the pre-adult period, when the dorsolateral prefrontal cortex in human and nonhuman primates is still undergoing significant maturation, may provide a greater understanding of schizophrenia-related cognitive deficits. Methods: The effects of repeated phencyclidine treatment on spine synapse number, dopamine turnover and BDNF expression in dorsolateral prefrontal cortex, and working memory accuracy were examined in pre-adult monkeys. Results: One week following phencyclidine treatment, juvenile and adolescent male monkeys demonstrated a greater loss of spine synapses in dorsolateral prefrontal cortex than adult male monkeys. Further studies indicated that in juvenile males, a cognitive deficit existed at 4 weeks following phencyclidine treatment, and this impairment was associated with decreased dopamine turnover, decreased brain derived neurotrophic factor messenger RNA, and a loss of dendritic spine synapses in dorsolateral prefrontal cortex. In contrast, female juvenile monkeys displayed no cognitive deficit at 4 weeks after phencyclidine treatment and no alteration in dopamine turnover or brain derived neurotrophic factor messenger RNA or spine synapse number in dorsolateral prefrontal cortex. In the combined group of male and female juvenile monkeys, significant linear correlations were detected between dopamine turnover, spine synapse number, and cognitive performance. Conclusions: As the incidence of schizophrenia is greater in males than females, these findings support the validity of the juvenile primate phencyclidine model and highlight its potential usefulness in understanding the deficits in dorsolateral prefrontal cortex in schizophrenia and developing novel treatments for the cognitive deficits associated with schizophrenia. PMID:25522392

Regulation of neuropeptide Y gene expression in rat brain.

PubMed

Lindefors, N; Brené, S; Herrera-Marschitz, M; Persson, H

1990-01-01

NPY mRNA expression was studied in rat brain using in situ hybridization and RNA blot analysis. Transsynaptic regulation of NPY gene expression was specifically studied in caudate-putamen and frontoparietal (somatosensory) cortex of rats with unilateral lesion of midbrain dopamine neurons and in sham-injected animals. NPY mRNA expression in these two brain regions and the regulation of midbrain dopamine neurons were compared with that of SOM, PPT, CCK and GAD mRNA expression. Neurons expressing NPY and SOM mRNA showed a similar distribution and the expression of both NPY and SOM appears to be regulated by dopamine in a similar fashion. Following a unilateral dopamine deafferentation, the numerical density of both NPY and SOM mRNA expressing neurons almost doubled in the lesioned rat caudate-putamen with no change in the average grain density over positive neurons. Hence, in the intact caudate-putamen dopamine appears to normally suppress expression of these two neuropeptide genes. An activation of both NPY and SOM mRNA expression in many non- or low-expressing neurons is seen when the level of dopamine is decreased. In the frontoparietal cortex, on the other hand, dopamine appears to stimulate NPY and SOM gene expression. RNA blot analysis shows clear-cut changes of NPY mRNA levels in both caudate-putamen and frontoparietal cortex consistent with the changes observed using in situ hybridization. No evidence was found for a change in CCK mRNA expression by the dopamine deafferentation, while PPT mRNA expression decreased in the deafferented caudate-putamen. Consequently, dopamine exerts dissimilar effects on the expression of different neuropeptide genes, that in turn do not respond in the same way in different brain regions. Indirect evidence is also presented indicating that dopamine regulates NPY mRNA expression in a subpopulation of neurons that possibly also express GAD mRNA, both in caudate-putamen and in frontoparietal cortex.

Memory trace reactivation and behavioral response during retrieval are differentially modulated by amygdalar glutamate receptors activity: interaction between amygdala and insular cortex

PubMed Central

Osorio-Gómez, Daniel; Guzmán-Ramos, Kioko

2017-01-01

The insular cortex (IC) is required for conditioned taste aversion (CTA) retrieval. However, it remains unknown which cortical neurotransmitters levels are modified upon CTA retrieval. Using in vivo microdialysis, we observed that there were clear elevations in extracellular glutamate, norepinephrine, and dopamine in and around the center of the gustatory zone of the IC during CTA retrieval. Additionally, it has been reported that the amygdala–IC interaction is highly involved in CTA memory establishment. Therefore, we evaluated the effects of infusions of an AMPA receptor antagonist (CNQX) and a NMDA receptor antagonist (APV) into the amygdala on CTA retrieval and IC neurotransmitter levels. Infusion of APV into the amygdala impaired glutamate augmentation within the IC, whereas dopamine and norepinephrine levels augmentation persisted and a reliable CTA expression was observed. Conversely, CNQX infusion into the amygdala impaired the aversion response, as well as norepinephrine and dopamine augmentations in the IC. Interestingly, CNQX infusion did not affect glutamate elevation in the IC. To evaluate the functional meaning of neurotransmitters elevations within the IC on CTA response, we infused specific antagonists for the AMPA, NMDA, D1, and β-adrenergic receptor before retrieval. Results showed that activation of AMPA, D1, and β-adrenergic receptors is necessary for CTA expression, whereas NMDA receptors are not involved in the aversion response. PMID:27980072

Adenosine transiently modulates stimulated dopamine release in the caudate putamen via A1 receptors

PubMed Central

Ross, Ashley E.; Venton, B. Jill

2014-01-01

Adenosine modulates dopamine in the brain via A1 and A2A receptors, but that modulation has only been characterized on a slow time scale. Recent studies have characterized a rapid signaling mode of adenosine that suggests a possible rapid modulatory role. Here, fast-scan cyclic voltammetry was used to characterize the extent to which transient adenosine changes modulate stimulated dopamine release (5 pulses at 60 Hz) in rat caudate putamen brain slices. Exogenous adenosine was applied and dopamine concentration monitored. Adenosine only modulated dopamine when it was applied 2 or 5 s before stimulation. Longer time intervals and bath application of 5 µM adenosine did not decrease dopamine release. Mechanical stimulation of endogenous adenosine 2s before dopamine stimulation also decreased stimulated dopamine release by 41 ± 7 %, similar to the 54 ± 6 % decrease in dopamine after exogenous adenosine application. Dopamine inhibition by transient adenosine was recovered within 10 minutes. The A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) blocked the dopamine modulation, whereas dopamine modulation was unaffected by the A2A receptor antagonist SCH 442416. Thus, transient adenosine changes can transiently modulate phasic dopamine release via A1 receptors. These data demonstrate that adenosine has a rapid, but transient, modulatory role in the brain. PMID:25219576

Inactivation of the prelimbic or infralimbic cortex impairs decision-making in the rat gambling task.

PubMed

Zeeb, Fiona D; Baarendse, P J J; Vanderschuren, L J M J; Winstanley, Catharine A

2015-12-01

Studies employing the Iowa Gambling Task (IGT) demonstrated that areas of the frontal cortex, including the ventromedial prefrontal cortex, orbitofrontal cortex (OFC), dorsolateral prefrontal cortex, and anterior cingulate cortex (ACC), are involved in the decision-making process. However, the precise role of these regions in maintaining optimal choice is not clear. We used the rat gambling task (rGT), a rodent analogue of the IGT, to determine whether inactivation of or altered dopamine signalling within discrete cortical sub-regions disrupts decision-making. Following training on the rGT, animals were implanted with guide cannulae aimed at the prelimbic (PrL) or infralimbic (IL) cortices, the OFC, or the ACC. Prior to testing, rats received an infusion of saline or a combination of baclofen and muscimol (0.125 μg of each/side) to inactivate the region and an infusion of a dopamine D2 receptor antagonist (0, 0.1, 0.3, and 1.0 μg/side). Rats tended to increase their choice of a disadvantageous option and decrease their choice of the optimal option following inactivation of either the IL or PrL cortex. In contrast, OFC or ACC inactivation did not affect decision-making. Infusion of a dopamine D2 receptor antagonist into any sub-region did not alter choice preference. Online activity of the IL or PrL cortex is important for maintaining an optimal decision-making strategy, but optimal performance on the rGT does not require frontal cortex dopamine D2 receptor activation. Additionally, these results demonstrate that the roles of different cortical regions in cost-benefit decision-making may be dissociated using the rGT.

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

PubMed Central

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

2015-01-01

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

Dopamine D1 and D3 Receptors Modulate Heroin-Induced Cognitive Impairment through Opponent Actions in Mice.

PubMed

Zhu, Yongsheng; Wang, Yunpeng; Lai, Jianghua; Wei, Shuguang; Zhang, Hongbo; Yan, Peng; Li, Yunxiao; Qiao, Xiaomeng; Yin, Fangyuan

2017-03-01

Chronic abuse of heroin leads to long-lasting and complicated cognitive impairment. Dopamine receptors are critically involved in the impulsive drug-driven behavior and the altered attention, processing speed, and mental flexibility that are associated with higher relapse rates. However, the effects of the different dopamine receptors and their possible involvement in heroin-induced cognitive impairment remain unclear. The 5-choice serial reaction time task was used to investigate the profiles of heroin-induced cognitive impairment in mice. The expression levels of dopamine D1- and D2-like receptors in the prefrontal cortex, nucleus accumbens, and caudate-putamen were determined. The effects of dopamine receptors on heroin-induced impulsivity in the 5-choice serial reaction time task were examined by agonist/antagonist treatment on D1 or D3 receptor mutant mice. Systemic heroin administration influences several variables in the 5-choice serial reaction time task, most notably premature responses, a measure of motor impulsivity. These behavioral impairments are associated with increased D1 receptor and decreased D3 receptor mRNA and protein levels in 3 observed brain areas. The heroin-evoked increase in premature responses is mimicked by a D1 agonist and prevented by a D1 antagonist or genetic ablation of the D1 receptor gene. In contrast, a D3 agonist decreases both basal and heroin-evoked premature responses, while genetic ablation of the D3 receptor gene results in increased basal and heroin-evoked premature responses. Heroin-induced impulsive behavior in the 5-choice serial reaction time task is oppositely modulated by D1 and D3 receptor activation. The D1 receptors in the cortical-mesolimbic region play an indispensable role in modulating such behaviors. © The Author 2016. Published by Oxford University Press on behalf of CINP.

Expectancy-related changes in firing of dopamine neurons depend on orbitofrontal cortex.

PubMed

Takahashi, Yuji K; Roesch, Matthew R; Wilson, Robert C; Toreson, Kathy; O'Donnell, Patricio; Niv, Yael; Schoenbaum, Geoffrey

2011-10-30

The orbitofrontal cortex has been hypothesized to carry information regarding the value of expected rewards. Such information is essential for associative learning, which relies on comparisons between expected and obtained reward for generating instructive error signals. These error signals are thought to be conveyed by dopamine neurons. To test whether orbitofrontal cortex contributes to these error signals, we recorded from dopamine neurons in orbitofrontal-lesioned rats performing a reward learning task. Lesions caused marked changes in dopaminergic error signaling. However, the effect of lesions was not consistent with a simple loss of information regarding expected value. Instead, without orbitofrontal input, dopaminergic error signals failed to reflect internal information about the impending response that distinguished externally similar states leading to differently valued future rewards. These results are consistent with current conceptualizations of orbitofrontal cortex as supporting model-based behavior and suggest an unexpected role for this information in dopaminergic error signaling.

The dopamine D2 receptor antagonist sulpiride modulates striatal BOLD signal during the manipulation of information in working memory.

PubMed

Dodds, Chris M; Clark, Luke; Dove, Anja; Regenthal, Ralf; Baumann, Frank; Bullmore, Ed; Robbins, Trevor W; Müller, Ulrich

2009-11-01

Dopamine (DA) plays an important role in working memory. However, the precise functions supported by different DA receptor subtypes in different neural regions remain unclear. The present study used pharmacological, event-related fMRI to test the hypothesis that striatal dopamine is important for the manipulation of information in working memory. Twenty healthy human subjects were scanned twice, once after placebo and once after sulpiride 400 mg, a selective DA D2 receptor antagonist, while performing a verbal working memory task requiring different levels of manipulation. Whilst there was no overall effect of sulpiride on task-dependent activation, individual variation in sulpiride plasma levels predicted the effect of working memory manipulation on activation in the putamen, suggesting a dose-dependent effect of DA antagonism on a striatally based manipulation process. These effects occurred in the context of a drug-induced improvement in performance on trials requiring the manipulation of information in working memory but not on simple retrieval trials. No significant drug effects were observed in the prefrontal cortex. These results support models of dopamine function that posit a 'gating' function for dopamine D2 receptors in the striatum, which enables the flexible updating and manipulation of information in working memory.

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 capable of glutamate cotransmission. With conditional expression of channelrhodopsin in dopamine neurons, we systematically explored dopamine neuron connections in the forebrain and identified regionally specific dopamine neuron excitatory connections. Establishing that only a subset of forebrain regions receive excitatory connections from dopamine neurons will help to determine the function of dopamine neuron glutamate cotransmission, which likely involves transmission of precise temporal signals and enhancement of the dynamic range of dopamine neuron signals. Copyright © 2015 the authors 0270-6474/15/3516259-13$15.00/0.

Region specific regulation of glutamic acid decarboxylase mRNA expression by dopamine neurons in rat brain.

PubMed

Lindefors, N; Brene, S; Herrera-Marschitz, M; Persson, H

1989-01-01

In situ hybridization histochemistry and RNA blots were used to study the expression of glutamic acid decarboxylase (GAD) mRNA in rats with or without a unilateral lesion of midbrain dopamine neurons. Two populations of GAD mRNA positive neurons were found in the intact caudate-putamen, substantia nigra and fronto-parietal cortex. In caudate-putamen, only one out of ten of the GAD mRNA positive neurons expressed high levels, while in substantia nigra every second of the positive neurons expressed high levels of GAD mRNA. Relatively few, but intensively labelled neurons were found in the intact fronto-parietal cerebral cortex. In addition, one out of six of the GAD mRNA positive neurons in the fronto-parietal cortex showed a low labeling. On the ipsilateral side, the forebrain dopamine deafferentation induced an increase in the number of neurons expressing high levels of GAD mRNA in caudate-putamen, and a decrease in fronto-parietal cortex. A smaller decrease was also seen in substantia nigra. However, the total number of GAD mRNA positive neurons were not significantly changed in any of these brain regions. The changes in the levels of GAD mRNA after the dopamine lesion were confirmed by RNA blot analysis. Hence, midbrain dopamine neurons appear to control neuronal expression of GAD mRNA by a tonic down-regulation in a fraction of GAD mRNA positive neurons in caudate-putamen, and a tonic up-regulation in a fraction of GAD mRNA positive neurons in fronto-parietal cortex and substantia nigra.

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

PubMed

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

2015-03-04

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

Chronic cocaine disrupts mesocortical learning mechanisms

PubMed Central

Buchta, William C.; Riegel, Arthur C.

2016-01-01

The addictive power of drugs of abuse such as cocaine comes from their ability to hijack natural reward and plasticity mechanisms mediated by dopamine signaling in the brain. Reward learning involves burst firing of midbrain dopamine neurons in response to rewards and cues predictive of reward. The resulting release of dopamine in terminal regions is thought to act as a teaching signaling to areas such as the prefrontal cortex and striatum. In this review, we posit that a pool of extrasynaptic dopaminergic D1-like receptors activated in response to dopamine neuron burst firing serve to enable synaptic plasticity in the prefrontal cortex in response to rewards and their cues. We propose that disruptions in these mechanisms following chronic cocaine use contribute to addiction pathology, in part due to the unique architecture of the mesocortical pathway. By blocking dopamine reuptake in the cortex, cocaine elevates dopamine signaling at these extra-synaptic receptors, prolonging D1-receptor activation and the subsequent activation of intracellular signaling cascades, and thus inducing long-lasting maladaptive plasticity. These cellular adaptations may account for many of the changes in cortical function observed in drug addicts, including an enduring vulnerability to relapse. Therefore, understanding and targeting these neuroadaptations may provide cognitive benefits and help prevent relapse in human drug addicts. PMID:25704202

[Neurotransmission in developmental disorders].

PubMed

Takeuchi, Yoshihiro

2008-11-01

Attention deficit/hyperactivity disorder (AD/HD) is a heterogeneous developmental disorder with an etiology that is not fully understood. AD/HD has been considered to occur due to a disturbance in cathecholaminergic neurotransmission, with particular emphasis on dopamine. The neurotransmission of dopamine in subcortical regions such as the basal ganglia and limbic areas is synaptic; on the other hand, dopamine neurotransmission in the frontal cortex is quite different, because there are very few dopamine transporters (DAT) in the frontal cortex that allow dopamine to diffuse away from the dopamine synapse ("volume transmission"). It is now clear that noradrenergic neurons play a key regulatory role in dopaminergic function in the frontal cortex. Furthermore, serotonergic neurons exert an inhibitory effect on midbrain dopamine cell bodies, and they have an influence on dopamine release in terminal regions. There is accumulating neurobiological evidence pointing toward a role of the serotonin system in AD/HD. The etiology of autism spectrum disorders (ASD) is still unclear, but information from genetics, neuropathology, brain imaging, and basic neuroscience has provided insights into the understanding of this developmental disorder. In addition to abnormal circuitry in specific limbic and neocortical areas of the cerebral cortex, impairments in brainstem, cerebellar, thalamic, and basal ganglia connections have been reported. Numerous studies have pointed to abnormalities in serotonin and glutamate neurotransmission. Three important aspects involved in the pathophysiology of ASD have been proposed. The first is cell migration, the second is unbalanced excitatory-inhibitory networks, and the third is synapse formation and pruning, the key factors being reelin, neurexin, and neuroligin. Serotonin is considered to play an important role in all of these aspects of the pathophysiology of ASD. Finally, I would like to emphasize that it is crucial in the field of child neurology medical examination and treatment should be based on the basic neuroscience, always taking "neurons" into consideration.

Activation of the mesocortical dopamine system by feeding: lack of a selective response to stress.

PubMed

Taber, M T; Fibiger, H C

1997-03-01

There is wide agreement that catecholamine systems in the prefrontal cortex are activated by stressful stimuli. To date, however, the extent to which other stimuli can increase the activity of these systems has received little attention. In the present study, the effects of tail pinch stress and feeding on dopamine and noradrenaline release in the prefrontal cortex of rats were examined using in vivo brain microdialysis. Both stimuli increased dopamine release, with peak effects reaching 212% above baseline for tail pinch and 165% above baseline for feeding. The effects of the two stimuli on peak dopamine release were not significantly different. Both stimuli also significantly increased noradrenaline release, with peak effects reaching 128% above baseline for tail pinch and 98% above baseline for feeding. The effects of the two stimuli on peak noradrenaline release were not significantly different. These results indicate that activation of catecholaminergic afferents to the prefrontal cortex is not specific to stress, but also occurs in response to non-stressors with positive motivational valence.

An integrative theory of the phasic and tonic modes of dopamine modulation in the prefrontal cortex.

PubMed

Dreher, Jean-Claude; Burnod, Yves

2002-01-01

This paper presents a model of both tonic and phasic dopamine (DA) effects on maintenance of working memory representations in the prefrontal cortex (PFC). The central hypothesis is that DA modulates the efficacy of inputs to prefrontal pyramidal neurons to prevent interferences for active maintenance. Phasic DA release, due to DA neurons discharges, acts at a short time-scale (a few seconds), while the tonic mode of DA release, independent of DA neurons firing, acts at a long time-scale (a few minutes). The overall effect of DA modulation is modeled as a threshold restricting incoming inputs arriving on PFC neurons. Phasic DA release temporary increases this threshold while tonic DA release progressively increases the basal level of this threshold. Thus, unlike the previous gating theory of phasic DA release, proposing that it facilitates incoming inputs at the time of their arrival, the effect of phasic DA release is supposed to restrict incoming inputs during a period of time after DA neuron discharges. The model links the cellular and behavioral levels during performance of a working memory task. It allows us to understand why a critical range of DA D1 receptors stimulation is required for optimal working memory performance and how D1 receptor agonists (respectively antagonists) increase perseverations (respectively distractability). Finally, the model leads to several testable predictions, including that the PFC regulates DA neurons firing rate to adapt to the delay of the task and that increase in tonic DA release may either improve or decrease performance, depending on the level of DA receptors stimulation at the beginning of the task.

Dopamine and the Development of Executive Dysfunction in Autism Spectrum Disorders

PubMed Central

Kriete, Trenton; Noelle, David C.

2015-01-01

Persons with autism regularly exhibit executive dysfunction (ED), including problems with deliberate goal-directed behavior, planning, and flexible responding in changing environments. Indeed, this array of deficits is sufficiently prominent to have prompted a theory that executive dysfunction is at the heart of these disorders. A more detailed examination of these behaviors reveals, however, that some aspects of executive function remain developmentaly appropriate. In particular, while people with autism often have difficulty with tasks requiring cognitive flexibility, their fundamental cognitive control capabilities, such as those involved in inhibiting an inappropriate but relatively automatic response, show no significant impairment on many tasks. In this article, an existing computational model of the prefrontal cortex and its role in executive control is shown to explain this dichotomous pattern of behavior by positing abnormalities in the dopamine-based modulation of frontal systems in individuals with autism. This model offers excellent qualitative and quantitative fits to performance on standard tests of cognitive control and cognitive flexibility in this clinical population. By simulating the development of the prefrontal cortex, the computational model also offers a potential explanation for an observed lack of executive dysfunction early in life. PMID:25811610

Dopamine and the development of executive dysfunction in autism spectrum disorders.

PubMed

Kriete, Trenton; Noelle, David C

2015-01-01

Persons with autism regularly exhibit executive dysfunction (ED), including problems with deliberate goal-directed behavior, planning, and flexible responding in changing environments. Indeed, this array of deficits is sufficiently prominent to have prompted a theory that executive dysfunction is at the heart of these disorders. A more detailed examination of these behaviors reveals, however, that some aspects of executive function remain developmentaly appropriate. In particular, while people with autism often have difficulty with tasks requiring cognitive flexibility, their fundamental cognitive control capabilities, such as those involved in inhibiting an inappropriate but relatively automatic response, show no significant impairment on many tasks. In this article, an existing computational model of the prefrontal cortex and its role in executive control is shown to explain this dichotomous pattern of behavior by positing abnormalities in the dopamine-based modulation of frontal systems in individuals with autism. This model offers excellent qualitative and quantitative fits to performance on standard tests of cognitive control and cognitive flexibility in this clinical population. By simulating the development of the prefrontal cortex, the computational model also offers a potential explanation for an observed lack of executive dysfunction early in life.

Cerebral interactions of pain and reward and their relevance for chronic pain.

PubMed

Becker, Susanne; Gandhi, Wiebke; Schweinhardt, Petra

2012-06-29

Pain and reward are opponent, interacting processes. Such interactions are enabled by neuroanatomical and neurochemical overlaps of brain systems that process pain and reward. Cerebral processing of hedonic ('liking') and motivational ('wanting') aspects of reward can be separated: the orbitofrontal cortex and opioids play an important role for the hedonic experience, and the ventral striatum and dopamine predominantly process motivation for reward. Supported by neuroimaging studies, we present here the hypothesis that the orbitofrontal cortex and opioids are responsible for pain modulation by hedonic experience, while the ventral striatum and dopamine mediate motivational effects on pain. A rewarding stimulus that appears to be particularly important in the context of pain is pain relief. Further, reward, including pain relief, leads to operant learning, which can affect pain sensitivity. Indirect evidence points at brain mechanisms that might underlie pain relief as a reward and related operant learning but studies are scarce. Investigating the cerebral systems underlying pain-reward interactions as well as related operant learning holds the potential of better understanding mechanisms that contribute to the development and maintenance of chronic pain, as detailed in the last section of this review. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Decoding the Dopamine Signal in Macaque Prefrontal Cortex: A Simulation Study Using the Cx3Dp Simulator

PubMed Central

Spühler, Isabelle Ayumi; Hauri, Andreas

2013-01-01

Dopamine transmission in the prefrontal cortex plays an important role in reward based learning, working memory and attention. Dopamine is thought to be released non-synaptically into the extracellular space and to reach distant receptors through diffusion. This simulation study examines how the dopamine signal might be decoded by the recipient neuron. The simulation was based on parameters from the literature and on our own quantified, structural data from macaque prefrontal area 10. The change in extracellular dopamine concentration was estimated at different distances from release sites and related to the affinity of the dopamine receptors. Due to the sparse and random distribution of release sites, a transient heterogeneous pattern of dopamine concentration emerges. Our simulation predicts, however, that at any point in the simulation volume there is sufficient dopamine to bind and activate high-affinity dopamine receptors. We propose that dopamine is broadcast to its distant receptors and any change from the local baseline concentration might be decoded by a transient change in the binding probability of dopamine receptors. Dopamine could thus provide a graduated ‘teaching’ signal to reinforce concurrently active synapses and cell assemblies. In conditions of highly reduced or highly elevated dopamine levels the simulations predict that relative changes in the dopamine signal can no longer be decoded, which might explain why cognitive deficits are observed in patients with Parkinson’s disease, or induced through drugs blocking dopamine reuptake. PMID:23951205

The Role of Dopamine in Normal Rodent Motor Cortex: Physiological Effects and Structural Correlates

DTIC Science & Technology

1999-04-05

things she does on a daily basis made the lab a great place to do research. Susan’s expertise in molecular techniques was evident from day one , and I...applied OA on the spontaneous activity (SA) of PTNs. the receptors that mediate these effects, and DA’s effects on glutamate induced excitation of PTNs...numerous neurons in the motor cortex and may have profound effects on motor cortex activity, through its influence on PTNs. iv The Role of Dopamine in

Selective activation of mesolimbic and mesocortical dopamine metabolism in rat brain by infusion of a stable substance P analogue into the ventral tegmental area.

PubMed

Elliott, P J; Alpert, J E; Bannon, M J; Iversen, S D

1986-01-15

Microinfusion of the metabolically stable substance P (SP) agonist, [pGlu5,MePhe8,Sar9]-SP5-11 (DiMe-C7), into the ventral tegmental area (VTA) of rat brain increased levels of the dopamine (DA) metabolite dihydroxyphenylacetic acid in the prefrontal cortex (+ 120%) and nucleus accumbens (+30%) but not in other regions of forebrain. In contrast, infusions of DiMe-C7 or SP into the lateral ventricles or microinfusions of SP into VTA failed to elicit increases in DOPAC levels in forebrain. DA levels were unaffected by SP or DiMe-C7 regardless of the route of administration. These data and previous studies suggest a role for endogenous SP in the modulation of mesocortical and mesolimbic DA neurones.

A Neurocomputational Model of Dopamine and Prefrontal-Striatal Interactions during Multicue Category Learning by Parkinson Patients

ERIC Educational Resources Information Center

Moustafa, Ahmed A.; Gluck, Mark A.

2011-01-01

Most existing models of dopamine and learning in Parkinson disease (PD) focus on simulating the role of basal ganglia dopamine in reinforcement learning. Much data argue, however, for a critical role for prefrontal cortex (PFC) dopamine in stimulus selection in attentional learning. Here, we present a new computational model that simulates…

Repeated exposure to delta 9-tetrahydrocannabinol reduces prefrontal cortical dopamine metabolism in the rat.

PubMed

Jentsch, J D; Verrico, C D; Le, D; Roth, R H

1998-05-01

Long-term abuse of marijuana by humans can induce profound behavioral deficits characterized by cognitive and memory impairments. In particular, deficits on tasks dependent on frontal lobe function have been reported in cannabis abusers. In the current study, we examined whether long-term exposure to delta9-tetrahydrocannabinol, the active ingredient in marijuana, altered the neurochemistry of the frontal cortex in rats. Two weeks administration of delta9-tetrahydrocannabinol reduced dopamine transmission in the medial prefrontal cortex, while dopamine metabolism in striatal regions was unaffected. These data are consistent with earlier findings of dopaminergic regulation of frontal cortical cognition. Thus, cognitive deficits in heavy abusers of cannabis may be subserved by drug-induced alterations in frontal cortical dopamine transmission.

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

A Novel Heterocyclic Compound CE-104 Enhances Spatial Working Memory in the Radial Arm Maze in Rats and Modulates the Dopaminergic System

PubMed Central

Aher, Yogesh D.; Subramaniyan, Saraswathi; Shanmugasundaram, Bharanidharan; Sase, Ajinkya; Saroja, Sivaprakasam R.; Holy, Marion; Höger, Harald; Beryozkina, Tetyana; Sitte, Harald H.; Leban, Johann J.; Lubec, Gert

2016-01-01

Various psychostimulants targeting monoamine neurotransmitter transporters (MATs) have been shown to rescue cognition in patients with neurological disorders and improve cognitive abilities in healthy subjects at low doses. Here, we examined the effects upon cognition of a chemically synthesized novel MAT inhibiting compound 2-(benzhydrylsulfinylmethyl)-4-methylthiazole (named as CE-104). The efficacy of CE-104 in blocking MAT [dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter] was determined using in vitro neurotransmitter uptake assay. The effect of the drug at low doses (1 and 10 mg/kg) on spatial memory was studied in male rats in the radial arm maze (RAM). Furthermore, the dopamine receptor and transporter complex levels of frontal cortex (FC) tissue of trained and untrained animals treated either with the drug or vehicle were quantified on blue native PAGE (BN-PAGE). The drug inhibited dopamine (IC50: 27.88 μM) and norepinephrine uptake (IC50: 160.40 μM), but had a negligible effect on SERT. In the RAM, both drug-dose groups improved spatial working memory during the performance phase of RAM as compared to vehicle. BN-PAGE Western blot quantification of dopamine receptor and transporter complexes revealed that D1, D2, D3, and DAT complexes were modulated due to training and by drug effects. The drug’s ability to block DAT and its influence on DAT and receptor complex levels in the FC is proposed as a possible mechanism for the observed learning and memory enhancement in the RAM. PMID:26941626

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

Adult, female rats given irregular, limited access to chocolate develop binge-eating behaviour with normal bodyweight and compulsive/perseverative and impulsive behaviours similar to those in binge-eating disorder. We investigated whether (a) dysregulated central nervous system dopaminergic and opioidergic systems are part of the psychopathology of binge-eating and (b) these neurotransmitter systems may mediate the actions of drugs ameliorating binge-eating disorder psychopathology. Binge-eating produced a 39% reduction of striatal D 1 receptors with 22% and 23% reductions in medial and lateral caudate putamen and a 22% increase of striatal μ-opioid receptors. There was no change in D 1 receptor density in nucleus accumbens, medial prefrontal cortex or dorsolateral frontal cortex, striatal D 2 receptors and dopamine reuptake transporter sites, or μ-opioid receptors in frontal cortex. There were no changes in ligand affinities. The concentrations of monoamines, metabolites and estimates of dopamine (dopamine/dihydroxyphenylacetic acid ratio) and serotonin/5-hydroxyindolacetic acid ratio turnover rates were unchanged in striatum and frontal cortex. However, turnover of dopamine and serotonin in the hypothalamus was increased ~20% and ~15%, respectively. Striatal transmission via D 1 receptors is decreased in binge-eating rats while μ-opioid receptor signalling may be increased. These changes are consistent with the attenuation of binge-eating by lisdexamfetamine, which increases catecholaminergic neurotransmission, and nalmefene, a μ-opioid antagonist.

Dopamine Beta Hydroxylase Genotype Identifies Individuals Less Susceptible to Bias in Computer-Assisted Decision Making

PubMed Central

Parasuraman, Raja; de Visser, Ewart; Lin, Ming-Kuan; Greenwood, Pamela M.

2012-01-01

Computerized aiding systems can assist human decision makers in complex tasks but can impair performance when they provide incorrect advice that humans erroneously follow, a phenomenon known as “automation bias.” The extent to which people exhibit automation bias varies significantly and may reflect inter-individual variation in the capacity of working memory and the efficiency of executive function, both of which are highly heritable and under dopaminergic and noradrenergic control in prefrontal cortex. The dopamine beta hydroxylase (DBH) gene is thought to regulate the differential availability of dopamine and norepinephrine in prefrontal cortex. We therefore examined decision-making performance under imperfect computer aiding in 100 participants performing a simulated command and control task. Based on two single nucleotide polymorphism (SNPs) of the DBH gene, −1041 C/T (rs1611115) and 444 G/A (rs1108580), participants were divided into groups of low and high DBH enzyme activity, where low enzyme activity is associated with greater dopamine relative to norepinephrine levels in cortex. Compared to those in the high DBH enzyme activity group, individuals in the low DBH enzyme activity group were more accurate and speedier in their decisions when incorrect advice was given and verified automation recommendations more frequently. These results indicate that a gene that regulates relative prefrontal cortex dopamine availability, DBH, can identify those individuals who are less susceptible to bias in using computerized decision-aiding systems. PMID:22761865

Effect of psilocin on extracellular dopamine and serotonin levels in the mesoaccumbens and mesocortical pathway in awake rats.

PubMed

Sakashita, Yuichi; Abe, Kenji; Katagiri, Nobuyuki; Kambe, Toshie; Saitoh, Toshiaki; Utsunomiya, Iku; Horiguchi, Yoshie; Taguchi, Kyoji

2015-01-01

Psilocin (3-[2-(dimethylamino)ethyl]-1H-indol-4-ol) is a hallucinogenic component of the Mexican mushroom Psilocybe mexicana and a skeletal serotonin (5-HT) analogue. Psilocin is the active metabolite of psilocybin (3-[2-(dimethylamino)ethyl]-1H-indol-4-yl dihydrogen phosphate). In the present study, we examined the effects of systemically administered psilocin on extracellular dopamine and 5-HT concentrations in the ventral tegmental area (VTA), nucleus accumbens, and medial prefrontal cortex of the dopaminergic pathway in awake rats using in vivo microdialysis. Intraperitoneal administration of psilocin (5, 10 mg/kg) significantly increased extracellular dopamine levels in the nucleus accumbens. Psilocin did not affect the extracellular 5-HT level in the nucleus accumbens. Conversely, systemic administration of psilocin (10 mg/kg) significantly increased extracellular 5-HT levels in the medial prefrontal cortex of rats, but dopamine was decreased in this region. However, neither extracellular dopamine nor 5-HT levels in the VTA were altered by administration of psilocin. Behaviorally, psilocin significantly increased the number of head twitches. Thus, psilocin affects the dopaminergic system in the nucleus accumbens. In the serotonergic system, psilocin contribute to a crucial effect in the medial prefrontal cortex. The present data suggest that psilocin increased both the extracellular dopamine and 5-HT concentrations in the mesoaccumbens and/or mesocortical pathway.

Antipsychotic dose modulates behavioral and neural responses to feedback during reinforcement learning in schizophrenia.

PubMed

Insel, Catherine; Reinen, Jenna; Weber, Jochen; Wager, Tor D; Jarskog, L Fredrik; Shohamy, Daphna; Smith, Edward E

2014-03-01

Schizophrenia is characterized by an abnormal dopamine system, and dopamine blockade is the primary mechanism of antipsychotic treatment. Consistent with the known role of dopamine in reward processing, prior research has demonstrated that patients with schizophrenia exhibit impairments in reward-based learning. However, it remains unknown how treatment with antipsychotic medication impacts the behavioral and neural signatures of reinforcement learning in schizophrenia. The goal of this study was to examine whether antipsychotic medication modulates behavioral and neural responses to prediction error coding during reinforcement learning. Patients with schizophrenia completed a reinforcement learning task while undergoing functional magnetic resonance imaging. The task consisted of two separate conditions in which participants accumulated monetary gain or avoided monetary loss. Behavioral results indicated that antipsychotic medication dose was associated with altered behavioral approaches to learning, such that patients taking higher doses of medication showed increased sensitivity to negative reinforcement. Higher doses of antipsychotic medication were also associated with higher learning rates (LRs), suggesting that medication enhanced sensitivity to trial-by-trial feedback. Neuroimaging data demonstrated that antipsychotic dose was related to differences in neural signatures of feedback prediction error during the loss condition. Specifically, patients taking higher doses of medication showed attenuated prediction error responses in the striatum and the medial prefrontal cortex. These findings indicate that antipsychotic medication treatment may influence motivational processes in patients with schizophrenia.

Multiple sites and actions of gabapentin-induced relief of ongoing experimental neuropathic pain

PubMed Central

Bannister, Kirsty; Qu, Chaoling; Navratilova, Edita; Oyarzo, Janice; Xie, Jennifer Yanhua; King, Tamara; Dickenson, Anthony H.; Porreca, Frank

2017-01-01

Gabapentin is a first-line therapy for neuropathic pain but its mechanisms and sites of action remain uncertain. We investigated gabapentin-induced modulation of neuropathic pain following spinal nerve ligation (SNL) in rats. Intravenous or intrathecal gabapentin reversed evoked mechanical hypersensitivity, produced conditioned place preference (CPP) and dopamine release in the nucleus accumbens (NAc) selectively in SNL rats. Spinal gabapentin also significantly inhibited dorsal horn wide dynamic range (WDR) neuronal responses to a range of evoked stimuli in SNL rats. In contrast, gabapentin microinjected bilaterally into the rostral anterior cingulate cortex (rACC), produced CPP and elicited NAc dopamine release selectively in SNL rats but did not reverse tactile allodynia and had marginal effects on WDR neuronal activity. Moreover, blockade of endogenous opioid signaling in the rACC prevented intravenous gabapentin-induced CPP and NAc dopamine release but failed to block its inhibition of tactile allodynia. Gabapentin therefore can potentially act to produce its pain relieving effects by (a) inhibition of injury-induced spinal neuronal excitability, evoked hypersensitivity and ongoing pain and (b) selective supraspinal modulation of affective qualities of pain, without alteration of reflexive behaviors. Consistent with previous findings of pain relief from non-opioid analgesics, gabapentin requires engagement of rACC endogenous opioid circuits and downstream activation of mesolimbic reward circuits reflected in learned pain motivated behaviors. These findings support the partial separation of sensory and affective dimensions of pain in this experimental model and suggest that modulation of affective-motivational qualities of pain may be the preferential mechanism of gabapentin’s analgesic effects in patients. PMID:28832395

The Role of Prefrontal Dopamine D1 Receptors in the Neural Mechanisms of Associative Learning

PubMed Central

Puig, M. Victoria; Miller, Earl K.

2013-01-01

Summary Dopamine is thought to play a major role in learning. However, while dopamine D1 receptors (D1Rs) in the prefrontal cortex (PFC) have been shown to modulate working memory-related neural activity, their role in the cellular basis of learning is unknown. We recorded activity from multiple electrodes while injecting the D1R antagonist SCH23390 in the lateral PFC as monkeys learned visuomotor associations. Blocking D1Rs impaired learning of novel associations and decreased cognitive flexibility, but spared performance of already familiar associations. This suggests a greater role for prefrontal D1Rs in learning new, than performing familiar, associations. There was a corresponding greater decrease in neural selectivity and increase in alpha and beta oscillations in local field potentials for novel than familiar associations. Our results suggest that weak stimulation of D1Rs observed in aging and psychiatric disorders may impair learning and PFC function by reducing neural selectivity and exacerbating neural oscillations associated with inattention and cognitive deficits. PMID:22681691

Reduced dopamine and glutamate neurotransmission in the nucleus accumbens of quinpirole-sensitized rats hints at inhibitory D2 autoreceptor function.

PubMed

Escobar, Angélica P; Cornejo, Francisca A; Olivares-Costa, Montserrat; González, Marcela; Fuentealba, José A; Gysling, Katia; España, Rodrigo A; Andrés, María E

2015-09-01

Dopamine from the ventral tegmental area and glutamate from several brain nuclei converge in the nucleus accumbens (NAc) to drive motivated behaviors. Repeated activation of D2 receptors with quinpirole (QNP) induces locomotor sensitization and compulsive behaviors, but the mechanisms are unknown. In this study, in vivo microdialysis and fast scan cyclic voltammetry in adult anesthetized rats were used to investigate the effect of repeated QNP on dopamine and glutamate neurotransmission within the NAc. Following eight injections of QNP, a significant decrease in phasic and tonic dopamine release was observed in rats that displayed locomotor sensitization. Either a systemic injection or the infusion of QNP into the NAc decreased dopamine release, and the extent of this effect was similar in QNP-sensitized and control rats, indicating that inhibitory D2 autoreceptor function is maintained despite repeated activation of D2 receptors and decreased dopamine extracellular levels. Basal extracellular levels of glutamate in the NAc were also significantly lower in QNP-treated rats than in controls. Moreover, the increase in NAc glutamate release induced by direct stimulation of medial prefrontal cortex was significantly lower in QNP-sensitized rats. Together, these results indicate that repeated activation of D2 receptors disconnects NAc from medial prefrontal cortex and ventral tegmental area. Repeated administration of the dopamine D2 receptor agonist quinpirole (QNP) induces locomotor sensitization. We found that the NAc of QNP-sensitized rats has reduced glutamate levels coming from prefrontal cortex together with a decreased phasic and tonic dopamine neurotransmission but a conserved presynaptic D2 receptor function. We suggest that locomotor sensitization is because of increased affinity state of D2 post-synaptic receptors. © 2015 International Society for Neurochemistry.

Involvement of Infralimbic Prefrontal Cortex but not Lateral Habenula in Dopamine Attenuation After Chronic Mild Stress.

PubMed

Moreines, Jared L; Owrutsky, Zoe L; Grace, Anthony A

2017-03-01

Emerging evidence supports a role for dopamine in major depressive disorder (MDD). We recently reported fewer spontaneously active ventral tegmental area (VTA) dopamine neurons (ie, reduced dopamine neuron population activity) in the chronic mild stress (CMS) rodent model of MDD. In this study, we examined the role of two brain regions that have been implicated in MDD in humans, the infralimbic prefrontal cortex (ILPFC)-that is, rodent homolog of Brodmann area 25 (BA25), and the lateral habenula (LHb) in the CMS-induced attenuation of dopamine neuron activity. The impact of activating the ILPFC or LHb was evaluated using single-unit extracellular recordings of identified VTA dopamine neurons. The involvement of each region in dopamine neuron attenuation following 5-7 weeks of CMS was then evaluated by selective inactivation. Activation of either ILPFC or LHb in normal rats potently suppressed dopamine neuron population activity, but in unique patterns. ILPFC activation selectively inhibited dopamine neurons in medial VTA, which were most impacted by CMS. Conversely, LHb activation selectively inhibited dopamine neurons in lateral VTA, which were unaffected by CMS. Moreover, only ILPFC inactivation restored dopamine neuron population activity to normal levels following CMS; LHb inactivation had no restorative effect. These data suggest that, in the CMS model of MDD, the ILPFC is the primary driver of diminished dopamine neuron responses. These findings support a neural substrate for ILPFC/BA25 linking affective and motivational circuitry dysfunction in MDD.

When is an error not a prediction error? An electrophysiological investigation.

PubMed

Holroyd, Clay B; Krigolson, Olave E; Baker, Robert; Lee, Seung; Gibson, Jessica

2009-03-01

A recent theory holds that the anterior cingulate cortex (ACC) uses reinforcement learning signals conveyed by the midbrain dopamine system to facilitate flexible action selection. According to this position, the impact of reward prediction error signals on ACC modulates the amplitude of a component of the event-related brain potential called the error-related negativity (ERN). The theory predicts that ERN amplitude is monotonically related to the expectedness of the event: It is larger for unexpected outcomes than for expected outcomes. However, a recent failure to confirm this prediction has called the theory into question. In the present article, we investigated this discrepancy in three trial-and-error learning experiments. All three experiments provided support for the theory, but the effect sizes were largest when an optimal response strategy could actually be learned. This observation suggests that ACC utilizes dopamine reward prediction error signals for adaptive decision making when the optimal behavior is, in fact, learnable.

Dopaminergic neurotransmission dysfunction induced by amyloid-β transforms cortical long-term potentiation into long-term depression and produces memory impairment.

PubMed

Moreno-Castilla, Perla; Rodriguez-Duran, Luis F; Guzman-Ramos, Kioko; Barcenas-Femat, Alejandro; Escobar, Martha L; Bermudez-Rattoni, Federico

2016-05-01

Alzheimer's disease (AD) is a neurodegenerative condition manifested by synaptic dysfunction and memory loss, but the mechanisms underlying synaptic failure are not entirely understood. Although dopamine is a key modulator of synaptic plasticity, dopaminergic neurotransmission dysfunction in AD has mostly been associated to noncognitive symptoms. Thus, we aimed to study the relationship between dopaminergic neurotransmission and synaptic plasticity in AD models. We used a transgenic model of AD (triple-transgenic mouse model of AD) and the administration of exogenous amyloid-β (Aβ) oligomers into wild type mice. We found that Aβ decreased cortical dopamine levels and converted in vivo long-term potentiation (LTP) into long-term depression (LTD) after high-frequency stimulation delivered at basolateral amygdaloid nucleus-insular cortex projection, which led to impaired recognition memory. Remarkably, increasing cortical dopamine and norepinephrine levels rescued both high-frequency stimulation -induced LTP and memory, whereas depletion of catecholaminergic levels mimicked the Aβ-induced shift from LTP to LTD. Our results suggest that Aβ-induced dopamine depletion is a core mechanism underlying the early synaptopathy and memory alterations observed in AD models and acts by modifying the threshold for the induction of cortical LTP and/or LTD. Copyright © 2016 Elsevier Inc. All rights reserved.

Restraint stress-induced central monoaminergic & oxidative changes in rats & their prevention by novel Ocimum sanctum compounds

PubMed Central

Ahmad, Ausaf; Rasheed, Naila; Chand, Kailash; Maurya, Rakesh; Banu, Naheed; Palit, Gautam

2012-01-01

Background & objectives: Ocimum sanctum (OS) is known to possess various therapeutic properties. We have earlier isolated and characterized three OS compounds; Ocimarin, Ocimumoside A and Ocimumoside B. However, their role in modulating stress-induced central changes is unexplored. Thus, the present study was aimed to investigate the effect of these OS compounds on restraint stress (RS)-induced changes in the monoaminergic and antioxidant systems in the frontal cortex, striatum and hippocampus of rats. Methods: RS was produced by immobilizing (restraining) the Sprague Dawley rats for a period of 2.5 h inside cylindrical steel tubes. The monoamine levels and the in vivo antioxidant status in brain regions were evaluated by HPLC-EC and spectrophotometric assays, respectively. Results: RS significantly increased the dopamine levels in the frontal cortex and decreased in the striatum and hippocampus, and accompanied with selective increase of dopamine metabolites compared to the NS control group. The serotonin and its metabolite levels were significantly increased, while noradrenaline levels were decreased by RS in the three brain regions studied. The activities of superoxide dismutase and glutathione peroxidase in the frontal cortex and striatum were significantly increased by RS with decreased glutathione levels and increased lipid peroxidation. Pre-treatment with Ocimumoside A and B (40 mg/kg po) for a period of 3 days prevented the RS-induced changes with an efficacy similar to that of standard anti-stress (Panax quinquefolium; 100 mg/kg po) and antioxidant (Melatonin; 20 mg/kg ip) drugs, while, Ocimarin failed to modulate these changes. OS compounds per se had no effect on these parameters. Interpretation & conclusions: The present findings showed the anti-stress potential of Ocimumoside A and B in relation to their simultaneous modulatory effects on the central monoaminergic and antioxidant systems implicating their therapeutic importance in stress-related disorders. Further studies are required to understand the mechanism of action of these compounds. PMID:22664506

High-anxiety rats are less sensitive to the rewarding affects of amphetamine on 50kHz USV.

PubMed

Lehner, Małgorzata H; Taracha, Ewa; Kaniuga, Ewelina; Wisłowska-Stanek, Aleksandra; Wróbel, Jacek; Sobolewska, Alicja; Turzyńska, Danuta; Skórzewska, Anna; Płaźnik, Adam

2014-12-15

This study assessed behaviour, as measured by 50kHz calls related to positive affect, in rats with different fear conditioned response strengths: low-anxiety rats (LR) and high-anxiety rats (HR), after amphetamine injection in a two-injection protocol (TIPS). The results showed that the first dose of amphetamine evoked similar behavioural effects in frequency-modulated (FM) 50kHz calls in the LR and HR groups. The second injection of amphetamine resulted in stronger FM 50kHz calls in LR compared with HR rats. The biochemical data ('ex vivo' analysis) showed that the LR rats had increased basal levels of dopamine in the amygdala, and increased homovanilic acid (HVA), dopamine's main metabolite, in the amygdala and prefrontal cortex compared with HR rats. The 'in vivo' analysis (microdialysis study) showed that the LR rats had increased HVA concentrations in the basolateral amygdala in response to an aversively conditioned context. Research has suggested that differences in dopaminergic system activity in the amygdala and prefrontal cortex may be one of the biological factors that underlie individual differences in response to fear stimuli, which may also affect the rewarding effects of amphetamine. Copyright © 2014 Elsevier B.V. All rights reserved.

COMT Genetic Reduction Produces Sexually Divergent Effects on Cortical Anatomy and Working Memory in Mice and Humans.

PubMed

Sannino, Sara; Gozzi, Alessandro; Cerasa, Antonio; Piras, Fabrizio; Scheggia, Diego; Managò, Francesca; Damiano, Mario; Galbusera, Alberto; Erickson, Lucy C; De Pietri Tonelli, Davide; Bifone, Angelo; Tsaftaris, Sotirios A; Caltagirone, Carlo; Weinberger, Daniel R; Spalletta, Gianfranco; Papaleo, Francesco

2015-09-01

Genetic variations in catechol-O-methyltransferase (COMT) that modulate cortical dopamine have been associated with pleiotropic behavioral effects in humans and mice. Recent data suggest that some of these effects may vary among sexes. However, the specific brain substrates underlying COMT sexual dimorphisms remain unknown. Here, we report that genetically driven reduction in COMT enzyme activity increased cortical thickness in the prefrontal cortex (PFC) and postero-parieto-temporal cortex of male, but not female adult mice and humans. Dichotomous changes in PFC cytoarchitecture were also observed: reduced COMT increased a measure of neuronal density in males, while reducing it in female mice. Consistent with the neuroanatomical findings, COMT-dependent sex-specific morphological brain changes were paralleled by divergent effects on PFC-dependent working memory in both mice and humans. These findings emphasize a specific sex-gene interaction that can modulate brain morphological substrates with influence on behavioral outcomes in healthy subjects and, potentially, in neuropsychiatric populations. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

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.

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.

Critical Involvement of the Motor Cortex in the Pathophysiology and Treatment of Parkinson’s Disease

PubMed Central

Lindenbach, David; Bishop, Christopher

2013-01-01

This review examines the involvement of the motor cortex in Parkinson’s disease (PD), a debilitating movement disorder typified by degeneration of dopamine cells of the substantia nigra. While much of PD research has focused on the caudate/putamen, many aspects of motor cortex function are abnormal in PD patients and in animal models of PD, implicating motor cortex involvement in disease symptoms and their treatment. Herein, we discuss several lines of evidence to support this hypothesis. Dopamine depletion alters regional metabolism in the motor cortex and also reduces interneuron activity, causing a breakdown in intracortical inhibition. This leads to functional reorganization of motor maps and excessive corticostriatal synchrony when movement is initiated. Recent work suggests that electrical stimulation of the motor cortex provides a clinical benefit for PD patients. Based on extant research, we identify a number of unanswered questions regarding the motor cortex in PD and argue that a better understanding of the contribution of the motor cortex to PD symptoms will facilitate the development of novel therapeutic approaches. PMID:24113323

Dopamine and noradrenaline efflux in the prefrontal cortex in the light and dark period: effects of novelty and handling and comparison to the nucleus accumbens.

PubMed

Feenstra, M G; Botterblom, M H; Mastenbroek, S

2000-01-01

We used on-line microdialysis measurements of dopamine and noradrenaline extracellular concentrations in the medial prefrontal cortex of awake, freely moving rats during the dark and the light period of the day to study whether (i) basal efflux would be higher in the active, dark period than in the inactive, light period; (ii) the activation induced by environmental stimuli would be dependent on these conditions. When determined one day after cannula placement, noradrenaline and dopamine levels were higher during the dark. Maximal relative increases induced by novelty and handling were 150% and 175-200%, respectively, and were very similar in the light and the dark, but the net increases were higher in the dark. Separate groups were tested one week after cannula placement to ensure recovery of possibly disturbed circadian rhythms. While basal levels in the dark were now approximately twice those in the light, the maximal relative and net increases after both novelty and handling were very similar. Basal levels of dopamine in the nucleus accumbens (one day after cannula placement) were not different in the light or dark, but were increased by novelty and handling to about 130% only in the light period, not in the dark. Thus, in the prefrontal cortex, dopamine strongly resembles noradrenaline, in that basal efflux was state dependent, whereas activation by stimuli was not. In the nucleus accumbens, basal dopamine efflux was not state dependent, but activation by stimuli was. These results suggest that there are differential effects of circadian phase on basal activity and responsiveness of the mesolimbic vs the mesocortical dopamine system.

Impaired Prefrontal Cortical Dopamine Release in Schizophrenia During a Cognitive Task: A [11C]FLB 457 Positron Emission Tomography Study.

PubMed

Rao, Naren; Northoff, Georg; Tagore, Abanti; Rusjan, Pablo; Kenk, Miran; Wilson, Alan; Houle, Sylvain; Strafella, Antonio; Remington, Gary; Mizrahi, Romina

2018-06-07

Evidence from several lines of research suggests decreased dopamine release in the prefrontal cortex as the neurochemical correlates of cognitive deficits in schizophrenia (SCZ). However, in vivo examination of cortical hypodopaminergia using positron emission tomography (PET) during cognitive task performance in SCZ remains to be investigated. We examined dopamine release in anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC), using PET while participants were performing a cognitive task. Thirteen drug-free patients with SCZ and 13 healthy volunteers (HV) matched for age and sex participated in the study. Data were acquired between 2011 and 2015. Two PET scans with [11C]FLB 457 were acquired while the participants were performing the Wisconsin Card Sorting Test (WCST) and a sensorimotor control task (SMCT). A magnetic resonance image was acquired for anatomical delineation. Differences in cortical dopamine release between SCZ and HV, indexed as percentage change in binding potential between WCST and SMCT (ΔBPND), were calculated in ACC and DLPFC. We observed significant differences in the ΔBPND in ACC (HV = 4.40 ± 6.00; SCZ = -11.48 ± 15.08; t = 3.52; P = .003) and a trend-level difference in ΔBPND in DLPFC (HV = -0.58 ± 8.45; SCZ = -7.79 ± 11.28; t = 1.84; P = .079), suggesting dopamine depletion in cortical brain regions in patients with SCZ while performing a cognitive task. These results provide the first in vivo evidence for reduced dopamine release or even dopamine depletion while performing cognitive task in ACC and DLPFC in patients with SCZ. The present results provide support for the frontal hypodopaminergia hypothesis of cognitive symptoms in SCZ.

Schizophrenia-Like Dopamine Release Abnormalities in a Mouse Model of NMDA Receptor Hypofunction.

PubMed

Nakao, Kazuhito; Jeevakumar, Vivek; Jiang, Sunny Zhihong; Fujita, Yuko; Diaz, Noelia B; Pretell Annan, Carlos A; Eskow Jaunarajs, Karen L; Hashimoto, Kenji; Belforte, Juan E; Nakazawa, Kazu

2018-01-31

Amphetamine-induced augmentation of striatal dopamine and its blunted release in prefrontal cortex (PFC) is a hallmark of schizophrenia pathophysiology. Although N-methyl-D-aspartate receptor (NMDAR) hypofunction is also implicated in schizophrenia, it remains unclear whether NMDAR hypofunction leads to dopamine release abnormalities. We previously demonstrated schizophrenia-like phenotypes in GABAergic neuron-specific NMDAR hypofunctional mutant mice, in which Ppp1r2-Cre dependent deletion of indispensable NMDAR channel subunit Grin1 is induced in corticolimbic GABAergic neurons including parvalbumin (PV)-positive neurons, in postnatal development, but not in adulthood. Here, we report enhanced dopaminomimetic-induced locomotor activity in these mutants, along with bidirectional, site-specific changes in in vivo amphetamine-induced dopamine release: nucleus accumbens (NAc) dopamine release was enhanced by amphetamine in postnatal Ppp1r2-Cre/Grin1 knockout (KO) mice, whereas dopamine release was dramatically reduced in the medial PFC (mPFC) compared to controls. Basal tissue dopamine levels in both the NAc and mPFC were unaffected. Interestingly, the magnitude and distribution of amphetamine-induced c-Fos expression in dopamine neurons was comparable between genotypes across dopaminergic input subregions in the ventral tegmental area (VTA). These effects appear to be both developmentally and cell-type specifically modulated, since PV-specific Grin1 KO mice could induce the same effects as seen in postnatal-onset Ppp1r2-Cre/Grin1 KO mice, but no such abnormalities were observed in somatostatin-Cre/Grin1 KO mice or adult-onset Ppp1r2-Cre/Grin1 KO mice. These results suggest that PV GABAergic neuron-NMDAR hypofunction in postnatal development confers bidirectional NAc hyper- and mPFC hypo-sensitivity to amphetamine-induced dopamine release, similar to that classically observed in schizophrenia pathophysiology. © The Author(s) 2018. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.

Dopamine D1 receptor activation maintains motor coordination and balance in rats.

PubMed

Avila-Luna, Alberto; Gálvez-Rosas, Arturo; Durand-Rivera, Alfredo; Ramos-Languren, Laura-Elisa; Ríos, Camilo; Arias-Montaño, José-Antonio; Bueno-Nava, Antonio

2018-02-01

Dopamine (DA) modulates motor coordination, and its depletion, as in Parkinson's disease, produces motor impairment. The basal ganglia, cerebellum and cerebral cortex are interconnected, have functional roles in motor coordination, and possess dopamine D 1 receptors (D 1 Rs), which are expressed at a particularly high density in the basal ganglia. In this study, we examined whether the activation of D 1 Rs modulates motor coordination and balance in the rat using a beam-walking test that has previously been used to detect motor coordination deficits. The systemic administration of the D 1 R agonist SKF-38393 at 2, 3, or 4 mg/kg did not alter the beam-walking scores, but the subsequent administration of the D 1 R antagonist SCH-23390 at 1 mg/kg did produce deficits in motor coordination, which were reversed by the full agonist SKF-82958. The co-administration of SKF-38393 and SCH-23390 did not alter the beam-walking scores compared with the control group, but significantly prevented the increase in beam-walking scores induced by SCH-23390. The effect of the D 1 R agonist to prevent and reverse the effect of the D 1 R antagonist in beam-walking scores is an indicator that the function of D 1 Rs is necessary to maintain motor coordination and balance in rats. Our results support that D 1 Rs mediate the SCH-23390-induced deficit in motor coordination.

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

PubMed

Bertolino, Alessandro; Taurisano, Paolo; Pisciotta, Nicola Marco; Blasi, Giuseppe; Fazio, Leonardo; Romano, Raffaella; Gelao, Barbara; Lo Bianco, Luciana; Lozupone, Madia; Di Giorgio, Annabella; Caforio, Grazia; Sambataro, Fabio; Niccoli-Asabella, Artor; Papp, Audrey; Ursini, Gianluca; Sinibaldi, Lorenzo; Popolizio, Teresa; Sadee, Wolfgang; Rubini, Giuseppe

2010-02-22

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

Genetically Determined Measures of Striatal D2 Signaling Predict Prefrontal Activity during Working Memory Performance

PubMed Central

Bertolino, Alessandro; Taurisano, Paolo; Pisciotta, Nicola Marco; Blasi, Giuseppe; Fazio, Leonardo; Romano, Raffaella; Gelao, Barbara; Bianco, Luciana Lo; Lozupone, Madia; Di Giorgio, Annabella; Caforio, Grazia; Sambataro, Fabio; Niccoli-Asabella, Artor; Papp, Audrey; Ursini, Gianluca; Sinibaldi, Lorenzo; Popolizio, Teresa; Sadee, Wolfgang; Rubini, Giuseppe

2010-01-01

Background Variation of the gene coding for D2 receptors (DRD2) has been associated with risk for schizophrenia and with working memory deficits. A functional intronic SNP (rs1076560) predicts relative expression of the two D2 receptors isoforms, D2S (mainly pre-synaptic) and D2L (mainly post-synaptic). However, the effect of functional genetic variation of DRD2 on striatal dopamine D2 signaling and on its correlation with prefrontal activity during working memory in humans is not known. Methods Thirty-seven healthy subjects were genotyped for rs1076560 (G>T) and underwent SPECT with [123I]IBZM (which binds primarily to post-synaptic D2 receptors) and with [123I]FP-CIT (which binds to pre-synaptic dopamine transporters, whose activity and density is also regulated by pre-synaptic D2 receptors), as well as BOLD fMRI during N-Back working memory. Results Subjects carrying the T allele (previously associated with reduced D2S expression) had striatal reductions of [123I]IBZM and of [123I]FP-CIT binding. DRD2 genotype also differentially predicted the correlation between striatal dopamine D2 signaling (as identified with factor analysis of the two radiotracers) and activity of the prefrontal cortex during working memory as measured with BOLD fMRI, which was positive in GG subjects and negative in GT. Conclusions Our results demonstrate that this functional SNP within DRD2 predicts striatal binding of the two radiotracers to dopamine transporters and D2 receptors as well as the correlation between striatal D2 signaling with prefrontal cortex activity during performance of a working memory task. These data are consistent with the possibility that the balance of excitatory/inhibitory modulation of striatal neurons may also affect striatal outputs in relationship with prefrontal activity during working memory performance within the cortico-striatal-thalamic-cortical pathway. PMID:20179754

Effects of S-citalopram, citalopram, and R-citalopram on the firing patterns of dopamine neurons in the ventral tegmental area, N-methyl-D-aspartate receptor-mediated transmission in the medial prefrontal cortex and cognitive function in the rat.

PubMed

Schilström, Björn; Konradsson-Geuken, Asa; Ivanov, Vladimir; Gertow, Jens; Feltmann, Kristin; Marcus, Monica M; Jardemark, Kent; Svensson, Torgny H

2011-05-01

Escitalopram, the S-enantiomer of citalopram, possesses superior efficacy compared to other selective serotonin reuptake inhibitors (SSRIs) in the treatment of major depression. Escitalopram binds to an allosteric site on the serotonin transporter, which further enhances the blockade of serotonin reuptake, whereas R-citalopram antagonizes this positive allosteric modulation. Escitalopram's effects on neurotransmitters other than serotonin, for example, dopamine and glutamate, are not well studied. Therefore, we here studied the effects of escitalopram, citalopram, and R-citalopram on dopamine cell firing in the ventral tegmental area, using single-cell recording in vivo and on NMDA receptor-mediated currents in pyramidal neurons in the medial prefrontal cortex using in vitro electrophysiology in rats. The cognitive effects of escitalopram and citalopram were also compared using the novel object recognition test. Escitalopram (40-640 μg/kg i.v.) increased both firing rate and burst firing of dopaminergic neurons, whereas citalopram (80-1280 μg/kg) had no effect on firing rate and only increased burst firing at high dosage. R-citalopram (40-640 μg/kg) had no significant effects. R-citalopram (320 μg/kg) antagonized the effects of escitalopram (320 μg/kg). A very low concentration of escitalopram (5 nM), but not citalopram (10 nM) or R-citalopram (5 nM), potentiated NMDA-induced currents in pyramidal neurons. Escitalopram's effect was antagonized by R-citalopram and blocked by the dopamine D(1) receptor antagonist SCH23390. Escitalopram, but not citalopram, improved recognition memory. Our data suggest that the excitatory effect of escitalopram on dopaminergic and NMDA receptor-mediated neurotransmission may have bearing on its cognitive-enhancing effect and superior efficacy compared to other SSRIs in major depression. Copyright © 2010 Wiley-Liss, Inc.

Temporal Profiles Dissociate Regional Extracellular Ethanol versus Dopamine Concentrations

PubMed Central

2015-01-01

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

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 dopamine of 200 nM showed that an effect of striatal ligand displacement could be detected only when task timing was greater than 120 min. The prefrontal and anterior cingulate cortices are involved in reward responsiveness that can be measured using (18)F-fallypride PET in a single scanning session. To measure both striatal and extrastriatal dopamine release, the height of dopamine released and task timing need to be considered in designing activation studies depending on regional D(2/3) density.

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. We propose that dopamine, by facilitating energy expenditure, should be protective against obesity. We suggest the apparent failure of this protective mechanism in Western societies with high prevalence of obesity arises as a consequence of sedentary lifestyles that thwart energy expenditure. PMID:22833718

DOPAMINE DEPLETION SLOWS RETINAL TRANSMISSION

EPA Science Inventory

In male hooded rats, depletion of norepinephrine and dopamine by a-methyl-paratyrosine (AMT) significantly increased the latencies of early peaks in flash-evoked potentials recorded from the visual cortex, lateral geniculate nucleus, and optic tract. These effects were not produc...

Acute effect of intravenously applied alcohol in the human striatal and extrastriatal D2 /D3 dopamine system.

PubMed

Pfeifer, Philippe; Tüscher, Oliver; Buchholz, Hans Georg; Gründer, Gerhard; Vernaleken, Ingo; Paulzen, Michael; Zimmermann, Ulrich S; Maus, Stephan; Lieb, Klaus; Eggermann, Thomas; Fehr, Christoph; Schreckenberger, Mathias

2017-09-01

Investigations on the acute effects of alcohol in the human mesolimbic dopamine D 2 /D 3 receptor system have yielded conflicting results. With respect to the effects of alcohol on extrastriatal D 2 /D 3 dopamine receptors no investigations have been reported yet. Therefore we applied PET imaging using the postsynaptic dopamine D 2 /D 3 receptor ligand [ 18 F]fallypride addressing the question, whether intravenously applied alcohol stimulates the extrastriatal and striatal dopamine system. We measured subjective effects of alcohol and made correlation analyses with the striatal and extrastriatal D 2 /D 3 binding potential. Twenty-four healthy male μ-opioid receptor (OPRM1)118G allele carriers underwent a standardized intravenous and placebo alcohol administration. The subjective effects of alcohol were measured with a visual analogue scale. For the evaluation of the dopamine response we calculated the binding potential (BP ND ) by using the simplified reference tissue model (SRTM). In addition, we calculated distribution volumes (target and reference regions) in 10 subjects for which metabolite corrected arterial samples were available. In the alcohol condition no significant dopamine response in terms of a reduction of BP ND was observed in striatal and extrastriatal brain regions. We found a positive correlation for 'liking' alcohol and the BP ND in extrastriatal brain regions (Inferior frontal cortex (IFC) (r = 0.533, p = 0.007), orbitofrontal cortex (OFC) (r = 0.416, p = 0.043) and prefrontal cortex (PFC) (r = 0.625, p = 0.001)). The acute alcohol effects on the D 2 /D 3 dopamine receptor binding potential of the striatal and extrastriatal system in our experiment were insignificant. A positive correlation of the subjective effect of 'liking' alcohol with cortical D 2 /D 3 receptors may hint at an addiction relevant trait. © 2016 Society for the Study of Addiction.

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.

Disruption of hippocampal–prefrontal cortex activity by dopamine D2R-dependent LTD of NMDAR transmission

PubMed Central

Banks, Paul James; Burroughs, Amelia Caroline; Barker, Gareth Robert Isaac; Brown, Jon Thomas; Warburton, Elizabeth Clea; Bashir, Zafar Iqbal

2015-01-01

Functional connectivity between the hippocampus and prefrontal cortex (PFC) is essential for associative recognition memory and working memory. Disruption of hippocampal–PFC synchrony occurs in schizophrenia, which is characterized by hypofunction of NMDA receptor (NMDAR)-mediated transmission. We demonstrate that activity of dopamine D2-like receptors (D2Rs) leads selectively to long-term depression (LTD) of hippocampal–PFC NMDAR-mediated synaptic transmission. We show that dopamine-dependent LTD of NMDAR-mediated transmission profoundly disrupts normal synaptic transmission between hippocampus and PFC. These results show how dopaminergic activation induces long-term hypofunction of NMDARs, which can contribute to disordered functional connectivity, a characteristic that is a hallmark of psychiatric disorders such as schizophrenia. PMID:26286993

Reducing prefrontal gamma-aminobutyric acid activity induces cognitive, behavioral, and dopaminergic abnormalities that resemble schizophrenia.

PubMed

Enomoto, Takeshi; Tse, Maric T; Floresco, Stan B

2011-03-01

Perturbations in gamma-aminobutyric acid (GABA)-related markers have been reported in the prefrontal cortex of schizophrenic patients. However, a preclinical assessment of how suppression of prefrontal cortex GABA activity may reflect behavioral and cognitive pathologies observed in schizophrenia is forthcoming. We assessed the effects of pharmacologic blockade of prefrontal cortex GABA(A) receptors in rats on executive functions and other behaviors related to schizophrenia, as well as neural activity of midbrain dopamine neurons. Blockade of prefrontal cortex GABA(A) receptors with bicuculline (12.5-50 ng) did not affect working memory accuracy but did increase response latencies, resembling speed of processing deficits observed in schizophrenia. Prefrontal cortex GABA(A) blockade did not impede simple discrimination or reversal learning but did impair set-shifting in a manner dependent on when these treatments were given. Reducing GABA activity before the set-shift impaired the ability to acquire a novel strategy, whereas treatment before the initial discrimination increased perseveration during the shift. Latent inhibition was unaffected by bicuculline infusions before the preexposure/conditioning phases, suggesting that reduced prefrontal cortex GABA activity does not impair "learned irrelevance." GABA(A) blockade increased locomotor activity and showed synergic effects with a subthreshold dose of amphetamine. Furthermore, reducing medial prefrontal cortex GABA activity selectively increased phasic burst firing of ventral tegmental area dopamine neurons, without altering the their overall population activity. These results suggest that prefrontal cortex GABA hypofunction may be a key contributing factor to deficits in speed of processing, cognitive flexibility, and enhanced phasic dopamine activity observed in schizophrenia. Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Prefrontal Dopamine in Associative Learning and Memory

PubMed Central

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

2014-01-01

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

Prefrontal dopamine in associative learning and memory.

PubMed

Puig, M V; Antzoulatos, E G; Miller, E K

2014-12-12

Learning to associate specific objects or actions with rewards and remembering the associations are everyday tasks crucial for our flexible adaptation to the environment. These higher-order cognitive processes depend on the prefrontal cortex (PFC) and frontostriatal circuits that connect areas in the frontal lobe with the striatum in the basal ganglia. Both structures are densely innervated by dopamine (DA) afferents that originate in the midbrain. Although the activity of DA neurons is thought to be important for learning, the exact role of DA transmission in frontostriatal circuits during learning-related tasks is still unresolved. Moreover, the neural substrates of this modulation are poorly understood. Here, we review our recent work in monkeys utilizing local pharmacology of DA agents in the PFC to investigate the cellular mechanisms of DA modulation of associative learning and memory. We show that blocking both D1 and D2 receptors in the lateral PFC impairs learning of new stimulus-response associations and cognitive flexibility, but not the memory of highly familiar associations. In addition, D2 receptors may also contribute to motivation. The learning deficits correlated with reductions of neural information about the associations in PFC neurons, alterations in global excitability and spike synchronization, and exaggerated alpha and beta neural oscillations. Our findings provide new insights into how DA transmission modulates associative learning and memory processes in frontostriatal systems. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Effect of morphine and lacosamide on levels of dopamine and 5-HIAA in brain regions of rats with induced hypoglycemia.

PubMed

Guzman, D Calderon; Garcia, E Hernandez; Mejia, G Barragan; Olguin, H Juarez; Gonzalez, J A Saldivar; Labra Ruiz, N A

2014-01-15

The study aimed to determine the effect of morphine and lacosamide on levels of dopamine and 5-HIAA in a hypoglycemic model. Female Wistar rats (n = 30), mean weight of 180 g were treated as follow: Group 1 (control) received 0.9% NaCl, Group II; morphine (10 mg kg(-1)), Group III; lacosamide (10 mg kg(-1)), Group IV; insulin (10 U.I. per rat), Group V; morphine (10 mg kg(-1))+insulin, Group VI; lacosamide (10 mg kg(-1))+ insulin. All administrations were made intraperitoneally every 24 h, for 5 days. Animals were sacrificed after the last dose to measure the levels of glucose in blood; dopamine and 5-HIAA in cortex, hemispheres and cerebellum/medulla oblongata regions. Levels of glucose decreased significantly in animals treated with morphine, lacosamide and all groups that received insulin alone or combined with respect to control group. Levels of Dopamine diminished significantly in cortex and increased significantly in hemispheres of animals that received morphine. In cortex, 5-HIAA increase significantly in the groups treated with morphine, morphine+insulin and lacosamide+insulin, however a significant decrease of the same substance was witnessed in cerebellum and medulla oblongata of animals that received morphine or lacosamide plus insulin. GSH increased significantly in cortex and cerebellum/medulla oblongata of animals treated with morphine and lacosamide alone or combined with insulin. Lipid peroxidation decreased significantly in cortex and cerebellum/medulla oblongata of groups that received lacosamide alone or combined with insulin. These results indicate that hypoglycemia induced changes in cellular regulation while morphine and lacosamide are accompanied by biochemical responses.

The prefrontal cortex: a target for antipsychotic drugs.

PubMed

Artigas, F

2010-01-01

At therapeutic doses, classical antipsychotic drugs occupy a large proportion of subcortical dopamine D2 receptors, whereas atypical antipsychotics preferentially occupy cortical 5-HT(2) receptors. However, the exact cellular and network basis of their therapeutic action is not fully understood. To review the mechanism of action of antipsychotic drugs with a particular emphasis on their action in the prefrontal cortex (PFC). The PFC controls a large number of higher brain functions altered in schizophrenia. Histological studies indicate the presence of a large proportion of PFC neurons expressing monoaminergic receptors sensitive to the action of atypical- and to a lesser extentclassical antipsychotic drugs. Functional studies also indicate that both drug families act at PFC level. Atypical antipsychotic drugs likely exert their therapeutic activity by a preferential action on PFC neurons, thus modulating the PFC output to basal ganglia circuits. Classical antipsychotics also interact with these PFC targets in addition to blocking massively striatal D2 receptors.

Molecular Modulation of Prefrontal Cortex: Rational Development of Treatments for Psychiatric Disorders

PubMed Central

Gamo, Nao J.; Arnsten, Amy F.T.

2011-01-01

Dysfunction of the prefrontal cortex (PFC) is a central feature of many psychiatric disorders, such as attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), schizophrenia and bipolar disorder. Thus, understanding molecular influences on PFC function through basic research in animals is essential to rational drug development. In this review, we discuss the molecular signaling events initiated by norepinephrine and dopamine that strengthen working memory function mediated by the dorsolateral PFC under optimal conditions, and weaken working memory function during uncontrollable stress. We also discuss how these intracellular mechanisms can be compromised in psychiatric disorders, and how novel treatments based on these findings may restore a molecular environment conducive to PFC regulation of behavior, thought and emotion. Examples of successful translation from animals to humans include guanfacine for the treatment of ADHD and related PFC disorders, and prazosin for the treatment of PTSD. PMID:21480691

Catechol-O-methyltransferase (COMT) influences the connectivity of the prefrontal cortex at rest

PubMed Central

Tunbridge, Elizabeth M.; Farrell, Sarah M.; Harrison, Paul J.; Mackay, Clare E.

2013-01-01

Catechol-O-methyltransferase (COMT) modulates dopamine in the prefrontal cortex (PFC) and influences PFC dopamine-dependent cognitive task performance. A human COMT polymorphism (Val158Met) alters enzyme activity and is associated with both the activation and functional connectivity of the PFC during task performance, particularly working memory. Here, we used functional magnetic resonance imaging and a data-driven, independent components analysis (ICA) approach to compare resting state functional connectivity within the executive control network (ECN) between young, male COMT Val158 (n = 27) and Met158 (n = 28) homozygotes. COMT genotype effects on grey matter were assessed using voxel-based morphometry. COMT genotype significantly modulated functional connectivity within the ECN, which included the head of the caudate, and anterior cingulate and frontal cortical regions. Val158 homozygotes showed greater functional connectivity between a cluster within the left ventrolateral PFC and the rest of the ECN (using a threshold of Z > 2.3 and a family-wise error cluster significance level of p < 0.05). This difference occurred in the absence of any alterations in grey matter. Our data show that COMT Val158Met affects the functional connectivity of the PFC at rest, complementing its prominent role in the activation and functional connectivity of this region during cognitive task performance. The results suggest that genotype-related differences in prefrontal dopaminergic tone result in neuroadaptive changes in basal functional connectivity, potentially including subtle COMT genotype-dependent differences in the relative coupling of task-positive and task-negative regions, which could in turn contribute to its effects on brain activation, connectivity, and behaviour. PMID:23228511

Functional variation of the dopamine D2 receptor gene is associated with emotional control as well as brain activity and connectivity during emotion processing in humans

PubMed Central

Blasi, Giuseppe; Bianco, Luciana Lo; Taurisano, Paolo; Gelao, Barbara; Romano, Raffaella; Fazio, Leonardo; Papazacharias, Apostolos; Di Giorgio, Annabella; Caforio, Grazia; Rampino, Antonio; Masellis, Rita; Papp, Audrey; Ursini, Gianluca; Sinibaldi, Lorenzo; Popolizio, Teresa; Sadee, Wolfgang; Bertolino, Alessandro

2010-01-01

Personality traits related to emotion processing are, at least in part, heritable and genetically determined. Dopamine D2 receptor signaling is involved in modulation of emotional behavior and activity of associated brain regions such as the amygdala and the prefrontal cortex. An intronic single nucleotide polymorphism within the D2 receptor gene (DRD2, rs1076560, guanine>thymine - G>T) shifts splicing of the two protein isoforms (D2 short, D2S, mainly presynaptic, and D2 long, D2L) and has been associated with modulation of memory performance and brain activity. Here, our aim was to investigate the association of DRD2 rs1076560 genotype with personality traits of emotional stability and with brain physiology during processing of emotionally relevant stimuli. DRD2 genotype and Big Five Questionnaire scores were evaluated in 134 healthy subjects demonstrating that GG subjects have reduced ‘emotion control’ compared with GT subjects. fMRI in a sample of 24 individuals indicated greater amygdala activity during implicit processing and greater dorsolateral prefrontal cortex (DLPFC) response during explicit processing of facial emotional stimuli in GG subjects compared with GT. Other results also demonstrate an interaction between DRD2 genotype and facial emotional expression on functional connectivity of both amygdala and dorsolateral prefrontal regions with overlapping medial prefrontal areas. Moreover, rs1076560 genotype is associated with differential relationships between amygdala/DLPFC functional connectivity and emotion control scores. These results suggest that genetically determined D2 signaling may explain part of personality traits related to emotion processing and individual variability in specific brain responses to emotionally relevant inputs. PMID:19940176

Functional variation of the dopamine D2 receptor gene is associated with emotional control as well as brain activity and connectivity during emotion processing in humans.

PubMed

Blasi, Giuseppe; Lo Bianco, Luciana; Taurisano, Paolo; Gelao, Barbara; Romano, Raffaella; Fazio, Leonardo; Papazacharias, Apostolos; Di Giorgio, Annabella; Caforio, Grazia; Rampino, Antonio; Masellis, Rita; Papp, Audrey; Ursini, Gianluca; Sinibaldi, Lorenzo; Popolizio, Teresa; Sadee, Wolfgang; Bertolino, Alessandro

2009-11-25

Personality traits related to emotion processing are, at least in part, heritable and genetically determined. Dopamine D(2) receptor signaling is involved in modulation of emotional behavior and activity of associated brain regions such as the amygdala and the prefrontal cortex. An intronic single nucleotide polymorphism within the D(2) receptor gene (DRD2) (rs1076560, guanine > thymine or G > T) shifts splicing of the two protein isoforms (D(2) short, mainly presynaptic, and D(2) long) and has been associated with modulation of memory performance and brain activity. Here, our aim was to investigate the association of DRD2 rs1076560 genotype with personality traits of emotional stability and with brain physiology during processing of emotionally relevant stimuli. DRD2 genotype and Big Five Questionnaire scores were evaluated in 134 healthy subjects demonstrating that GG subjects have reduced "emotion control" compared with GT subjects. Functional magnetic resonance imaging in a sample of 24 individuals indicated greater amygdala activity during implicit processing and greater dorsolateral prefrontal cortex (DLPFC) response during explicit processing of facial emotional stimuli in GG subjects compared with GT. Other results also demonstrate an interaction between DRD2 genotype and facial emotional expression on functional connectivity of both amygdala and dorsolateral prefrontal regions with overlapping medial prefrontal areas. Moreover, rs1076560 genotype is associated with differential relationships between amygdala/DLPFC functional connectivity and emotion control scores. These results suggest that genetically determined D(2) signaling may explain part of personality traits related to emotion processing and individual variability in specific brain responses to emotionally relevant inputs.

Chronic alcohol disrupts dopamine receptor activity and the cognitive function of the medial prefrontal cortex.

PubMed

Trantham-Davidson, Heather; Burnett, Elizabeth J; Gass, Justin T; Lopez, Marcelo F; Mulholland, Patrick J; Centanni, Samuel W; Floresco, Stan B; Chandler, L Judson

2014-03-05

Dopamine (DA) receptors in the medial prefrontal cortex (mPFC) exert powerful effects on cognition by modulating the balance between excitatory and inhibitory neurotransmission. The present study examined the impact of chronic intermittent ethanol (CIE) exposure on cognitive function and DA receptor-mediated neurotransmission in the rat mPFC. Consistent with alterations in executive function in alcoholics, CIE-exposed rats exhibited deficits in behavioral flexibility in an operant set-shifting task. Since alterations in dopaminergic neurotransmission in the mPFC have been implicated in a number of behavioral disorders including addiction, studies were then performed in the adult acute slice preparation to examine changes in DA receptor function in the mPFC following CIE exposure. In slices obtained from control rats, DA receptor stimulation was observed to exert complex actions on neuronal firing and synaptic neurotransmission that were not only dependent upon the particular receptor subtype but also whether it was a pyramidal cell or a fast-spiking interneuron. In contrast to slices from control rats, there was a near complete loss of the modulatory actions of D2/D4 receptors on cell firing and neurotransmission in slices obtained immediately, 1 and 4 weeks after the last day of CIE exposure. This loss did not appear to be associated with changes in receptor expression. In contrast, CIE exposure did not alter D1 receptor function or mGluR1 modulation of firing. These studies are consistent with the suggestion that chronic alcohol exposure disrupts cognitive function at least in part through disruption of D2 and D4 receptor signaling in mPFC.

Correlation of individual differences in schizotypal personality traits with amphetamine-induced dopamine release in striatal and extrastriatal brain regions.

PubMed

Woodward, Neil D; Cowan, Ronald L; Park, Sohee; Ansari, M Sib; Baldwin, Ronald M; Li, Rui; Doop, Mikisha; Kessler, Robert M; Zald, David H

2011-04-01

Schizotypal personality traits are associated with schizophrenia spectrum disorders, and individuals with schizophrenia spectrum disorders demonstrate increased dopamine transmission in the striatum. The authors sought to determine whether individual differences in normal variation in schizotypal traits are correlated with dopamine transmission in the striatum and in extrastriatal brain regions. Sixty-three healthy volunteers with no history of psychiatric illness completed the Schizotypal Personality Questionnaire and underwent positron emission tomography imaging with [(18)F]fallypride at baseline and after administration of oral d-amphetamine (0.43 mg/kg). Dopamine release, quantified by subtracting each participant's d-amphetamine scan from his or her baseline scan, was correlated with Schizotypal Personality Questionnaire total and factor scores using region-of-interest and voxel-wise analyses. Dopamine release in the striatum was positively correlated with overall schizotypal traits. The association was especially robust in the associative subdivision of the striatum. Voxel-wise analyses identified additional correlations between dopamine release and schizotypal traits in the left middle frontal gyrus and left supramarginal gyrus. Exploratory analyses of Schizotypal Personality Questionnaire factor scores revealed correlations between dopamine release and disorganized schizotypal traits in the striatum, thalamus, medial prefrontal cortex, temporal lobe, insula, and inferior frontal cortex. The association between dopamine signaling and psychosis phenotypes extends to individual differences in normal variation in schizotypal traits and involves dopamine transmission in both striatal and extrastriatal brain regions. Amphetamine-induced dopamine release may be a useful endophenotype for investigating the genetic basis of schizophrenia spectrum disorders.

Neuropeptide gene expression in brain is differentially regulated by midbrain dopamine neurons.

PubMed

Lindefors, N; Brené, S; Herrera-Marschitz, M; Persson, H

1990-01-01

In situ hybridization was used to study the expression of prepro-neuropeptide Y (NPY), preprosomatostatin (SOM), preprotachykinin (PPT) and preprocholecystokinin (CCK) mRNA in caudate-putamen and frontoparietal cortex of rat brain with unilateral lesion of midbrain dopamine neurons. Neurons expressing NPY and SOM mRNA showed a similar distribution and the expression of both NPY and SOM appears to be regulated by dopamine in a similar fashion. Following a dopamine deafferentation, the numerical density of both NPY and SOM mRNA producing neurons almost doubled in the lesioned caudate-putamen with no change in the average grain density over positive neurons. Hence, in the intact caudate-putamen dopamine appears to suppress expression of these two neuropeptide genes leading to an activation of both NPY and SOM mRNA expression in many non- or low-expressing neurons when the level of dopamine is decreased. In the fronto-parietal cortex, on the other hand, dopamine appears to stimulate NPY and SOM gene expression. Thus, in the absence of dopamine about half of the NPY positive neurons disappeared. However, for SOM the number of positive neurons did not change, but rather most positive neurons appeared to have down-regulated their SOM mRNA expression. No evidence was found for a change in CCK mRNA expression by the dopamine deafferentation, while PPT mRNA expression decreased in the deafferented caudate-putamen. Consequently, dopamine exerts dissimilar effects on the expression of different neuropeptide genes, that in turn do not respond in the same way in different brain regions.

Potential antidepressant-like activity of silymarin in the acute restraint stress in mice: Modulation of corticosterone and oxidative stress response in cerebral cortex and hippocampus.

PubMed

Thakare, Vishnu N; Dhakane, Valmik D; Patel, Bhoomika M

2016-10-01

Silymarin is a polyphenolic flavanoid of Silybum marianum, elicited neuroprotection and antidepressant like activity in stressed model. It was found to increase 5-hydroxytryptamine (5-HT) levels in the cortex and dopamine (DA) and norepinephrine (NE) in the cerebellum in normal mice. The aim of the present study was to investigate the potential antidepressant-like activity of silymarin in the acute restraint stress (ARS) in mice. The ARS was induced by immobilizing the mice for a period of 7h using rodent restraint device preventing them for any physical movement. One hour prior to ARS, silymarin was administered at doses of 100mg/kg and 200mg/kg per oral to non stressed and ARS mice. Various behavioral parameters like immobility time in force swim test, locomotor activity in open field test, and biochemical alterations, serum corticosterone, 5-HT, DA, NE level, malondialdehyde (MDA), and antioxidant enzymes (GSH, CAT and SOD) in hippocampus and cerebral cortex in non stressed and ARS subjected mice were investigated. Experimental findings reveals mice subjected to ARS exhibited significant increase immobility time, serum corticosterone, MDA formation and impaired SOD and CAT activities in hippocampus and cerebral cortex as compared to non stressed mice. Silymarin treatment (100mg/kg and 200mg/kg) significantly attenuated immobility time, corticosterone and restored the antioxidant enzymes after ARS. The present experimental findings indicate that silymarin exhibits antidepressant like activity probably either through alleviating oxidative stress by modulation of corticosterone response, and antioxidant defense system in hippocampus and cerebral cortex in ARS mice. Copyright © 2016. Published by Elsevier Urban & Partner Sp. z o.o.

Metabotropic glutamate receptor modulation of dopamine release in the nucleus accumbens shell is unaffected by phencyclidine pretreatment: In vitro assessment using fast-scan cyclic voltammetry rat brain slices.

PubMed

Gupta, Ishan; Young, Andrew M J

2018-05-15

The non-competitive glutamate antagonist, phencyclidine is used in rodents to model behavioural deficits see in schizophrenia. Importantly, these deficits endure long after the cessation of short-term chronic treatment (sub-chronic), indicating that the drug treatment causes long-term changes in the physiology and/or chemistry of the brain. There is evidence that this may occur through glutamatergic modulation of mesolimbic dopamine release, perhaps involving metabotropic glutamate receptors (mGluR). This study sought to investigate the effect of sub-chronic phencyclidine pretreatment on modulation of dopamine neurotransmission by metabotropic glutamate receptors 2 and 5 (mGluR2 and mGluR5) in the nucleus accumbens shell in vitro, with the hypothesis that phencyclidine pretreatment would disrupt the mGluR-mediated modulation of dopamine release. We showed that the orthosteric mGluR2 agonist LY379268 (0.1 µM, 1 µM and 10 µM) and mGluR5 positive allosteric modulator CDPPB (1 µM and 10 µM) both attenuated potassium-evoked dopamine release, underscoring their role in modulating dopamine neurotransmission in the nucleus accumbens. Sub-chronic PCP treatment, which caused cognitive deficits measured by performance in the novel object recognition task, modelling aspects of behavioral deficits seen in schizophrenia, induced neurobiological changes that enhanced dopamine release in the nucleus accumbens, but had no effect on mGluR2 or mGluR5 mediated changes in dopamine release. Therefore it is unlikely that schizophrenia-related behavioural changes seen after sub-chronic phencyclidine pre-treatment are mediated through mGluR modulation of dopamine release. Copyright © 2018 Elsevier B.V. All rights reserved.

Improvement by methylphenidate and atomoxetine of social interaction deficits and recognition memory impairment in a mouse model of valproic acid-induced autism.

PubMed

Hara, Yuta; Ago, Yukio; Taruta, Atsuki; Katashiba, Keisuke; Hasebe, Shigeru; Takano, Erika; Onaka, Yusuke; Hashimoto, Hitoshi; Matsuda, Toshio; Takuma, Kazuhiro

2016-09-01

Rodents exposed prenatally to valproic acid (VPA) show autism-related behavioral abnormalities. We recently found that prenatal VPA exposure causes a reduction of dopaminergic activity in the prefrontal cortex of male, but not female, mice. This suggests that reduced prefrontal dopaminergic activity is associated with behavioral abnormalities in VPA-treated mice. In the present study, we examined whether the attention deficit/hyperactivity disorder drugs methylphenidate and atomoxetine (which increase dopamine release in the prefrontal cortex, but not striatum, in mice) could alleviate the behavioral abnormalities and changes in dendritic spine morphology induced by prenatal VPA exposure. We found that methylphenidate and atomoxetine increased prefrontal dopamine and noradrenaline release in VPA-treated mice. Acute treatment with methylphenidate or atomoxetine did not alleviate the social interaction deficits or recognition memory impairment in VPA-treated mice, while chronic treatment for 2 weeks did. Methylphenidate or atomoxetine for 2 weeks also improved the prenatal VPA-induced decrease in dendritic spine density in the prefrontal cortex. The effects of these drugs on behaviors and dendritic spine morphology were antagonized by concomitant treatment with the dopamine-D1 receptor antagonist SCH39166 or the dopamine-D2 receptor antagonist raclopride, but not by the α2 -adrenoceptor antagonist idazoxan. These findings suggest that chronic treatment with methylphenidate or atomoxetine improves abnormal behaviors and diminishes the reduction in spine density in VPA-treated mice via a prefrontal dopaminergic system-dependent mechanism. Autism Res 2016, 9: 926-939. © 2015 International Society for Autism Research, Wiley Periodicals, Inc. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

Risk of punishment influences discrete and coordinated encoding of reward-guided actions by prefrontal cortex and VTA neurons

PubMed Central

Park, Junchol

2017-01-01

Actions motivated by rewards are often associated with risk of punishment. Little is known about the neural representation of punishment risk during reward-seeking behavior. We modeled this circumstance in rats by designing a task where actions were consistently rewarded but probabilistically punished. Spike activity and local field potentials were recorded during task performance simultaneously from VTA and mPFC, two reciprocally connected regions implicated in reward-seeking and aversive behaviors. At the single unit level, we found that ensembles of putative dopamine and non-dopamine VTA neurons and mPFC neurons encode the relationship between action and punishment. At the network level, we found that coherent theta oscillations synchronize VTA and mPFC in a bottom-up direction, effectively phase-modulating the neuronal spike activity in the two regions during punishment-free actions. This synchrony declined as a function of punishment probability, suggesting that during reward-seeking actions, risk of punishment diminishes VTA-driven neural synchrony between the two regions. PMID:29058673

Mesocortical dopamine depletion and anxiety-related behavior in the rat: sex and hemisphere differences.

PubMed

Sullivan, R M; Dufresne, M M; Siontas, D; Chehab, S; Townsend, J; Laplante, F

2014-10-03

The mesocortical dopamine (DA) system of the rat plays an important role in prefrontal cortex (PFC) regulation of stress and emotion and exhibits functional hemispheric asymmetry for such processing. Since few studies examine sex differences in this context, we compared the effects of left vs. right unilateral PFC DA depletion in males and females in several behavioral situations associated with anxiety or aversion. Adult rats received unilateral injections of 6-hydroxydopamine (6-OHDA) or vehicle in the ventromedial (vm) PFC. Behavioral tests included a predator odor burying test, elevated plus maze and sucrose consumption with simple taste aversion. Tissue analysis confirmed that vmPFCs injected with 6-OHDA were depleted of DA (75-85%) compared to controls. Burying behavior and sucrose consumption were affected only by left lesions, similarly in both sexes. However, risk assessment behaviors were affected by right lesions in opposite directions in males and females. Behaviors modified preferentially by the left cortex thus showed less evidence of sex differences than those modulated by the right. While mesocortical DA depletion effects are lateralized, the nature of these effects can vary with sex and specific behavior. Such findings may be clinically significant, given the large gender differences in the incidence of mood and anxiety disorders, which also show many lateralized prefrontal abnormalities. Copyright © 2014 Elsevier Inc. All rights reserved.

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-dependent periadolescent maturation of corticostriatal functional connectivity in mouse.

PubMed

Galiñanes, Gregorio L; Taravini, Irene R E; Murer, M Gustavo

2009-02-25

Altered corticostriatal information processing associated with early dopamine systems dysfunction may contribute to attention deficit/hyperactivity disorder (ADHD). Mice with neonatal dopamine-depleting lesions exhibit hyperactivity that wanes after puberty and is reduced by psychostimulants, reminiscent of some aspects of ADHD. To assess whether the maturation of corticostriatal functional connectivity is altered by early dopamine depletion, we examined preadolescent and postadolescent urethane-anesthetized mice with or without dopamine-depleting lesions. Specifically, we assessed (1) synchronization between striatal neuron discharges and oscillations in frontal cortex field potentials and (2) striatal neuron responses to frontal cortex stimulation. In adult control mice striatal neurons were less spontaneously active, less responsive to cortical stimulation, and more temporally tuned to cortical rhythms than in infants. Striatal neurons from hyperlocomotor mice required more current to respond to cortical input and were less phase locked to ongoing oscillations, resulting in fewer neurons responding to refined cortical commands. By adulthood some electrophysiological deficits waned together with hyperlocomotion, but striatal spontaneous activity remained substantially elevated. Moreover, dopamine-depleted animals showing normal locomotor scores exhibited normal corticostriatal synchronization, suggesting that the lesion allows, but is not sufficient, for the emergence of corticostriatal changes and hyperactivity. Although amphetamine normalized corticostriatal tuning in hyperlocomotor mice, it reduced horizontal activity in dopamine-depleted animals regardless of their locomotor phenotype, suggesting that amphetamine modified locomotion through a parallel mechanism, rather than that modified by dopamine depletion. In summary, functional maturation of striatal activity continues after infancy, and early dopamine depletion delays the maturation of core functional capacities of the corticostriatal system.

Dopamine-dependent periadolescent maturation of corticostriatal functional connectivity in mouse

PubMed Central

Galiñanes, Gregorio L.; Taravini, Irene R.E.; Murer, M. Gustavo

2009-01-01

Altered corticostriatal information processing associated with early dopamine systems dysfunction may contribute to attention deficit/hyperactivity disorder (ADHD). Mice with neonatal dopamine-depleting lesions exhibit hyperactivity that wanes after puberty and is reduced by psychostimulants, reminiscent of some aspects of ADHD. To assess whether the maturation of corticostriatal functional connectivity is altered by early dopamine depletion, we examined pre- and post-adolescent urethane-anesthetized mice with or without dopamine-depleting lesions. Specifically, we assessed (1) synchronization between striatal neuron discharges and oscillations in frontal cortex field potentials and (2) striatal neuron responses to frontal cortex stimulation. In adult control mice striatal neurons were less spontaneously active, less responsive to cortical stimulation and more temporally tuned to cortical rhythms than in infants. Striatal neurons from hyperlocomotor mice required more current to respond to cortical input and were less phase-locked to ongoing oscillations, resulting in fewer neurons responding to refined cortical commands. By adulthood some electrophysiological deficits waned together with hyperlocomotion, but striatal spontaneous activity remained substantially elevated. Moreover, dopamine-depleted animals showing normal locomotor scores exhibited normal corticostriatal synchronization, suggesting that the lesion allows, but is not sufficient, for the emergence of corticostriatal changes and hyperactivity. Although amphetamine normalized corticostriatal tuning in hyperlocomotor mice, it reduced horizontal activity in dopamine-depleted animals irrespective of their locomotor phenotype, suggesting that amphetamine modified locomotion through a parallel mechanism, rather than that modified by dopamine depletion. In summary, functional maturation of striatal activity continues after infancy, and early dopamine depletion delays the maturation of core functional capacities of the corticostriatal system. PMID:19244524

Effects of pramipexole on the processing of rewarding and aversive taste stimuli.

PubMed

McCabe, Ciara; Harwood, James; Brouwer, Sietske; Harmer, Catherine J; Cowen, Philip J

2013-07-01

Pramipexole, a D2/D3 dopamine receptor agonist, has been implicated in the development of impulse control disorders in patients with Parkinson's disease. Investigation of single doses of pramipexole in healthy participants in reward-based learning tasks has shown inhibition of the neural processing of reward, presumptively through stimulation of dopamine autoreceptors. This study aims to examine the effects of pramipexole on the neural response to the passive receipt of rewarding and aversive sight and taste stimuli. We used functional magnetic resonance imaging to examine the neural responses to the sight and taste of pleasant (chocolate) and aversive (mouldy strawberry) stimuli in 16 healthy volunteers who received a single dose of pramipexole (0.25 mg) and placebo in a double-blind, within-subject, design. Relative to placebo, pramipexole treatment reduced blood oxygen level-dependent activation to the chocolate stimuli in the areas known to play a key role in reward, including the ventromedial prefrontal cortex, the orbitofrontal cortex, striatum, thalamus and dorsal anterior cingulate cortex. Pramipexole also reduced activation to the aversive condition in the dorsal anterior cingulate cortex. There were no effects of pramipexole on the subjective ratings of the stimuli. Our results are consistent with an ability of acute, low-dose pramipexole to diminish dopamine-mediated responses to both rewarding and aversive taste stimuli, perhaps through an inhibitory action of D2/3 autoreceptors on phasic burst activity of midbrain dopamine neurones. The ability of pramipexole to inhibit aversive processing might potentiate its adverse behavioural effects and could also play a role in its proposed efficacy in treatment-resistant depression.

Occupancy of striatal and extrastriatal dopamine D2/D3 receptors by olanzapine and haloperidol.

PubMed

Kessler, Robert M; Ansari, Mohammad Sib; Riccardi, Patrizia; Li, Rui; Jayathilake, Karuna; Dawant, Benoit; Meltzer, Herbert Y

2005-12-01

There have been conflicting reports as to whether olanzapine produces lower occupancy of striatal dopamine D(2)/D(3) receptor than typical antipsychotic drugs and preferential occupancy of extrastriatal dopamine D(2)/D(3) receptors. We performed [(18)F] fallypride PET studies in six schizophrenic subjects treated with olanzapine and six schizophrenic subjects treated with haloperidol to examine the occupancy of striatal and extrastriatal dopamine receptors by these antipsychotic drugs. [(18)F] setoperone PET studies were performed in seven olanzapine-treated subjects to determine 5-HT(2A) receptor occupancy. Occupancy of dopamine D(2)/D(3) receptors by olanzapine was not significantly different from that seen with haloperidol in the putamen, ventral striatum, medial thalamus, amygdala, or temporal cortex, that is, 67.5-78.2% occupancy; olanzapine produced no preferential occupancy of dopamine D(2)/D(3) receptors in the ventral striatum, medial thalamus, amygdala, or temporal cortex. There was, however, significantly lower occupancy of substantia nigra/VTA dopamine D(2)/D(3) receptors in olanzapine-treated compared to haloperidol-treated subjects, that is, 40.2 vs 59.3% (p=0.0014, corrected for multiple comparisons); in olanzapine-treated subjects, the substantia nigra/VTA was the only region with significantly lower dopamine D(2)/D(3) receptor occupancy than the putamen, that is, 40.2 vs 69.2% (p<0.001, corrected for multiple comparison). Occupancy of 5-HT(2A) receptors was 85-93% in the olanzapine- treated subjects. The results of this study demonstrated that olanzapine does not produce preferential occupancy of extrastriatal dopamine D(2)/D(3) receptors but does spare substantia nigra/VTA receptors. Sparing of substantia nigra/VTA dopamine D(2)/D(3) receptor occupancy may contribute to the low incidence of extrapyramidal side effects in olanzapine-treated patients.

Genetic Feedback Regulation of Frontal Cortical Neuronal Ensembles Through Activity-Dependent Arc Expression and Dopaminergic Input.

PubMed

Mastwal, Surjeet; Cao, Vania; Wang, Kuan Hong

2016-01-01

Mental functions involve coordinated activities of specific neuronal ensembles that are embedded in complex brain circuits. Aberrant neuronal ensemble dynamics is thought to form the neurobiological basis of mental disorders. A major challenge in mental health research is to identify these cellular ensembles and determine what molecular mechanisms constrain their emergence and consolidation during development and learning. Here, we provide a perspective based on recent studies that use activity-dependent gene Arc/Arg3.1 as a cellular marker to identify neuronal ensembles and a molecular probe to modulate circuit functions. These studies have demonstrated that the transcription of Arc is activated in selective groups of frontal cortical neurons in response to specific behavioral tasks. Arc expression regulates the persistent firing of individual neurons and predicts the consolidation of neuronal ensembles during repeated learning. Therefore, the Arc pathway represents a prototypical example of activity-dependent genetic feedback regulation of neuronal ensembles. The activation of this pathway in the frontal cortex starts during early postnatal development and requires dopaminergic (DA) input. Conversely, genetic disruption of Arc leads to a hypoactive mesofrontal dopamine circuit and its related cognitive deficit. This mutual interaction suggests an auto-regulatory mechanism to amplify the impact of neuromodulators and activity-regulated genes during postnatal development. Such a mechanism may contribute to the association of mutations in dopamine and Arc pathways with neurodevelopmental psychiatric disorders. As the mesofrontal dopamine circuit shows extensive activity-dependent developmental plasticity, activity-guided modulation of DA projections or Arc ensembles during development may help to repair circuit deficits related to neuropsychiatric disorders.

Role of Prefrontal Cortex in Learning and Generalizing Hierarchical Rules in 8-Month-Old Infants.

PubMed

Werchan, Denise M; Collins, Anne G E; Frank, Michael J; Amso, Dima

2016-10-05

Recent research indicates that adults and infants spontaneously create and generalize hierarchical rule sets during incidental learning. Computational models and empirical data suggest that, in adults, this process is supported by circuits linking prefrontal cortex (PFC) with striatum and their modulation by dopamine, but the neural circuits supporting this form of learning in infants are largely unknown. We used near-infrared spectroscopy to record PFC activity in 8-month-old human infants during a simple audiovisual hierarchical-rule-learning task. Behavioral results confirmed that infants adopted hierarchical rule sets to learn and generalize spoken object-label mappings across different speaker contexts. Infants had increased activity over right dorsal lateral PFC when rule sets switched from one trial to the next, a neural marker related to updating rule sets into working memory in the adult literature. Infants' eye blink rate, a possible physiological correlate of striatal dopamine activity, also increased when rule sets switched from one trial to the next. Moreover, the increase in right dorsolateral PFC activity in conjunction with eye blink rate also predicted infants' generalization ability, providing exploratory evidence for frontostriatal involvement during learning. These findings provide evidence that PFC is involved in rudimentary hierarchical rule learning in 8-month-old infants, an ability that was previously thought to emerge later in life in concert with PFC maturation. Hierarchical rule learning is a powerful learning mechanism that allows rules to be selected in a context-appropriate fashion and transferred or reused in novel contexts. Data from computational models and adults suggests that this learning mechanism is supported by dopamine-innervated interactions between prefrontal cortex (PFC) and striatum. Here, we provide evidence that PFC also supports hierarchical rule learning during infancy, challenging the current dogma that PFC is an underdeveloped brain system until adolescence. These results add new insights into the neurobiological mechanisms available to support learning and generalization in very early postnatal life, providing evidence that PFC and the frontostriatal circuitry are involved in organizing learning and behavior earlier in life than previously known. Copyright © 2016 the authors 0270-6474/16/3610314-09$15.00/0.

Role of Prefrontal Cortex in Learning and Generalizing Hierarchical Rules in 8-Month-Old Infants

PubMed Central

Werchan, Denise M.; Collins, Anne G.E.; Frank, Michael J.

2016-01-01

Recent research indicates that adults and infants spontaneously create and generalize hierarchical rule sets during incidental learning. Computational models and empirical data suggest that, in adults, this process is supported by circuits linking prefrontal cortex (PFC) with striatum and their modulation by dopamine, but the neural circuits supporting this form of learning in infants are largely unknown. We used near-infrared spectroscopy to record PFC activity in 8-month-old human infants during a simple audiovisual hierarchical-rule-learning task. Behavioral results confirmed that infants adopted hierarchical rule sets to learn and generalize spoken object–label mappings across different speaker contexts. Infants had increased activity over right dorsal lateral PFC when rule sets switched from one trial to the next, a neural marker related to updating rule sets into working memory in the adult literature. Infants' eye blink rate, a possible physiological correlate of striatal dopamine activity, also increased when rule sets switched from one trial to the next. Moreover, the increase in right dorsolateral PFC activity in conjunction with eye blink rate also predicted infants' generalization ability, providing exploratory evidence for frontostriatal involvement during learning. These findings provide evidence that PFC is involved in rudimentary hierarchical rule learning in 8-month-old infants, an ability that was previously thought to emerge later in life in concert with PFC maturation. SIGNIFICANCE STATEMENT Hierarchical rule learning is a powerful learning mechanism that allows rules to be selected in a context-appropriate fashion and transferred or reused in novel contexts. Data from computational models and adults suggests that this learning mechanism is supported by dopamine-innervated interactions between prefrontal cortex (PFC) and striatum. Here, we provide evidence that PFC also supports hierarchical rule learning during infancy, challenging the current dogma that PFC is an underdeveloped brain system until adolescence. These results add new insights into the neurobiological mechanisms available to support learning and generalization in very early postnatal life, providing evidence that PFC and the frontostriatal circuitry are involved in organizing learning and behavior earlier in life than previously known. PMID:27707968

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.

Salience Network and Parahippocampal Dopamine Dysfunction in Memory-Impaired Parkinson Disease

PubMed Central

Christopher, Leigh; Duff-Canning, Sarah; Koshimori, Yuko; Segura, Barbara; Boileau, Isabelle; Chen, Robert; Lang, Anthony E.; Houle, Sylvain; Rusjan, Pablo; Strafella, Antonio P.

2016-01-01

Objective Patients with Parkinson disease (PD) and mild cognitive impairment (MCI) are vulnerable to dementia and frequently experience memory deficits. This could be the result of dopamine dysfunction in corticostriatal networks (salience, central executive networks, and striatum) and/or the medial temporal lobe. Our aim was to investigate whether dopamine dysfunction in these regions contributes to memory impairment in PD. Methods We used positron emission tomography imaging to compare D2 receptor availability in the cortex and striatal (limbic and associative) dopamine neuron integrity in 4 groups: memory-impaired PD (amnestic MCI; n=9), PD with nonamnestic MCI (n=10), PD without MCI (n=11), and healthy controls (n=14). Subjects were administered a full neuropsychological test battery for cognitive performance. Results Memory-impaired patients demonstrated more significant reductions in D2 receptor binding in the salience network (insular cortex and anterior cingulate cortex [ACC] and the right parahippocampal gyrus [PHG]) compared to healthy controls and patients with no MCI. They also presented reductions in the right insula and right ACC compared to nonamnestic MCI patients. D2 levels were correlated with memory performance in the right PHG and left insula of amnestic patients and with executive performance in the bilateral insula and left ACC of all MCI patients. Associative striatal dopamine denervation was significant in all PD patients. Interpretation Dopaminergic differences in the salience network and the medial temporal lobe contribute to memory impairment in PD. Furthermore, these findings indicate the vulnerability of the salience network in PD and its potential role in memory and executive dysfunction. PMID:25448687

D2 receptor genotype and striatal dopamine signaling predict motor cortical activity and behavior in humans.

PubMed

Fazio, Leonardo; Blasi, Giuseppe; Taurisano, Paolo; Papazacharias, Apostolos; Romano, Raffaella; Gelao, Barbara; Ursini, Gianluca; Quarto, Tiziana; Lo Bianco, Luciana; Di Giorgio, Annabella; Mancini, Marina; Popolizio, Teresa; Rubini, Giuseppe; Bertolino, Alessandro

2011-02-14

Pre-synaptic D2 receptors regulate striatal dopamine release and DAT activity, key factors for modulation of motor pathways. A functional SNP of DRD2 (rs1076560 G>T) is associated with alternative splicing such that the relative expression of D2S (mainly pre-synaptic) vs. D2L (mainly post-synaptic) receptor isoforms is decreased in subjects with the T allele with a putative increase of striatal dopamine levels. To evaluate how DRD2 genotype and striatal dopamine signaling predict motor cortical activity and behavior in humans, we have investigated the association of rs1076560 with BOLD fMRI activity during a motor task. To further evaluate the relationship of this circuitry with dopamine signaling, we also explored the correlation between genotype based differences in motor brain activity and pre-synaptic striatal DAT binding measured with [(123)I] FP-CIT SPECT. Fifty healthy subjects, genotyped for DRD2 rs1076560 were studied with BOLD-fMRI at 3T while performing a visually paced motor task with their right hand; eleven of these subjects also underwent [(123)I]FP-CIT SPECT. SPM5 random-effects models were used for statistical analyses. Subjects carrying the T allele had greater BOLD responses in left basal ganglia, thalamus, supplementary motor area, and primary motor cortex, whose activity was also negatively correlated with reaction time at the task. Moreover, left striatal DAT binding and activity of left supplementary motor area were negatively correlated. The present results suggest that DRD2 genetic variation was associated with focusing of responses in the whole motor network, in which activity of predictable nodes was correlated with reaction time and with striatal pre-synaptic dopamine signaling. Our results in humans may help shed light on genetic risk for neurobiological mechanisms involved in the pathophysiology of disorders with dysregulation of striatal dopamine like Parkinson's disease. Copyright © 2010 Elsevier Inc. All rights reserved.

Nicotine and cigarette smoke modulate Nrf2-BDNF-dopaminergic signal and neurobehavioral disorders in adult rat cerebral cortex.

PubMed

Naha, Nibedita; Gandhi, D N; Gautam, A K; Prakash, J Ravi

2018-05-01

Nicotine and cigarette smoking (CS) are associated with addiction behavior, drug-seeking, and abuse. However, the mechanisms that mediate this association especially, the role of brain-derived neurotrophic factor (BDNF), dopamine (DA), and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling in the cerebral cortex, are not fully known. Therefore, we hypothesized that overexpression of BDNF and DA, and suppression of Nrf2 contribute to several pathological and behavioral alterations in adult cerebral cortex. Methodology/Principal Observations: We treated Wistar rats with different doses of oral nicotine and passive CS for 4-week (short-term) and 12-week (long-term) duration, where doses closely mimic the human smoking scenario. Our result showed dose-dependent association of anxiogenic and depressive behavior, and cognitive interference with neurodegeneration and DNA damage in the cerebral cortex upon exposure to nicotine/CS as compared to the control. Further, the results are linked to upregulation of oxidative stress, overexpression of BDNF, DA, and DA marker, tyrosine hydroxylase (TH), with concomitant downregulation of ascorbate and Nrf2 expression in the exposed cerebral cortex when compared with the control. Overall, our data strongly suggest that the intervention of DA and BDNF, and depletion of antioxidants are important factors during nicotine/CS-induced cerebral cortex pathological changes leading to neurobehavioral impairments, which could underpin the novel therapeutic approaches targeted at tobacco smoking/nicotine's neuropsychological disorders including cognition and drug addiction.

Haloperidol impairs auditory filial imprinting and modulates monoaminergic neurotransmission in an imprinting-relevant forebrain area of the domestic chick.

PubMed

Gruss, M; Bock, J; Braun, K

2003-11-01

In vivo microdialysis and behavioural studies in the domestic chick have shown that glutamatergic as well as monoaminergic neurotransmission in the medio-rostral neostriatum/hyperstriatum ventrale (MNH) is altered after auditory filial imprinting. In the present study, using pharmaco-behavioural and in vivo microdialysis approaches, the role of dopaminergic neurotransmission in this juvenile learning event was further evaluated. The results revealed that: (i) the systemic application of the potent dopamine receptor antagonist haloperidol (7.5 mg/kg) strongly impairs auditory filial imprinting; (ii) systemic haloperidol induces a tetrodotoxin-sensitive increase of extracellular levels of the dopamine metabolite, homovanillic acid, in the MNH, whereas the levels of glutamate, taurine and the serotonin metabolite, 5-hydroxyindole-3-acetic acid, remain unchanged; (iii) haloperidol (0.01, 0.1, 1 mm) infused locally into the MNH increases glutamate, taurine and 5- hydroxyindole-3-acetic acid levels in a dose-dependent manner, whereas homovanillic acid levels remain unchanged; (iv) systemic haloperidol infusion reinforces the N-methyl-d-aspartate receptor-mediated inhibitory modulation of the dopaminergic neurotransmission within the MNH. These results indicate that the modulation of dopaminergic function and its interaction with other neurotransmitter systems in a higher associative forebrain region of the juvenile avian brain displays similar neurochemical characteristics as the adult mammalian prefrontal cortex. Furthermore, we were able to show that the pharmacological manipulation of monoaminergic regulatory mechanisms interferes with learning and memory formation, events which in a similar fashion might occur in young or adult mammals.

Dopaminergic Modulation of Excitatory Transmission in the Anterior Cingulate Cortex of Adult Mice

PubMed Central

Darvish-Ghane, Soroush; Yamanaka, Manabu

2016-01-01

Dopamine (DA) possesses potent neuromodulatory properties in the central nervous system. In the anterior cingulate cortex, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPAR) are key ion channels in mediating nerve injury induced long-term potentiation (LTP) and chronic pain phenotype. In the present study, we reported the effects of DA on glutamate mediated excitatory post-synaptic currents (EPSCs) in pyramidal neurons of layer II/III of the ACC in adult mice. Bath application of DA (50 μM) caused a significant, rapid and reversible inhibition of evoked EPSCs (eEPSC). This inhibitory effect is dose-related and was absent in lower concentration of DA (5 μM). Furthermore, selective postsynaptic application of GDP-β-S (1.6 mM) in the internal solution completely abolished the inhibitory effects of DA (50 μM). We also investigated modulation of spontaneous EPSCs (sEPSCs) and TTX sensitive, miniature EPSCs (mEPSCs) by DA. Our results indicated mixed effects of potentiation and inhibition of frequency and amplitude for sEPSCs and mEPSCs. Furthermore, high doses of SCH23390 (100 μM) and sulpiride (100 μM) revealed that, inhibition of eEPSCs is mediated by postsynaptic D2-receptors (D2R). Our finding posits a pre- and postsynaptic mode of pyramidal neuron EPSC modulation in mice ACC by DA. PMID:27317578

A neural network model of normal and abnormal auditory information processing.

PubMed

Du, X; Jansen, B H

2011-08-01

The ability of the brain to attenuate the response to irrelevant sensory stimulation is referred to as sensory gating. A gating deficiency has been reported in schizophrenia. To study the neural mechanisms underlying sensory gating, a neuroanatomically inspired model of auditory information processing has been developed. The mathematical model consists of lumped parameter modules representing the thalamus (TH), the thalamic reticular nucleus (TRN), auditory cortex (AC), and prefrontal cortex (PC). It was found that the membrane potential of the pyramidal cells in the PC module replicated auditory evoked potentials, recorded from the scalp of healthy individuals, in response to pure tones. Also, the model produced substantial attenuation of the response to the second of a pair of identical stimuli, just as seen in actual human experiments. We also tested the viewpoint that schizophrenia is associated with a deficit in prefrontal dopamine (DA) activity, which would lower the excitatory and inhibitory feedback gains in the AC and PC modules. Lowering these gains by less than 10% resulted in model behavior resembling the brain activity seen in schizophrenia patients, and replicated the reported gating deficits. The model suggests that the TRN plays a critical role in sensory gating, with the smaller response to a second tone arising from a reduction in inhibition of TH by the TRN. Copyright © 2011 Elsevier Ltd. All rights reserved.

Modulating risky decision-making in Parkinson's disease by transcranial direct current stimulation.

PubMed

Benussi, A; Alberici, A; Cantoni, V; Manenti, R; Brambilla, M; Dell'Era, V; Gazzina, S; Manes, M; Cristillo, V; Padovani, A; Cotelli, M; Borroni, B

2017-05-01

Performance on gambling tasks in Parkinson's disease (PD) is of particular interest, as pathological gambling is often associated with dopamine replacement therapy in these patients. We aimed to evaluate the effects of transcranial direct current stimulation (tDCS) over the right dorsolateral prefrontal cortex (DLPFC) in modulating gambling behaviour in PD. We assessed the effects of cathodal tDCS over the right DLPFC during the Iowa Gambling Task in 20 patients with PD, compared with sham stimulation. We then conducted a second experimental design, assessing the effects of anodal tDCS over the right DLPFC. We observed that cathodal tDCS over the right DLPFC increased Iowa Gambling Task scores compared with sham stimulation. In the second experimental design, we did not find significant differences between anodal and sham tDCS. Cathodal tDCS over the right DLPFC possibly reduces the pathological overdrive in frontostriatal networks in patients with PD on dopaminergic medication, thus modulating impulsive and risky decision-making. © 2017 EAN.

Regulation of embryonic neurotransmitter and tyrosine hydroxylase protein levels by ascorbic acid

PubMed Central

Meredith, M. Elizabeth; May, James M.

2013-01-01

Scope: Ascorbic acid (ascorbate) is required to recycle tetrahydrobiopterin, which is necessary for neurotransmitter synthesis by the rate-limiting enzymes tyrosine and tryptophan hydroxylases. We sought to determine whether ascorbate might regulate embryonic brain cortex monoamine synthesis utilizing transgenic mouse models with varying intracellular ascorbate levels. Methods and Results: In embryos lacking the sodium-dependent vitamin C transporter 2 (SVCT2), very low levels of brain ascorbate decreased cortex levels of norepinephrine and dopamine by approximately 33%, but had no effect on cortex serotonin or its metabolite, 5-hydroxyindole acetic acid. This decrease in ascorbate also led to a decrease in protein levels of tyrosine hydroxylase, but not of tryptophan hydroxylase. Increased cortex ascorbate in embryos carrying extra copies of the SVCT2 resulted in increased levels of dopamine and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), as well as serotonin and 5-hydroxyindole acetic acid. Conclusion: The dependence of embryonic brain cortex neurotransmitter synthesis and tyrosine hydroxylase expression on intracellular ascorbate emphasizes the importance of receiving adequate ascorbate during development. PMID:24095796

Dopaminergic regulation of sleep and cataplexy in a murine model of narcolepsy.

PubMed

Burgess, Christian R; Tse, Gavin; Gillis, Lauren; Peever, John H

2010-10-01

To determine if the dopaminergic system modulates cataplexy, sleep attacks and sleep-wake behavior in narcoleptic mice. Hypocretin/orexin knockout (i.e., narcoleptic) and wild-type mice were administered amphetamine and specific dopamine receptor modulators to determine their effects on sleep, cataplexy and sleep attacks. Hypocretin knockout (n = 17) and wild-type mice (n = 21). Cataplexy, sleep attacks and sleep-wake behavior were identified using electroencephalogram, electromyogram and videography. These behaviors were monitored for 4 hours after an i.p. injection of saline, amphetamine and specific dopamine receptor modulators (D1- and D2-like receptor modulators). Amphetamine (2 mg/kg), which increases brain dopamine levels, decreased sleep attacks and cataplexy by 61% and 67%, suggesting that dopamine transmission modulates such behaviors. Dopamine receptor modulation also had powerful effects on sleep attacks and cataplexy. Activation (SKF 38393; 20 mg/kg) and blockade (SCH 23390; 1 mg/kg) of D1-like receptors decreased and increased sleep attacks by 77% and 88%, without affecting cataplexy. Pharmacological activation of D2-like receptors (quinpirole; 0.5 mg/kg) increased cataplectic attacks by 172% and blockade of these receptors (eticlopride; 1 mg/kg) potently suppressed them by 97%. Manipulation of D2-like receptors did not affect sleep attacks. We show that the dopaminergic system plays a role in regulating both cataplexy and sleep attacks in narcoleptic mice. We found that cataplexy is modulated by a D2-like receptor mechanism, whereas dopamine modulates sleep attacks by a D1-like receptor mechanism. These results support a role for the dopamine system in regulating sleep attacks and cataplexy in a murine model of narcolepsy.

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

Michaelides, M.; Wang, G.; Michaelides, M.

Methylphenidate (MP) is widely used to treat attention deficit hyperactivity disorder (ADHD). Variable number of tandem repeats polymorphisms in the dopamine D4 receptor (D{sub 4}) gene have been implicated in vulnerability to ADHD and the response to MP. Here we examined the contribution of dopamine D4 receptors (D4Rs) to baseline brain glucose metabolism and to the regional metabolic responses to MP. We compared brain glucose metabolism (measured with micro-positron emission tomography and [{sup 18}F]2-fluoro-2-deoxy-D-glucose) at baseline and after MP (10 mg/kg, i.p.) administration in mice with genetic deletion of the D{sub 4}. Images were analyzed using a novel automated imagemore » registration procedure. Baseline D{sub 4}{sup -/-} mice had lower metabolism in the prefrontal cortex (PFC) and greater metabolism in the cerebellar vermis (CBV) than D{sub 4}{sup +/+} and D{sub 4}{sup +/-} mice; when given MP, D{sub 4}{sup -/-} mice increased metabolism in the PFC and decreased it in the CBV, whereas in D{sub 4}{sup +/+} and D{sub 4}{sup +/-} mice, MP decreased metabolism in the PFC and increased it in the CBV. These findings provide evidence that D4Rs modulate not only the PFC, which may reflect the activation by dopamine of D4Rs located in this region, but also the CBV, which may reflect an indirect modulation as D4Rs are minimally expressed in this region. As individuals with ADHD show structural and/or functional abnormalities in these brain regions, the association of ADHD with D4Rs may reflect its modulation of these brain regions. The differential response to MP as a function of genotype could explain differences in brain functional responses to MP between patients with ADHD and healthy controls and between patients with ADHD with different D{sub 4} polymorphisms.« less

[Walking abnormalities in children].

PubMed

Segawa, Masaya

2010-11-01

Walking is a spontaneous movement termed locomotion that is promoted by activation of antigravity muscles by serotonergic (5HT) neurons. Development of antigravity activity follows 3 developmental epochs of the sleep-wake (S-W) cycle and is modulated by particular 5HT neurons in each epoch. Activation of antigravity activities occurs in the first epoch (around the age of 3 to 4 months) as restriction of atonia in rapid eye movement (REM) stage and development of circadian S-W cycle. These activities strengthen in the second epoch, with modulation of day-time sleep and induction of crawling around the age of 8 months and induction of walking by 1 year. Around the age of 1 year 6 months, absence of guarded walking and interlimb cordination is observed along with modulation of day-time sleep to once in the afternoon. Bipedal walking in upright position occurs in the third epoch, with development of a biphasic S-W cycle by the age of 4-5 years. Patients with infantile autism (IA), Rett syndrome (RTT), or Tourette syndrome (TS) show failure in the development of the first, second, or third epoch, respectively. Patients with IA fail to develop interlimb coordination; those with RTT, crawling and walking; and those with TS, walking in upright posture. Basic pathophysiology underlying these condition is failure in restricting atonia in REM stage; this induces dysfunction of the pedunculopontine nucleus and consequently dys- or hypofunction of the dopamine (DA) neurons. DA hypofunction in the developing brain, associated with compensatory upward regulation of the DA receptors causes psychobehavioral disorders in infancy (IA), failure in synaptogenesis in the frontal cortex and functional development of the motor and associate cortexes in late infancy through the basal ganglia (RTT), and failure in functional development of the prefrontal cortex through the basal ganglia (TS). Further, locomotion failure in early childhood causes failure in development of functional specialization of the cortex through the spinal stepping generator-fastigial nucleus-thalamus-cortex pathway. Early detection of locomotion failure and early adjustment of this condition through environmental factors can prevent the development of higher cortical dysfunction.

Making sense: Dopamine activates conscious self‐monitoring through medial prefrontal cortex

PubMed Central

Joensson, Morten; Thomsen, Kristine Rømer; Andersen, Lau M.; Gross, Joachim; Mouridsen, Kim; Sandberg, Kristian; Østergaard, Leif

2015-01-01

Abstract When experiences become meaningful to the self, they are linked to synchronous activity in a paralimbic network of self‐awareness and dopaminergic activity. This network includes medial prefrontal and medial parietal/posterior cingulate cortices, where transcranial magnetic stimulation may transiently impair self‐awareness. Conversely, we hypothesize that dopaminergic stimulation may improve self‐awareness and metacognition (i.e., the ability of the brain to consciously monitor its own cognitive processes). Here, we demonstrate improved noetic (conscious) metacognition by oral administration of 100 mg dopamine in minimal self‐awareness. In a separate experiment with extended self‐awareness dopamine improved the retrieval accuracy of memories of self‐judgment (autonoetic, i.e., explicitly self‐conscious) metacognition. Concomitantly, magnetoencephalography (MEG) showed increased amplitudes of oscillations (power) preferentially in the medial prefrontal cortex. Given that electromagnetic activity in this region is instrumental in self‐awareness, this explains the specific effect of dopamine on explicit self‐awareness and autonoetic metacognition. Hum Brain Mapp 36:1866–1877, 2015. © 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.. PMID:25627861

In vivo dopaminergic and serotonergic dysfunction in DCTN1 gene mutation carriers

PubMed Central

Felicio, Andre C.; Dinelle, Katherine; Agarwal, Pankaj A.; McKenzie, Jessamyn; Heffernan, Nicole; Road, Jeremy D.; Appel-Cresswell, Silke; Wszolek, Zbigniew K.; Farrer, Matthew J.; Schulzer, Michael; Sossi, Vesna; Stoessl, A. Jon

2014-01-01

Introduction We have used positron emission tomography (PET) to assess dopaminergic and serotonergic terminal density in three subjects carrying a mutation in the DCT1 gene, two clinically affected with Perry syndrome. Methods All subjects had brain imaging using 18F-6-fluoro-L-dopa (FDOPA, dopamine synthesis and storage), (+)-11C-dihydrotetrabenazine (DTBZ, vesicular monoamine transporter type 2), and 11C-raclopride (RAC, dopamine D2/D3 receptors). One subject also underwent PET with 11C-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB, serotonin transporter). Results FDOPA-PET and DTBZ-PET in the affected individuals showed a reduction of striatal tracer uptake. Also, RAC-PET showed higher uptake in these area. DASB-PET showed significant uptake changes in left orbitofrontal cortex, bilateral anterior insula, left dorsolateral prefrontal cortex, left orbitofrontal cortex, left posterior cingulate cortex, left caudate and left ventral striatum. Conclusions Our data showed evidence of both striatal dopaminergic and widespread cortical/subcortical serotonergic dysfunctions in individuals carrying a mutation in the DCTN1 gene. PMID:24797316

The effects of DAT1 genotype on fMRI activation in an emotional go/no-go task.

PubMed

Brown, Brenna K; Murrell, Jill; Karne, Harish; Anand, Amit

2017-02-01

Dopaminergic brain circuits participate in emotional processing and impulsivity. The dopamine transporter (DAT) modulates dopamine reuptake. A variable number tandem repeat (VNTR) in the dopamine transporter gene (DAT1) affects DAT expression. The influence of DAT1 genotype on neural activation during emotional processing and impulse inhibition has not been examined. Forty-two healthy subjects were classified as 9DAT (n = 17) or 10DAT (n = 25) based on DAT1 genotype (9DAT = 9R/9R and 9R/10R; 10DAT = 10R/10R). Subjects underwent fMRI during non-emotional and emotional go/no-go tasks. Subjects were instructed to inhibit responses to letters, happy faces, or sad faces in separate blocks. Accuracy and reaction time did not differ between groups. Within group results showed activation in regions previously implicated in emotional processing and response inhibition. Between groups results showed increased activation in 9DAT individuals during inhibition. During letter inhibition, 9DAT individuals exhibited greater activation in right inferior parietal regions. During sad inhibition, 9DAT Individuals exhibited greater activation in frontal, posterior cingulate, precuneus, right cerebellar, left paracentral, and right occipital brain regions. The interaction between DAT genotype and response type in sad versus letter stimuli showed increased activation in 9DAT individuals during sad no-go responses in the anterior cingulate cortex, extending into frontal-orbital regions. 9DAT individuals have greater activation than 10DAT individuals during neutral and sad inhibition, showing that genotypic variation influencing basal dopamine levels can alter the neural basis of emotional processing and response inhibition. This may indicate that 9R carriers exert more effort to overcome increased basal dopamine activation when inhibiting responses in emotional contexts.

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

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

Oxytocin-Induced Changes in Monoamine Level in Symmetric Brain Structures of Isolated Aggressive C57Bl/6 Mice.

PubMed

Karpova, I V; Mikheev, V V; Marysheva, V V; Bychkov, E R; Proshin, S N

2016-03-01

Changes in activity of monoaminergic systems of the left and right brain hemispheres after administration of saline and oxytocin were studied in male C57Bl/6 mice subjected to social isolation. The concentrations of dopamine, norepinephrine, serotonin, and their metabolites dihydroxyphenylacetic, homovanillic, and 5-hydroxyindoleacetic acids were measured in the cerebral cortex, hippocampus, olfactory tubercle, and striatum of the left and right brain hemispheres by HPLC. In isolated aggressive males treated intranasally with saline, the content of serotonin and 5-hydroxyindoleacetic acid was significantly higher in the right hippocampus. Oxytocin reduces aggression caused by long-term social isolation, but has no absolute ability to suppress this type of behavior. Oxytocin reduced dopamine content in the left cortex and serotonin content in the right hippocampus and left striatum. Furthermore, oxytocin evened the revealed asymmetry in serotonin and 5-hydroxyindoleacetic acid concentrations in the hippocampus. At the same time, asymmetry in dopamine concentration appeared in the cortex with predominance of this transmitter in the right hemisphere. The data are discussed in the context of lateralization of neurotransmitter systems responsible for intraspecific aggression caused by long-term social isolation.

Dopamine modulation of transient receptor potential vanilloid type 1 (TRPV1) receptor in dorsal root ganglia neurons.

PubMed

Chakraborty, Saikat; Rebecchi, Mario; Kaczocha, Martin; Puopolo, Michelino

2016-03-15

The transient receptor potential vanilloid type 1 (TRPV1) receptor plays a key role in the modulation of nociceptor excitability. To address whether dopamine can modulate the activity of TRPV1 channels in nociceptive neurons, the effects of dopamine and dopamine receptor agonists were tested on the capsaicin-activated current recorded from acutely dissociated small diameter (<27 μm) dorsal root ganglia (DRG) neurons. Dopamine or SKF 81297 (an agonist at D1/D5 receptors), caused inhibition of both inward and outward currents by ∼60% and ∼48%, respectively. The effect of SKF 81297 was reversed by SCH 23390 (an antagonist at D1/D5 receptors), confirming that it was mediated by activation of D1/D5 dopamine receptors. In contrast, quinpirole (an agonist at D2 receptors) had no significant effect on the capsaicin-activated current. Inhibition of the capsaicin-activated current by SKF 81297 was mediated by G protein coupled receptors (GPCRs), and highly dependent on external calcium. The inhibitory effect of SKF 81297 on the capsaicin-activated current was not affected when the protein kinase A (PKA) activity was blocked with H89, or when the protein kinase C (PKC) activity was blocked with bisindolylmaleimide II (BIM). In contrast, when the calcium-calmodulin-dependent protein kinase II (CaMKII) was blocked with KN-93, the inhibitory effect of SKF 81297 on the capsaicin-activated current was greatly reduced, suggesting that activation of D1/D5 dopamine receptors may be preferentially linked to CaMKII activity. We suggest that modulation of TRPV1 channels by dopamine in nociceptive neurons may represent a way for dopamine to modulate incoming noxious stimuli. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

Neural Dynamics of Autistic Repetitive Behaviors and Fragile X Syndrome: Basal Ganglia Movement Gating and mGluR-Modulated Adaptively Timed Learning.

PubMed

Grossberg, Stephen; Kishnan, Devika

2018-01-01

This article develops the iSTART neural model that proposes how specific imbalances in cognitive, emotional, timing, and motor processes that involve brain regions like prefrontal cortex, temporal cortex, amygdala, hypothalamus, hippocampus, and cerebellum may interact together to cause behavioral symptoms of autism. These imbalances include underaroused emotional depression in the amygdala/hypothalamus, learning of hyperspecific recognition categories that help to cause narrowly focused attention in temporal and prefrontal cortices, and breakdowns of adaptively timed motivated attention and motor circuits in the hippocampus and cerebellum. The article expands the model's explanatory range by, first, explaining recent data about Fragile X syndrome (FXS), mGluR, and trace conditioning; and, second, by explaining distinct causes of stereotyped behaviors in individuals with autism. Some of these stereotyped behaviors, such as an insistence on sameness and circumscribed interests, may result from imbalances in the cognitive and emotional circuits that iSTART models. These behaviors may be ameliorated by operant conditioning methods. Other stereotyped behaviors, such as repetitive motor behaviors, may result from imbalances in how the direct and indirect pathways of the basal ganglia open or close movement gates, respectively. These repetitive behaviors may be ameliorated by drugs that augment D2 dopamine receptor responses or reduce D1 dopamine receptor responses. The article also notes the ubiquitous role of gating by basal ganglia loops in regulating all the functions that iSTART models.

Neural Dynamics of Autistic Repetitive Behaviors and Fragile X Syndrome: Basal Ganglia Movement Gating and mGluR-Modulated Adaptively Timed Learning

PubMed Central

Grossberg, Stephen; Kishnan, Devika

2018-01-01

This article develops the iSTART neural model that proposes how specific imbalances in cognitive, emotional, timing, and motor processes that involve brain regions like prefrontal cortex, temporal cortex, amygdala, hypothalamus, hippocampus, and cerebellum may interact together to cause behavioral symptoms of autism. These imbalances include underaroused emotional depression in the amygdala/hypothalamus, learning of hyperspecific recognition categories that help to cause narrowly focused attention in temporal and prefrontal cortices, and breakdowns of adaptively timed motivated attention and motor circuits in the hippocampus and cerebellum. The article expands the model’s explanatory range by, first, explaining recent data about Fragile X syndrome (FXS), mGluR, and trace conditioning; and, second, by explaining distinct causes of stereotyped behaviors in individuals with autism. Some of these stereotyped behaviors, such as an insistence on sameness and circumscribed interests, may result from imbalances in the cognitive and emotional circuits that iSTART models. These behaviors may be ameliorated by operant conditioning methods. Other stereotyped behaviors, such as repetitive motor behaviors, may result from imbalances in how the direct and indirect pathways of the basal ganglia open or close movement gates, respectively. These repetitive behaviors may be ameliorated by drugs that augment D2 dopamine receptor responses or reduce D1 dopamine receptor responses. The article also notes the ubiquitous role of gating by basal ganglia loops in regulating all the functions that iSTART models. PMID:29593596

Decrease of lymphoproliferative response by amphetamine is mediated by dopamine from the nucleus accumbens: influence on splenic met-enkephalin levels.

PubMed

Assis, María Amparo; Valdomero, Analía; García-Keller, Constanza; Sotomayor, Claudia; Cancela, Liliana Marina

2011-05-01

Despite the mesocorticolimbic dopaminergic pathway being one of the main substrates underlying stimulating and reinforcing effects induced by psychostimulant drugs, there is little information regarding its role in their effects at the immune level. We have previously demonstrated that acute exposure to amphetamine (5 mg/kg, i.p.) induced an inhibitory effect on the splenic T-cell proliferative response, along with an increase in the methionine(met)-enkephalin content at limbic and immune levels, 4 days after drug administration. In this study, we investigated if a possible dopamine mechanism underlies these amphetamine-induced effects by administering D1 and D2 dopaminergic antagonists or a dopaminergic terminal neurotoxin before the drug. Pre-treatment with either SCH-23390 (0.1 mg/kg, i.p.) or raclopride (0.1 mg/kg, i.p.), a D1 or D2 dopaminergic receptor antagonist, respectively, abrogated the effects of amphetamine on the lymphoproliferative response and on met-enkephalin levels of the spleen. The amphetamine-induced increase in limbic met-enkephalin content was suppressed by SCH-23390 but not by raclopride pre-treatment. Finally, an intra-accumbens 6-hydroxy-dopamine injection administered 2 weeks previously prevented amphetamine-induced effects on the lymphoproliferative response and on met-enkephalin levels in the prefrontal cortex and spleen. These findings strongly suggest that D1 and D2 dopaminergic receptors are involved in amphetamine-induced effects at immune level as regards the lymphoproliferative response and the changes in spleen met-enkephalin content, whereas limbic met-enkephalin levels were modulated only by the D1 dopaminergic receptors. In addition, this study showed that a mesolimbic component modulated amphetamine-induced effects on the immune response, as previously shown at a behavioral level. Copyright © 2011 Elsevier Inc. All rights reserved.

Consequences of Variations in Genes that affect Dopamine in Prefrontal Cortex

PubMed Central

Diamond, Adele

2008-01-01

Patricia Goldman-Rakic played a groundbreaking role in investigating the cognitive functions subserved by dorsolateral prefrontal cortex and the key role of dopamine in that. The work discussed here builds on that including: 1) Studies of children predicted to have lower levels of prefrontal dopamine but otherwise basically normal brains (children treated for phenylketonuria [PKU]). Those studies changed medical guidelines, improving the children’s lives. 2) Studies of visual impairments (in contrast sensitivity and motion perception) in PKU children due to reduced retinal dopamine and due to excessive phenylalanine during the first postnatal weeks. Those studies, too, changed medical guidelines. 3) Studies of working memory and inhibitory control differences in typically developing children due to differences in catechol-O-methyltransferase (COMT) genotype, which selectively affect prefrontal dopamine levels. 4) Studies of gender differences in the effect of COMT genotype on cognitive performance in older adults. 5) A hypothesis about fundamental differences between attention deficit hyperactivity disorder (ADHD) that includes hyperactivity and ADHD of the inattentive type. Those disorders are hypothesized to differ in the affected neural system, underlying genetics, responsiveness to medication, comorbidities, and cognitive and behavioral profiles. These sound quite disparate but they all grew systematically out the base laid down by Patricia Goldman-Rakic. PMID:17725999

Individual differences in schedule-induced polydipsia: neuroanatomical dopamine divergences.

PubMed

Pellón, Ricardo; Ruíz, Ana; Moreno, Margarita; Claro, Francisco; Ambrosio, Emilio; Flores, Pilar

2011-02-02

Autoradiography analysis of D1 and D2 dopamine receptors and c-Fos activity were performed in brain of rats classified as low drinkers (LD) and high drinkers (HD) according to schedule-induced polydipsia (SIP) performance. Previous studies have shown that groups selected according to their rate of drinking in SIP differ in behavioral response to dopaminergic drugs. This study reports differences between LD and HD rats in dopamine D1 and D2 receptor binding through different mesocorticolimbic brain areas. LD and HD rats showed opposite patterns of binding in dopamine D1 and D2 receptors in the nucleus accumbens, medial prefrontal cortex, amygdala, ventral tegmental area and substantia nigra. Whereas LD rats showed higher binding than HD rats for D1 receptors, HD rats showed higher binding than LD rats for D2 receptors (except in substantia nigra that were roughly similar). These neuroanatomical differences in dopamine receptor binding were also associated with an elevated c-Fos count in the medial prefrontal cortex of HD rats. In tandem with previous evidence, our results suggest a different dopaminergic function between LD and HD, and points to SIP as a behavioral model for distinguishing populations possibly vulnerable to dopaminergic function disorders. Copyright © 2010 Elsevier B.V. All rights reserved.

Dosage-dependent non-linear effect of L-dopa on human motor cortex plasticity.

PubMed

Monte-Silva, Katia; Liebetanz, David; Grundey, Jessica; Paulus, Walter; Nitsche, Michael A

2010-09-15

The neuromodulator dopamine affects learning and memory formation and their likely physiological correlates, long-term depression and potentiation, in animals and humans. It is known from animal experiments that dopamine exerts a dosage-dependent, inverted U-shaped effect on these functions. However, this has not been explored in humans so far. In order to reveal a non-linear dose-dependent effect of dopamine on cortical plasticity in humans, we explored the impact of 25, 100 and 200 mg of L-dopa on transcranial direct current (tDCS)-induced plasticity in twelve healthy human subjects. The primary motor cortex served as a model system, and plasticity was monitored by motor evoked potential amplitudes elicited by transcranial magnetic stimulation. As compared to placebo medication, low and high dosages of L-dopa abolished facilitatory as well as inhibitory plasticity, whereas the medium dosage prolonged inhibitory plasticity, and turned facilitatory plasticity into inhibition. Thus the results show clear non-linear, dosage-dependent effects of dopamine on both facilitatory and inhibitory plasticity, and support the assumption of the importance of a specific dosage of dopamine optimally suited to improve plasticity. This might be important for the therapeutic application of dopaminergic agents, especially for rehabilitative purposes, and explain some opposing results in former studies.

Small effect of dopamine release and no effect of dopamine depletion on [18F]fallypride binding in healthy humans.

PubMed

Cropley, Vanessa L; Innis, Robert B; Nathan, Pradeep J; Brown, Amira K; Sangare, Janet L; Lerner, Alicja; Ryu, Yong Hoon; Sprague, Kelly E; Pike, Victor W; Fujita, Masahiro

2008-06-01

Molecular imaging has been used to estimate both drug-induced and tonic dopamine release in the striatum and most recently extrastriatal areas of healthy humans. However, to date, studies of drug-induced and tonic dopamine release have not been performed in the same subjects. This study performed positron emission tomography (PET) with [18F]fallypride in healthy subjects to assess (1) the reproducibility of [18F]fallypride and (2) both D-amphetamine-induced and alpha-methyl-p-tyrosine (AMPT)-induced changes in dopamin release on [(18)F]fallypride binding in striatal and extrastriatal areas. Subjects underwent [18F]fallypride PET studies at baseline and following oral D-amphetamine administration (0.5 mg/kg) and oral AMPT administration (3 g/70 kg/day over 44 h). Binding potential (BP) (BP(ND)) of [18F]fallypride was calculated in striatal and extrastriatal areas using a reference region method. Percent change in regional BP(ND) was computed and correlated with change in cognition and mood. Test-retest variability of [18F]fallypride was low in both striatal and extrastriatal regions. D-Amphetamine significantly decreased BP(ND) by 8-14% in striatal subdivisions, caudate, putamen, substantia nigra, medial orbitofrontal cortex, and medial temporal cortex. Correlation between change in BP(ND) and verbal fluency was seen in the thalamus and substantia nigra. In contrast, depletion of endogenous dopamine with AMPT did not effect [18F]fallypride BP(ND) in both striatum and extrastriatal regions. These findings indicate that [18F]fallypride is useful for measuring amphetamine-induced dopamine release, but may be unreliable for estimating tonic dopamine levels, in striatum and extrastriatal regions of healthy humans.

Principles of motivation revealed by the diverse functions of neuropharmacological and neuroanatomical substrates underlying feeding behavior

PubMed Central

Baldo, Brian A.; Pratt, Wayne E.; Will, Matthew J.; Hanlon, Erin C.; Bakshi, Vaishali P.; Cador, Martine

2013-01-01

Circuits that participate in specific subcomponents of feeding (e.g., gustatory perception, peripheral feedback relevant to satiety and energy balance, reward coding, etc.) are found at all levels of the neural axis. Further complexity is conferred by the wide variety of feeding-modulatory neurotransmitters and neuropeptides that act within these circuits. An ongoing challenge has been to refine the understanding of the functional specificity of these neurotransmitters and circuits, and there have been exciting advances in recent years. We focus here on foundational work of Dr. Ann Kelley that identified distinguishable actions of striatal opioid peptide modulation and dopamine transmission in subcomponents of reward processing. We also discuss her work in overlaying these neuropharmacological effects upon anatomical pathways that link the telencephalon (cortex and basal ganglia) with feeding-control circuits in the hypothalamus. Using these seminal contributions as a starting point, we will discuss new findings that expand our understanding of (1) the specific, differentiable motivational processes that are governed by central dopamine and opioid transmission, (2) the manner in which other striatal neuromodulators, specifically acetylcholine, endocannabinoids and adenosine, modulate these motivational processes (including via interactions with opioid systems), and (3) the organization of the cortical-subcortical network that subserves opioid-driven feeding. The findings discussed here strengthen the view that incentive-motivational properties of food are coded by substrates and neural circuits that are distinguishable from those that mediate the acute hedonic experience of food reward. Striatal opioid transmission modulates reward processing by engaging frontotemporal circuits, possibly via a hypothalamic-thalamic axis, that ultimately impinges upon hypothalamic modules dedicated to autonomic function and motor pattern control. We will conclude by discussing implications for understanding disorders of “non-homeostatic” feeding. PMID:23466532

Principles of motivation revealed by the diverse functions of neuropharmacological and neuroanatomical substrates underlying feeding behavior.

PubMed

Baldo, Brian A; Pratt, Wayne E; Will, Matthew J; Hanlon, Erin C; Bakshi, Vaishali P; Cador, Martine

2013-11-01

Circuits that participate in specific subcomponents of feeding (e.g., gustatory perception, peripheral feedback relevant to satiety and energy balance, reward coding, etc.) are found at all levels of the neural axis. Further complexity is conferred by the wide variety of feeding-modulatory neurotransmitters and neuropeptides that act within these circuits. An ongoing challenge has been to refine the understanding of the functional specificity of these neurotransmitters and circuits, and there have been exciting advances in recent years. We focus here on foundational work of Dr. Ann Kelley that identified distinguishable actions of striatal opioid peptide modulation and dopamine transmission in subcomponents of reward processing. We also discuss her work in overlaying these neuropharmacological effects upon anatomical pathways that link the telencephalon (cortex and basal ganglia) with feeding-control circuits in the hypothalamus. Using these seminal contributions as a starting point, we will discuss new findings that expand our understanding of (1) the specific, differentiable motivational processes that are governed by central dopamine and opioid transmission, (2) the manner in which other striatal neuromodulators, specifically acetylcholine, endocannabinoids and adenosine, modulate these motivational processes (including via interactions with opioid systems), and (3) the organization of the cortical-subcortical network that subserves opioid-driven feeding. The findings discussed here strengthen the view that incentive-motivational properties of food are coded by substrates and neural circuits that are distinguishable from those that mediate the acute hedonic experience of food reward. Striatal opioid transmission modulates reward processing by engaging frontotemporal circuits, possibly via a hypothalamic-thalamic axis, that ultimately impinges upon hypothalamic modules dedicated to autonomic function and motor pattern control. We will conclude by discussing implications for understanding disorders of "non-homeostatic" feeding. Copyright © 2013 Elsevier Ltd. All rights reserved.

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

ERIC Educational Resources Information Center

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

2010-01-01

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

The Neuropsychology of Ventral Prefrontal Cortex: Decision-Making and Reversal Learning

ERIC Educational Resources Information Center

Clark, L.; Cools, R.; Robbins, T. W.

2004-01-01

Converging evidence from human lesion, animal lesion, and human functional neuroimaging studies implicates overlapping neural circuitry in ventral prefrontal cortex in decision-making and reversal learning. The ascending 5-HT and dopamine neurotransmitter systems have a modulatory role in both processes. There is accumulating evidence that…

Prefrontal Cortex Cognitive Deficits in Children Treated Early and Continuously for PKU.

ERIC Educational Resources Information Center

Diamond, Adele; Prevor, Meredith B.; Druin, Donald P.; Callender, Glenda

1997-01-01

Hypothesized that elevated ratio of phenylalanine to tyrosine in blood of children with phenylketonuria uniquely affects cognitive functions dependent on prefrontal cortex because of the special sensitivity of prefrontally projecting dopamine neurons to small decreases in tyrosine. Found that children whose phenylalanine levels were three to five…

Dopamine does double duty in motivating cognitive effort

PubMed Central

Westbrook, Andrew; Braver, Todd S.

2015-01-01

Cognitive control is subjectively costly, suggesting that engagement is modulated in relationship to incentive state. Dopamine appears to play key roles. In particular, dopamine may mediate cognitive effort by two broad classes of functions: 1) modulating the functional parameters of working memory circuits subserving effortful cognition, and 2) mediating value-learning and decision-making about effortful cognitive action. Here we tie together these two lines of research, proposing how dopamine serves “double duty”, translating incentive information into cognitive motivation. PMID:26889810

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

Effects of dopamine D1-like and D2-like antagonists on cocaine discrimination in muscarinic receptor knockout mice.

PubMed

Thomsen, Morgane; Caine, Simon Barak

2016-04-05

Muscarinic and dopamine brain systems interact intimately, and muscarinic receptor ligands, like dopamine ligands, can modulate the reinforcing and discriminative stimulus (S(D)) effects of cocaine. To enlighten the dopamine/muscarinic interactions as they pertain to the S(D) effects of cocaine, we evaluated whether muscarinic M1, M2 or M4 receptors are necessary for dopamine D1 and/or D2 antagonist mediated modulation of the S(D) effects of cocaine. Knockout mice lacking M1, M2, or M4 receptors, as well as control wild-type mice and outbred Swiss-Webster mice, were trained to discriminate 10mg/kg cocaine from saline in a food-reinforced drug discrimination procedure. Effects of pretreatments with the dopamine D1 antagonist SCH 23390 and the dopamine D2 antagonist eticlopride were evaluated. In intact mice, both SCH 23390 and eticlopride attenuated the cocaine discriminative stimulus effect, as expected. SCH 23390 similarly attenuated the cocaine discriminative stimulus effect in M1 knockout mice, but not in mice lacking M2 or M4 receptors. The effects of eticlopride were comparable in each knockout strain. These findings demonstrate differences in the way that D1 and D2 antagonists modulate the S(D) effects of cocaine, D1 modulation being at least partially dependent upon activity at the inhibitory M2/M4 muscarinic subtypes, while D2 modulation appeared independent of these systems. Copyright © 2016 Elsevier B.V. All rights reserved.

The catechol-O-methyltransferase (COMT) Val158Met genotype modulates working memory-related dorsolateral prefrontal response and performance in bipolar disorder.

PubMed

Miskowiak, K W; Kjaerstad, H L; Støttrup, M M; Svendsen, A M; Demant, K M; Hoeffding, L K; Werge, T M; Burdick, K E; Domschke, K; Carvalho, A F; Vieta, E; Vinberg, M; Kessing, L V; Siebner, H R; Macoveanu, J

2017-05-01

Cognitive dysfunction affects a substantial proportion of patients with bipolar disorder (BD), and genetic-imaging paradigms may aid in the elucidation of mechanisms implicated in this symptomatic domain. The Val allele of the functional Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene is associated with reduced prefrontal cortex dopamine and exaggerated working memory-related prefrontal activity. This functional magnetic resonance imaging (fMRI) study investigated for the first time whether the COMT Val158Met genotype modulates prefrontal activity during spatial working memory in BD. Sixty-four outpatients with BD in full or partial remission were stratified according to COMT Val158Met genotype (ValVal [n=13], ValMet [n=34], and MetMet [n=17]). The patients completed a spatial n-back working memory task during fMRI and the Cambridge Neuropsychological Test Automated Battery (CANTAB) Spatial Working Memory test outside the scanner. During high working memory load (2-back vs 1-back), Val homozygotes displayed decreased activity relative to ValMet individuals, with Met homozygotes displaying intermediate levels of activity in the right dorsolateral prefrontal cortex (dlPFC) (P=.016). Exploratory whole-brain analysis revealed a bilateral decrease in working memory-related dlPFC activity in the ValVal group vs the ValMet group which was not associated with differences in working memory performance during fMRI. Outside the MRI scanner, Val carriers performed worse in the CANTAB Spatial Working Memory task than Met homozygotes (P≤.006), with deficits being most pronounced in Val homozygotes. The association between Val allelic load, dlPFC activity and WM impairment points to a putative role of aberrant PFC dopamine tonus in the cognitive impairments in BD. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Regionally Selective Requirement for D[subscript 1]/D[subscript 5] Dopaminergic Neurotransmission in the Medial Prefrontal Cortex in Object-in-Place Associative Recognition Memory

ERIC Educational Resources Information Center

Savalli, Giorgia; Bashir, Zafar I.; Warburton, E. Clea

2015-01-01

Object-in-place (OiP) memory is critical for remembering the location in which an object was last encountered and depends conjointly on the medial prefrontal cortex, perirhinal cortex, and hippocampus. Here we examined the role of dopamine D[subscript 1]/D[subscript 5] receptor neurotransmission within these brain regions for OiP memory. Bilateral…

Glutamate synaptic inputs to ventral tegmental area neurons in the rat derive primarily from subcortical sources.

PubMed

Omelchenko, N; Sesack, S R

2007-05-25

Dopamine and GABA neurons in the ventral tegmental area project to the nucleus accumbens and prefrontal cortex and modulate locomotor and reward behaviors as well as cognitive and affective processes. Both midbrain cell types receive synapses from glutamate afferents that provide an essential control of behaviorally-linked activity patterns, although the sources of glutamate inputs have not yet been completely characterized. We used antibodies against the vesicular glutamate transporter subtypes 1 and 2 (VGlut1 and VGlut2) to investigate the morphology and synaptic organization of axons containing these proteins as putative markers of glutamate afferents from cortical versus subcortical sites, respectively, in rats. We also characterized the ventral tegmental area cell populations receiving VGlut1+ or VGlut2+ synapses according to their transmitter phenotype (dopamine or GABA) and major projection target (nucleus accumbens or prefrontal cortex). By light and electron microscopic examination, VGlut2+ as opposed to VGlut1+ axon terminals were more numerous, had a larger average size, synapsed more proximally, and were more likely to form convergent synapses onto the same target. Both axon types formed predominantly asymmetric synapses, although VGlut2+ terminals more often formed synapses with symmetric morphology. No absolute selectivity was observed for VGlut1+ or VGlut2+ axons to target any particular cell population. However, the synapses onto mesoaccumbens neurons more often involved VGlut2+ terminals, whereas mesoprefrontal neurons received relatively equal synaptic inputs from VGlut1+ and VGlut2+ profiles. The distinct morphological features of VGlut1 and VGlut2 positive axons suggest that glutamate inputs from presumed cortical and subcortical sources, respectively, differ in the nature and intensity of their physiological actions on midbrain neurons. More specifically, our findings imply that subcortical glutamate inputs to the ventral tegmental area expressing VGlut2 predominate over cortical sources of excitation expressing VGlut1 and are more likely to drive the behaviorally-linked bursts in dopamine cells that signal future expectancy or attentional shifting.

Novel Dopamine Therapeutics for Cognitive Deficits in Schizophrenia.

PubMed

Arnsten, Amy F T; Girgis, Ragy R; Gray, David L; Mailman, Richard B

2017-01-01

Schizophrenia is characterized by profound cognitive deficits that are not alleviated by currently available medications. Many of these cognitive deficits involve dysfunction of the newly evolved, dorsolateral prefrontal cortex (dlPFC). The brains of patients with schizophrenia show evidence of dlPFC pyramidal cell dendritic atrophy, likely reductions in cortical dopamine, and possible changes in dopamine D 1 receptors (D 1 R). It has been appreciated for decades that optimal levels of dopamine are essential for dlPFC working memory function, with many beneficial actions arising from D 1 R stimulation. D 1 R are concentrated on dendritic spines in the primate dlPFC, where their stimulation produces an inverted-U dose response on dlPFC neuronal firing and cognitive performance during working memory tasks. Research in both academia and the pharmaceutical industry has led to the development of selective D 1 agonists, e.g., the first full D 1 agonist, dihydrexidine, which at low doses improved working memory in monkeys. Dihydrexidine has begun to be tested in patients with schizophrenia or schizotypal disorder. Initial results are encouraging, but studies are limited by the pharmacokinetics of the drug. These data, however, have spurred efforts toward the discovery and development of improved or novel new compounds, including D 1 agonists with better pharmacokinetics, functionally selective D 1 ligands, and D 1 R positive allosteric modulators. One or several of these approaches should allow optimization of the beneficial effects of D 1 R stimulation in the dlPFC that can be translated into clinical practice. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Dopamine and response selection: an Acute Phenylalanine/Tyrosine Depletion study.

PubMed

Ramdani, Céline; Vidal, Franck; Dagher, Alain; Carbonnell, Laurence; Hasbroucq, Thierry

2018-04-01

The role of dopaminergic system in decision-making is well documented, and evidence suggests that it could play a significant role in response selection processes. The N-40 is a fronto-central event-related potential, generated by the supplementary motor areas (SMAs) and a physiological index of response selection processes. The aim of the present study was to determine whether infraclinical effects of dopamine depletion on response selection processes could be evidenced via alterations of the N-40. We obtained a dopamine depletion in healthy volunteers with the acute phenylalanine and tyrosine depletion (APTD) method which consists in decreasing the availability of dopamine precursors. Subjects realized a Simon task in the APTD condition and in the control condition. When the stimulus was presented on the same side as the required response, the stimulus-response association was congruent and when the stimulus was presented on the opposite side of the required response, the stimulus-response association was incongruent. The N-40 was smaller for congruent associations than for incongruent associations. Moreover, the N-40 was sensitive to the level of dopaminergic activity with a decrease in APTD condition compared to control condition. This modulation of the N-40 by dopaminergic level could not be explained by a global decrease of cerebral electrogenesis, since negativities and positivities indexing the recruitment of the primary motor cortex (anatomically adjacent to the SMA) were unaffected by APTD. The specific sensitivity of N-40 to ATPD supports the model of Keeler et al. (Neuroscience 282:156-175, 2014) according to which the dopaminergic system is involved in response selection.

Dopaminergic Modulation of Cortical Plasticity in Alzheimer's Disease Patients

PubMed Central

Koch, Giacomo; Di Lorenzo, Francesco; Bonnì, Sonia; Giacobbe, Viola; Bozzali, Marco; Caltagirone, Carlo; Martorana, Alessandro

2014-01-01

In animal models of Alzheimer's disease (AD), mechanisms of cortical plasticity such as long-term potentiation (LTP) and long-term depression (LTD) are impaired. In AD patients, LTP-like cortical plasticity is abolished, whereas LTD seems to be preserved. Dopaminergic transmission has been hypothesized as a new player in ruling mechanisms of cortical plasticity in AD. We aimed at investigating whether administration of the dopamine agonist rotigotine (RTG) could modulate cortical plasticity in AD patients, as measured by theta burst stimulation (TBS) protocols of repetitive transcranial stimulation applied over the primary motor cortex. Thirty mild AD patients were tested in three different groups before and after 4 weeks of treatment with RTG, rivastigmine (RVT), or placebo (PLC). Each patient was evaluated for plasticity induction of LTP/LTD-like effects using respectively intermittent TBS (iTBS) or continuous TBS protocols. Short-latency afferent inhibition (SAI) protocol was performed to indirectly assess central cholinergic activity. A group of age-matched healthy controls was recruited for baseline comparisons. Results showed that at baseline, AD patients were characterized by impaired LTP-like cortical plasticity, as assessed by iTBS. These reduced levels of LTP-like cortical plasticity were increased and normalized after RTG administration. No effect was induced by RVT or PLC on LTP. LTD-like cortical plasticity was not modulated in any condition. Cholinergic activity was increased by both RTG and RVT. Our findings reveal that dopamine agonists may restore the altered mechanisms of LTP-like cortical plasticity in AD patients, thus providing novel implications for therapies based on dopaminergic stimulation. PMID:24859851

Progressive motor cortex functional reorganization following 6-hydroxydopamine lesioning in rats.

PubMed

Viaro, Riccardo; Morari, Michele; Franchi, Gianfranco

2011-03-23

Many studies have attempted to correlate changes of motor cortex activity with progression of Parkinson's disease, although results have been controversial. In the present study we used intracortical microstimulation (ICMS) combined with behavioral testing in 6-hydroxydopamine hemilesioned rats to evaluate the impact of dopamine depletion on movement representations in primary motor cortex (M1) and motor behavior. ICMS allows for motor-effective stimulation of corticofugal neurons in motor areas so as to obtain topographic movements representations based on movement type, area size, and threshold currents. Rats received unilateral 6-hydroxydopamine in the nigrostriatal bundle, causing motor impairment. Changes in M1 were time dependent and bilateral, although stronger in the lesioned than the intact hemisphere. Representation size and threshold current were maximally impaired at 15 d, although inhibition was still detectable at 60-120 d after lesion. Proximal forelimb movements emerged at the expense of the distal ones. Movement lateralization was lost mainly at 30 d after lesion. Systemic L-3,4-dihydroxyphenylalanine partially attenuated motor impairment and cortical changes, particularly in the caudal forelimb area, and completely rescued distal forelimb movements. Local application of the GABA(A) antagonist bicuculline partially restored cortical changes, particularly in the rostral forelimb area. The local anesthetic lidocaine injected into the M1 of the intact hemisphere restored movement lateralization in the lesioned hemisphere. This study provides evidence for motor cortex remodeling after unilateral dopamine denervation, suggesting that cortical changes were associated with dopamine denervation, pathogenic intracortical GABA inhibition, and altered interhemispheric activity.

Menstrual cycle phase modulates reward-related neural function in women.

PubMed

Dreher, Jean-Claude; Schmidt, Peter J; Kohn, Philip; Furman, Daniella; Rubinow, David; Berman, Karen Faith

2007-02-13

There is considerable evidence from animal studies that the mesolimbic and mesocortical dopamine systems are sensitive to circulating gonadal steroid hormones. Less is known about the influence of estrogen and progesterone on the human reward system. To investigate this directly, we used functional MRI and an event-related monetary reward paradigm to study women with a repeated-measures, counterbalanced design across the menstrual cycle. Here we show that during the midfollicular phase (days 4-8 after onset of menses) women anticipating uncertain rewards activated the orbitofrontal cortex and amygdala more than during the luteal phase (6-10 days after luteinizing hormone surge). At the time of reward delivery, women in the follicular phase activated the midbrain, striatum, and left fronto-polar cortex more than during the luteal phase. These data demonstrate augmented reactivity of the reward system in women during the midfollicular phase when estrogen is unopposed by progesterone. Moreover, investigation of between-sex differences revealed that men activated ventral putamen more than women during anticipation of uncertain rewards, whereas women more strongly activated the anterior medial prefrontal cortex at the time of reward delivery. Correlation between brain activity and gonadal steroid levels also revealed that the amygdalo-hippocampal complex was positively correlated with estradiol level, regardless of menstrual cycle phase. Together, our findings provide evidence of neurofunctional modulation of the reward system by gonadal steroid hormones in humans and establish a neurobiological foundation for understanding their impact on vulnerability to drug abuse, neuropsychiatric diseases with differential expression across males and females, and hormonally mediated mood disorders.

Modulation of attention network activation under antidepressant agents in healthy subjects.

PubMed

Graf, Heiko; Abler, Birgit; Hartmann, Antonie; Metzger, Coraline D; Walter, Martin

2013-07-01

While antidepressants are supposed to exert similar effects on mood and drive via various mechanisms of action, diverging effects are observed regarding side-effects and accordingly on neural correlates of motivation, emotion, reward and salient stimuli processing as a function of the drugs impact on neurotransmission. In the context of erotic stimulation, a unidirectional modulation of attentional functioning despite opposite effects on sexual arousal has been suggested for the selective serotonin reuptake-inhibitor (SSRI) paroxetine and the selective dopamine and noradrenaline reuptake-inhibitor (SDNRI) bupropion. To further elucidate the effects of antidepressant-related alterations of neural attention networks, we investigated 18 healthy males under subchronic administration (7 d) of paroxetine (20 mg), bupropion (150 mg) and placebo within a randomized placebo-controlled cross-over double-blind functional magnetic resonance imaging (fMRI) design during an established preceding attention task. Neuropsychological effects beyond the fMRI-paradigm were assessed by measuring alertness and divided attention. Comparing preceding attention periods of salient vs. neutral pictures, we revealed congruent effects of both drugs vs. placebo within the anterior midcingulate cortex, dorsolateral prefrontal cortex, anterior prefrontal cortex, superior temporal gyrus, anterior insula and the thalamus. Relatively decreased activation in this network was paralleled by slower reaction times in the divided attention task in both verum conditions compared to placebo. Our results suggest similar effects of antidepressant treatments on behavioural and neural attentional functioning by diverging neurochemical pathways. Concurrent alterations of brain regions within a fronto-parietal and cingulo-opercular attention network for top-down control could point to basic neural mechanisms of antidepressant action irrespective of receptor profiles.

The potential role of dopamine D3 receptor neurotransmission in cognition

PubMed Central

Nakajima, Shinichiro; Gerretsen, Philip; Takeuchi, Hiroyoshi; Caravaggio, Fernando; Chow, Tiffany; Le Foll, Bernard; Mulsant, Benoit; Pollock, Bruce; Graff-Guerrero, Ariel

2013-01-01

Currently available treatments have limited pro-cognitive effects for neuropsychiatric disorders, such as schizophrenia, Parkinson’s disease and Alzheimer’s disease. The primary objective of this work is to review the literature on the role of dopamine D3 receptors in cognition, and propose dopamine D3 receptor antagonists as possible cognitive enhancers for neuropsychiatric disorders. A literature search was performed to identify animal and human studies on D3 receptors and cognition using PubMed, MEDLINE and EMBASE. The search terms included “dopamine D3 receptor” and “cognition”. The literature search identified 164 articles. The results revealed: (1) D3 receptors are associated with cognitive functioning in both healthy individuals and those with neuropsychiatric disorders; (2) D3 receptor blockade appears to enhance while D3 receptor agonism seems to impair cognitive function, including memory, attention, learning, processing speed, social recognition and executive function independent of age; and (3) D3 receptor antagonists may exert their pro-cognitive effect by enhancing the release of acetylcholine in the prefrontal cortex, disinhibiting the activity of dopamine neurons projecting to the nucleus accumbens or prefrontal cortex, or activating CREB signaling in the hippocampus. These findings suggest that D3 receptor blockade may enhance cognitive performance in healthy individuals and treat cognitive dysfunction in individuals with a neuropsychiatric disorder. Clinical trials are needed to confirm these effects. PMID:23791072

The Michelin red guide of the brain: role of dopamine in goal-oriented navigation.

PubMed

Retailleau, Aude; Boraud, Thomas

2014-01-01

Spatial learning has been recognized over the years to be under the control of the hippocampus and related temporal lobe structures. Hippocampal damage often causes severe impairments in the ability to learn and remember a location in space defined by distal visual cues. Such cognitive disabilities are found in Parkinsonian patients. We recently investigated the role of dopamine in navigation in the 6-Hydroxy-dopamine (6-OHDA) rat, a model of Parkinson's disease (PD) commonly used to investigate the pathophysiology of dopamine depletion (Retailleau et al., 2013). We demonstrated that dopamine (DA) is essential to spatial learning as its depletion results in spatial impairments. Our results showed that the behavioral effect of DA depletion is correlated with modification of the neural encoding of spatial features and decision making processes in hippocampus. However, the origin of these alterations in the neural processing of the spatial information needs to be clarified. It could result from a local effect: dopamine depletion disturbs directly the processing of relevant spatial information at hippocampal level. Alternatively, it could result from a more distributed network effect: dopamine depletion elsewhere in the brain (entorhinal cortex, striatum, etc.) modifies the way hippocampus processes spatial information. Recent experimental evidence in rodents, demonstrated indeed, that other brain areas are involved in the acquisition of spatial information. Amongst these, the cortex-basal ganglia (BG) loop is known to be involved in reinforcement learning and has been identified as an important contributor to spatial learning. In particular, it has been shown that altered activity of the BG striatal complex can impair the ability to perform spatial learning tasks. The present review provides a glimpse of the findings obtained over the past decade that support a dialog between these two structures during spatial learning under DA control.

Neuropsychiatric Phenotypes Produced by GABA Reduction in Mouse Cortex and Hippocampus.

PubMed

Kolata, Stefan M; Nakao, Kazuhito; Jeevakumar, Vivek; Farmer-Alroth, Emily L; Fujita, Yuko; Bartley, Aundrea F; Jiang, Sunny Zhihong; Rompala, Gregory R; Sorge, Robert E; Jimenez, Dennisse V; Martinowich, Keri; Mateo, Yolanda; Hashimoto, Kenji; Dobrunz, Lynn E; Nakazawa, Kazu

2018-05-01

Whereas cortical GAD67 reduction and subsequent GABA level decrease are consistently observed in schizophrenia and depression, it remains unclear how these GABAergic abnormalities contribute to specific symptoms. We modeled cortical GAD67 reduction in mice, in which the Gad1 gene is genetically ablated from ~50% of cortical and hippocampal interneurons. Mutant mice showed a reduction of tissue GABA in the hippocampus and cortex including mPFC, and exhibited a cluster of effort-based behavior deficits including decreased home-cage wheel running and increased immobility in both tail suspension and forced swim tests. Since saccharine preference, progressive ratio responding to food, and learned helplessness task were normal, such avolition-like behavior could not be explained by anhedonia or behavioral despair. In line with the prevailing view that dopamine in anterior cingulate cortex (ACC) plays a role in evaluating effort cost for engaging in actions, we found that tail-suspension triggered dopamine release in ACC of controls, which was severely attenuated in the mutant mice. Conversely, ACC dopamine release by progressive ratio responding to reward, during which animals were allowed to effortlessly perform the nose-poking, was not affected in mutants. These results suggest that cortical GABA reduction preferentially impairs the effort-based behavior which requires much effort with little benefit, through a deficit of ACC dopamine release triggered by high-effort cost behavior, but not by reward-seeking behavior. Collectively, a subset of negative symptoms with a reduced willingness to expend costly effort, often observed in patients with schizophrenia and depression, may be attributed to cortical GABA level reduction.

Effects of levodopa on corticostriatal circuits supporting working memory in Parkinson's disease.

PubMed

Simioni, Alison C; Dagher, Alain; Fellows, Lesley K

2017-08-01

Working memory dysfunction is common in Parkinson's disease, even in its early stages, but its neural basis is debated. Working memory performance likely reflects a balance between corticostriatal dysfunction and compensatory mechanisms. We tested this hypothesis by examining working memory performance with a letter n-back task in 19 patients with mild-moderate Parkinson's disease and 20 demographically matched healthy controls. Parkinson's disease patients were tested after an overnight washout of their usual dopamine replacement therapy, and again after a standard dose of levodopa. FMRI was used to assess task-related activation and resting state functional connectivity; changes in BOLD signal were related to performance to disentangle pathological and compensatory processes. Parkinson's disease patients off dopamine replacement therapy displayed significantly reduced spatial extent of task-related activation in left prefrontal and bilateral parietal cortex, and poorer working memory performance, compared to controls. Amongst the Parkinson's disease patients off dopamine replacement therapy, relatively better performance was associated with greater activation of right dorsolateral prefrontal cortex compared to controls, consistent with compensatory right hemisphere recruitment. Administration of levodopa remediated the working memory deficit in the Parkinson's disease group, and resulted in a different pattern of performance-correlated activity, with a shift to greater left ventrolateral prefrontal cortex activation in patients on, compared to off dopamine replacement therapy. Levodopa also significantly increased resting-state functional connectivity between caudate and right parietal cortex (within the right fronto-parietal attentional network). The strength of this connectivity contributed to better performance in patients and controls, suggesting a general compensatory mechanism. These findings argue that Parkinson's disease patients can recruit additional neural resources, here, the right fronto-parietal network, to optimize working memory performance despite impaired corticostriatal function. Levodopa seems to both boost engagement of a task-specific prefrontal region, and strengthen a putative compensatory caudate-cortical network to support this executive function. Copyright © 2017 Elsevier Ltd. All rights reserved.

Endogenous dopamine (DA) modulates (3H)spiperone binding in vivo in rat brain

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

Bischoff, S.; Krauss, J.; Grunenwald, C.

1991-01-01

(3H)spiperone (SPI) binding in vivo, biochemical parameters and behavior were measured after modulating DA levels by various drug treatments. DA releasers and uptake inhibitors increased SPI binding in rat striatum. In other brain areas, the effects were variable, but only the pituitary remained unaffected. Surprisingly, nomifensine decreased SPI binding in frontal cortex. The effects of these drugs were monitored by measuring DA, serotonin (5-HT) and their metabolites in the same rats. The increased SPI binding in striatum was parallel to the locomotor stimulation with the following rank order: amfonelic acid greater than nomifensine greater than D-amphetamine greater than or equalmore » to methylphenidate greater than amineptine greater than bupropion. Decreasing DA levels with reserpine or alpha-methyl-para-tyrosine reduced SPI binding by 45% in striatum only when both drugs were combined. In contrast, reserpine enhanced SPI binding in pituitary. Thus, the amount of releasable DA seems to modulate SPI binding characteristics. It is suggested that in vivo, DA receptors are submitted to dynamic regulation in response to changes in intrasynaptic concentrations of DA.« less

Novelty-Sensitive Dopaminergic Neurons in the Human Substantia Nigra Predict Success of Declarative Memory Formation.

PubMed

Kamiński, Jan; Mamelak, Adam N; Birch, Kurtis; Mosher, Clayton P; Tagliati, Michele; Rutishauser, Ueli

2018-05-07

The encoding of information into long-term declarative memory is facilitated by dopamine. This process depends on hippocampal novelty signals, but it remains unknown how midbrain dopaminergic neurons are modulated by declarative-memory-based information. We recorded individual substantia nigra (SN) neurons and cortical field potentials in human patients performing a recognition memory task. We found that 25% of SN neurons were modulated by stimulus novelty. Extracellular waveform shape and anatomical location indicated that these memory-selective neurons were putatively dopaminergic. The responses of memory-selective neurons appeared 527 ms after stimulus onset, changed after a single trial, and were indicative of recognition accuracy. SN neurons phase locked to frontal cortical theta-frequency oscillations, and the extent of this coordination predicted successful memory formation. These data reveal that dopaminergic neurons in the human SN are modulated by memory signals and demonstrate a progression of information flow in the hippocampal-basal ganglia-frontal cortex loop for memory encoding. Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.

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.

Alterations in primary motor cortex neurotransmission and gene expression in hemi-parkinsonian rats with drug-induced dyskinesia.

PubMed

Lindenbach, D; Conti, M M; Ostock, C Y; Dupre, K B; Bishop, C

2015-12-03

Treatment of Parkinson's disease (PD) with dopamine replacement relieves symptoms of poverty of movement, but often causes drug-induced dyskinesias. Accumulating clinical and pre-clinical evidence suggests that the primary motor cortex (M1) is involved in the pathophysiology of PD and that modulating cortical activity may be a therapeutic target in PD and dyskinesia. However, surprisingly little is known about how M1 neurotransmitter tone or gene expression is altered in PD, dyskinesia or associated animal models. The present study utilized the rat unilateral 6-hydroxydopamine (6-OHDA) model of PD/dyskinesia to characterize structural and functional changes taking place in M1 monoamine innervation and gene expression. 6-OHDA caused dopamine pathology in M1, although the lesion was less severe than in the striatum. Rats with 6-OHDA lesions showed a PD motor impairment and developed dyskinesia when given L-DOPA or the D1 receptor agonist, SKF81297. M1 expression of two immediate-early genes (c-Fos and ARC) was strongly enhanced by either L-DOPA or SKF81297. At the same time, expression of genes specifically involved in glutamate and GABA signaling were either modestly affected or unchanged by lesion and/or treatment. We conclude that M1 neurotransmission and signal transduction in the rat 6-OHDA model of PD/dyskinesia mirror features of human PD, supporting the utility of the model to study M1 dysfunction in PD and the elucidation of novel pathophysiological mechanisms and therapeutic targets. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Hemispheric asymmetry in stress processing in rat prefrontal cortex and the role of mesocortical dopamine.

PubMed

Sullivan, R M

2004-06-01

The prefrontal cortex (PFC) is known to play an important role not only in the regulation of emotion, but in the integration of affective states with appropriate modulation of autonomic and neuroendocrine stress regulatory systems. The present review highlights findings in the rat which helps to elucidate the complex nature of prefrontal involvement in emotion and stress regulation. The medial PFC is particularly important in this regard and while dorsomedial regions appear to play a suppressive role in such regulation, the ventromedial (particularly infralimbic) region appears to activate behavioral, neuroendocrine and sympathetic autonomic systems in response to stressful situations. This may be especially true of spontaneous stress-related behavior or physiological responses to relatively acute stressors. The role of the medial PFC is somewhat more complex in conditions involving learned adjustments to stressful situations, such as the extinction of conditioned fear responses, but it is clear that the medial PFC is important in incorporating stressful experience for future adaptive behavior. It is also suggested that mesocortical dopamine plays an important adaptive role in this region by preventing excessive behavioral and physiological stress reactivity. The rat brain shows substantial hemispheric specialization in many respects, and while the right PFC is normally dominant in the activation of stress-related systems, the left may play a role in countering this activation through processes of interhemispheric inhibition. This proposed basic template for the lateralization of stress regulatory systems is suggested to be associated with efficient stress and emotional self-regulation, and also to be shaped by both early postnatal experience and gender differences.

Inverted-U shaped dopamine actions on human working memory and cognitive control

PubMed Central

Cools, R; D’Esposito, M

2011-01-01

Brain dopamine has long been implicated in cognitive control processes, including working memory. However, the precise role of dopamine in cognition is not well understood, partly because there is large variability in the response to dopaminergic drugs both across different behaviors and across different individuals. We review evidence from a series of studies with experimental animals, healthy humans and patients with Parkinson’s disease, which highlight two important factors that contribute to this large variability. First, the existence of an optimum dopamine level for cognitive function implicates the need to take into account baseline levels of dopamine when isolating dopamine’s effects. Second, cognitive control is a multi-factorial phenomenon, requiring a dynamic balance between cognitive stability and cognitive flexibility. These distinct components might implicate the prefrontal cortex and the striatum respectively. Manipulating dopamine will thus have paradoxical consequences for distinct cognitive control processes depending on distinct basal or optimal levels of dopamine in different brain regions. PMID:21531388

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

PubMed Central

Holly, Elizabeth N.; Miczek, Klaus A.

2015-01-01

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

Basal ganglia circuit loops, dopamine and motivation: A review and enquiry

PubMed Central

Ikemoto, Satoshi; Yang, Chen; Tan, Aaron

2015-01-01

Dopamine neurons located in the midbrain play a role in motivation that regulates approach behavior (approach motivation). In addition, activation and inactivation of dopamine neurons regulate mood and induce reward and aversion, respectively. Accumulating evidence suggests that such motivational role of dopamine neurons is not limited to those located in the ventral tegmental area, but also in the substantia nigra. The present paper reviews previous rodent work concerning dopamine’s role in approach motivation and the connectivity of dopamine neurons, and proposes two working models: One concerns the relationship between extracellular dopamine concentration and approach motivation. High, moderate and low concentrations of extracellular dopamine induce euphoric, seeking and aversive states, respectively. The other concerns circuit loops involving the cerebral cortex, basal ganglia, thalamus, epithalamus, and midbrain through which dopaminergic activity alters approach motivation. These models should help to generate hypothesis-driven research and provide insights for understanding altered states associated with drugs of abuse and affective disorders. PMID:25907747

Continuous theta-burst stimulation (cTBS) over the lateral prefrontal cortex alters reinforcement learning bias.

PubMed

Ott, Derek V M; Ullsperger, Markus; Jocham, Gerhard; Neumann, Jane; Klein, Tilmann A

2011-07-15

The prefrontal cortex is known to play a key role in higher-order cognitive functions. Recently, we showed that this brain region is active in reinforcement learning, during which subjects constantly have to integrate trial outcomes in order to optimize performance. To further elucidate the role of the dorsolateral prefrontal cortex (DLPFC) in reinforcement learning, we applied continuous theta-burst stimulation (cTBS) either to the left or right DLPFC, or to the vertex as a control region, respectively, prior to the performance of a probabilistic learning task in an fMRI environment. While there was no influence of cTBS on learning performance per se, we observed a stimulation-dependent modulation of reward vs. punishment sensitivity: Left-hemispherical DLPFC stimulation led to a more reward-guided performance, while right-hemispherical cTBS induced a more avoidance-guided behavior. FMRI results showed enhanced prediction error coding in the ventral striatum in subjects stimulated over the left as compared to the right DLPFC. Both behavioral and imaging results are in line with recent findings that left, but not right-hemispherical stimulation can trigger a release of dopamine in the ventral striatum, which has been suggested to increase the relative impact of rewards rather than punishment on behavior. Copyright © 2011 Elsevier Inc. All rights reserved.

Diurnal influences on electrophysiological oscillations and coupling in the dorsal striatum and cerebellar cortex of the anesthetized rat

PubMed Central

Frederick, Ariana; Bourget-Murray, Jonathan; Chapman, C. Andrew; Amir, Shimon; Courtemanche, Richard

2014-01-01

Circadian rhythms modulate behavioral processes over a 24 h period through clock gene expression. What is largely unknown is how these molecular influences shape neural activity in different brain areas. The clock gene Per2 is rhythmically expressed in the striatum and the cerebellum and its expression is linked with daily fluctuations in extracellular dopamine levels and D2 receptor activity. Electrophysiologically, dopamine depletion enhances striatal local field potential (LFP) oscillations. We investigated if LFP oscillations and synchrony were influenced by time of day, potentially via dopamine mechanisms. To assess the presence of a diurnal effect, oscillatory power and coherence were examined in the striatum and cerebellum of rats under urethane anesthesia at four different times of day zeitgeber time (ZT1, 7, 13 and 19—indicating number of hours after lights turned on in a 12:12 h light-dark cycle). We also investigated the diurnal response to systemic raclopride, a D2 receptor antagonist. Time of day affected the proportion of LFP oscillations within the 0–3 Hz band and the 3–8 Hz band. In both the striatum and the cerebellum, slow oscillations were strongest at ZT1 and weakest at ZT13. A 3–8 Hz oscillation was present when the slow oscillation was lowest, with peak 3–8 Hz activity occurring at ZT13. Raclopride enhanced the slow oscillations, and had the greatest effect at ZT13. Within the striatum and with the cerebellum, 0–3 Hz coherence was greatest at ZT1, when the slow oscillations were strongest. Coherence was also affected the most by raclopride at ZT13. Our results suggest that neural oscillations in the cerebellum and striatum, and the synchrony between these areas, are modulated by time of day, and that these changes are influenced by dopamine manipulation. This may provide insight into how circadian gene transcription patterns influence network electrophysiology. Future experiments will address how these network alterations are linked with behavior. PMID:25309348

Histamine H3 receptors and its antagonism as a novel mechanism for antipsychotic effect: a current preclinical & clinical perspective.

PubMed

Mahmood, Danish

2016-10-01

Histamine H 3 receptors are present as autoreceptors on histaminergic neurons and as heteroreceptors on nonhistaminergic neurones. They control the release and synthesis of histamine and several other key neurotransmitters in the brain. H 3 antagonism may be a novel approach to develop a new class of antipsychotic medications given the gathering evidence reporting therapeutic efficacy in several central nervous system disorders. Several medications such as cariprazine, lurasidone, LY214002, bexarotene, rasagiline, raloxifene, BL-1020 and ITI-070 are being developed to treat the negative symptoms and cognitive impairments of schizophrenia. These medications works through diverse mechanisms which include agonism at metabotropic glutamate receptor (mGluR2/3), partial agonism at dopamine D 2 , D 3 and serotonin 5-HT 1A receptors, antagonism at D 2 , 5-HT 2A, 5-HT 2B and 5-HT 7 receptors, combined dopamine antagonism with GABA agonist activity, inhibition of monoamine oxidase-B, modulation of oestrogen receptor, and activation of nuclear retinoid X receptor. However, still specific safe therapy for psychosis remains at large. Schizophrenia is a severe neuropsychiatric disorder result both from hyper- and hypo-dopaminergic transmission causing positive and negative symptoms, respectively. Pharmacological stimulation of dopamine release in the prefrontal cortex has been a viable approach in treating negative symptoms and cognitive deficits of schizophrenia symptoms that are currently not well treated and continue to represent significant unmet medical challenges. Administration of H 3 antagonists/inverse agonists increase extracellular dopamine concentrations in rat prefrontal cortex, but not in the striatum suggesting that antagonism via H 3 receptor may be a potential target for treating negative symptoms and cognitive deficits associated with schizophrenia. Further, insights are emerging into the potential role of histamine H 3 receptors as a target of antiobesity therapeutics which is one of the limiting adverse effects of second generation schizophrenia medications. The recent failures of two promising H 3 compounds in clinical trial dampened the interest in seeking antipsychotic like activities of H 3 receptor antagonists. However, due to the inconclusive nature of many of these studies, the development of H 3 compounds via H 3 antagonism/inverse agonism approach still hold lot of promises and may be developed as a novel class of drugs for schizophrenia and its related complications e.g. weight gain.

Behavioural, neurochemical and neuroendocrine effects of the endogenous β-carboline harmane in fear-conditioned rats.

PubMed

Smith, Karen L; Ford, Gemma K; Jessop, David S; Finn, David P

2013-02-01

The putative endogenous imidazoline binding site ligand harmane enhances neuronal activation in response to psychological stress and alters behaviour in animal models of anxiety and antidepressant efficacy. However, the neurobiological mechanisms underlying harmane's psychotropic effects are poorly understood. We investigated the effects of intraperitoneal injection of harmane (2.5 and 10 mg/kg) on fear-conditioned behaviour, hypothalamo-pituitary-adrenal axis activity, and monoaminergic activity within specific fear-associated areas of the rat brain. Harmane had no significant effect on the duration of contextually induced freezing or 22 kHz ultrasonic vocalisations and did not alter the contextually induced suppression of motor activity, including rearing. Harmane reduced the duration of rearing and tended to increase freezing in non-fear-conditioned controls, suggesting potential sedative effects. Harmane increased plasma ACTH and corticosterone concentrations, and serotonin (in hypothalamus, amygdaloid cortex, prefrontal cortex and hippocampus) and noradrenaline (prefrontal cortex) content, irrespective of fear-conditioning. Furthermore, harmane reduced dopamine and serotonin turnover in the PFC and hypothalamus, and serotonin turnover in the amygdaloid cortex in both fear-conditioned and non-fear-conditioned rats. In contrast, harmane increased dopamine and noradrenaline content and reduced dopamine turnover in the amygdala of fear-conditioned rats only, suggesting differential effects on catecholaminergic transmission in the presence and absence of fear. The precise mechanism(s) mediating these effects of harmane remain to be determined but may involve its inhibitory action on monoamine oxidases. These findings support a role for harmane as a neuromodulator, altering behaviour, brain neurochemistry and neuroendocrine function.

Disrupted reinforcement signaling in the orbitofrontal cortex and caudate in youths with conduct disorder or oppositional defiant disorder and a high level of psychopathic traits.

PubMed

Finger, Elizabeth C; Marsh, Abigail A; Blair, Karina S; Reid, Marguerite E; Sims, Courtney; Ng, Pamela; Pine, Daniel S; Blair, R James R

2011-02-01

Dysfunction in the amygdala and orbitofrontal cortex has been reported in youths and adults with psychopathic traits. The specific nature of the functional irregularities within these structures remains poorly understood. The authors used a passive avoidance task to examine the responsiveness of these systems to early stimulus-reinforcement exposure, when prediction errors are greatest and learning maximized, and to reward in youths with psychopathic traits and comparison youths. While performing the passive avoidance learning task, 15 youths with conduct disorder or oppositional defiant disorder plus a high level of psychopathic traits and 15 healthy subjects completed a 3.0-T fMRI scan. Relative to the comparison youths, the youths with a disruptive behavior disorder plus psychopathic traits showed less orbitofrontal responsiveness both to early stimulus-reinforcement exposure and to rewards, as well as less caudate response to early stimulus-reinforcement exposure. There were no group differences in amygdala responsiveness to these two task measures, but amygdala responsiveness throughout the task was lower in the youths with psychopathic traits. Compromised sensitivity to early reinforcement information in the orbitofrontal cortex and caudate and to reward outcome information in the orbitofrontal cortex of youths with conduct disorder or oppositional defiant disorder plus psychopathic traits suggests that the integrated functioning of the amygdala, caudate, and orbitofrontal cortex may be disrupted. This provides a functional neural basis for why such youths are more likely to repeat disadvantageous decisions. New treatment possibilities are raised, as pharmacologic modulations of serotonin and dopamine can affect this form of learning.

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

Biological and social influences on cognitive control processes dependent on prefrontal cortex

PubMed Central

Diamond, Adele

2014-01-01

Cognitive control functions (“executive functions” [EFs] such as attentional control, self-regulation, working memory, and inhibition) that depend on prefrontal cortex (PFC) are critical for success in school and in life. Many children begin school lacking needed EF skills. Disturbances in EFs occur in many mental health disorders, such as ADHD and depression. This chapter addresses modulation of EFs by biology (genes and neurochemistry) and the environment (including school programs) with implications for clinical disorders and for education. Unusual properties of the prefrontal dopamine system contribute to PFC’s vulnerability to environmental and genetic variations that have little effect elsewhere. EFs depend on a late-maturing brain region (PFC), yet they can be improved even in infants and preschoolers, without specialists or fancy equipment. Research shows that activities often squeezed out of school curricula (play, physical education, and the arts) rather than detracting from academic achievement help improve EFs and enhance academic outcomes. Such practices may also head off problems before they lead to diagnoses of EF impairments, including ADHD. Many issues are not simply education issues or health issues; they are both. PMID:21489397

A review of reward processing and motivational impairment in schizophrenia.

PubMed

Strauss, Gregory P; Waltz, James A; Gold, James M

2014-03-01

This article reviews and synthesizes research on reward processing in schizophrenia, which has begun to provide important insights into the cognitive and neural mechanisms associated with motivational impairments. Aberrant cortical-striatal interactions may be involved with multiple reward processing abnormalities, including: (1) dopamine-mediated basal ganglia systems that support reinforcement learning and the ability to predict cues that lead to rewarding outcomes; (2) orbitofrontal cortex-driven deficits in generating, updating, and maintaining value representations; (3) aberrant effort-value computations, which may be mediated by disrupted anterior cingulate cortex and midbrain dopamine functioning; and (4) altered activation of the prefrontal cortex, which is important for generating exploratory behaviors in environments where reward outcomes are uncertain. It will be important for psychosocial interventions targeting negative symptoms to account for abnormalities in each of these reward processes, which may also have important interactions; suggestions for novel behavioral intervention strategies that make use of external cues, reinforcers, and mobile technology are discussed.

COMT and DRD2/ANKK-1 gene-gene interaction account for resetting of gamma neural oscillations to auditory stimulus-driven attention.

PubMed

Garcia-Garcia, Manuel; Via, Marc; Zarnowiec, Katarzyna; SanMiguel, Iria; Escera, Carles; Clemente, Immaculada C

2017-01-01

Attention capture by potentially relevant environmental stimuli is critical for human survival, yet it varies considerably among individuals. A large series of studies has suggested that attention capture may depend on the cognitive balance between maintenance and manipulation of mental representations and the flexible switch between goal-directed representations and potentially relevant stimuli outside the focus of attention; a balance that seems modulated by a prefrontostriatal dopamine pathway. Here, we examined inter-individual differences in the cognitive control of attention through studying the effects of two single nucleotide polymorphisms regulating dopamine at the prefrontal cortex and the striatum (i.e., COMTMet108/158Val and ANKK1/DRD2TaqIA) on stimulus-driven attention capture. Healthy adult participants (N = 40) were assigned to different groups according to the combination of the polymorphisms COMTMet108/158Val and ANKK1/DRD2TaqIA, and were instructed to perform on a well-established distraction protocol. Performance in individuals with a balance between prefrontal dopamine display and striatal receptor density was slowed down by the occurrence of unexpected distracting events, while those with a rather unbalanced dopamine activity were able maintain task performance with no time delay, yet at the expense of a slightly lower accuracy. This advantage, associated to their distinct genetic profiles, was paralleled by an electrophysiological mechanism of phase-resetting of gamma neural oscillation to the novel, distracting events. Taken together, the current results suggest that the epistatic interaction between COMTVal108/158Met and ANKK1/DRD2 TaqIa genetic polymorphisms lies at the basis of stimulus-driven attention capture.

L-Dopa Modulates Functional Connectivity in Striatal Cognitive and Motor Networks: A Double-Blind Placebo-Controlled Study

PubMed Central

Kelly, Clare; de Zubicaray, Greig; Di Martino, Adriana; Copland, David A.; Reiss, Philip T.; Klein, Donald F.; Castellanos, F. Xavier; Milham, Michael P.; McMahon, Katie

2010-01-01

Functional connectivity (FC) analyses of resting-state fMRI data allow for the mapping of large-scale functional networks, and provide a novel means of examining the impact of dopaminergic challenge. Here, using a double-blind, placebo-controlled design, we examined the effect of L-dopa, a dopamine precursor, on striatal resting-state FC in 19 healthy young adults. We examined the FC of 6 striatal regions-of-interest previously shown to elicit networks known to be associated with motivational, cognitive and motor subdivisions of the caudate and putamen (Di Martino et al., Cerebral Cortex, 2008). In addition to replicating the previously demonstrated patterns of striatal FC, we observed robust effects of L-dopa. Specifically, L-dopa increased FC in motor pathways connecting the putamen ROIs with the cerebellum and brainstem. While L-dopa also increased FC between the inferior ventral striatum and ventrolateral prefrontal cortex, it disrupted ventral striatal and dorsal caudate FC with the default mode network. These alterations in FC are consistent with studies that have demonstrated dopaminergic modulation of cognitive and motor striatal networks in healthy participants. Recent studies have demonstrated altered resting state FC in several conditions believed to be characterized by abnormal dopaminergic neurotransmission. Our findings suggest that the application of similar experimental pharmacological manipulations in such populations may further our understanding of the role of dopaminergic neurotransmission in those conditions. PMID:19494158

Neuroprotective effect of curcumin in arsenic-induced neurotoxicity in rats.

PubMed

Yadav, Rajesh S; Shukla, Rajendra K; Sankhwar, Madhu Lata; Patel, Devendra K; Ansari, Reyaz W; Pant, Aditya B; Islam, Fakhrul; Khanna, Vinay K

2010-09-01

Our recent studies have shown that arsenic-induced neurobehavioral toxicity is protected by curcumin by modulating oxidative stress and dopaminergic functions in rats. In addition, the neuroprotective effect of curcumin has been investigated on arsenic-induced alterations in biogenic amines, their metabolites and nitric oxide (NO), which play an important role in neurotransmission process. Decrease in the levels of dopamine (DA, 28%), norepinephrine (NE, 54%), epinephrine (EPN, 46%), serotonin (5-HT, 44%), 3,4-dihydroxyphenylacetic acid (DOPAC, 20%) and homovanillic acid (HVA, 31%) in corpus striatum; DA (51%), NE (22%), EPN (47%), 5-HT (25%), DOPAC (34%) and HVA (41%) in frontal cortex and DA (35%), NE (35%), EPN (29%), 5-HT (54%), DOPAC (37%) and HVA (46%) in hippocampus, observed in arsenic (sodium arsenite, 20 mg/kg body weight, p.o., 28 days) treated rats exhibited a trend of recovery in rats simultaneously treated with arsenic and curcumin (100 mg/kg body weight, p.o., 28 days). Increased levels of NO in corpus striatum (2.4-fold), frontal cortex (6.1-fold) and hippocampus (6.2-fold) in arsenic-treated rats were found decreased in rats simultaneously treated with arsenic and curcumin. It is evident that curcumin modulates levels of brain biogenic amines and NO in arsenic-exposed rats and these results further strengthen its neuroprotective efficacy. Copyright © 2010 Elsevier Inc. All rights reserved.

Role of Serotonin and Dopamine System Interactions in the Neurobiology of Impulsive Aggression and its Comorbidity with other Clinical Disorders

PubMed Central

Seo, Dongju; Patrick, Christopher J.; Kennealy, Patrick J.

2008-01-01

Impulsive aggression is characterized by an inability to regulate affect as well as aggressive impulses, and is highly comorbid with other mental disorders including depression, suicidal behavior, and substance abuse. In an effort to elucidate the neurobiological underpinnings of impulsive aggression and to help account for its connections with these other disorders, this paper reviews relevant biochemical, brain imaging, and genetic studies. The review suggests that dysfunctional interactions between serotonin and dopamine systems in the prefrontal cortex may be an important mechanism underlying the link between impulsive aggression and its comorbid disorders. Specifically, serotonin hypofunction may represent a biochemical trait that predisposes individuals to impulsive aggression, with dopamine hyperfunction contributing in an additive fashion to the serotonergic deficit. The current paper proposes a modified diathesis-stress model of impulsive aggression in which the underlying biological diathesis may be deficient serotonergic function in the ventral prefrontal cortex. This underlying disposition can be manifested behaviorally as impulsive aggression towards oneself and others, and as depression under precipitating life stressors. Substance abuse associated with impulsive aggression is understood in the context of dopamine dysregulation resulting from serotonergic deficiency. Also discussed are future research directions in the neurobiology of impulsive aggression and its comorbid disorders. PMID:19802333

Activation of dopamine D3 receptors inhibits reward-related learning induced by cocaine.

PubMed

Kong, H; Kuang, W; Li, S; Xu, M

2011-03-10

Memories of learned associations between the rewarding properties of drugs and environmental cues contribute to craving and relapse in humans. The mesocorticolimbic dopamine (DA) system is involved in reward-related learning induced by drugs of abuse. DA D3 receptors are preferentially expressed in mesocorticolimbic DA projection areas. Genetic and pharmacological studies have shown that DA D3 receptors suppress locomotor-stimulant effects of cocaine and reinstatement of cocaine-seeking behaviors. Activation of the extracellular signal-regulated kinase (ERK) induced by acute cocaine administration is also inhibited by D3 receptors. How D3 receptors modulate cocaine-induced reward-related learning and associated changes in cell signaling in reward circuits in the brain, however, have not been fully investigated. In the present study, we show that D3 receptor mutant mice exhibit potentiated acquisition of conditioned place preference (CPP) at low doses of cocaine compared to wild-type mice. Activation of ERK and CaMKIIα, but not the c-Jun N-terminal kinase and p38, in the nucleus accumbens, amygdala and prefrontal cortex is also potentiated in D3 receptor mutant mice compared to that in wild-type mice following CPP expression. These results support a model in which D3 receptors modulate reward-related learning induced by low doses of cocaine by inhibiting activation of ERK and CaMKIIα in reward circuits in the brain. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

A Transposon in Comt Generates mRNA Variants and Causes Widespread Expression and Behavioral Differences among Mice

PubMed Central

Wang, Xusheng; Miles, Michael F.; Lu, Lu; Williams, Robert W.

2010-01-01

Background Catechol-O-methyltransferase (COMT) is a key enzyme responsible for the degradation of dopamine and norepinephrine. COMT activity influences cognitive and emotional states in humans and aggression and drug responses in mice. This study identifies the key sequence variant that leads to differences in Comt mRNA and protein levels among mice, and that modulates synaptic function and pharmacological and behavioral traits. Methodology/Principal Findings We examined Comt expression in multiple tissues in over 100 diverse strains and several genetic crosses. Differences in expression map back to Comt and are generated by a 230 nt insertion of a B2 short interspersed element (B2 SINE) in the proximal 3′ UTR of Comt in C57BL/6J. This transposon introduces a premature polyadenylation signal and creates a short 3′ UTR isoform. The B2 SINE is shared by a subset of strains, including C57BL/6J, A/J, BALB/cByJ, and AKR/J, but is absent in others, including DBA/2J, FVB/NJ, SJL/J, and wild subspecies. The short isoform is associated with increased protein expression in prefrontal cortex and hippocampus relative to the longer ancestral isoform. The Comt variant causes downstream differences in the expression of genes involved in synaptic function, and also modulates phenotypes such as dopamine D1 and D2 receptor binding and pharmacological responses to haloperidol. Conclusions/Significance We have precisely defined the B2 SINE as the source of variation in Comt and demonstrated that a transposon in a 3′ UTR can alter mRNA isoform use and modulate behavior. The recent fixation of the variant in a subset of strains may have contributed to the rapid divergence of inbred strains. PMID:20808911

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.

Methylphenidate attenuates limbic brain inhibition after cocaine-cues exposure in cocaine abusers.

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

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

Dopamine (phasic release) is implicated in conditioned responses. Imaging studies in cocaine abusers show decreases in striatal dopamine levels, which we hypothesize may enhance conditioned responses since tonic dopamine levels modulate phasic dopamine release. To test this we assessed the effects of increasing tonic dopamine levels (using oral methylphenidate) on brain activation induced by cocaine-cues in cocaine abusers. Brain metabolism (marker of brain function) was measured with PET and {sup 18}FDG in 24 active cocaine abusers tested four times; twice watching a Neutral video (nature scenes) and twice watching a Cocaine-cues video; each video was preceded once by placebo andmore » once by methylphenidate (20 mg). The Cocaine-cues video increased craving to the same extent with placebo (68%) and with methylphenidate (64%). In contrast, SPM analysis of metabolic images revealed that differences between Neutral versus Cocaine-cues conditions were greater with placebo than methylphenidate; whereas with placebo the Cocaine-cues decreased metabolism (p<0.005) in left limbic regions (insula, orbitofrontal, accumbens) and right parahippocampus, with methylphenidate it only decreased in auditory and visual regions, which also occurred with placebo. Decreases in metabolism in these regions were not associated with craving; in contrast the voxel-wise SPM analysis identified significant correlations with craving in anterior orbitofrontal cortex (p<0.005), amygdala, striatum and middle insula (p<0.05). This suggests that methylphenidate's attenuation of brain reactivity to Cocaine-cues is distinct from that involved in craving. Cocaine-cues decreased metabolism in limbic regions (reflects activity over 30 minutes), which contrasts with activations reported by fMRI studies (reflects activity over 2-5 minutes) that may reflect long-lasting limbic inhibition following activation. Studies to evaluate the clinical significance of methylphenidate's blunting of cue-induced limbic inhibition may help identify potential benefits of this medication in cocaine addiction.« less

Methylphenidate Attenuates Limbic Brain Inhibition after Cocaine-Cues Exposure in Cocaine Abusers

PubMed Central

Volkow, Nora D.; Wang, Gene-Jack; Tomasi, Dardo; Telang, Frank; Fowler, Joanna S.; Pradhan, Kith; Jayne, Millard; Logan, Jean; Goldstein, Rita Z.; Alia-Klein, Nelly; Wong, Christopher

2010-01-01

Dopamine (phasic release) is implicated in conditioned responses. Imaging studies in cocaine abusers show decreases in striatal dopamine levels, which we hypothesize may enhance conditioned responses since tonic dopamine levels modulate phasic dopamine release. To test this we assessed the effects of increasing tonic dopamine levels (using oral methylphenidate) on brain activation induced by cocaine-cues in cocaine abusers. Brain metabolism (marker of brain function) was measured with PET and 18FDG in 24 active cocaine abusers tested four times; twice watching a Neutral video (nature scenes) and twice watching a Cocaine-cues video; each video was preceded once by placebo and once by methylphenidate (20 mg). The Cocaine-cues video increased craving to the same extent with placebo (68%) and with methylphenidate (64%). In contrast, SPM analysis of metabolic images revealed that differences between Neutral versus Cocaine-cues conditions were greater with placebo than methylphenidate; whereas with placebo the Cocaine-cues decreased metabolism (p<0.005) in left limbic regions (insula, orbitofrontal, accumbens) and right parahippocampus, with methylphenidate it only decreased in auditory and visual regions, which also occurred with placebo. Decreases in metabolism in these regions were not associated with craving; in contrast the voxel-wise SPM analysis identified significant correlations with craving in anterior orbitofrontal cortex (p<0.005), amygdala, striatum and middle insula (p<0.05). This suggests that methylphenidate's attenuation of brain reactivity to Cocaine-cues is distinct from that involved in craving. Cocaine-cues decreased metabolism in limbic regions (reflects activity over 30 minutes), which contrasts with activations reported by fMRI studies (reflects activity over 2–5 minutes) that may reflect long-lasting limbic inhibition following activation. Studies to evaluate the clinical significance of methylphenidate's blunting of cue-induced limbic inhibition may help identify potential benefits of this medication in cocaine addiction. PMID:20634975

Role of Dopamine Type 1 Receptors and Dopamine- and cAMP-Regulated Phosphoprotein Mr 32 kDa in Δ9-Tetrahydrocannabinol-Mediated Induction of ΔFosB in the Mouse Forebrain.

PubMed

Lazenka, Matthew F; Tomarchio, Aaron J; Lichtman, Aron H; Greengard, Paul; Flajolet, Marc; Selley, Dana E; Sim-Selley, Laura J

2015-09-01

Δ(9)-Tetrahydrocannabinol (THC), the main psychoactive component of marijuana, produces motor and motivational effects via interactions with the dopaminergic system in the caudate-putamen and nucleus accumbens. However, the molecular events that underlie these interactions after THC treatment are not well understood. Our study shows that pretreatment with dopamine D1 receptor (D1R) antagonists before repeated administration of THC attenuated induction of Δ FBJ murine osteosarcoma viral oncogene homolog B (ΔFosB) in the nucleus accumbens, caudate-putamen, amygdala, and prefrontal cortex. Anatomical studies showed that repeated THC administration induced ΔFosB in D1R-containing striatal neurons. Dopamine signaling in the striatum involves phosphorylation-specific effects of the dopamine- and cAMP-regulated phosphoprotein Mr 32 kDa (DARPP-32), which regulates protein kinase A signaling. Genetic deletion of DARPP-32 attenuated ΔFosB expression measured after acute, but not repeated, THC administration in both the caudate-putamen and nucleus accumbens. THC was then acutely or repeatedly administered to wild-type (WT) and DARPP-32 knockout (KO) mice, and in vivo responses were measured. DARPP-32 KO mice exhibited enhanced acute THC-mediated hypolocomotion and developed greater tolerance to this response relative to the WT mice. Agonist-stimulated guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPγS) binding showed that cannabinoid-stimulated G-protein activity did not differ between DARPP-32 KO and WT mice treated with vehicle or repeated THC. These results indicate that D1Rs play a major role in THC-mediated ΔFosB induction in the forebrain, whereas the role of DARPP-32 in THC-mediated ΔFosB induction and modulation of motor activity appears to be more complex. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

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.

Nucleus Accumbens Acetylcholine Receptors Modulate Dopamine and Motivation.

PubMed

Collins, Anne L; Aitken, Tara J; Greenfield, Venuz Y; Ostlund, Sean B; Wassum, Kate M

2016-11-01

Environmental reward-predictive cues can motivate reward-seeking behaviors. Although this influence is normally adaptive, it can become maladaptive in disordered states, such as addiction. Dopamine release in the nucleus accumbens core (NAc) is known to mediate the motivational impact of reward-predictive cues, but little is known about how other neuromodulatory systems contribute to cue-motivated behavior. Here, we examined the role of the NAc cholinergic receptor system in cue-motivated behavior using a Pavlovian-to-instrumental transfer task designed to assess the motivating influence of a reward-predictive cue over an independently-trained instrumental action. Disruption of NAc muscarinic acetylcholine receptor activity attenuated, whereas blockade of nicotinic receptors augmented cue-induced invigoration of reward seeking. We next examined a potential dopaminergic mechanism for this behavioral effect by combining fast-scan cyclic voltammetry with local pharmacological acetylcholine receptor manipulation. The data show evidence of opposing modulation of cue-evoked dopamine release, with muscarinic and nicotinic receptor antagonists causing suppression and augmentation, respectively, consistent with the behavioral effects of these manipulations. In addition to demonstrating cholinergic modulation of naturally-evoked and behaviorally-relevant dopamine signaling, these data suggest that NAc cholinergic receptors may gate the expression of cue-motivated behavior through modulation of phasic dopamine release.

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

PubMed

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

2017-05-01

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

Object recognition impairment in Fmr1 knockout mice is reversed by amphetamine: involvement of dopamine in the medial prefrontal cortex.

PubMed

Ventura, R; Pascucci, T; Catania, M V; Musumeci, S A; Puglisi-Allegra, S

2004-09-01

Fragile X syndrome is an X-linked form of mental retardation including, among others, symptoms such as stereotypic behaviour, hyperactivity, hyperarousal, and cognitive deficits. We hypothesized that hyperactivity and/or compromised attentional, cognitive functions may lead to impaired performance in cognitive tasks in Fmr1 knockout mice, the most widely used animal model of fragile X syndrome, and suggested that psychostimulant treatment may improve performance by acting on one or both components. Since hyperactivity and cognitive functions have been suggested to depend on striatal and prefrontal cortex dopaminergic dysfunction, we assessed whether amphetamine produced beneficial, positive effects by acting on dopaminergic corticostriatal systems. Our results show that Fmr1 knockout mice are not able to discriminate between a familiar object and a novel one in the object recognition test, thus showing a clear-cut cognitive impairment that, to date, has been difficult to demonstrate in other cognitive tasks. Amphetamine improved performance of Fmr1 knockout mice, leading to enhanced ability to discriminate novel versus familiar objects, without significantly affecting locomotor activity. In agreement with behavioural data, amphetamine produced a greater increase in dopamine release in the prefrontal cortex of Fmr1 knockout compared with the wild-type mice, while a weak striatal dopaminergic response was observed in Fmr1 knockout mice. Our data support the view that the psychostimulant ameliorates performance in Fmr1 knockout mice by improving merely cognitive functions through its action on prefrontal cortical dopamine, irrespective of its action on motor hyperactivity. These results indicate that prefrontal cortical dopamine plays a major role in cognitive impairments characterizing Fmr1 knockout mice, thus pointing to an important aetiological factor in the fragile X syndrome.

Adolescent social defeat alters markers of adult dopaminergic function.

PubMed

Novick, Andrew M; Forster, Gina L; Tejani-Butt, Shanaz M; Watt, Michael J

2011-08-10

Stressful experiences during adolescence can alter the trajectory of neural development and contribute to psychiatric disorders in adulthood. We previously demonstrated that adolescent male rats exposed to repeated social defeat stress show changes in mesocorticolimbic dopamine content both at baseline and in response to amphetamine when tested in adulthood. In the present study we examined whether markers of adult dopamine function are also compromised by adolescent experience of social defeat. Given that the dopamine transporter as well as dopamine D1 receptors act as regulators of psychostimulant action, are stress sensitive and undergo changes during adolescence, quantitative autoradiography was used to measure [(3)H]-GBR12935 binding to the dopamine transporter and [(3)H]-SCH23390 binding to dopamine D1 receptors, respectively. Our results indicate that social defeat during adolescence led to higher dopamine transporter binding in the infralimbic region of the medial prefrontal cortex and higher dopamine D1 receptor binding in the caudate putamen, while other brain regions analyzed were comparable to controls. Thus it appears that social defeat during adolescence causes specific changes to the adult dopamine system, which may contribute to behavioral alterations and increased drug seeking. Copyright © 2011 Elsevier Inc. All rights reserved.

Somatodendritic dopamine release: recent mechanistic insights

PubMed Central

Rice, Margaret E.; Patel, Jyoti C.

2015-01-01

Dopamine (DA) is a key transmitter in motor, reward and cogitative pathways, with DA dysfunction implicated in disorders including Parkinson's disease and addiction. Located in midbrain, DA neurons of the substantia nigra pars compacta project via the medial forebrain bundle to the dorsal striatum (caudate putamen), and DA neurons in the adjacent ventral tegmental area project to the ventral striatum (nucleus accumbens) and prefrontal cortex. In addition to classical vesicular release from axons, midbrain DA neurons exhibit DA release from their cell bodies and dendrites. Somatodendritic DA release leads to activation of D2 DA autoreceptors on DA neurons that inhibit their firing via G-protein-coupled inwardly rectifying K+ channels. This helps determine patterns of DA signalling at distant axonal release sites. Somatodendritically released DA also acts via volume transmission to extrasynaptic receptors that modulate local transmitter release and neuronal activity in the midbrain. Thus, somatodendritic release is a pivotal intrinsic feature of DA neurons that must be well defined in order to fully understand the physiology and pathophysiology of DA pathways. Here, we review recent mechanistic aspects of somatodendritic DA release, with particular emphasis on the Ca2+ dependence of release and the potential role of exocytotic proteins. PMID:26009764

Consequences of peripheral chemoreflex inhibition with low-dose dopamine in humans

PubMed Central

Niewinski, Piotr; Tubek, Stanislaw; Banasiak, Waldemar; Paton, Julian F R; Ponikowski, Piotr

2014-01-01

Low-dose dopamine inhibits peripheral chemoreceptors and attenuates the hypoxic ventilatory response (HVR) in humans. However, it is unknown: (1) whether it also modulates the haemodynamic reactions to acute hypoxia, (2) whether it also modulates cardiac baroreflex sensitivity (BRS) and (3) if there is any effect of dopamine withdrawal. We performed a double-blind, placebo-controlled study on 11 healthy male volunteers. At sea level over 2 days every subject was administered low-dose dopamine (2 μg kg–1 min–1) or saline infusion, during which we assessed both ventilatory and haemodynamic responses to acute hypoxia. Separately, we evaluated effects of initiation and withdrawal of each infusion and BRS. The initiation of dopamine infusion did not affect minute ventilation (MV) or mean blood pressure (MAP), but increased both heart rate (HR) and cardiac output. Concomitantly, it decreased systemic vascular resistance. Dopamine blunted the ventilatory, MAP and HR reactions (hypertension, tachycardia) to acute hypoxia. Dopamine attenuated cardiac BRS to falling blood pressure. Dopamine withdrawal evoked an increase in MV. The magnitude of the increment in MV due to dopamine withdrawal correlated with the size of the HVR and depended on the duration of dopamine administration. The ventilatory reaction to dopamine withdrawal constitutes a novel index of peripheral chemoreceptor function. PMID:24396060

Dopamine modulates an intrinsic mGluR5-mediated depolarization underlying prefrontal persistent activity

PubMed Central

Sidiropoulou, Kyriaki; Lu, Fang-Min; Fowler, Melissa A.; Xiao, Rui; Phillips, Christopher; Ozkan, Emin D.; Zhu, Michael X.; White, Francis J.; Cooper, Donald C.

2009-01-01

Intrinsic properties of neurons that enable them to maintain depolarized, persistently activated states in the absence of sustained input are poorly understood. In short-term memory tasks, individual prefrontal cortical (PFC) neurons are capable of maintaining persistent action potential output during delay periods between informative cues and behavioral responses. Dopamine and drugs of abuse alter PFC function and working memory possibly by modulating intrinsic neuronal properties. Here we use patch-clamp recording of layer 5 PFC pyramidal neurons to identify an action potential burst-evoked intrinsic mGluR5-mediated postsynaptic depolarization that initiates an activated state. Depolarization occurs in the absence of recurrent synaptic activity and is reduced by a postsynaptic dopamine D1/5 receptor pathway. The depolarization is substantially diminished following behavioral sensitization to cocaine; moreover the D1/5 receptor modulation is lost. We propose the burst-evoked intrinsic depolarization to be a novel form of short-term cellular memory that is modulated by dopamine and cocaine experience. PMID:19169252

Mediation by neurotensin-receptors of effects of neurotensin on self-stimulation of the medial prefrontal cortex.

PubMed Central

Fernández, R.; Sabater, R.; Sáez, J. A.; Montes, R.; Alba, F.; Ferrer, J. M.

1996-01-01

1 Intracortical microinjections of neurotensin (NT) selectively decreased intracranial self-stimulation (ICSS) of the medial prefrontal cortex in the rat. 2 To elucidate whether this effect is mediated by NT receptors or by the formation of NT-dopamine complexes, we investigated the effects on ICSS of intracortical microinjections of neurotensin (1-11), an NT fragment that forms extracellular complexes with dopamine but does not bind to NT receptors. 3 We also studied the effects of the peripheral administration of SR 48692, a selective antagonist of NT receptors, on the inhibition of ICSS produced by the intracortical administration of NT. 4 Unilateral microinjections of neurotensin (1-11) at doses of 10, 20 and 40 nmol into the medial prefrontal cortex did not change the basal ICSS rate of this area. 5 The intraperitoneal administration of SR 48692 at doses of 0.08 and 0.16 mg kg-1 30 min before microinjection of 10 nmol of NT into the medial prefrontal cortex, antagonized the inhibition of ICSS produced by the neuropeptide. 6 These results demonstrate that the inhibitory effect of NT on ICSS is mediated by NT receptors. PMID:8886412

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

Dilts, R.P.; Kalivas, P.W.

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

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

PubMed

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

2013-04-01

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

State-dependent spike and local field synchronization between motor cortex and substantia nigra in hemiparkinsonian rats.

PubMed

Brazhnik, Elena; Cruz, Ana V; Avila, Irene; Wahba, Marian I; Novikov, Nikolay; Ilieva, Neda M; McCoy, Alex J; Gerber, Colin; Walters, Judith R

2012-06-06

Excessive beta frequency oscillatory and synchronized activity has been reported in the basal ganglia of parkinsonian patients and animal models of the disease. To gain insight into processes underlying this activity, this study explores relationships between oscillatory activity in motor cortex and basal ganglia output in behaving rats after dopamine cell lesion. During inattentive rest, 7 d after lesion, increases in motor cortex-substantia nigra pars reticulata (SNpr) coherence emerged in the 8-25 Hz range, with significant increases in local field potential (LFP) power in SNpr but not motor cortex. In contrast, during treadmill walking, marked increases in both motor cortex and SNpr LFP power, as well as coherence, emerged in the 25-40 Hz band with a peak frequency at 30-35 Hz. Spike-triggered waveform averages showed that 77% of SNpr neurons, 77% of putative cortical interneurons, and 44% of putative pyramidal neurons were significantly phase-locked to the increased cortical LFP activity in the 25-40 Hz range. Although the mean lag between cortical and SNpr LFPs fluctuated around zero, SNpr neurons phase-locked to cortical LFP oscillations fired, on average, 17 ms after synchronized spiking in motor cortex. High coherence between LFP oscillations in cortex and SNpr supports the view that cortical activity facilitates entrainment and synchronization of activity in basal ganglia after loss of dopamine. However, the dramatic increases in cortical power and relative timing of phase-locked spiking in these areas suggest that additional processes help shape the frequency-specific tuning of the basal ganglia-thalamocortical network during ongoing motor activity.

The Psychoactive Designer Drug and Bath Salt Constituent MDPV Causes Widespread Disruption of Brain Functional Connectivity

PubMed Central

Colon-Perez, Luis M; Tran, Kelvin; Thompson, Khalil; Pace, Michael C; Blum, Kenneth; Goldberger, Bruce A; Gold, Mark S; Bruijnzeel, Adriaan W; Setlow, Barry; Febo, Marcelo

2016-01-01

The abuse of ‘bath salts' has raised concerns because of their adverse effects, which include delirium, violent behavior, and suicide ideation in severe cases. The bath salt constituent 3,4-methylenedioxypyrovalerone (MDPV) has been closely linked to these and other adverse effects. The abnormal behavioral pattern produced by acute high-dose MDPV intake suggests possible disruptions of neural communication between brain regions. Therefore, we determined if MDPV exerts disruptive effects on brain functional connectivity, particularly in areas of the prefrontal cortex. Male rats were imaged following administration of a single dose of MDPV (0.3, 1.0, or 3.0 mg/kg) or saline. Resting state brain blood oxygenation level-dependent (BOLD) images were acquired at 4.7 T. To determine the role of dopamine transmission in MDPV-induced changes in functional connectivity, a group of rats received the dopamine D1/D2 receptor antagonist cis-flupenthixol (0.5 mg/kg) 30 min before MDPV. MDPV dose-dependently reduced functional connectivity. Detailed analysis of its effects revealed that connectivity between frontal cortical and striatal areas was reduced. This included connectivity between the prelimbic prefrontal cortex and other areas of the frontal cortex and the insular cortex with hypothalamic, ventral, and dorsal striatal areas. Although the reduced connectivity appeared widespread, connectivity between these regions and somatosensory cortex was not as severely affected. Dopamine receptor blockade did not prevent the MDPV-induced decrease in functional connectivity. The results provide a novel signature of MDPV's in vivo mechanism of action. Reduced brain functional connectivity has been reported in patients suffering from psychosis and has been linked to cognitive dysfunction, audiovisual hallucinations, and negative affective states akin to those reported for MDPV-induced intoxication. The present results suggest that disruption of functional connectivity networks involving frontal cortical and striatal regions could contribute to the adverse effects of MDPV. PMID:26997298

Prefrontal Dopamine D1 and D2 Receptors Regulate Dissociable Aspects of Decision Making via Distinct Ventral Striatal and Amygdalar Circuits.

PubMed

Jenni, Nicole L; Larkin, Joshua D; Floresco, Stan B

2017-06-28

Mesocortical dopamine (DA) regulates a variety of cognitive functions via actions on D 1 and/or D 2 receptors. For example, risk/reward decision making is modulated differentially by these two receptors within the prefrontal cortex (PFC), with D 2 receptors enabling flexible decision making and D 1 receptors promoting persistence in choice biases. However, it is unclear how DA mediates opposing patterns of behavior by acting on different receptors within the same terminal region. We explored the possibility that DA may act on separate networks of PFC neurons that are modulated by D 1 or D 2 receptors and in turn interface with divergent downstream structures such as the basolateral amygdala (BLA) or nucleus accumbens (NAc). Decision making was assessed using a probabilistic discounting task in which well trained male rats chose between small/certain or large/risky rewards, with the odds of obtaining the larger reward changing systematically within a session. Selective disruption of D 1 or D 2 modulation of separate PFC output pathways was achieved using unilateral intra-PFC infusions of DA antagonists combined with contralateral inactivation of the BLA or NAc. Disrupting D 2 (but not D 1 ) modulation of PFC→BLA circuitry impaired adjustments in decision biases in response to changes in reward probabilities. In contrast, disrupting D 1 modulation of PFC→NAc networks reduced risky choice, attenuating reward sensitivity and increasing sensitivity to reward omissions. These findings reveal that mesocortical DA can facilitate dissociable components of reward seeking and action selection by acting on different functional networks of PFC neurons that can be distinguished by the subcortical projection targets with which they interface. SIGNIFICANCE STATEMENT Prefrontal cortical dopamine regulates a variety of executive functions governed by the frontal lobes via actions on D 1 and D 2 receptors. These receptors can in some instances mediate different patterns of behavior, but the mechanisms underlying these dissociable actions are unclear. Using a selective disconnection approach, we reveal that D 1 and D 2 receptors can facilitate diverse aspects of decision making by acting on separate networks of prefrontal neurons that interface with distinct striatal or amygdalar targets. These findings reveal an additional level of complexity in how mesocortical DA regulates different forms of cognition via actions on different receptors, highlighting how it may act upon distinct cortical microcircuits to drive different patterns of behavior. Copyright © 2017 the authors 0270-6474/17/376200-14$15.00/0.

High-Frequency Stimulation of the Subthalamic Nucleus Activates Motor Cortex Pyramidal Tract Neurons by a Process Involving Local Glutamate, GABA and Dopamine Receptors in Hemi-Parkinsonian Rats.

PubMed

Chuang, Chi-Fen; Wu, Chen-Wei; Weng, Ying; Hu, Pei-San; Yeh, Shin-Rung; Chang, Yen-Chung

2018-04-30

Deep brain stimulation (DBS) is widely used to treat advanced Parkinson’s disease (PD). Here, we investigated how DBS applied on the subthalamic nucleus (STN) influenced the neural activity in the motor cortex. Rats, which had the midbrain dopaminergic neurons partially depleted unilaterally, called the hemi-Parkinsonian rats, were used as a study model. c-Fos expression in the neurons was used as an indicator of neural activity. Application of high-frequency stimulation (HFS) upon the STN was used to mimic the DBS treatment. The motor cortices in the two hemispheres of hemi-Parkinsonian rats were found to contain unequal densities of c-Fos-positive (Fos+) cells, and STN-HFS rectified this bilateral imbalance. In addition, STN-HFS led to the intense c-Fos expression in a group of motor cortical neurons which exhibited biochemical and anatomical characteristics resembling those of the pyramidal tract (PT) neurons sending efferent projections to the STN. The number of PT neurons expressing high levels of c-Fos was significantly reduced by local application of the antagonists of non-N-methyl-D-aspartate (non-NMDA) glutamate receptors, gammaaminobutyric acid A (GABAA) receptors and dopamine receptors in the upper layers of the motor cortex. The results indicate that the coincident activations of synapses and dopamine receptors in the motor cortex during STN-HFS trigger the intense expression of c-Fos of the PT neurons. The implications of the results on the cellular mechanism underlying the therapeutic effects of STN-DBS on the movement disorders of PD are also discussed.

Differential Involvement of Dopamine D1 Receptor and MEK Signaling Pathway in the Ventromedial Prefrontal Cortex in Consolidation and Reconsolidation of Recognition Memory

ERIC Educational Resources Information Center

Maroun, Mouna; Akirav, Irit

2009-01-01

We investigated MEK and D1 receptors in the ventromedial prefrontal cortex (vmPFC) in consolidation and reconsolidation of recognition memory in rats nonhabituated to the experimental context (NH) or with reduced arousal due to extensive prior habituation (H). The D1 receptor antagonist enhanced consolidation and impaired reconsolidation in NH but…

Lateralized sex differences in stress-induced dopamine release in the rat.

PubMed

Sullivan, Ron M; Dufresne, Marc M; Waldron, Jay

2009-02-18

This study examined the possibility that hemispheric differences in stress-induced brain activation vary as a function of sex. Using in-vivo voltammetry, increases in extracellular dopamine release in response to predator odour and tail pinch stress were recorded bilaterally and simultaneously in either the infralimbic cortex or basolateral amygdala. In both stress-sensitive brain regions, significant sex x hemisphere interactions were observed, with males and females showing greater dopamine activation in right-brain and left-brain structures, respectively. Cortical asymmetries in dopamine release also showed sex-specific correlations with stress-induced neuroendocrine activation. Given the intriguing human parallels, we suggest that differential cerebral lateralization may be highly relevant to the disproportionately high incidence of stress-related disorders such as depression and anxiety seen in women.

GHSR-D2R heteromerization modulates dopamine signaling through an effect on G protein conformation.

PubMed

Damian, Marjorie; Pons, Véronique; Renault, Pedro; M'Kadmi, Céline; Delort, Bartholomé; Hartmann, Lucie; Kaya, Ali I; Louet, Maxime; Gagne, Didier; Ben Haj Salah, Khoubaib; Denoyelle, Séverine; Ferry, Gilles; Boutin, Jean A; Wagner, Renaud; Fehrentz, Jean-Alain; Martinez, Jean; Marie, Jacky; Floquet, Nicolas; Galès, Céline; Mary, Sophie; Hamm, Heidi E; Banères, Jean-Louis

2018-04-24

The growth hormone secretagogue receptor (GHSR) and dopamine receptor (D2R) have been shown to oligomerize in hypothalamic neurons with a significant effect on dopamine signaling, but the molecular processes underlying this effect are still obscure. We used here the purified GHSR and D2R to establish that these two receptors assemble in a lipid environment as a tetrameric complex composed of two each of the receptors. This complex further recruits G proteins to give rise to an assembly with only two G protein trimers bound to a receptor tetramer. We further demonstrate that receptor heteromerization directly impacts on dopamine-mediated Gi protein activation by modulating the conformation of its α-subunit. Indeed, association to the purified GHSR:D2R heteromer triggers a different active conformation of Gαi that is linked to a higher rate of GTP binding and a faster dissociation from the heteromeric receptor. This is an additional mechanism to expand the repertoire of GPCR signaling modulation that could have implications for the control of dopamine signaling in normal and physiopathological conditions.

Prefrontal cortical network activity: Opposite effects of psychedelic hallucinogens and D1/D5 dopamine receptor activation

PubMed Central

Lambe, Evelyn K.; Aghajanian, George K.

2007-01-01

The fine-tuning of network activity provides a modulating influence on how information is processed and interpreted in the brain. Here, we use brain slices of rat prefrontal cortex to study how recurrent network activity is affected by neuromodulators known to alter normal cortical function. We previously determined that glutamate spillover and stimulation of extrasynaptic NMDA receptors are required to support hallucinogen-induced cortical network activity. Since microdialysis studies suggest that psychedelic hallucinogens and dopamine D1/D5 receptor agonists have opposite effects on extracellular glutamate in prefrontal cortex, we hypothesized that these two families of psychoactive drugs would have opposite effects on cortical network activity. We found that network activity can be enhanced by DOI (a psychedelic hallucinogen that is a partial agonist of serotonin 5-HT2A/2C receptors) and suppressed by the selective D1/D5 agonist SKF 38393. This suppression could be mimicked by direct activation of adenylyl cyclase with forskolin or by addition of a cAMP analog. These findings are consistent with previous work showing that activation of adenylyl cyclase can upregulate neuronal glutamate transporters, thereby decreasing synaptic spillover of glutamate. Consistent with this hypothesis, a low concentration of the glutamate transporter inhibitor TBOA restored electrically-evoked recurrent activity in the presence of a selective D1/D5 agonist, whereas recurrent activity in the presence of a low level of the GABAA antagonist bicuculline was not resistant to suppression by the D1/D5 agonist. The tempering of network UP states by D1/D5 receptor activation may have implications for the proposed use of D1/D5 agonists in the treatment of schizophrenia. PMID:17293055

Transcranial direct current stimulation improves short-term memory in an animal model of attention-deficit/hyperactivity disorder.

PubMed

Leffa, Douglas Teixeira; de Souza, Andressa; Scarabelot, Vanessa Leal; Medeiros, Liciane Fernandes; de Oliveira, Carla; Grevet, Eugenio Horacio; Caumo, Wolnei; de Souza, Diogo Onofre; Rohde, Luis Augusto Paim; Torres, Iraci L S

2016-02-01

Attention deficit hyperactivity disorder (ADHD) is characterized by impairing levels of hyperactivity, impulsivity and inattention. However, different meta-analyses have reported disruptions in short and long-term memory in ADHD patients. Previous studies indicate that mnemonic dysfunctions might be the result of deficits in attentional circuits, probably due to ineffective dopaminergic modulation of hippocampal synaptic plasticity. In this study we aimed to evaluate the potential therapeutic effects of a neuromodulatory technique, transcranial direct current stimulation (tDCS), in short-term memory (STM) deficits presented by the spontaneous hypertensive rats (SHR), the most widely used animal model of ADHD. Adult male SHR and Wistar Kyoto rats (WKY) were subjected to a constant electrical current of 0.5 mA intensity applied on the frontal cortex for 20 min/day during 8 days. STM was evaluated with an object recognition test conducted in an open field. Exploration time and locomotion were recorded, and brain regions were dissected to determine dopamine and BDNF levels. SHR spent less time exploring the new object when compared to WKY, and tDCS improved object recognition deficits in SHR without affecting WKY performance. Locomotor activity was higher in SHR and it was not affected by tDCS. After stimulation, dopamine levels were increased in the hippocampus and striatum of both strains, while BDNF levels were increased only in the striatum of WKY. These findings suggest that tDCS on the frontal cortex might be able to improve STM deficits present in SHR, which is potentially related to dopaminergic neurotransmission in the hippocampus and striatum of those animals. Copyright © 2016. Published by Elsevier B.V.

Ventral Tegmental Area Dopamine Cell Activation during Male Rat Sexual Behavior Regulates Neuroplasticity and d-Amphetamine Cross-Sensitization following Sex Abstinence.

PubMed

Beloate, Lauren N; Omrani, Azar; Adan, Roger A; Webb, Ian C; Coolen, Lique M

2016-09-21

Experience with sexual behavior causes cross-sensitization of amphetamine reward, an effect dependent on a period of sexual reward abstinence. We previously showed that ΔFosB in the nucleus accumbens (NAc) is a key mediator of this cross-sensitization, potentially via dopamine receptor activation. However, the role of mesolimbic dopamine for sexual behavior or cross-sensitization between natural and drug reward is unknown. This was tested using inhibitory designer receptors exclusively activated by designer drugs in ventral tegmental area (VTA) dopamine cells. rAAV5/hSvn-DIO-hm4D-mCherry was injected into the VTA of TH::Cre adult male rats. Males received clozapine N-oxide (CNO) or vehicle injections before each of 5 consecutive days of mating or handling. Following an abstinence period of 7 d, males were tested for amphetamine conditioned place preference (CPP). Next, males were injected with CNO or vehicle before mating or handling for analysis of mating-induced cFos, sex experience-induced ΔFosB, and reduction of VTA dopamine soma size. Results showed that CNO did not affect mating behavior. Instead, CNO prevented sexual experience-induced cross-sensitization of amphetamine CPP, ΔFosB in the NAc and medial prefrontal cortex, and decreases in VTA dopamine soma size. Expression of hm4D-mCherry was specific to VTA dopamine cells and CNO blocked excitation and mating-induced cFos expression in VTA dopamine cells. These findings provide direct evidence that VTA dopamine activation is not required for initiation or performance of sexual behavior. Instead, VTA dopamine directly contributes to increased vulnerability for drug use following loss of natural reward by causing neuroplasticity in the mesolimbic pathway during the natural reward experience. Drugs of abuse act on the neural pathways that mediate natural reward learning and memory. Exposure to natural reward behaviors can alter subsequent drug-related reward. Specifically, experience with sexual behavior, followed by a period of abstinence from sexual behavior, causes increased reward for amphetamine in male rats. This study demonstrates that activation of ventral tegmental area dopamine neurons during sexual experience regulates cross-sensitization of amphetamine reward. Finally, ventral tegmental area dopamine cell activation is essential for experience-induced neural adaptations in the nucleus accumbens, prefrontal cortex, and ventral tegmental area. These findings demonstrate a role of mesolimbic dopamine in the interaction between natural and drug rewards, and identify mesolimbic dopamine as a key mediator of changes in vulnerability for drug use after loss of natural reward. Copyright © 2016 the authors 0270-6474/16/369949-13$15.00/0.

Ventral striatal dopamine reflects behavioral and neural signatures of model-based control during sequential decision making.

PubMed

Deserno, Lorenz; Huys, Quentin J M; Boehme, Rebecca; Buchert, Ralph; Heinze, Hans-Jochen; Grace, Anthony A; Dolan, Raymond J; Heinz, Andreas; Schlagenhauf, Florian

2015-02-03

Dual system theories suggest that behavioral control is parsed between a deliberative "model-based" and a more reflexive "model-free" system. A balance of control exerted by these systems is thought to be related to dopamine neurotransmission. However, in the absence of direct measures of human dopamine, it remains unknown whether this reflects a quantitative relation with dopamine either in the striatum or other brain areas. Using a sequential decision task performed during functional magnetic resonance imaging, combined with striatal measures of dopamine using [(18)F]DOPA positron emission tomography, we show that higher presynaptic ventral striatal dopamine levels were associated with a behavioral bias toward more model-based control. Higher presynaptic dopamine in ventral striatum was associated with greater coding of model-based signatures in lateral prefrontal cortex and diminished coding of model-free prediction errors in ventral striatum. Thus, interindividual variability in ventral striatal presynaptic dopamine reflects a balance in the behavioral expression and the neural signatures of model-free and model-based control. Our data provide a novel perspective on how alterations in presynaptic dopamine levels might be accompanied by a disruption of behavioral control as observed in aging or neuropsychiatric diseases such as schizophrenia and addiction.

Effect of in vivo exposure to ambient fine particles (PM2.5) on the density of dopamine D2-like receptors and dopamine-induced [35S]-GTPγS binding in rat prefrontal cortex and striatum membranes.

PubMed

Andrade-Oliva, María-de-Los-Angeles; Aztatzi-Aguilar, Octavio-Gamaliel; García-Sierra, Francisco; De Vizcaya-Ruiz, Andrea; Arias-Montaño, José-Antonio

2018-06-01

Male Sprague-Dawley rats (8-9 weeks-old) were exposed for three days (acute exposure) or eight weeks (subchronic exposure) to purified air or concentrated ambient fine particles, PM 2.5 (≤2.5 μm; 15 to 18-fold of ambient air; 370-445 μg/m 3 ). In membranes from rat prefrontal cortex (PFC) or striatum, the density and function of dopamine D 2 -like receptors (D 2 Rs) were assessed by [ 3 H]-spiperone binding and dopamine-stimulated [ 35 S]-GTPγS binding, respectively. Glial activation was evaluated by immunoperoxidase labeling of the glial fibrillary acidic protein (GFAP). In the PFC, no significant changes in D 2 R density or signaling were observed after the acute and subchronic exposure to PM 2.5 . In the striatum, acute exposure to PM 2.5 decreased D 2 R density, with no effect on signaling efficacy, whereas subchronic exposure did not affect D 2 R density but reduced signaling efficacy. Both acute and subchronic exposure to PM 2.5 induced reactive gliosis in the striatum but not in the PFC. These results indicate that exposure to PM 2.5 induces astrocyte activation and alters striatal dopaminergic transmission. Copyright © 2018 Elsevier B.V. All rights reserved.

Spatial Frequency Selectivity Is Impaired in Dopamine D2 Receptor Knockout Mice

PubMed Central

Souza, Bruno Oliveira Ferreira; Abou Rjeili, Mira; Quintana, Clémentine; Beaulieu, Jean M.; Casanova, Christian

2018-01-01

Dopamine is a neurotransmitter implicated in several brain functions, including vision. In the present study, we investigated the impacts of the lack of D2 dopamine receptors on the structure and function of the primary visual cortex (V1) of D2-KO mice using optical imaging of intrinsic signals. Retinotopic maps were generated in order to measure anatomo-functional parameters such as V1 shape, cortical magnification factor, scatter, and ocular dominance. Contrast sensitivity and spatial frequency selectivity (SF) functions were computed from responses to drifting gratings. When compared to control mice, none of the parameters of the retinotopic maps were affected by D2 receptor loss of function. While the contrast sensitivity function of D2-KO mice did not differ from their wild-type counterparts, SF selectivity function was significantly affected as the optimal SF and the high cut-off frequency (p < 0.01) were higher in D2-KO than in WT mice. These findings show that the lack of function of D2 dopamine receptors had no influence on cortical structure whereas it had a significant impact on the spatial frequency selectivity and high cut-off. Taken together, our results suggest that D2 receptors play a specific role on the processing of spatial features in early visual cortex while they do not seem to participate in its development. PMID:29379422

Neurotransmitters behind pain relief with transcranial magnetic stimulation - positron emission tomography evidence for release of endogenous opioids.

PubMed

Lamusuo, S; Hirvonen, J; Lindholm, P; Martikainen, I K; Hagelberg, N; Parkkola, R; Taiminen, T; Hietala, J; Helin, S; Virtanen, A; Pertovaara, A; Jääskeläinen, S K

2017-10-01

Repetitive transcranial magnetic stimulation (rTMS) at M1/S1 cortex has been shown to alleviate neuropathic pain. To investigate the possible neurobiological correlates of cortical neurostimulation for the pain relief. We studied the effects of M1/S1 rTMS on nociception, brain dopamine D2 and μ-opioid receptors using a randomized, sham-controlled, double-blinded crossover study design and 3D-positron emission tomography (PET). Ten healthy subjects underwent active and sham rTMS treatments to the right M1/S1 cortex with E-field navigated device. Dopamine D2 and μ-receptor availabilities were assessed with PET radiotracers [ 11 C]raclopride and [ 11 C]carfentanil after each rTMS treatment. Thermal quantitative sensory testing (QST), contact heat evoked potential (CHEP) and blink reflex (BR) recordings were performed between the PET scans. μ-Opioid receptor availability was lower after active than sham rTMS (P ≤ 0.0001) suggested release of endogenous opioids in the right ventral striatum, medial orbitofrontal, prefrontal and anterior cingulate cortices, and left insula, superior temporal gyrus, dorsolateral prefrontal cortex and precentral gyrus. There were no differences in striatal dopamine D2 receptor availability between active and sham rTMS, consistent with lack of long-lasting measurable dopamine release. Active rTMS potentiated the dopamine-regulated habituation of the BR compared to sham (P = 0.02). Thermal QST and CHEP remained unchanged after active rTMS. rTMS given to M1/S1 activates the endogenous opioid system in a wide brain network associated with processing of pain and other salient stimuli. Direct enhancement of top-down opioid-mediated inhibition may partly explain the clinical analgesic effects of rTMS. Neurobiological correlates of rTMS for the pain relief are unclear. rTMS on M1/S1 with 11 C-carfentanyl-PET activates endogenous opioids. Thermal and heat pain thresholds remain unchanged. rTMS induces top-down opioid-mediated inhibition but not change the sensory discrimination of painful stimuli. © 2017 European Pain Federation - EFIC®.

Monoaminergic modulation of photoreception in ascidian: evidence for a proto-hypothalamo-retinal territory

PubMed Central

2012-01-01

Background The retina of craniates/vertebrates has been proposed to derive from a photoreceptor prosencephalic territory in ancestral chordates, but the evolutionary origin of the different cell types making the retina is disputed. Except for photoreceptors, the existence of homologs of retinal cells remains uncertain outside vertebrates. Methods The expression of genes expressed in the sensory vesicle of the ascidian Ciona intestinalis including those encoding components of the monoaminergic neurotransmission systems, was analyzed by in situ hybridization or in vivo transfection of the corresponding regulatory elements driving fluorescent reporters. Modulation of photic responses by monoamines was studied by electrophysiology combined with pharmacological treatments. Results We show that many molecular characteristics of dopamine-synthesizing cells located in the vicinity of photoreceptors in the sensory vesicle of the ascidian Ciona intestinalis are similar to those of amacrine dopamine cells of the vertebrate retina. The ascidian dopamine cells share with vertebrate amacrine cells the expression of the key-transcription factor Ptf1a, as well as that of dopamine-synthesizing enzymes. Surprisingly, the ascidian dopamine cells accumulate serotonin via a functional serotonin transporter, as some amacrine cells also do. Moreover, dopamine cells located in the vicinity of the photoreceptors modulate the light-off induced swimming behavior of ascidian larvae by acting on alpha2-like receptors, instead of dopamine receptors, supporting a role in the modulation of the photic response. These cells are located in a territory of the ascidian sensory vesicle expressing genes found both in the retina and the hypothalamus of vertebrates (six3/6, Rx, meis, pax6, visual cycle proteins). Conclusion We propose that the dopamine cells of the ascidian larva derive from an ancestral multifunctional cell population located in the periventricular, photoreceptive field of the anterior neural tube of chordates, which also gives rise to both anterior hypothalamus and the retina in craniates/vertebrates. It also shows that the existence of multiple cell types associated with photic responses predates the formation of the vertebrate retina. PMID:22642675

Refinement of learned skilled movement representation in motor cortex deep output layer

PubMed Central

Li, Qian; Ko, Ho; Qian, Zhong-Ming; Yan, Leo Y. C.; Chan, Danny C. W.; Arbuthnott, Gordon; Ke, Ya; Yung, Wing-Ho

2017-01-01

The mechanisms underlying the emergence of learned motor skill representation in primary motor cortex (M1) are not well understood. Specifically, how motor representation in the deep output layer 5b (L5b) is shaped by motor learning remains virtually unknown. In rats undergoing motor skill training, we detect a subpopulation of task-recruited L5b neurons that not only become more movement-encoding, but their activities are also more structured and temporally aligned to motor execution with a timescale of refinement in tens-of-milliseconds. Field potentials evoked at L5b in vivo exhibit persistent long-term potentiation (LTP) that parallels motor performance. Intracortical dopamine denervation impairs motor learning, and disrupts the LTP profile as well as the emergent neurodynamical properties of task-recruited L5b neurons. Thus, dopamine-dependent recruitment of L5b neuronal ensembles via synaptic reorganization may allow the motor cortex to generate more temporally structured, movement-encoding output signal from M1 to downstream circuitry that drives increased uniformity and precision of movement during motor learning. PMID:28598433

Assessing the Molecular Genetics of the Development of Executive Attention in Children: Focus on Genetic Pathways Related to the Anterior Cingulate Cortex and Dopamine

PubMed Central

Brocki, Karin; Clerkin, Suzanne M.; Guise, Kevin G.; Fan, Jin; Fossella, John A.

2009-01-01

It is well-known that children show gradual and protracted improvement in an array of behaviors involved in the conscious control of thought and emotion. Non-invasive neuroimaging in developing populations has revealed many neural correlates of behavior, particularly in the developing cingulate cortex and fronto-striatal circuits. These brain regions, themselves, undergo protracted molecular and cellular change in the first two decades of human development and, as such, are ideal regions of interest for cognitive- and imaging-genetic studies that seek to link processes at the biochemical and synaptic levels to brain activity and behavior. We review our research to-date that employs both adult and child-friendly versions of the Attention Network Task (ANT) in an effort to begin to describe the role of specific genes in the assembly of a functional attention system. Presently, we constrain our predictions for genetic association studies by focusing on the role of the anterior cingulate cortex (ACC) and of dopamine in the development of executive attention. PMID:19344637

Acute phenylalanine/tyrosine depletion of phasic dopamine in the rat brain.

PubMed

Shnitko, Tatiana A; Taylor, Sarah C; Stringfield, Sierra J; Zandy, Shannon L; Cofresí, Roberto U; Doherty, James M; Lynch, William B; Boettiger, Charlotte A; Gonzales, Rueben A; Robinson, Donita L

2016-06-01

Dopamine plays a critical role in striatal and cortical function, and depletion of the dopamine precursors phenylalanine and tyrosine is used in humans to temporarily reduce dopamine and probe the role of dopamine in behavior. This method has been shown to alter addiction-related behaviors and cognitive functioning presumably by reducing dopamine transmission, but it is unclear what specific aspects of dopamine transmission are altered. We performed this study to confirm that administration of an amino acid mixture omitting phenylalanine and tyrosine (Phe/Tyr[-]) reduces tyrosine tissue content in the prefrontal cortex (PFC) and nucleus accumbens (NAc), and to test the hypothesis that Phe/Tyr[-] administration reduces phasic dopamine release in the NAc. Rats were injected with a Phe/Tyr[-] amino acid mixture, a control amino acid mixture, or saline. High-performance liquid chromatography was used to determine the concentration of tyrosine, dopamine, or norepinephrine in tissue punches from the PFC and ventral striatum. In a separate group of rats, phasic dopamine release was measured with fast-scan cyclic voltammetry in the NAc core after injection with either the Phe/Tyr[-] mixture or the control amino acid solution. Phe/Tyr[-] reduced tyrosine content in the PFC and NAc, but dopamine and norepinephrine tissue content were not reduced. Moreover, Phe/Tyr[-] decreased the frequency of dopamine transients, but not their amplitude, in freely moving rats. These results indicate that depletion of tyrosine via Phe/Tyr[-] decreases phasic dopamine transmission, providing insight into the mechanism by which this method modifies dopamine-dependent behaviors in human imaging studies.

Comparative Proteomic Analysis of Carbonylated Proteins from the Striatum and Cortex of Pesticide-Treated Mice

PubMed Central

Coughlan, Christina; Walker, Douglas I.; Lohr, Kelly M.; Richardson, Jason R.; Saba, Laura M.; Caudle, W. Michael; Fritz, Kristofer S.; Roede, James R.

2015-01-01

Epidemiological studies indicate exposures to the herbicide paraquat (PQ) and fungicide maneb (MB) are associated with increased risk of Parkinson's disease (PD). Oxidative stress appears to be a premier mechanism that underlies damage to the nigrostriatal dopamine system in PD and pesticide exposure. Enhanced oxidative stress leads to lipid peroxidation and production of reactive aldehydes; therefore, we conducted proteomic analyses to identify carbonylated proteins in the striatum and cortex of pesticide-treated mice in order to elucidate possible mechanisms of toxicity. Male C57BL/6J mice were treated biweekly for 6 weeks with saline, PQ (10 mg/kg), MB (30 mg/kg), or the combination of PQ and MB (PQMB). Treatments resulted in significant behavioral alterations in all treated mice and depleted striatal dopamine in PQMB mice. Distinct differences in 4-hydroxynonenal-modified proteins were observed in the striatum and cortex. Proteomic analyses identified carbonylated proteins and peptides from the cortex and striatum, and pathway analyses revealed significant enrichment in a variety of KEGG pathways. Further analysis showed enrichment in proteins of the actin cytoskeleton in treated samples, but not in saline controls. These data indicate that treatment-related effects on cytoskeletal proteins could alter proper synaptic function, thereby resulting in impaired neuronal function and even neurodegeneration. PMID:26345149

Glucose-monitoring neurons in the mediodorsal prefrontal cortex.

PubMed

Nagy, Bernadett; Szabó, István; Papp, Szilárd; Takács, Gábor; Szalay, Csaba; Karádi, Zoltán

2012-03-20

The mediodorsal prefrontal cortex (mdPFC), a key structure of the limbic neural circuitry, plays important roles in the central regulation of feeding. As an integrant part of the forebrain dopamine (DA) system, it performs complex roles via interconnections with various brain areas where glucose-monitoring (GM) neurons have been identified. The main goal of the present experiments was to examine whether similar GM neurons exist in the mediodorsal prefrontal cortex. To search for such chemosensory cells here, and to estimate their involvement in the DA circuitry, extracellular single neuron activity of the mediodorsal prefrontal cortex of anesthetized Wistar and Sprague-Dawley rats was recorded by means of tungsten wire multibarreled glass microelectrodes during microelectrophoretic administration of d-glucose and DA. One fourth of the neurons tested changed in firing rate in response to glucose, thus, proved to be elements of the forebrain GM neural network. DA responsive neurons in the mdPFC were found to represent similar proportion of all cells; the glucose-excited units were shown to display excitatory whereas the glucose-inhibited neurons were demonstrated to exert mainly inhibitory responses to dopamine. The glucose-monitoring neurons of the mdPFC and their distinct DA sensitivity are suggested to be of particular significance in adaptive processes of the central feeding control. Copyright © 2012 Elsevier B.V. All rights reserved.

State-Dependent Spike and Local Field Synchronization between Motor Cortex and Substantia Nigra in Hemiparkinsonian Rats

PubMed Central

Brazhnik, Elena; Cruz, Ana V.; Avila, Irene; Wahba, Marian I.; Novikov, Nikolay; Ilieva, Neda M.; McCoy, Alex J.; Gerber, Colin; Walters, Judith. R.

2012-01-01

Excessive beta frequency oscillatory and synchronized activity has been reported in the basal ganglia of Parkinsonian patients and animal models of the disease. To gain insight into processes underlying this activity, this study explores relationships between oscillatory activity in motor cortex and basal ganglia output in behaving rats after dopamine cell lesion. During inattentive rest, seven days after lesion, increases in motor cortex-substantia nigra pars reticulata (SNpr) coherence emerged in the 8–25 Hz range, with significant increases in local field potential (LFP) power in SNpr but not motor cortex. In contrast, during treadmill walking, marked increases in both motor cortex and SNpr LFP power, as well as coherence, emerged in the 25–40 Hz band with a peak frequency at 30–35 Hz. Spike-triggered waveform averages showed that 77% of SNpr neurons, 77% of putative cortical interneurons and 44% of putative pyramidal neurons were significantly phase-locked to the increased cortical LFP activity in the 25–40 Hz range. Although the mean lag between cortical and SNpr LFPs fluctuated around zero, SNpr neurons phase-locked to cortical LFP oscillations fired, on average, 17 ms after synchronized spiking in motor cortex. High coherence between LFP oscillations in cortex and SNpr supports the view that cortical activity facilitates entrainment and synchronization of activity in basal ganglia after loss of dopamine. However, the dramatic increases in cortical power and relative timing of phase-locked spiking in these areas suggest that additional processes help shape the frequency-specific tuning of the basal ganglia-thalamocortical network during ongoing motor activity. PMID:22674263

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

PubMed

Urra, Javier A; Villaroel-Espíndola, Franz; Covarrubias, Alejandra A; Rodríguez-Gil, Joan Enric; Ramírez-Reveco, Alfredo; Concha, Ilona I

2014-01-01

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

Presence and Function of Dopamine Transporter (DAT) in Stallion Sperm: Dopamine Modulates Sperm Motility and Acrosomal Integrity

PubMed Central

Covarrubias, Alejandra A.; Rodríguez-Gil, Joan Enric; Ramírez-Reveco, Alfredo; Concha, Ilona I.

2014-01-01

Dopamine is a catecholamine with multiple physiological functions, playing a key role in nervous system; however its participation in reproductive processes and sperm physiology is controversial. High dopamine concentrations have been reported in different portions of the feminine and masculine reproductive tract, although the role fulfilled by this catecholamine in reproductive physiology is as yet unknown. We have previously shown that dopamine type 2 receptor is functional in boar sperm, suggesting that dopamine acts as a physiological modulator of sperm viability, capacitation and motility. In the present study, using immunodetection methods, we revealed the presence of several proteins important for the dopamine uptake and signalling in mammalian sperm, specifically monoamine transporters as dopamine (DAT), serotonin (SERT) and norepinephrine (NET) transporters in equine sperm. We also demonstrated for the first time in equine sperm a functional dopamine transporter using 4-[4-(Dimethylamino)styryl]-N-methylpyridinium iodide (ASP+), as substrate. In addition, we also showed that dopamine (1 mM) treatment in vitro, does not affect sperm viability but decreases total and progressive sperm motility. This effect is reversed by blocking the dopamine transporter with the selective inhibitor vanoxerine (GBR12909) and non-selective inhibitors of dopamine reuptake such as nomifensine and bupropion. The effect of dopamine in sperm physiology was evaluated and we demonstrated that acrosome integrity and thyrosine phosphorylation in equine sperm is significantly reduced at high concentrations of this catecholamine. In summary, our results revealed the presence of monoamine transporter DAT, NET and SERT in equine sperm, and that the dopamine uptake by DAT can regulate sperm function, specifically acrosomal integrity and sperm motility. PMID:25402186

Cocaine cue-induced dopamine release in the human prefrontal cortex.

PubMed

Milella, Michele S; Fotros, Aryandokht; Gravel, Paul; Casey, Kevin F; Larcher, Kevin; Verhaeghe, Jeroen A J; Cox, Sylvia M L; Reader, Andrew J; Dagher, Alain; Benkelfat, Chawki; Leyton, Marco

2016-08-01

Accumulating evidence indicates that drug-related cues can induce dopamine (DA) release in the striatum of substance abusers. Whether these same cues provoke DA release in the human prefrontal cortex remains unknown. We used high-resolution positron emission tomography with [18F]fallypride to measure cortical and striatal DA D2/3 receptor availability in the presence versus absence of drug-related cues in volunteers with current cocaine dependence. Twelve individuals participated in our study. Among participants reporting a craving response (9 of 12), exposure to the cocaine cues significantly decreased [18F]fallypride binding potential (BPND) values in the medial orbitofrontal cortex and striatum. In all 12 participants, individual differences in the magnitude of craving correlated with BPND changes in the medial orbitofrontal cortex, dorsolateral prefrontal cortex, anterior cingulate, and striatum. Consistent with the presence of autoreceptors on mesostriatal but not mesocortical DA cell bodies, midbrain BPND values were significantly correlated with changes in BPND within the striatum but not the cortex. The lower the midbrain D2 receptor levels, the greater the striatal change in BPND and self-reported craving. Limitations of this study include its modest sample size, with only 2 female participants. Newer tracers might have greater sensitivity to cortical DA release. In people with cocaine use disorders, the presentation of drug-related cues induces DA release within cortical and striatal regions. Both effects are associated with craving, but only the latter is regulated by midbrain autoreceptors. Together, the results suggest that cortical and subcortical DA responses might both influence drug-focused incentive motivational states, but with separate regulatory mechanisms.

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

N-Methyl-d-aspartate Modulation of Nucleus Accumbens Dopamine Release by Metabotropic Glutamate Receptors: Fast Cyclic Voltammetry Studies in Rat Brain Slices in Vitro.

PubMed

Yavas, Ersin; Young, Andrew M J

2017-02-15

The N-methyl-d-aspartate (NMDA) receptor antagonist, phencyclidine, induces behavioral changes in rodents mimicking symptoms of schizophrenia, possibly mediated through dysregulation of glutamatergic control of mesolimbic dopamine release. We tested the hypothesis that NMDA receptor activation modulates accumbens dopamine release, and that phencyclidine pretreatment altered this modulation. NMDA caused a receptor-specific, dose-dependent decrease in electrically stimulated dopamine release in nucleus accumbens brain slices. This decrease was unaffected by picrotoxin, making it unlikely to be mediated through GABAergic neurones, but was decreased by the metabotropic glutamate receptor antagonist, (RS)-α-methyl-4-sulfonophenylglycine, indicating that NMDA activates mechanisms controlled by these receptors to decrease stimulated dopamine release. The effect of NMDA was unchanged by in vivo pretreatment with phencyclidine (twice daily for 5 days), with a washout period of at least 7 days before experimentation, which supports the hypothesis that there is no enduring direct effect of PCP at NMDA receptors after this pretreatment procedure. We propose that NMDA depression of accumbal dopamine release is mediated by metabotropic glutamate receptors located pre- or perisynaptically, and suggest that NMDA evoked increased extrasynaptic spillover of glutamate is sufficient to activate these receptors that, in turn, inhibit dopamine release. Furthermore, we suggest that enduring functional changes brought about by subchronic phencyclidine pretreatment, modeling deficits in schizophrenia, are downstream effects consequent on chronic blockade of NMDA receptors, rather than direct effects on NMDA receptors themselves.

Dopaminergic inputs in the dentate gyrus direct the choice of memory encoding.

PubMed

Du, Huiyun; Deng, Wei; Aimone, James B; Ge, Minyan; Parylak, Sarah; Walch, Keenan; Zhang, Wei; Cook, Jonathan; Song, Huina; Wang, Liping; Gage, Fred H; Mu, Yangling

2016-09-13

Rewarding experiences are often well remembered, and such memory formation is known to be dependent on dopamine modulation of the neural substrates engaged in learning and memory; however, it is unknown how and where in the brain dopamine signals bias episodic memory toward preceding rather than subsequent events. Here we found that photostimulation of channelrhodopsin-2-expressing dopaminergic fibers in the dentate gyrus induced a long-term depression of cortical inputs, diminished theta oscillations, and impaired subsequent contextual learning. Computational modeling based on this dopamine modulation indicated an asymmetric association of events occurring before and after reward in memory tasks. In subsequent behavioral experiments, preexposure to a natural reward suppressed hippocampus-dependent memory formation, with an effective time window consistent with the duration of dopamine-induced changes of dentate activity. Overall, our results suggest a mechanism by which dopamine enables the hippocampus to encode memory with reduced interference from subsequent experience.

Dopaminergic inputs in the dentate gyrus direct the choice of memory encoding

PubMed Central

Du, Huiyun; Deng, Wei; Aimone, James B.; Ge, Minyan; Parylak, Sarah; Walch, Keenan; Zhang, Wei; Cook, Jonathan; Song, Huina; Wang, Liping; Gage, Fred H.; Mu, Yangling

2016-01-01

Rewarding experiences are often well remembered, and such memory formation is known to be dependent on dopamine modulation of the neural substrates engaged in learning and memory; however, it is unknown how and where in the brain dopamine signals bias episodic memory toward preceding rather than subsequent events. Here we found that photostimulation of channelrhodopsin-2–expressing dopaminergic fibers in the dentate gyrus induced a long-term depression of cortical inputs, diminished theta oscillations, and impaired subsequent contextual learning. Computational modeling based on this dopamine modulation indicated an asymmetric association of events occurring before and after reward in memory tasks. In subsequent behavioral experiments, preexposure to a natural reward suppressed hippocampus-dependent memory formation, with an effective time window consistent with the duration of dopamine-induced changes of dentate activity. Overall, our results suggest a mechanism by which dopamine enables the hippocampus to encode memory with reduced interference from subsequent experience. PMID:27573822

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…

Modulation of frontostriatal interaction aligns with reduced primary reward processing under serotonergic drugs.

PubMed

Abler, Birgit; Grön, Georg; Hartmann, Antonie; Metzger, Coraline; Walter, Martin

2012-01-25

Recently, functional interactions between anteroventral prefrontal cortex and nucleus accumbens (NAcc) have been shown to relate to behavior counteracting reward-desiring (Diekhof and Gruber, 2010). Downregulation of the reward system by serotonin has also been suggested as the mode of action accounting for unsatisfactory effects of serotonin reuptake inhibitors (SSRIs) such as insufficient alleviation or even increase of anhedonia, and loss of interest. However, understanding of the in vivo mechanisms of SSRI-related alteration of the human reward system is still incomplete. Using functional magnetic resonance imaging (fMRI) within a double-blind cross-over within-subjects study design and administering the SSRI paroxetine, the dopamine/norepinephrine reuptake inhibitor bupropione, and placebo for 7 d each, we investigated a group of 18 healthy male subjects. Under paroxetine, subjects showed significantly decreased activation of the bilateral NAcc during processing of primary rewards (erotic videos), but not under bupropion. Similar to the previous study, analysis of psychophysiological interactions revealed that this downregulation relied on negative interactions between left and right NAcc fMRI signals and the bilateral anteroventral prefrontal cortex that now were significantly enhanced under paroxetine and reduced under bupropion. Individual drug-dependent modulations of interacting brain regions were significantly associated with individual expressions of impulsivity as a personality trait. Our results corroborate and extend previous insights on interregional crosstalk from secondary to primary rewards and demonstrate parallels between active inhibitory control of and serotonergic effects on the dopaminergic reward system's activity.

Valeriana wallichii root extract improves sleep quality and modulates brain monoamine level in rats.

PubMed

Sahu, Surajit; Ray, Koushik; Yogendra Kumar, M S; Gupta, Shilpa; Kauser, Hina; Kumar, Sanjeev; Mishra, Kshipra; Panjwani, Usha

2012-07-15

The present study was performed to investigate the effects of Valeriana wallichi (VW) aqueous root extract on sleep-wake profile and level of brain monoamines on Sprague-Dawley rats. Electrodes and transmitters were implanted to record EEG and EMG in freely moving condition and the changes were recorded telemetrically after oral administration of VW in the doses of 100, 200 and 300 mg/kg body weight. Sleep latency was decreased and duration of non-rapid eye movement (NREM) sleep was increased in a dose dependent manner. A significant decrease of sleep latency and duration of wakefulness were observed with VW at doses of 200 and 300 mg/kg. Duration of NREM sleep as well as duration of total sleep was increased significantly after treatment with VW at the doses of 200 and 300 mg/kg. VW also increased EEG slow wave activity during NREM sleep at the doses of 200 and 300 mg/kg. Level of norepinephrine (NE), dopamine (DA), dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT) and hydroxy indole acetic acid (HIAA) were measured in frontal cortex and brain stem after VW treatment at the dose of 200mg/kg. NE and 5HT level were decreased significantly in both frontal cortex and brain stem. DA and HIAA level significantly decreased only in cortex. DOPAC level was not changed in any brain region studied. In conclusion it can be said that VW water extract has a sleep quality improving effect which may be dependent upon levels of monoamines in cortex and brainstem. Copyright © 2012 Elsevier GmbH. All rights reserved.

Cannabinoid transmission in the prelimbic cortex bidirectionally controls opiate reward and aversion signaling through dissociable kappa versus μ-opiate receptor dependent mechanisms.

PubMed

Ahmad, Tasha; Lauzon, Nicole M; de Jaeger, Xavier; Laviolette, Steven R

2013-09-25

Cannabinoid, dopamine (DA), and opiate receptor pathways play integrative roles in emotional learning, associative memory, and sensory perception. Modulation of cannabinoid CB1 receptor transmission within the medial prefrontal cortex (mPFC) regulates the emotional valence of both rewarding and aversive experiences. Furthermore, CB1 receptor substrates functionally interact with opiate-related motivational processing circuits, particularly in the context of reward-related learning and memory. Considerable evidence demonstrates functional interactions between CB1 and DA signaling pathways during the processing of motivationally salient information. However, the role of mPFC CB1 receptor transmission in the modulation of behavioral opiate-reward processing is not currently known. Using an unbiased conditioned place preference paradigm with rats, we examined the role of intra-mPFC CB1 transmission during opiate reward learning. We report that activation or inhibition of CB1 transmission within the prelimbic cortical (PLC) division of the mPFC bidirectionally regulates the motivational valence of opiates; whereas CB1 activation switched morphine reward signaling into an aversive stimulus, blockade of CB1 transmission potentiated the rewarding properties of normally sub-reward threshold conditioning doses of morphine. Both of these effects were dependent upon DA transmission as systemic blockade of DAergic transmission prevented CB1-dependent modulation of morphine reward and aversion behaviors. We further report that CB1-mediated intra-PLC opiate motivational signaling is mediated through a μ-opiate receptor-dependent reward pathway, or a κ-opiate receptor-dependent aversion pathway, directly within the ventral tegmental area. Our results provide evidence for a novel CB1-mediated motivational valence switching mechanism within the PLC, controlling dissociable subcortical reward and aversion pathways.

Cortical Dopamine Transmission as Measured with the [11C]FLB 457 – Amphetamine PET Imaging Paradigm Is Not Influenced by COMT Genotype

PubMed Central

Narendran, Rajesh; Tumuluru, Divya; May, Maureen A.; Chowdari, Kodavali V.; Himes, Michael L.; Fasenmyer, Kelli; Frankle, W. Gordon; Nimgaonkar, Vishwajit L.

2016-01-01

Basic investigations link a Val158Met polymorphism (rs4680) in the catechol-O-methyltransferase (COMT) gene to not only its enzymatic activity, but also to its dopaminergic tone in the prefrontal cortex. Previous PET studies have documented the relationship between COMT Val158Met polymorphism and D1 and D2/3 receptor binding potential (BP), and interpreted them in terms of dopaminergic tone. The use of baseline dopamine D1 and D2/3 receptor binding potential (BPND) as a proxy for dopaminergic tone is problematic because they reflect both endogenous dopamine levels (a change in radiotracer's apparent affinity) and receptor density. In this analysis of 31 healthy controls genotyped for the Val158Met polymorphism (Val/Val, Val/Met, and Met/Met), we used amphetamine-induced displacement of [11C]FLB 457 as a direct measure of dopamine release. Our analysis failed to show a relationship between COMT genotype status and prefrontal cortical dopamine release. COMT genotype was also not predictive of baseline dopamine D2/3 receptor BPND. PMID:27322568

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

PubMed

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

2016-10-01

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

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.

DARPP-32: from neurotransmission to cancer

PubMed Central

Belkhiri, Abbes; Zhu, Shoumin; El-Rifai, Wael

2016-01-01

Dopamine and cAMP-regulated phosphoprotein Mr 32,000 (DARPP-32), also known as phosphoprotein phosphatase-1 regulatory subunit 1B (PPP1R1B), was initially discovered as a substrate of dopamine-activated protein kinase A (PKA) in the neostriatum in the brain. While phosphorylation at Thr-34 by PKA converts DARPP-32 into a potent inhibitor of protein phosphatase 1 (PP1), phosphorylation at Thr-75 transforms DARPP-32 into an inhibitor of PKA. Through regulation of DARPP-32 phosphorylation and modulation of protein phosphatase and kinase activities, DARPP-32 plays a critical role in mediating the biochemical, electrophysiological, and behavioral effects controlled by dopamine and other neurotransmitters in response to drugs of abuse and psychostimulants. Altered expression of DARPP-32 and its truncated isoform (t-DARPP), specifically in the prefrontal cortex, has been associated with schizophrenia and bipolar disorder. Moreover, cleavage of DARPP-32 by calpain has been implicated in Alzheimer's disease. Amplification of the genomic locus of DARPP-32 at 17q12 has been described in several cancers. DARPP-32 and t-DARPP are frequently overexpressed at the mRNA and protein levels in adenocarcinomas of the breast, prostate, colon, and stomach. Several studies demonstrated the pro-survival, pro-invasion, and pro-angiogenic functions of DARPP-32 in cancer. Overexpression of DARPP-32 and t-DARPP also promotes chemotherapeutic drug resistance and cell proliferation in gastric and breast cancers through regulation of pro-oncogenic signal transduction pathways. The expansion of DARPP-32 research from neurotransmission to cancer underscores the broad scope and implication of this protein in disparate human diseases. PMID:26872373

A Frontal Dopamine System for Reflective Exploratory Behavior

PubMed Central

Blanco, Nathaniel J.; Love, Bradley C.; Cooper, Jessica A.; McGeary, John E.; Knopik, Valerie S.; Maddox, W. Todd

2015-01-01

The COMT gene modulates dopamine levels in prefrontal cortex with Met allele carriers having lower COMT enzyme activity and, therefore, higher dopamine levels compared to Val/Val homozygotes. Concordantly, Val/Val homozygotes tend to perform worse and display increased (interpreted as inefficient) frontal activation in certain cognitive tasks. In a sample of 209 participants, we test the hypothesis that Met carriers will be advantaged in a decision-making task that demands sequencing exploratory and exploitive choices to minimize uncertainty about the reward structure in the environment. Previous work suggests that optimal performance depends on limited cognitive resources supported by prefrontal systems. If so, Met carriers should outperform Val/Val homozygotes, particularly under dual-task conditions that tax limited cognitive resources. In accord with these a priori predictions, Met carriers were more resilient in the face of cognitive load, continuing to explore in a sophisticated manner. We fit computational models that embody sophisticated reflective and simple reflexive strategies to further evaluate participants' exploration behavior. The Ideal Actor model reflectively updates beliefs and plans ahead, taking into account the information gained by each choice and making choices that maximize long-term payoffs. In contrast, the Naïve Reinforcement Learning (RL) model instantiates the reflexive account of choice, in which the values of actions are based only on the rewards experienced so far. Its beliefs are updated reflexively in response to observed changes in rewards. Converging with standard analyses, Met carriers were best characterized by the Ideal Actor model, whereas Val/Val homozygotes were best characterized by the Naive RL model, particularly under dual-task conditions. PMID:26004676

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

Schizophrenia: a tale of two critical periods for prefrontal cortical development

PubMed Central

Selemon, L D; Zecevic, N

2015-01-01

Schizophrenia is a disease of abnormal brain development. Considerable evidence now indicates that environmental factors have a causative role in schizophrenia. Elevated incidence of the disease has been linked to a wide range of disturbances in the prenatal environment and to social factors and drug intake during adolescence. Here we examine neurodevelopment of the prefrontal cortex in the first trimester of gestation and during adolescence to gain further insight into the neurodevelopmental processes that may be vulnerable in schizophrenia. Early embryonic development of the prefrontal cortex is characterized by cell proliferation, including renewal of progenitor cells, generation of early transient cell populations and neurogenesis of subcortical populations. Animal models show that curtailing early gestational cell proliferation produces schizophrenia-like pathology in the prefrontal cortex and mimics key behavioral and cognitive symptoms of the disease. At the other end of the spectrum, elimination of excitatory synapses is the fundamental process occurring during adolescent maturation in the prefrontal cortex. Adverse social situations that elevate stress increase dopamine stimulation of the mesocortical pathway and may lead to exaggerated synaptic pruning during adolescence. In a non-human primate model, dopamine hyperstimulation has been shown to decrease prefrontal pyramidal cell spine density and to be associated with profound cognitive dysfunction. Development of the prefrontal cortex in its earliest stage in gestation and in its final stage in adolescence represents two critical periods of vulnerability for schizophrenia in which cell proliferation and synaptic elimination, respectively, may be influenced by environmental factors. PMID:26285133

Attenuating GABAA Receptor Signaling in Dopamine Neurons Selectively Enhances Reward Learning and Alters Risk Preference in Mice

PubMed Central

Parker, Jones G.; Wanat, Matthew J.; Soden, Marta E.; Ahmad, Kinza; Zweifel, Larry S.; Bamford, Nigel S.; Palmiter, Richard D.

2011-01-01

Phasic dopamine transmission encodes the value of reward-predictive stimuli and influences both learning and decision-making. Altered dopamine signaling is associated with psychiatric conditions characterized by risky choices such as pathological gambling. These observations highlight the importance of understanding how dopamine neuron activity is modulated. While excitatory drive onto dopamine neurons is critical for generating phasic dopamine responses, emerging evidence suggests that inhibitory signaling also modulates these responses. To address the functional importance of inhibitory signaling in dopamine neurons, we generated mice lacking the β3 subunit of the GABAA receptor specifically in dopamine neurons (β3-KO mice) and examined their behavior in tasks that assessed appetitive learning, aversive learning, and risk preference. Dopamine neurons in midbrain slices from β3-KO mice exhibited attenuated GABA-evoked inhibitory post-synaptic currents. Furthermore, electrical stimulation of excitatory afferents to dopamine neurons elicited more dopamine release in the nucleus accumbens of β3-KO mice as measured by fast-scan cyclic voltammetry. β3-KO mice were more active than controls when given morphine, which correlated with potential compensatory upregulation of GABAergic tone onto dopamine neurons. β3-KO mice learned faster in two food-reinforced learning paradigms, but extinguished their learned behavior normally. Enhanced learning was specific for appetitive tasks, as aversive learning was unaffected in β3-KO mice. Finally, we found that β3-KO mice had enhanced risk preference in a probabilistic selection task that required mice to choose between a small certain reward and a larger uncertain reward. Collectively, these findings identify a selective role for GABAA signaling in dopamine neurons in appetitive learning and decision-making. PMID:22114279

Dopamine D1 Receptors Regulate Protein Synthesis-Dependent Long-Term Recognition Memory via Extracellular Signal-Regulated Kinase 1/2 in the Prefrontal Cortex

ERIC Educational Resources Information Center

Nagai, Taku; Takuma, Kazuhiro; Kamei, Hiroyuki; Ito, Yukio; Nakamichi, Noritaka; Ibi, Daisuke; Nakanishi, Yutaka; Murai, Masaaki; Mizoguchi, Hiroyuki; Nabeshima, Toshitaka; Yamada, Kiyofumi

2007-01-01

Several lines of evidence suggest that extracellular signal-regulated kinase1/2 (ERK1/2) and dopaminergic system is involved in learning and memory. However, it remains to be determined if the dopaminergic system and ERK1/2 pathway contribute to cognitive function in the prefrontal cortex (PFC). The amount of phosphorylated ERK1/2 was increased in…

Prefrontal cortex, caloric restriction and stress during aging: studies on dopamine and acetylcholine release, BDNF and working memory.

PubMed

Del Arco, Alberto; Segovia, Gregorio; de Blas, Marta; Garrido, Pedro; Acuña-Castroviejo, Dario; Pamplona, Reinald; Mora, Francisco

2011-01-01

This study was designed to investigate whether long-term caloric restriction during the life span of the rat changes the effects of an acute mild stress on the release of dopamine and acetylcholine in the prefrontal cortex (PFC) and on working memory performance. Spontaneous motor activity was also monitored and levels of BDNF measured in the prefrontal cortex, amygdala and hippocampus. Male Wistar rats (3 months of age) were housed during 3, 12, 21 and 27 months (6, 15, 24 and 30 months of age at the end of housing) in caloric restriction (CR; 40% food intake restriction) or control conditions. After behavioural testing, animals were further subdivided into two other groups. In one of the groups BDNF protein levels were determined. In the other group rats were implanted with guide cannulas into the PFC to perform microdialysis experiments. In CR rats the release of dopamine produced by handling stress did not differ from the response found in control rats of 6, 15 and 24 months of age. The release of acetylcholine was not changed at the ages of 6 and 15 months but reduced at the age of 24 months. Stress did not change dopamine or acetylcholine release in CR and control rats of 30 months of age. BDNF levels were increased in the hippocampus and amygdala, but not in the PFC, of 6 and 15 months CR rats. Spontaneous motor activity was increased in all groups of CR rats. Age, however, decreased motor activity in CR and control rats. Both experimental groups showed similar working memory performance in a delayed alternation task in basal conditions and after a situation of acute stress. These results suggest that CR does not modify the function of the PFC in response to an acute stress nor the changes found as a result of the normal process of aging. Copyright © 2010 Elsevier B.V. All rights reserved.

Dopaminergic modulation of locomotor network activity in the neonatal mouse spinal cord

PubMed Central

Sharples, Simon A.; Humphreys, Jennifer M.; Jensen, A. Marley; Dhoopar, Sunny; Delaloye, Nicole; Clemens, Stefan

2015-01-01

Dopamine is now well established as a modulator of locomotor rhythms in a variety of developing and adult vertebrates. However, in mice, while all five dopamine receptor subtypes are present in the spinal cord, it is unclear which receptor subtypes modulate the rhythm. Dopamine receptors can be grouped into two families—the D1/5 receptor group and the D2/3/4 group, which have excitatory and inhibitory effects, respectively. Our data suggest that dopamine exerts contrasting dose-dependent modulatory effects via the two receptor families. Our data show that administration of dopamine at concentrations >35 μM slowed and increased the regularity of a locomotor rhythm evoked by bath application of 5-hydroxytryptamine (5-HT) and N-methyl-d(l)-aspartic acid (NMA). This effect was independent of the baseline frequency of the rhythm that was manipulated by altering the NMA concentration. We next examined the contribution of the D1- and D2-like receptor families on the rhythm. Our data suggest that the D1-like receptor contributes to enhancement of the stability of the rhythm. Overall, the D2-like family had a pronounced slowing effect on the rhythm; however, quinpirole, the D2-like agonist, also enhanced rhythm stability. These data indicate a receptor-dependent delegation of the modulatory effects of dopamine on the spinal locomotor pattern generator. PMID:25652925

Single or combined treatment with L-DOPA and quinpirole differentially modulate expression and phosphorylation of key regulatory kinases in neuroblastoma cells.

PubMed

Fuzzati-Armentero, Marie Therese; Ghezzi, Cristina; Nisticò, Robert; Oda, Adriano; Blandini, Fabio

2013-09-27

In the past decades, the clinical use of dopamine agonists has expanded from adjunct therapy in patients with a deteriorating response to L-3,4-dihydroxyphenylalanine (L-DOPA) to monotherapy for the treatment of early PD. Dopamine agonists provide their antiparkinsonian benefit through stimulation of brain postsynaptic type 2 dopamine receptors that exert their effect through classical cAMP-dependent mechanisms, as well as cAMP-independent cellular signaling cascades, including the Akt/glycogen synthase kinase 3 (GSK3) pathway. Alterations of Akt/GSK3 have been observed and may contribute to the neurodegenerative processes and the development of L-DOPA-induced dyskinesia. The effects L-DOPA and quinpirole, a dopamine agonist, on the two key regulatory kinases, Akt and GSK3, were evaluated in neuroblastoma cell line. L-DOPA and dopamine agonist dose-dependently and differentially modulated Akt and GSK3 expression and phosphorylation when added alone or combined. The combined treatment inverted or potentiated the modulatory properties of the single compound. The drug- and concentration-dependent balance of dopamine receptor stimulation over auto-oxidation may distinctively modulate GSK3 isoforms and Akt. Our results indicate that particular attention must be given to drug concentration and combination when multiple therapies are applied for the clinical treatment of PD patients. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Low Striatal Dopamine D2-type Receptor Availability is Linked to Simulated Drug Choice in Methamphetamine Users.

PubMed

Moeller, Scott J; Okita, Kyoji; Robertson, Chelsea L; Ballard, Michael E; Konova, Anna B; Goldstein, Rita Z; Mandelkern, Mark A; London, Edythe D

2018-03-01

Individuals with drug use disorders seek drugs over other rewarding activities, and exhibit neurochemical deficits related to dopamine, which is involved in value-based learning and decision-making. Thus, a dopaminergic disturbance may underpin drug-biased choice in addiction. Classical drug-choice assessments, which offer drug-consumption opportunities, are inappropriate for addicted individuals seeking treatment or abstaining. Fifteen recently abstinent methamphetamine users and 15 healthy controls completed two laboratory paradigms of 'simulated' drug choice (choice for drug-related vs affectively pleasant, unpleasant, and neutral images), and underwent positron emission tomography measurements of dopamine D2-type receptor availability, indicated by binding potential (BP ND ) for [ 18 F]fallypride. Thirteen of the methamphetamine users and 10 controls also underwent [ 11 C]NNC112 PET scans to measure dopamine D1-type receptor availability. Group analyses showed that, compared with controls, methamphetamine users chose to view more methamphetamine-related images on one task, with a similar trend on the second task. Regression analyses showed that, on both tasks, the more methamphetamine users chose to view methamphetamine images, specifically vs pleasant images (the most frequently chosen images across all participants), the lower was their D2-type BP ND in the lateral orbitofrontal cortex, an important region in value-based choice. No associations were observed with D2-type BP ND in striatal regions, or with D1-type BP ND in any region. These results identify a neurochemical correlate for a laboratory drug-seeking paradigm that can be administered to treatment-seeking and abstaining drug-addicted individuals. More broadly, these results refine the central hypothesis that dopamine-system deficits contribute to drug-biased decision-making in addiction, here showing a role for the orbitofrontal cortex.

Acute treatment with doxorubicin induced neurochemical impairment of the function of dopamine system in rat brain structures.

PubMed

Antkiewicz-Michaluk, Lucyna; Krzemieniecki, Krzysztof; Romanska, Irena; Michaluk, Jerzy; Krygowska-Wajs, Anna

2016-06-01

The clinical studies have shown that chemotherapy may impair cognitive functions especially in the patients treated for breast cancer. It should be mention that only few studies have made use of animals to investigate the effects of chemotherapy on the brain function. Doxorubicin (Adriamycin) is an anthracycline antibiotic commonly used for chemotherapy of breast cancer. This study examined the effect of doxorubicin (1.5 and 3.0mg/kg ip) after acute administration on the levels of dopamine, noradrenaline, serotonin and their metabolites in the rat brain structures connected with cognition and psychiatric disorders. The data indicate that doxorubicin produced a significant and specific for the dopamine system inhibition of its activity in the investigated structures connected with the fall of dopamine concentration (decrease from 25 to 30% in the frontal cortex; from 30 to 60% in the hippocampus and about 20% of the control in the striatum, p<0.05) and its extraneuronal metabolite, 3-MT (from 35% in the frontal cortex to 60% in the hippocampus of the control level, p<0.01). However, doxorubicin did not affect others monoaminergic transmitters in the brain: noradrenaline and serotonin. Summing up, these data indicate that a single injection of doxorubicin produced a clear and significant inhibition of dopamine system activity in all investigated structures with the strongest effect in the hippocampus what may lead to the disturbances of the cognitive functions at the patients treated for cancer. Moreover, such treatment did not significantly affect others monoaminergic transmitters such as noradrenaline and serotonin. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Methamphetamine-related psychiatric symptoms and reduced brain dopamine transporters studied with PET.

PubMed

Sekine, Y; Iyo, M; Ouchi, Y; Matsunaga, T; Tsukada, H; Okada, H; Yoshikawa, E; Futatsubashi, M; Takei, N; Mori, N

2001-08-01

A positron emission tomography (PET) study has suggested that dopamine transporter density of the caudate/putamen is reduced in methamphetamine users. The authors measured nucleus accumbens and prefrontal cortex density, in addition to caudate/putamen density, in methamphetamine users and assessed the relation of these measures to the subjects' clinical characteristics. PET and 2-beta-carbomethoxy-3beta-(4-[(11)C] fluorophenyl)tropane, a dopamine transporter ligand, were used to measure dopamine transporter density in 11 male methamphetamine users and nine male comparison subjects who did not use methamphetamine. Psychiatric symptoms in methamphetamine users were evaluated by using the Brief Psychiatric Rating Scale and applying a craving score. The dopamine transporter density in all three of the regions observed was significantly lower in the methamphetamine users than the comparison subjects. The severity of psychiatric symptoms was significantly correlated with the duration of methamphetamine use. The dopamine transporter reduction in the caudate/putamen and nucleus accumbens was significantly associated with the duration of methamphetamine use and closely related to the severity of persistent psychiatric symptoms. These findings suggest that longer use of methamphetamine may cause more severe psychiatric symptoms and greater reduction of dopamine transporter density in the brain. They also show that the dopamine transporter reduction may be long-lasting, even if methamphetamine use ceases. Further, persistent psychiatric symptoms in methamphetamine users, including psychotic symptoms, may be attributable to the reduction of dopamine transporter density.

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.

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

PubMed

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

2017-07-01

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

Prefrontal Markers and Cognitive Performance Are Dissociated during Progressive Dopamine Lesion

PubMed Central

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

2016-01-01

Dopamine is thought to directly influence the neurophysiological mechanisms of both performance monitoring and cognitive control—two processes that are critically linked in the production of adapted behaviour. Changing dopamine levels are also thought to induce cognitive changes in several neurological and psychiatric conditions. But the working model of this system as a whole remains untested. Specifically, although many researchers assume that changing dopamine levels modify neurophysiological mechanisms and their markers in frontal cortex, and that this in turn leads to cognitive changes, this causal chain needs to be verified. Using longitudinal recordings of frontal neurophysiological markers over many months during progressive dopaminergic lesion in non-human primates, we provide data that fail to support a simple interaction between dopamine, frontal function, and cognition. Feedback potentials, which are performance-monitoring signals sometimes thought to drive successful control, ceased to differentiate feedback valence at the end of the lesion, just before clinical motor threshold. In contrast, cognitive control performance and beta oscillatory markers of cognitive control were unimpaired by the lesion. The differing dynamics of these measures throughout a dopamine lesion suggests they are not all driven by dopamine in the same way. These dynamics also demonstrate that a complex non-linear set of mechanisms is engaged in the brain in response to a progressive dopamine lesion. These results question the direct causal chain from dopamine to frontal physiology and on to cognition. They imply that biomarkers of cognitive functions are not directly predictive of dopamine loss. PMID:27824858

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

PubMed Central

2012-01-01

Background In the fruit fly, Drosophila melanogaster, serotonin functions both as a neurotransmitter to regulate larval feeding, and in the development of the stomatogastric feeding circuit. There is an inverse relationship between neuronal serotonin levels during late embryogenesis and the complexity of the serotonergic fibers projecting from the larval brain to the foregut, which correlate with perturbations in feeding, the functional output of the circuit. Dopamine does not modulate larval feeding, and dopaminergic fibers do not innervate the larval foregut. Since dopamine can function in central nervous system development, separate from its role as a neurotransmitter, the role of neuronal dopamine was assessed on the development, and mature function, of the 5-HT larval feeding circuit. Results Both decreased and increased neuronal dopamine levels in late embryogenesis during development of this circuit result in depressed levels of larval feeding. Perturbations in neuronal dopamine during this developmental period also result in greater branch complexity of the serotonergic fibers innervating the gut, as well as increased size and number of the serotonin-containing vesicles along the neurite length. This neurotrophic action for dopamine is modulated by the D2 dopamine receptor expressed during late embryogenesis in central 5-HT neurons. Animals carrying transgenic RNAi constructs to knock down both dopamine and serotonin synthesis in the central nervous system display normal feeding and fiber architecture. However, disparate levels of neuronal dopamine and serotonin during development of the circuit result in abnormal gut fiber architecture and feeding behavior. Conclusions These results suggest that dopamine can exert a direct trophic influence on the development of a specific neural circuit, and that dopamine and serotonin may interact with each other to generate the neural architecture necessary for normal function of the circuit. PMID:22413901

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 Akt1 kinase since striatal dopamine hyperstimulation is associated with psychosis and schizophrenia. Here, using PET with [ 11 C]raclopride, we identified in the AKT1 gene a new variable number tandem repeat (VNTR) marker associated with baseline striatal dopamine D2/D3 receptor availability and with methylphenidate-induced striatal dopamine increases in healthy volunteers. Our results confirm the involvement of the AKT1 gene in modulating striatal dopamine signaling in the human brain. Future studies are needed to assess the association of this new VNTR AKT1 variant in schizophrenia and drug-induced psychoses. Copyright © 2017 the authors 0270-6474/17/374983-10$15.00/0.

Alterations in cortical and extrastriatal subcortical dopamine function in schizophrenia: systematic review and meta-analysis of imaging studies.

PubMed

Kambeitz, Joseph; Abi-Dargham, Anissa; Kapur, Shitij; Howes, Oliver D

2014-06-01

The hypothesis that cortical dopaminergic alterations underlie aspects of schizophrenia has been highly influential. To bring together and evaluate the imaging evidence for dopaminergic alterations in cortical and other extrastriatal regions in schizophrenia. Electronic databases were searched for in vivo molecular studies of extrastriatal dopaminergic function in schizophrenia. Twenty-three studies (278 patients and 265 controls) were identified. Clinicodemographic and imaging variables were extracted and effect sizes determined for the dopaminergic measures. There were sufficient data to permit meta-analyses for the temporal cortex, thalamus and substantia nigra but not for other regions. The meta-analysis of dopamine D2/D3 receptor availability found summary effect sizes of d = -0.32 (95% CI -0.68 to 0.03) for the thalamus, d = -0.23 (95% CI -0.54 to 0.07) for the temporal cortex and d = 0.04 (95% CI -0.92 to 0.99) for the substantia nigra. Confidence intervals were wide and all included no difference between groups. Evidence for other measures/regions is limited because of the small number of studies and in some instances inconsistent findings, although significant differences were reported for D2/D3 receptors in the cingulate and uncus, for D1 receptors in the prefrontal cortex and for dopamine transporter availability in the thalamus. There is a relative paucity of direct evidence for cortical dopaminergic alterations in schizophrenia, and findings are inconclusive. This is surprising given the wide influence of the hypothesis. Large, well-controlled studies in drug-naive patients are warranted to definitively test this hypothesis. Royal College of Psychiatrists.

Dopamine alters glutamate receptor desensitization in retinal horizontal cells of the perch (Perca fluviatilis).

PubMed Central

Schmidt, K F; Kruse, M; Hatt, H

1994-01-01

The patch-clamp technique in combination with a fast liquid filament application system was used to study the effect of dopamine on the glutamate receptor desensitization in horizontal cells of the perch (Perca fluviatilis). Kinetics of ligand-gated ion channels in fish horizontal cells are modulated by dopamine. This modulation is presumably mediated by a cAMP-dependent protein phosphorylation. Before incubation with dopamine, the glutamate receptors of horizontal cells activate and desensitize with fast time constants. In the whole-cell recording mode, fast application of the agonists L-glutamate, quisqualate, or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid prior to the dopamine incubation gives rise to fast transient currents with peak values of about 200 pA that desensitize within 100 ms. Kainate as agonist produced higher steady-state currents but no transient currents. After incubation of the cells with dopamine for 3 min, the desensitization was significantly reduced and the agonists L-glutamate, quisqualate, or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid induced steady-state currents with amplitudes that were similar to the previously observed transient currents. Kainate-induced currents were only slightly affected. Fast desensitizing currents upon fast application of L-glutamate were also recorded from outside-out patches that were excised from horizontal cells before incubation with dopamine. The currents from excised patches desensitized to a steady-state level of about 0.2 of the peak amplitude with time constants of less than 2 ms. When the outside-out patches were excised from cells after dopamine incubation, steady-state currents were enhanced and no transient currents were observed. The results may indicate that the dopamine-dependent modulation of glutamate-induced currents, which is presumably mediated by a protein phosphorylation, is due to an alteration of the desensitization of the glutamate receptors. PMID:7520178

Interaction of childhood urbanicity and variation in dopamine genes alters adult prefrontal function as measured by functional magnetic resonance imaging (fMRI).

PubMed

Reed, Jessica L; D'Ambrosio, Enrico; Marenco, Stefano; Ursini, Gianluca; Zheutlin, Amanda B; Blasi, Giuseppe; Spencer, Barbara E; Romano, Raffaella; Hochheiser, Jesse; Reifman, Ann; Sturm, Justin; Berman, Karen F; Bertolino, Alessandro; Weinberger, Daniel R; Callicott, Joseph H

2018-01-01

Brain phenotypes showing environmental influence may help clarify unexplained associations between urban exposure and psychiatric risk. Heritable prefrontal fMRI activation during working memory (WM) is such a phenotype. We hypothesized that urban upbringing (childhood urbanicity) would alter this phenotype and interact with dopamine genes that regulate prefrontal function during WM. Further, dopamine has been hypothesized to mediate urban-associated factors like social stress. WM-related prefrontal function was tested for main effects of urbanicity, main effects of three dopamine genes-catechol-O-methyltransferase (COMT), dopamine receptor D1 (DRD1), and dopamine receptor D2 (DRD2)-and, importantly, dopamine gene-by-urbanicity interactions. For COMT, three independent human samples were recruited (total n = 487). We also studied 253 subjects genotyped for DRD1 and DRD2. 3T fMRI activation during the N-back WM task was the dependent variable, while childhood urbanicity, dopamine genotype, and urbanicity-dopamine interactions were independent variables. Main effects of dopamine genes and of urbanicity were found. Individuals raised in an urban environment showed altered prefrontal activation relative to those raised in rural or town settings. For each gene, dopamine genotype-by-urbanicity interactions were shown in prefrontal cortex-COMT replicated twice in two independent samples. An urban childhood upbringing altered prefrontal function and interacted with each gene to alter genotype-phenotype relationships. Gene-environment interactions between multiple dopamine genes and urban upbringing suggest that neural effects of developmental environmental exposure could mediate, at least partially, increased risk for psychiatric illness in urban environments via dopamine genes expressed into adulthood.

Dopamine D1 receptor activation contributes to light-adapted changes in retinal inhibition to rod bipolar cells.

PubMed

Flood, Michael Daniel; Moore-Dotson, Johnnie M; Eggers, Erika D

2018-05-30

Dopamine modulation of retinal signaling has been shown to be an important part of retinal adaptation to increased background light levels but the role of dopamine modulation of retinal inhibition is not clear. We previously showed that light adaptation causes a large reduction in inhibition to rod bipolar cells, potentially to match the decrease in excitation after rod saturation. In this study we determined how dopamine D1 receptors in the inner retina contribute to this modulation. We found that D1 receptor activation significantly decreased the magnitude of inhibitory light responses from rod bipolar cells, while D1 receptor blockade during light adaptation partially prevented this decline. To determine what mechanisms were involved in the modulation of inhibitory light responses, we measured the effect of D1 receptor activation on spontaneous currents and currents evoked from electrically stimulating amacrine cell inputs to rod bipolar cells. D1 receptor activation decreased the frequency of spontaneous inhibition with no change in event amplitudes, suggesting a presynaptic change in amacrine cell activity in agreement with previous reports that rod bipolar cells lack D1 receptors. Additionally, we found that D1 receptor activation reduced the amplitude of electrically-evoked responses, showing that D1 receptors can modulate amacrine cells directly. Our results suggest that D1 receptor activation can replicate a large portion, but not all of the effects of light adaptation, likely by modulating release from amacrine cells onto rod bipolar cells.

Cocaine cue–induced dopamine release in the human prefrontal cortex

PubMed Central

Milella, Michele S.; Fotros, Aryandokht; Gravel, Paul; Casey, Kevin F.; Larcher, Kevin; Verhaeghe, Jeroen A.J.; Cox, Sylvia M.L.; Reader, Andrew J.; Dagher, Alain; Benkelfat, Chawki; Leyton, Marco

2016-01-01

Background Accumulating evidence indicates that drug-related cues can induce dopamine (DA) release in the striatum of substance abusers. Whether these same cues provoke DA release in the human prefrontal cortex remains unknown. Methods We used high-resolution positron emission tomography with [18F]fallypride to measure cortical and striatal DA D2/3 receptor availability in the presence versus absence of drug-related cues in volunteers with current cocaine dependence. Results Twelve individuals participated in our study. Among participants reporting a craving response (9 of 12), exposure to the cocaine cues significantly decreased [18F]fallypride binding potential (BPND) values in the medial orbitofrontal cortex and striatum. In all 12 participants, individual differences in the magnitude of craving correlated with BPND changes in the medial orbitofrontal cortex, dorsolateral prefrontal cortex, anterior cingulate, and striatum. Consistent with the presence of autoreceptors on mesostriatal but not mesocortical DA cell bodies, midbrain BPND values were significantly correlated with changes in BPND within the striatum but not the cortex. The lower the midbrain D2 receptor levels, the greater the striatal change in BPND and self-reported craving. Limitations Limitations of this study include its modest sample size, with only 2 female participants. Newer tracers might have greater sensitivity to cortical DA release. Conclusion In people with cocaine use disorders, the presentation of drug-related cues induces DA release within cortical and striatal regions. Both effects are associated with craving, but only the latter is regulated by midbrain autoreceptors. Together, the results suggest that cortical and subcortical DA responses might both influence drug-focused incentive motivational states, but with separate regulatory mechanisms. PMID:26900792

The 5-HT1A/1B-receptor agonist eltoprazine increases both catecholamine release in the prefrontal cortex and dopamine release in the nucleus accumbens and decreases motivation for reward and "waiting" impulsivity, but increases "stopping" impulsivity.

PubMed

Korte, S Mechiel; Prins, Jolanda; Van den Bergh, Filip S; Oosting, Ronald S; Dupree, Rudy; Korte-Bouws, Gerdien A H; Westphal, Koen G C; Olivier, Berend; Denys, Damiaan A; Garland, Alexis; Güntürkün, Onur

2017-01-05

The 5-HT 1A/1B -receptor agonist eltoprazine has a behavioral drug signature that resembles that of a variety of psychostimulant drugs, despite the differences in receptor binding profile. These psychostimulants are effective in treating impulsivity disorders, most likely because they increase norepinephrine (NE) and dopamine (DA) levels in the prefrontal cortex. Both amphetamine and methylphenidate, however, also increase dopamine levels in the nucleus accumbens (NAc), which has a significant role in motivation, pleasure, and reward. How eltoprazine affects monoamine release in the medial prefrontal cortex (mPFC), the orbitofrontal cortex (OFC), and the NAc is unknown. It is also unknown whether eltoprazine affects different forms of impulsivity and brain reward mechanisms. Therefore, in the present study, we investigate the effects of eltoprazine in rats in the following sequence: 1) the activity of the monoaminergic systems using in vivo microdialysis, 2) motivation for reward measured using the intracranial self-stimulation (ICSS) procedure, and finally, 3) "waiting" impulsivity in the delay-aversion task, and the "stopping" impulsivity in the stop-signal task. The microdialysis studies clearly showed that eltoprazine increased DA and NE release in both the mPFC and OFC, but only increased DA concentration in the NAc. In contrast, eltoprazine decreased 5-HT release in the mPFC and NAc (undetectable in the OFC). Remarkably, eltoprazine decreased impulsive choice, but increased impulsive action. Furthermore, brain stimulation was less rewarding following eltoprazine treatment. These results further support the long-standing hypothesis that "waiting" and "stopping" impulsivity are regulated by distinct neural circuits, because 5-HT 1A/1B -receptor activation decreases impulsive choice, but increases impulsive action. Copyright © 2016 Elsevier B.V. All rights reserved.

Dopamine modulates the neural representation of subjective value of food in hungry subjects.

PubMed

Medic, Nenad; Ziauddeen, Hisham; Vestergaard, Martin D; Henning, Elana; Schultz, Wolfram; Farooqi, I Sadaf; Fletcher, Paul C

2014-12-10

Although there is a rich literature on the role of dopamine in value learning, much less is known about its role in using established value estimations to shape decision-making. Here we investigated the effect of dopaminergic modulation on value-based decision-making for food items in fasted healthy human participants. The Becker-deGroot-Marschak auction, which assesses subjective value, was examined in conjunction with pharmacological fMRI using a dopaminergic agonist and an antagonist. We found that dopamine enhanced the neural response to value in the inferior parietal gyrus/intraparietal sulcus, and that this effect predominated toward the end of the valuation process when an action was needed to record the value. Our results suggest that dopamine is involved in acting upon the decision, providing additional insight to the mechanisms underlying impaired decision-making in healthy individuals and clinical populations with reduced dopamine levels. Copyright © 2014 the authors 0270-6474/14/3416856-09$15.00/0.

Dopaminergic inputs in the dentate gyrus direct the choice of memory encoding

DOE PAGES

Du, Huiyun; Deng, Wei; Aimone, James B.; ...

2016-09-13

Rewarding experiences are often well remembered, and such memory formation is known to be dependent on dopamine modulation of the neural substrates engaged in learning and memory; however, it is unknown how and where in the brain dopamine signals bias episodic memory toward preceding rather than subsequent events. Here we found that photostimulation of channelrhodopsin-2–expressing dopaminergic fibers in the dentate gyrus induced a long-term depression of cortical inputs, diminished theta oscillations, and impaired subsequent contextual learning. Computational modeling based on this dopamine modulation indicated an asymmetric association of events occurring before and after reward in memory tasks. In subsequent behavioralmore » experiments, preexposure to a natural reward suppressed hippocampus-dependent memory formation, with an effective time window consistent with the duration of dopamine-induced changes of dentate activity. Altogether, our results suggest a mechanism by which dopamine enables the hippocampus to encode memory with reduced interference from subsequent experience.« less

Dopaminergic inputs in the dentate gyrus direct the choice of memory encoding

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

Du, Huiyun; Deng, Wei; Aimone, James B.

Rewarding experiences are often well remembered, and such memory formation is known to be dependent on dopamine modulation of the neural substrates engaged in learning and memory; however, it is unknown how and where in the brain dopamine signals bias episodic memory toward preceding rather than subsequent events. Here we found that photostimulation of channelrhodopsin-2–expressing dopaminergic fibers in the dentate gyrus induced a long-term depression of cortical inputs, diminished theta oscillations, and impaired subsequent contextual learning. Computational modeling based on this dopamine modulation indicated an asymmetric association of events occurring before and after reward in memory tasks. In subsequent behavioralmore » experiments, preexposure to a natural reward suppressed hippocampus-dependent memory formation, with an effective time window consistent with the duration of dopamine-induced changes of dentate activity. Altogether, our results suggest a mechanism by which dopamine enables the hippocampus to encode memory with reduced interference from subsequent experience.« less

Dopaminergic modulation of hemodynamic signal variability and the functional connectome during cognitive performance.

PubMed

Alavash, Mohsen; Lim, Sung-Joo; Thiel, Christiane; Sehm, Bernhard; Deserno, Lorenz; Obleser, Jonas

2018-05-15

Dopamine underlies important aspects of cognition, and has been suggested to boost cognitive performance. However, how dopamine modulates the large-scale cortical dynamics during cognitive performance has remained elusive. Using functional MRI during a working memory task in healthy young human listeners, we investigated the effect of levodopa (l-dopa) on two aspects of cortical dynamics, blood oxygen-level-dependent (BOLD) signal variability and the functional connectome of large-scale cortical networks. We here show that enhanced dopaminergic signaling modulates the two potentially interrelated aspects of large-scale cortical dynamics during cognitive performance, and the degree of these modulations is able to explain inter-individual differences in l-dopa-induced behavioral benefits. Relative to placebo, l-dopa increased BOLD signal variability in task-relevant temporal, inferior frontal, parietal and cingulate regions. On the connectome level, however, l-dopa diminished functional integration across temporal and cingulo-opercular regions. This hypo-integration was expressed as a reduction in network efficiency and modularity in more than two thirds of the participants and to different degrees. Hypo-integration co-occurred with relative hyper-connectivity in paracentral lobule and precuneus, as well as posterior putamen. Both, l-dopa-induced BOLD signal variability modulation and functional connectome modulations proved predictive of an individual's l-dopa-induced benefits in behavioral performance, namely response speed and perceptual sensitivity. Lastly, l-dopa-induced modulations of BOLD signal variability were correlated with l-dopa-induced modulation of nodal connectivity and network efficiency. Our findings underline the role of dopamine in maintaining the dynamic range of, and communication between, cortical systems, and their explanatory power for inter-individual differences in benefits from dopamine during cognitive performance. Copyright © 2018 Elsevier Inc. All rights reserved.

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 of prefrontal and striatal glutamate for ventral striatal presynaptic dopamine levels. Such glutamate-dopamine relationships improve our understanding of neurochemical interactions in prefrontostriatal circuits and have implications for the neurobiology of mental disease. Copyright © 2015 the authors 0270-6474/15/359615-07$15.00/0.

Amperozide, a putative anti-psychotic drug: Uptake inhibition and release of dopamine in vitro in the rat brain

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

Eriksson, E.

1990-01-01

The effects of amperozide (a diphenylbutylpiperazinecarboxamide derivative) on the uptake and release of {sup 3}H-dopamine in vitro were investigated. Amperozide inhibited the amphetamine-stimulated release of dopamine from perfused rat striatal tissue in a dose-dependent manner. With 1 and 10 {mu}m amperozide there was significant inhibition of the amphetamine-stimulated release of dopamine, to 44 and 36 % of control. In contrast, 10 {mu}M amperozide significantly strengthened the electrically stimulated release of dopamine from perfused striatal slices. Amperozide 1-10 {mu}M had no significant effect on the potassium-stimulated release of dopamine, 10 {mu}M amperozide also slightly increased the basal release of {sup 3}H-dopaminemore » from perfused striatal tissue. These effects on various types of release are similar to those reported for uptake inhibitors. The uptake of dopamine in striatal tissue was inhibited by amperozide with IC{sub 50} values of 18 {mu}M for uptake in chopped tissue and 1.0 {mu}M for uptake in synaptosomes. Amperozide also inhibited the uptake of serotonin in synaptosomes from frontal cortex, IC{sub 50} = 0.32 {mu}M and the uptake of noradrenaline in cortical synaptosomes, IC{sub 50} = 0.78 {mu}M.« less

Maternal High-Fat Diet and Obesity Impact Palatable Food Intake and Dopamine Signaling in Nonhuman Primate Offspring

PubMed Central

Rivera, Heidi M.; Kievit, Paul; Kirigiti, Melissa A.; Bauman, Leigh Ann; Baquero, Karalee; Blundell, Peter; Dean, Tyler A.; Valleau, Jeanette C.; Takahashi, Diana L.; Frazee, Tim; Douville, Luke; Majer, Jordan; Smith, M. Susan; Grove, Kevin L.; Sullivan, Elinor L.

2015-01-01

Objective To utilize a nonhuman primate model to examine the impact of maternal high-fat diet (HFD) consumption and pre-pregnancy obesity on offspring intake of palatable food. We will also examine whether maternal HFD consumption impaired development of the dopamine system, critical for the regulation of hedonic feeding. Methods The impact of exposure to maternal HFD and obesity on offspring consumption of diets of varying composition was assessed after weaning. We also examined the influence of maternal HFD consumption on the development of the prefrontal cortex-dopamine system at 13 months of age. Results During a preference test, offspring exposed to maternal obesity and HFD consumption displayed increased intake of food high in fat and sugar content relative to offspring from lean control mothers. Maternal HFD consumption suppressed offspring dopamine signaling (as assessed by immunohistochemistry) relative to control offspring. Specifically, there was decreased abundance of dopamine fibers and of dopamine receptor 1 and 2 protein. Conclusion Our findings reveal that offspring exposed to both maternal HFD consumption and maternal obesity during early development are at increased risk for obesity due to overconsumption of palatable energy-dense food, a behavior that may be related to reduced central dopamine signaling. PMID:26530932

Comodulation of dopamine and serotonin on prefrontal cortical rhythms: a theoretical study

PubMed Central

Wang, Da-Hui; Wong-Lin, KongFatt

2013-01-01

The prefrontal cortex (PFC) is implicated to play an important role in cognitive control. Abnormal PFC activities and rhythms have been observed in some neurological and neuropsychiatric disorders, and evidences suggest influences from the neuromodulators dopamine (DA) and serotonin (5-HT). Despite the high level of interest in these brain systems, the combined effects of DA and 5-HT modulation on PFC dynamics remain unknown. In this work, we build a mathematical model that incorporates available experimental findings to systematically study the comodulation of DA and 5-HT on the network behavior, focusing on beta and gamma band oscillations. Single neuronal model shows pyramidal cells with 5-HT1A and 2A receptors can be non-monotonically modulated by 5-HT. Two-population excitatory-inhibitory type network consisting of pyramidal cells with D1 receptors can provide rich repertoires of oscillatory behavior. In particular, 5-HT and DA can modulate the amplitude and frequency of the oscillations, which can emerge or cease, depending on receptor types. Certain receptor combinations are conducive for the robustness of the oscillatory regime, or the existence of multiple discrete oscillatory regimes. In a multi-population heterogeneous model that takes into account possible combination of receptors, we demonstrate that robust network oscillations require high DA concentration. We also show that selective D1 receptor antagonists (agonists) tend to suppress (enhance) network oscillations, increase the frequency from beta toward gamma band, while selective 5-HT1A antagonists (agonists) act in opposite ways. Selective D2 or 5-HT2A receptor antagonists (agonists) can lead to decrease (increase) in oscillation amplitude, but only 5-HT2A antagonists (agonists) can increase (decrease) the frequency. These results are comparable to some pharmacological effects. Our work illustrates the complex mechanisms of DA and 5-HT when operating simultaneously through multiple receptors. PMID:23935568

Prefrontal cortical regulation of brainwide circuit dynamics and reward-related behavior

PubMed Central

Grosenick, Logan; Warden, Melissa R.; Amatya, Debha; Katovich, Kiefer; Mehta, Hershel; Patenaude, Brian; Ramakrishnan, Charu; Kalanithi, Paul; Etkin, Amit; Knutson, Brian; Glover, Gary H.; Deisseroth, Karl

2016-01-01

Motivation for reward drives adaptive behaviors, whereas impairment of reward perception and experience (anhedonia) can contribute to psychiatric diseases, including depression and schizophrenia. We sought to test the hypothesis that the medial prefrontal cortex (mPFC) controls interactions among specific subcortical regions that govern hedonic responses. By using optogenetic functional magnetic resonance imaging to locally manipulate but globally visualize neural activity in rats, we found that dopamine neuron stimulation drives striatal activity, whereas locally increased mPFC excitability reduces this striatal response and inhibits the behavioral drive for dopaminergic stimulation. This chronic mPFC overactivity also stably suppresses natural reward-motivated behaviors and induces specific new brainwide functional interactions, which predict the degree of anhedonia in individuals. These findings describe a mechanism by which mPFC modulates expression of reward-seeking behavior, by regulating the dynamical interactions between specific distant subcortical regions. PMID:26722001

Dopamine elevates intracellular zinc concentration in cultured rat embryonic cortical neurons through the cAMP-nitric oxide signaling cascade.

PubMed

Hung, Hui-Hsing; Kao, Lung-Sen; Liu, Pei-Shan; Huang, Chien-Chang; Yang, De-Ming; Pan, Chien-Yuan

2017-07-01

Zinc ion (Zn 2+ ), the second most abundant transition metal after iron in the body, is essential for neuronal activity and also induces toxicity if the concentration is abnormally high. Our previous results show that exposure of cultured cortical neurons to dopamine elevates intracellular Zn 2+ concentrations ([Zn 2+ ] i ) and induces autophagosome formation but the mechanism is not clear. In this study, we characterized the signaling pathway responsible for the dopamine-induced elevation of [Zn 2+ ] i and the effect of [Zn 2+ ] i in modulating the autophagy in cultured rat embryonic cortical neurons. N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), a membrane-permeable Zn 2+ chelator, could rescue the cell death and suppress the autophagosome puncta number induced by dopamine. Dopamine treatment increased the lipidation level of the endogenous microtubule-associated protein 1A/1B-light chain 3 (LC3 II), an autophagosome marker. TPEN added 1h before, but not after, dopamine treatment suppressed the dopamine-induced elevation of LC3 II level. Inhibitors of the dopamine D1-like receptor, protein kinase A (PKA), and NOS suppressed the dopamine-induced elevation of [Zn 2+ ] i . PKA activators and NO generators directly increased [Zn 2+ ] i in cultured neurons. Through cell fractionation, proteins with m.w. values between 5 and 10kD were found to release Zn 2+ following NO stimulation. In addition, TPEN pretreatment and an inhibitor against PKA could suppress the LC3 II level increased by NO and dopamine, respectively. Therefore, our results demonstrate that dopamine-induced elevation of [Zn 2+ ] i is mediated by the D1-like receptor-PKA-NO pathway and is important in modulating the cell death and autophagy. Copyright © 2017 Elsevier Inc. All rights reserved.

Serotonergic and dopaminergic modulation of attentional processes.

PubMed

Boulougouris, Vasileios; Tsaltas, Eleftheria

2008-01-01

Disturbances in attentional processes are a common feature of several psychiatric disorders such as schizophrenia, attention deficit/hyperactivity disorder and Huntington's disease. The use of animal models has been useful in defining various candidate neural systems thus enabling us to translate basic laboratory science to the clinic and vice-versa. In this chapter, a comparative and integrated account is provided on the neuroanatomical and neurochemical modulation of basic behavioural operations such as selective attention, vigilance, set-shifting and executive control focusing on the comparative functions of the serotonin and dopamine systems in the cognitive control exerted by the prefrontal cortex. Specifically, we have reviewed evidence emerging from several behavioural paradigms in experimental animals and humans each of which centres on a different aspect of the attentional function. These paradigms offering both human and animal variants include the five-choice serial reaction time task (5CSRTT), attentional set-shifting and stop-signal reaction time task. In each case, the types of operation that are measured by the given paradigm and their neural correlates are defined. Then, the role of the ascending dopaminergic and serotonergic systems in the neurochemical modulation of its behavioural output are examined, and reference is made to clinical implications for neurological and neuropsychiatric disorders which exhibit deficits in these cognitive tests.

Dopamine D2 receptor levels in striatum, thalamus, substantia nigra, limbic regions, and cortex in schizophrenic subjects.

PubMed

Kessler, Robert M; Woodward, Neil D; Riccardi, Patrizia; Li, Rui; Ansari, M Sib; Anderson, Sharlett; Dawant, Benoit; Zald, David; Meltzer, Herbert Y

2009-06-15

Studies in schizophrenic patients have reported dopaminergic abnormalities in striatum, substantia nigra, thalamus, anterior cingulate, hippocampus, and cortex that have been related to positive symptoms and cognitive impairments. [(18)F]fallypride positron emission tomography studies were performed in off-medication or never-medicated schizophrenic subjects (n = 11, 6 men, 5 women; mean age of 30.5 +/- 8.0 [SD] years; 4 drug-naive) and age-matched healthy subjects (n = 11, 5 men, 6 women, mean age of 31.6 +/- 9.2 [SD]) to examine dopamine D(2) receptor (DA D(2)r) levels in the caudate, putamen, ventral striatum, medial thalamus, posterior thalamus, substantia nigra, amygdala, temporal cortex, anterior cingulate, and hippocampus. In schizophrenic subjects, increased DA D(2)r levels were seen in the substantia nigra bilaterally; decreased levels were seen in the left medial thalamus. Correlations of symptoms with ROI data demonstrated a significant correlation of disorganized thinking/nonparanoid delusions with the right temporal cortex ROI (r = .94, p = .0001), which remained significant after correction for multiple comparisons (p < .03). Correlations of symptoms with parametric images of DA D(2)r levels revealed no significant clusters of correlations with negative symptoms but significant clusters of positive correlations of total positive symptoms, delusions and bizarre behavior with the lateral and anterior temporal cortex, and hallucinations with the left ventral striatum. The results of this study demonstrate abnormal DA D(2)r-mediated neurotransmission in the substantia nigra consistent with nigral dysfunction in schizophrenia and suggest that both temporal cortical and ventral striatal DA D(2)r mediate positive symptoms.

A periodic network of neurochemical modules in the inferior colliculus.

PubMed

Chernock, Michelle L; Larue, David T; Winer, Jeffery A

2004-02-01

A new organization has been found in shell nuclei of rat inferior colliculus. Chemically specific modules with a periodic distribution fill about half of layer 2 of external cortex and dorsal cortex. Modules contain clusters of small glutamic acid decarboxylase-positive neurons and large boutons at higher density than in other inferior colliculus subdivisions. The modules are also present in tissue stained for parvalbumin, cytochrome oxidase, nicotinamide adenine dinucleotide phosphate-diaphorase, and acetylcholinesterase. Six to seven bilaterally symmetrical modules extend from the caudal extremity of the external cortex of the inferior colliculus to its rostral pole. Modules are from approximately 800 to 2200 microm long and have areas between 5000 and 40,000 microm2. Modules alternate with immunonegative regions. Similar modules are found in inbred and outbred strains of rat, and in both males and females. They are absent in mouse, squirrel, cat, bat, macaque monkey, and barn owl. Modules are immunonegative for glycine, calbindin, serotonin, and choline acetyltransferase. The auditory cortex and ipsi- and contralateral inferior colliculi project to the external cortex. Somatic sensory influences from the dorsal column nuclei and spinal trigeminal nucleus are the primary ascending sensory input to the external cortex; ascending auditory input to layer 2 is sparse. If the immunopositive modular neurons receive this input, the external cortex could participate in spatial orientation and somatic motor control through its intrinsic and extrinsic projections.

Catechol-O-methyltransferase (COMT) gene modulates private self-consciousness and self-flexibility.

PubMed

Wang, Bei; Ru, Wenzhao; Yang, Xing; Yang, Lu; Fang, Pengpeng; Zhu, Xu; Shen, Guomin; Gao, Xiaocai; Gong, Pingyuan

2016-08-01

Dopamine levels in the brain influence human consciousness. Inspired by the role of Catechol-O-methyltransferase (COMT) in inactivating dopamine in the brain, we investigated to what extent COMT could modulate individual's self-consciousness dispositions and self-consistency by genotyping the COMT Val158Met (rs4680) polymorphism and measuring self-consciousness and self-consistency and congruence in a college student population. The results indicated that COMT Val158Met polymorphism significantly modulated the private self-consciousness. The individuals with Val/Val genotype, corresponding to lower dopamine levels in the brain, were more likely to be aware of their feelings and beliefs. The results also indicated that this polymorphism modulated one's self-flexibility. The individuals with Val/Val genotype showed higher levels of stereotype in self-concept compared with those with Met/Met genotype. These findings suggest that COMT is a predictor of the individual differences in self-consciousness and self-flexibility. Copyright © 2016 Elsevier Inc. All rights reserved.

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

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

PubMed

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

2017-11-01

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

MAOA-VNTR polymorphism modulates context-dependent dopamine release and aggressive behavior in males.

PubMed

Schlüter, Thorben; Winz, Oliver; Henkel, Karsten; Eggermann, Thomas; Mohammadkhani-Shali, Siamak; Dietrich, Claudia; Heinzel, Alexander; Decker, Michel; Cumming, Paul; Zerres, Klaus; Piel, Markus; Mottaghy, Felix M; Vernaleken, Ingo

2016-01-15

A recent [(18)F]FDOPA-PET study reports negative correlations between dopamine synthesis rates and aggressive behavior. Since dopamine is among the substrates for monoamine oxidase A (MAOA), this investigation examines whether functional allelic variants of the MAOA tandem repeat (VNTR) promotor polymorphism, which is known to modulate aggressive behavior, influences dopamine release and aggression in response to violent visual stimuli. We selected from a genetic prescreening sample, strictly case-matched groups of 2×12 healthy male subjects with VNTRs predictive of high (MAOA-High) and low (MAOA-Low) MAOA expression. Subjects underwent pairs of PET sessions (dopamine D2/3 ligand [(18)F]DMFP) while viewing a movie of neutral content, versus violent content. Directly afterwards, aggressive behavior was assessed by the Point Subtraction Aggression Paradigm (PSAP). Finally, PET data of 23 participants and behavioral data of 22 participants were analyzed due to post hoc exclusion criteria. In the genetic prescreening sample MAOA-Low carriers had significantly increased scores on the Buss-Perry Aggression Questionnaire. In the PET-study-group, aggressive behavior under the emotional neutral condition was significantly higher in the MAOA-Low group. Interestingly, the two MAOA-groups showed inverse dopaminergic and behavioral reactions to the violent movie: The MAOA-High group showed higher dopamine release and increased aggression after the violent movie; MAOA-Low subjects showed decreases in aggressive behavior and no consistent dopamine release. These results indicate a possible impact of the MAOA-promotor polymorphism on the neurobiological modulation of aggressive behavior. However, the data do not support approaches stating that MAOA-Low fosters aggression by a simple pro-dopaminergic mechanism. Copyright © 2015 Elsevier Inc. All rights reserved.

ZNF804A variants confer risk for heroin addiction and affect decision making and gray matter volume in heroin abusers.

PubMed

Sun, Yan; Zhao, Li-Yan; Wang, Gui-Bin; Yue, Wei-Hua; He, Yong; Shu, Ni; Lin, Qi-Xiang; Wang, Fan; Li, Jia-Li; Chen, Na; Wang, Hui-Min; Kosten, Thomas R; Feng, Jia-Jia; Wang, Jun; Tang, Yu-De; Liu, Shu-Xue; Deng, Gui-Fa; Diao, Gan-Huan; Tan, Yun-Long; Han, Hong-Bin; Lin, Lu; Shi, Jie

2016-05-01

Drug addiction shares common neurobiological pathways and risk genes with other psychiatric diseases, including psychosis. One of the commonly identified risk genes associated with broad psychosis has been ZNF804A. We sought to test whether psychosis risk variants in ZNF804A increase the risk of heroin addiction by modulating neurocognitive performance and gray matter volume (GMV) in heroin addiction. Using case-control genetic analysis, we compared the distribution of ZNF804A variants (genotype and haplotype) in 1035 heroin abusers and 2887 healthy subjects. We also compared neurocognitive performance (impulsivity, global cognitive ability and decision-making ability) in 224 subjects and GMV in 154 subjects based on the ZNF804A variants. We found significant differences in the distribution of ZNF804A intronic variants (rs1344706 and rs7597593) allele and haplotype frequencies between the heroin and control groups. Decision-making impairment was worse in heroin abusers who carried the ZNF804A risk allele and haplotype. Subjects who carried more risk alleles and haplotypes of ZNF804A had greater GMV in the bilateral insular cortex, right temporal cortex and superior parietal cortex. The interaction between heroin addiction and ZNF804A variants affected GMV in the left sensorimotor cortex. Our findings revealed several ZNF804A variants that were significantly associated with the risk of heroin addiction, and these variants affected decision making and GMV in heroin abusers compared with controls. The precise neural mechanisms that underlie these associations are unknown, which requires future investigations of the effects of ZNF804A on both dopamine neurotransmission and the relative increases in the volume of various brain areas. © 2015 Society for the Study of Addiction.

Emotional disorders induced by Hemopressin and RVD-hemopressin(α) administration in rats.

PubMed

Leone, Sheila; Recinella, Lucia; Chiavaroli, Annalisa; Martinotti, Sara; Ferrante, Claudio; Mollica, Adriano; Macedonio, Giorgia; Stefanucci, Azzurra; Dvorácskó, Szabolcs; Tömböly, Csaba; De Petrocellis, Luciano; Vacca, Michele; Brunetti, Luigi; Orlando, Giustino

2017-12-01

The endocannabinoid (eCB) system plays an important role in regulating emotional disorders, and is involved, directly or indirectly, in psychiatric diseases, such as anxiety and depression. Hemopressin, a hemoglobin α chain-derived peptide, and RVD-hemopressin(α), a N-terminally extended form of hemopressin, act as antagonist/inverse agonist and negative allosteric modulator of the cannabinoid 1 (CB1) receptor, respectively. Considering the possible involvement of these peptides on emotional behaviour, the aim of our study was to investigate the behavioural effects of a single intraperitoneal (ip) injection of hemopressin (0.05mg/kg) and RVD-hemopressin(α) (0.05mg/kg), using a series of validated behavioural tests (locomotor activity/open field test, light-dark exploration test, forced swim test) in rats. Prefrontal cortex levels of norepinephrine (NE), dopamine (DA) and serotonin (5-hydroxytryptamine, 5-HT) and the gene expression of monoamine oxidase (MAO-B) and catechol-O-methyltransferase (COMT) were measured by high performance liquid chromatography (HPLC) analysis and real-time reverse transcription polymerase chain reaction (RT-PCR), respectively. Hemopressin administration induced anxiogenic and depressive behaviour, decreased monoamine steady state levels in prefrontal cortex, and increased the gene expression of the enzymes involved in their catabolism. By contrast, RVD- hemopressin(α) induced anxiolytic and antidepressive effects, increased monoamines and decreased the enzymes in prefrontal cortex. In conclusion, in the present study we demonstrated behavioral effects induced by peripheral hemopressin and RVD-hemopressin(α) injections, that could involve modulatory effects on monoaminergic signaling, in the prefrontal cortex. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Alterations in amino acid levels in mouse brain regions after adjunctive treatment of brexpiprazole with fluoxetine: comparison with (R)-ketamine.

PubMed

Ma, Min; Ren, Qian; Fujita, Yuko; Yang, Chun; Dong, Chao; Ohgi, Yuta; Futamura, Takashi; Hashimoto, Kenji

2017-11-01

Brexpiprazole, a serotonin-dopamine activity modulator, is approved in the USA as an adjunctive therapy to antidepressants for treating major depressive disorders. Similar to the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine, the combination of brexpiprazole and fluoxetine has demonstrated antidepressant-like effects in animal models of depression. The present study was conducted to examine whether the combination of brexpiprazole and fluoxetine could affect the tissue levels of amino acids [glutamate, glutamine, γ-aminobutyric acid (GABA), D-serine, L-serine, and glycine] that are associated with NMDAR neurotransmission. The tissue levels of amino acids in the frontal cortex, striatum, hippocampus, and cerebellum were measured after a single [or repeated (14 days)] oral administration of vehicle, fluoxetine (10 mg/kg), brexpiprazole (0.1 mg/kg), or a combination of the two drugs. Furthermore, we measured the tissue levels of amino acids after a single administration of the NMDAR antagonist (R)-ketamine. A single injection of the combination of fluoxetine and brexpiprazole significantly increased GABA levels in the striatum, the D-serine/L-serine ratio in the frontal cortex, and the glycine/L-serine ratio in the hippocampus. A repeated administration of the combination significantly altered the tissue levels of amino acids in all regions. Interestingly, a repeated administration of the combination significantly decreased the D-serine/L-serine ratio in the frontal cortex, striatum, and hippocampus. In contrast, a single administration of (R)-ketamine significantly increased the D-serine/L-serine ratio in the frontal cortex. These results suggested that alterations in the tissue levels of these amino acids may be involved in the antidepressant-like effects of the combination of brexpiprazole and fluoxetine.

Distribution of messenger RNAs for D1 dopamine receptors and DARPP-32 in striatum and cerebral cortex of the cynomolgus monkey: relationship to D1 dopamine receptors.

PubMed

Brené, S; Hall, H; Lindefors, N; Karlsson, P; Halldin, C; Sedvall, G

1995-07-01

Messenger RNAs for the D1 dopamine receptor and dopamine- and cyclic AMP-regulated phosphoprotein of relative mass 32,000 (DARPP-32) were examined by in situ hybridization in the cynomolgus monkey brain. The messenger RNA distribution was compared to the distribution of D1 dopamine receptors using [3H]SCH 23390 autoradiography. In the caudate nucleus and putamen, D1 dopamine receptor messenger RNA-positive cells were unevenly distributed. Clusters of cells with an approximately three-fold higher intensity of labeling, as compared to surrounding regions, were found. Some of these D1 dopamine receptor messenger RNA intensive cell clusters in the caudate nucleus appeared to some extent to be matched to regions of higher intensity of [3H]SCH 23390 binding. The distribution of cells expressing DARPP-32 messenger RNA in the caudate nucleus and putamen was found to be non-clustered. In neocortical regions, cells of different sizes expressing D1 dopamine receptor messenger RNA were present in layers II-VI. D1 dopamine receptor messenger RNA-positive cells were most abundant in layer V. Unexpectedly, no DARPP-32 messenger RNA signal was detected in neocortex. Chronic SCH 23390 administration did not change the relative levels of messenger RNAs for the D1 dopamine receptor and DARPP-32 or [3H]SCH 23390 binding as measured by quantitative image analysis. The clustered distribution of D1 dopamine receptor messenger RNA is in contrast to that of DARPP-32 messenger RNA. This suggests that D1 dopamine receptors may play a more significant role in regulating DARPP-32 function in patch regions as compared to matrix regions. D1 dopamine receptor messenger RNA-expressing cells could also be visualized in several layers of the primate neocortex, implying that dopamine acts through D1 dopamine receptors within functionally different neuronal circuits of the neocortex.

Oleic Acid Protects Against Oxidative Stress Exacerbated by Cytarabine and Doxorubicin in Rat Brain.

PubMed

Guzmán, David Calderón; Brizuela, Norma Osnaya; Herrera, Maribel Ortíz; Olguín, Hugo Juárez; García, Ernestina Hernández; Peraza, Armando Valenzuela; Mejía, Gerardo Barragán

2016-01-01

The objective of this study was to analyze the effect of doxorubicin and cytarabine on biogenic amines and oxidative biomarkers in the brain of rats treated with oleic acid. Thirty-six Wistar rats distributed in 6 groups, were treated as follows: group 1 (control), NaCl 0.9%; group 2 doxorubicin (1mg/kg); group 3 cytarabine (70mg /kg); group 4 oleic acid (1500μl/kg); group 5 doxorubicin + oleic acid; group 6 cytarabine + oleic acid. All compounds were administered intraperitoneally for 5 days. The Rats were sacrificed after receiving the last administration and their brains were dissected in cortex, hemispheres, and cerebellum/medulla oblongata. Blood samples were obtained on sacrifice to assess the levels of glucose and triglycerides. In each brain region, lipoperoxidation (TBARS), H2O2, Na+, K+ ATPase, glutathione (GSH), serotonin metabolites (5-HIAA) and dopamine were measured using validated methods. Cytarabine decreased the levels of dopamine, TBARS, GSH, H2O2 and ATPase in all regions. Doxorubicin combined with oleic acid increased the levels of GSH in cortex, and decreased ATPase in cerebellum/medulla oblongata. These results suggest that the reduction of dopamine and oxidant effect during cytarabine treatment could result in brain injury but could be prevented by oleic acid supplementation.

Role of Dopamine 2 Receptor in Impaired Drug-Cue Extinction in Adolescent Rats.

PubMed

Zbukvic, Isabel C; Ganella, Despina E; Perry, Christina J; Madsen, Heather B; Bye, Christopher R; Lawrence, Andrew J; Kim, Jee Hyun

2016-06-01

Adolescent drug users display resistance to treatment such as cue exposure therapy (CET), as well as increased liability to relapse. The basis of CET is extinction learning, which involves dopamine signaling in the medial prefrontal cortex (mPFC). This system undergoes dramatic alterations during adolescence. Therefore, we investigated extinction of a cocaine-associated cue in adolescent and adult rats. While cocaine self-administration and lever-alone extinction were not different between the two ages, we observed that cue extinction reduced cue-induced reinstatement in adult but not adolescent rats. Infusion of the selective dopamine 2 receptor (D2R)-like agonist quinpirole into the infralimbic cortex (IL) of the mPFC prior to cue extinction significantly reduced cue-induced reinstatement in adolescents. This effect was replicated by acute systemic treatment with the atypical antipsychotic aripiprazole (Abilify), a partial D2R-like agonist. These data suggest that adolescents may be more susceptible to relapse due to a deficit in cue extinction learning, and highlight the significance of D2R signaling in the IL for cue extinction during adolescence. These findings inspire new tactics for improving adolescent CET, with aripiprazole representing an exciting potential pharmacological adjunct for behavioral therapy. © The Author 2016. Published by Oxford University Press.

Cocaine-conditioned odor cues without chronic exposure: Implications for the development of addiction vulnerability.

PubMed

Lowen, Steven B; Rohan, Michael L; Gillis, Timothy E; Thompson, Britta S; Wellons, Clara B W; Andersen, Susan L

2015-01-01

Adolescents are highly vulnerable to addiction and are four times more likely to become addicted at first exposure than at any other age. The dopamine D1 receptor, which is typically overexpressed in the normal adolescent prefrontal cortex, is involved in drug cue responses and is associated with relapse in animal models. In human drug addicts, imaging methods have detected increased activation in response to drug cues in reward- and habit-associated brain regions. These same methods can be applied more quantitatively to rodent models. Here, changes in neuronal activation in response to cocaine-conditioned cues were observed using functional magnetic resonance imaging in juvenile rats that were made to over-express either D1 receptors or green fluorescent protein by viral-mediated transduction. Reduced activation was observed in the amygdala and dopamine cell body regions in the low cue-preferring/control juvenile rats in response to cocaine cues. In contrast, increased activation was observed in the dorsal striatum, nucleus accumbens, prefrontal cortex, and dopamine cell bodies in high cue-preferring/D1 juveniles. The increase in cue salience that is mediated by increased D1 receptor density, rather than excessive cocaine experience, appears to underlie the transition from aversion to reward in cue-induced neural response and may form the basis for habit-forming vulnerability.

Influence of compulsivity of drug abuse on dopaminergic modulation of attentional bias in stimulant dependence.

PubMed

Ersche, Karen D; Bullmore, Edward T; Craig, Kevin J; Shabbir, Shaila S; Abbott, Sanja; Müller, Ulrich; Ooi, Cinly; Suckling, John; Barnes, Anna; Sahakian, Barbara J; Merlo-Pich, Emilio V; Robbins, Trevor W

2010-06-01

There are no effective pharmacotherapies for stimulant dependence but there are many plausible targets for development of novel therapeutics. We hypothesized that dopamine-related targets are relevant for treatment of stimulant dependence, and there will likely be individual differences in response to dopaminergic challenges. To measure behavioral and brain functional markers of drug-related attentional bias in stimulant-dependent individuals studied repeatedly after short-term dosing with dopamine D(2)/D(3) receptor antagonist and agonist challenges. Randomized, double-blind, placebo-controlled, parallel-groups, crossover design using pharmacological functional magnetic resonance imaging. Clinical research unit (GlaxoSmithKline) and local community in Cambridge, England. Stimulant-dependent individuals (n = 18) and healthy volunteers (n = 18). Amisulpride (400 mg), pramipexole dihydrochloride (0.5 mg), or placebo were administered in counterbalanced order at each of 3 repeated testing sessions. Attentional bias for stimulant-related words was measured during functional magnetic resonance imaging by a drug-word Stroop paradigm; trait impulsivity and compulsivity of dependence were assessed at baseline by questionnaire. Drug users demonstrated significant attentional bias for drug-related words, which was correlated with greater activation of the left prefrontal and right cerebellar cortex. Attentional bias was greater in people with highly compulsive patterns of stimulant abuse; the effects of dopaminergic challenges on attentional interference and related frontocerebellar activation were different between high- and low-compulsivity subgroups. Greater attentional bias for and greater prefrontal activation by stimulant-related words constitute a candidate neurocognitive marker for dependence. Individual differences in compulsivity of stimulant dependence had significant effects on attentional bias, its brain functional representation, and its short-term modulation by dopaminergic challenges.

Nicotine and caffeine modulate haloperidol-induced changes in postsynaptic density transcripts expression: Translational insights in psychosis therapy and treatment resistance.

PubMed

de Bartolomeis, Andrea; Iasevoli, Felice; Marmo, Federica; Buonaguro, Elisabetta Filomena; Avvisati, Livia; Latte, Gianmarco; Tomasetti, Carmine

2018-04-01

Caffeine and nicotine are widely used by schizophrenia patients and may worsen psychosis and affect antipsychotic therapies. However, they have also been accounted as augmentation strategies in treatment-resistant schizophrenia. Despite both substances are known to modulate dopamine and glutamate transmission, little is known about the molecular changes induced by these compounds in association to antipsychotics, mostly at the level of the postsynaptic density (PSD), a site of dopamine-glutamate interplay. Here we investigated whether caffeine and nicotine, alone or combined with haloperidol, elicited significant changes in the levels of both transcripts and proteins of the PSD members Homer1 and Arc, which have been implicated in synaptic plasticity, schizophrenia pathophysiology, and antipsychotics molecular action. Homer1a mRNA expression was significantly reduced by caffeine and nicotine, alone or combined with haloperidol, compared to haloperidol. Haloperidol induced significantly higher Arc mRNA levels than both caffeine and caffeine plus haloperidol in the striatum. Arc mRNA expression was significantly higher by nicotine plus haloperidol vs. haloperidol in the cortex, while in striatum gene expression by nicotine was significantly lower than that by both haloperidol and nicotine plus haloperidol. Both Homer1a and Arc protein levels were significantly increased by caffeine, nicotine, and nicotine plus haloperidol. Homer1b mRNA expression was significantly increased by nicotine and nicotine plus haloperidol, while protein levels were unaffected. Locomotor activity was not significantly affected by caffeine, while it was reduced by nicotine. These data indicate that both caffeine and nicotine trigger relevant molecular changes in PSD sites when given in association with haloperidol. Copyright © 2018 Elsevier B.V. and ECNP. All rights reserved.

Dopamine D1 receptor activation maintains motor coordination in injured rats but does not accelerate the recovery of the motor coordination deficit.

PubMed

Avila-Luna, Alberto; Gálvez-Rosas, Arturo; Alfaro-Rodríguez, Alfonso; Reyes-Legorreta, Celia; Garza-Montaño, Paloma; González-Piña, Rigoberto; Bueno-Nava, Antonio

2018-01-15

The sensorimotor cortex and the striatum are interconnected by the corticostriatal pathway, suggesting that cortical injury alters the striatal function that is associated with skilled movements and motor learning, which are functions that may be modulated by dopamine (DA). In this study, we explored motor coordination and balance in order to investigate whether the activation of D 1 receptors (D 1 Rs) modulates functional recovery after cortical injury. The results of the beam-walking test showed motor deficit in the injured group at 24, 48 and 96h post-injury, and the recovery time was observed at 192h after cortical injury. In the sham and injured rats, systemic administration of the D 1 R antagonist SCH-23390 (1mg/kg) alone at 24, 48, 96 and 192h significantly (P<0.01) increased the motor deficit, while administration of the D 1 R agonist SKF-38393 alone (2, 3 and 4mg/kg) at 24, 48, 96 and 192h post-injury did not produce a significant difference; however, the co-administration of SKF-38393 and SCH-23390 prevented the antagonist-induced increase in the motor deficit. The cortical+striatal injury showed significantly increased the motor deficit at 24, 48, 96 and 192h post-injury (P<0.01) but did not show recovery at 192h. In conclusion, the administration of the D 1 R agonist did not accelerate the motor recovery, but the activation of D 1 Rs maintained motor coordination, confirming that an intact striatum may be necessary for achieving recovery. Copyright © 2017 Elsevier B.V. All rights reserved.

Influence of Compulsivity of Drug Abuse on Dopaminergic Modulation of Attentional Bias in Stimulant Dependence

PubMed Central

Ersche, Karen D.; Bullmore, Edward T.; Craig, Kevin J.; Shabbir, Shaila S.; Abbott, Sanja; Müller, Ulrich; Ooi, Cinly; Suckling, John; Barnes, Anna; Sahakian, Barbara J.; Merlo-Pich, Emilio V.; Robbins, Trevor W.

2013-01-01

Context There are no effective pharmacotherapies for stimulant dependence but there are many plausible targets for development of novel therapeutics. We hypothesized that dopamine-related targets are relevant for treatment of stimulant dependence, and there will likely be individual differences in response to dopaminergic challenges. Objective To measure behavioral and brain functional markers of drug-related attentional bias in stimulant-dependent individuals studied repeatedly after short-term dosing with dopamine D2/D3 receptor antagonist and agonist challenges. Design Randomized, double-blind, placebo-controlled, parallel-groups, crossover design using pharmacological functional magnetic resonance imaging. Setting Clinical research unit (GlaxoSmithKline) and local community in Cambridge, England. Participants Stimulant-dependent individuals (n=18) and healthy volunteers (n=18). Interventions Amisulpride (400 mg), pramipexole dihydrochloride (0.5 mg), or placebo were administered in counterbalanced order at each of 3 repeated testing sessions. Main Outcome Measures Attentional bias for stimulant-related words was measured during functional magnetic resonance imaging by a drug-word Stroop paradigm; trait impulsivity and compulsivity of dependence were assessed at baseline by questionnaire. Results Drug users demonstrated significant attentional bias for drug-related words, which was correlated with greater activation of the left prefrontal and right cerebellar cortex. Attentional bias was greater in people with highly compulsive patterns of stimulant abuse; the effects of dopaminergic challenges on attentional interference and related frontocerebellar activation were different between high- and low-compulsivity subgroups. Conclusions Greater attentional bias for and greater prefrontal activation by stimulant-related words constitute a candidate neurocognitive marker for dependence. Individual differences in compulsivity of stimulant dependence had significant effects on attentional bias, its brain functional representation, and its short-term modulation by dopaminergic challenges. PMID:20530013

Opiate-associated contextual memory formation and retrieval are differentially modulated by dopamine D1 and D2 signaling in hippocampal-prefrontal connectivity.

PubMed

Wang, Yunpeng; Zhang, Hongying; Cui, Jingjing; Zhang, Jing; Yin, Fangyuan; Guo, Hao; Lai, Jianghua; Xing, Bo

2018-04-17

Contextual memory driven by abused drugs such as opiates has a central role in maintenance and relapse of drug-taking behaviors. Although dopamine (DA) signaling favors memory storage and retrieval via regulation of hippocampal-prefrontal connectivity, its role in modulating opiate-associated contextual memory is largely unknown. Here, we report roles of DA signaling within the hippocampal-prefrontal circuit for opiate-related memories. Combining-conditioned place preference (CPP) with molecular analyses, we investigated the DA D1 receptor (D1R) and extracellular signal-regulated kinase (ERK)-cAMP-response element binding protein (CREB) signaling, as well as DA D2 receptor (D2R) and protein kinase B (PKB or Akt)/glycogen synthase kinase 3 (GSK3) signaling in the ventral hippocampus (vHip) and medial prefrontal cortex (mPFC) during the formation of opiate-related associative memories. Morphine-CPP acquisition increased the activity of the D1R-ERK-CREB pathway in both the vHip and mPFC. Morphine-CPP reinstatement was associated with the D2R-mediated hyperactive GSK3 via Akt inhibition in the vHip and PFC. Furthermore, integrated D1R-ERK-CREB and D2R-Akt-GSK3 pathways in the vHip-mPFC circuit are required for the acquisition and retrieval of the morphine contextual memory, respectively. Moreover, blockage of D1R or D2R signaling could alleviate normal Hip-dependent spatial memory. These results suggest that D1R and D2R signaling are differentially involved in the acquisition and retrieval of morphine contextual memory, and DA signaling in the vHip-mPFC connection contributes to morphine-associated and normal memory, largely depending on opiate exposure states.

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.

A frontal dopamine system for reflective exploratory behavior.

PubMed

Blanco, Nathaniel J; Love, Bradley C; Cooper, Jessica A; McGeary, John E; Knopik, Valerie S; Maddox, W Todd

2015-09-01

The COMT gene modulates dopamine levels in prefrontal cortex with Met allele carriers having lower COMT enzyme activity and, therefore, higher dopamine levels compared to Val/Val homozygotes. Concordantly, Val/Val homozygotes tend to perform worse and display increased (interpreted as inefficient) frontal activation in certain cognitive tasks. In a sample of 209 participants, we test the hypothesis that Met carriers will be advantaged in a decision-making task that demands sequencing exploratory and exploitive choices to minimize uncertainty about the reward structure in the environment. Previous work suggests that optimal performance depends on limited cognitive resources supported by prefrontal systems. If so, Met carriers should outperform Val/Val homozygotes, particularly under dual-task conditions that tax limited cognitive resources. In accord with these a priori predictions, Met carriers were more resilient in the face of cognitive load, continuing to explore in a sophisticated manner. We fit computational models that embody sophisticated reflective and simple reflexive strategies to further evaluate participants' exploration behavior. The Ideal Actor model reflectively updates beliefs and plans ahead, taking into account the information gained by each choice and making choices that maximize long-term payoffs. In contrast, the Naïve Reinforcement Learning (RL) model instantiates the reflexive account of choice, in which the values of actions are based only on the rewards experienced so far. Its beliefs are updated reflexively in response to observed changes in rewards. Converging with standard analyses, Met carriers were best characterized by the Ideal Actor model, whereas Val/Val homozygotes were best characterized by the Naive RL model, particularly under dual-task conditions. Copyright © 2015 Elsevier Inc. All rights reserved.

The effects of the dopamine agonist rotigotine on hemispatial neglect following stroke.

PubMed

Gorgoraptis, Nikos; Mah, Yee-Haur; Machner, Bjoern; Singh-Curry, Victoria; Malhotra, Paresh; Hadji-Michael, Maria; Cohen, David; Simister, Robert; Nair, Ajoy; Kulinskaya, Elena; Ward, Nick; Greenwood, Richard; Husain, Masud

2012-08-01

Hemispatial neglect following right-hemisphere stroke is a common and disabling disorder, for which there is currently no effective pharmacological treatment. Dopamine agonists have been shown to play a role in selective attention and working memory, two core cognitive components of neglect. Here, we investigated whether the dopamine agonist rotigotine would have a beneficial effect on hemispatial neglect in stroke patients. A double-blind, randomized, placebo-controlled ABA design was used, in which each patient was assessed for 20 testing sessions, in three phases: pretreatment (Phase A1), on transdermal rotigotine for 7-11 days (Phase B) and post-treatment (Phase A2), with the exact duration of each phase randomized within limits. Outcome measures included performance on cancellation (visual search), line bisection, visual working memory, selective attention and sustained attention tasks, as well as measures of motor control. Sixteen right-hemisphere stroke patients were recruited, all of whom completed the trial. Performance on the Mesulam shape cancellation task improved significantly while on rotigotine, with the number of targets found on the left side increasing by 12.8% (P = 0.012) on treatment and spatial bias reducing by 8.1% (P = 0.016). This improvement in visual search was associated with an enhancement in selective attention but not on our measures of working memory or sustained attention. The positive effect of rotigotine on visual search was not associated with the degree of preservation of prefrontal cortex and occurred even in patients with significant prefrontal involvement. Rotigotine was not associated with any significant improvement in motor performance. This proof-of-concept study suggests a beneficial role of dopaminergic modulation on visual search and selective attention in patients with hemispatial neglect following stroke.

The effects of the dopamine agonist rotigotine on hemispatial neglect following stroke

PubMed Central

Gorgoraptis, Nikos; Mah, Yee-Haur; Machner, Bjoern; Singh-Curry, Victoria; Malhotra, Paresh; Hadji-Michael, Maria; Cohen, David; Simister, Robert; Nair, Ajoy; Kulinskaya, Elena; Ward, Nick; Greenwood, Richard

2012-01-01

Hemispatial neglect following right-hemisphere stroke is a common and disabling disorder, for which there is currently no effective pharmacological treatment. Dopamine agonists have been shown to play a role in selective attention and working memory, two core cognitive components of neglect. Here, we investigated whether the dopamine agonist rotigotine would have a beneficial effect on hemispatial neglect in stroke patients. A double-blind, randomized, placebo-controlled ABA design was used, in which each patient was assessed for 20 testing sessions, in three phases: pretreatment (Phase A1), on transdermal rotigotine for 7–11 days (Phase B) and post-treatment (Phase A2), with the exact duration of each phase randomized within limits. Outcome measures included performance on cancellation (visual search), line bisection, visual working memory, selective attention and sustained attention tasks, as well as measures of motor control. Sixteen right-hemisphere stroke patients were recruited, all of whom completed the trial. Performance on the Mesulam shape cancellation task improved significantly while on rotigotine, with the number of targets found on the left side increasing by 12.8% (P = 0.012) on treatment and spatial bias reducing by 8.1% (P = 0.016). This improvement in visual search was associated with an enhancement in selective attention but not on our measures of working memory or sustained attention. The positive effect of rotigotine on visual search was not associated with the degree of preservation of prefrontal cortex and occurred even in patients with significant prefrontal involvement. Rotigotine was not associated with any significant improvement in motor performance. This proof-of-concept study suggests a beneficial role of dopaminergic modulation on visual search and selective attention in patients with hemispatial neglect following stroke. PMID:22761293

Effects of dopaminergic genes, prenatal adversities, and their interaction on attention-deficit/hyperactivity disorder and neural correlates of response inhibition.

PubMed

van der Meer, Dennis; Hartman, Catharina A; van Rooij, Daan; Franke, Barbara; Heslenfeld, Dirk J; Oosterlaan, Jaap; Faraone, Stephen V; Buitelaar, Jan K; Hoekstra, Pieter J

2017-03-01

Attention-deficit/hyperactivity disorder (ADHD) is often accompanied by impaired response inhibition; both have been associated with aberrant dopamine signalling. Given that prenatal exposure to alcohol or smoking is known to affect dopamine-rich brain regions, we hypothesized that individuals carrying the ADHD risk alleles of the dopamine receptor D4 ( DRD4 ) and dopamine transporter ( DAT1 ) genes may be especially sensitive to their effects. Functional MRI data, information on prenatal adversities and genetic data were available for 239 adolescents and young adults participating in the multicentre ADHD cohort study NeuroIMAGE (average age 17.3 yr). We analyzed the effects of DRD4 and DAT1 , prenatal exposure to alcohol and smoking and their interactions on ADHD severity, response inhibition and neural activity. We found no significant gene × environment interaction effects. We did find that the DRD4 7-repeat allele was associated with less superior frontal and parietal brain activity and with greater activity in the frontal pole and occipital cortex. Prenatal exposure to smoking was also associated with lower superior frontal activity, but with greater activity in the parietal lobe. Further, those exposed to alcohol had more activity in the lateral orbitofrontal cortex, and the DAT1 risk variant was associated with lower cerebellar activity. Retrospective reports of maternal substance use and the cross-sectional study design restrict causal inference. While we found no evidence of gene × environment interactions, the risk factors under investigation influenced activity of brain regions associated with response inhibition, suggesting they may add to problems with inhibiting behaviour.

Postnatal functional inactivation of the entorhinal cortex or ventral subiculum has different consequences for latent inhibition-related striatal dopaminergic responses in adult rats.

PubMed

Meyer, F; Peterschmitt, Y; Louilot, A

2009-05-01

Latent inhibition has been found to be disrupted in patients with acute schizophrenia. Striatal dopaminergic dysregulation is commonly acknowledged in schizophrenia. This disease may be consecutive to a functional disconnection between integrative regions, stemming from neurodevelopmental failures. Various anomalies suggesting early abnormal brain development have been described in the entorhinal cortex (ENT) and ventral subiculum (SUB) of patients. This study examines the consequences of a neonatal transitory blockade of the left ENT or left SUB for latent inhibition-related dopamine responses in the anterior part of the dorsal striatum using in-vivo voltammetry in freely moving adult rats. Reversible inactivation of both structures in different animals was achieved by local microinjection of tetrodotoxin (TTX) at postnatal day 8. Results obtained during the retention session of a three-stage latent inhibition protocol showed that the functional neonatal disconnection of the ENT or SUB caused the behavioural latent inhibition expression in pre-exposed (PE)-TTX-conditioned adult rats to disappear. After postnatal inactivation of the SUB, PE-TTX-conditioned rats displayed a reversal of the latent inhibition-related striatal dopamine responses, whereas after neonatal blockade of the ENT, dopamine changes in PE-TTX-conditioned rats monitored in the anterior striatum were between those observed in PE-phosphate-buffered-saline-conditioned and non-PE-TTX-conditioned animals. These data suggest that neonatal functional inactivation of the SUB disrupts latent inhibition-related striatal dopamine responses in adult animals more than that of the ENT. They may help improve understanding of the pathophysiology of schizophrenia.

The Effects of Medium Spiny Neuron Morphologcial Changes on Basal Ganglia Network under External Electric Field: A Computational Modeling Study.

PubMed

Zhang, Xiaohan; Liu, Shenquan; Zhan, Feibiao; Wang, Jing; Jiang, Xiaofang

2017-01-01

The damage of dopaminergic neurons that innervate the striatum has been considered to be the proximate cause of Parkinson's disease (PD). In the dopamine-denervated state, the loss of dendritic spines and the decrease of dendritic length may prevent medium spiny neuron (MSN) from receiving too much excitatory stimuli from the cortex, thereby reducing the symptom of Parkinson's disease. However, the reduction in dendritic spine density obtained by different experiments is significantly different. We developed a biological-based network computational model to quantify the effect of dendritic spine loss and dendrites tree degeneration on basal ganglia (BG) signal regulation. Through the introduction of error index (EI), which was used to measure the attenuation of the signal, we explored the amount of dendritic spine loss and dendritic trees degradation required to restore the normal regulatory function of the network, and found that there were two ranges of dendritic spine loss that could reduce EI to normal levels in the case of dopamine at a certain level, this was also true for dendritic trees. However, although these effects were the same, the mechanisms of these two cases were significant difference. Using the method of phase diagram analysis, we gained insight into the mechanism of signal degradation. Furthermore, we explored the role of cortex in MSN morphology changes dopamine depletion-induced and found that proper adjustments to cortical activity do stop the loss in dendritic spines induced by dopamine depleted. These results suggested that modifying cortical drive onto MSN might provide a new idea on clinical therapeutic strategies for Parkinson's disease.

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

Asenapine Effects on Cognitive and Monoamine Dysfunction Elicited by Subchronic Phencyclidine Administration

PubMed Central

Elsworth, John D.; Groman, Stephanie; Jentsch, J. David; Valles, Rodrigo; Shahid, Mohammed; Wong, Erik; Marston, Hugh; Roth, Robert H.

2013-01-01

Purpose Repeated, intermittent administration of the psychotropic NMDA antagonist phencyclidine (PCP) to laboratory animals causes impairment in cognitive and executive functions, modeling important sequelae of schizophrenia; these effects are thought to be due to a dysregulation of neurotransmission within the prefrontal cortex. Atypical antipsychotic drugs have been reported to have measurable, if incomplete, effects on cognitive dysfunction in this model, and these effects may be due to their ability to normalize a subset of the physiological deficits occurring within the prefrontal cortex. Asenapine is an atypical antipsychotic approved in the US for the treatment of schizophrenia and for the treatment, as monotherapy or adjunctive therapy to lithium or valproate, of acute manic or mixed episodes associated bipolar I disorder. To understand its cognitive and neurochemical actions more fully, we explored the effects of short- and long-term dosing with asenapine on measures of cognitive and motor function in normal monkeys and in those previously exposed for 2 weeks to PCP; we further studied the impact of treatment with asenapine on dopamine and serotonin turnover in discrete brain regions from the same cohort. Methods Monkeys were trained to perform reversal learning and object retrieval procedures before twice-daily administration of PCP (0.3 mg/kg intramuscular) or saline for 14 days. Tests confirmed cognitive deficits in PCP-exposed animals before beginning twice-daily administration of saline (control) or asenapine (50, 100, or 150 μg/kg, intramuscular). Dopamine and serotonin turnover were assessed in 15 specific brain regions by high-pressure liquid chromatography measures of the ratio of parent amine to its major metabolite. Results On average, PCP-treated monkeys made twice as many errors in the reversal task as did control monkeys. Asenapine facilitated reversal learning performance in PCP-exposed monkeys, with improvements at trend level after 1 week of administration and reaching significance after 2–4 weeks of dosing. In week 4, the improvement with asenapine 150 μg/kg (p=0.01) rendered the performance of PCP-exposed monkeys indistinguishable from that of normal monkeys without compromising fine motor function. Asenapine administration (150 μg/kg twice daily) produced an increase in dopamine and serotonin turnover in most brain regions of control monkeys and asenapine (50–150 μg/kg) increased dopamine and serotonin turnover in several brain regions of subchronic PCP-treated monkeys. No significant changes in the steady-state levels of dopamine or serotonin were observed in any brain region except for the central amygdala, in which a significant depletion of dopamine was observed in PCP-treated control monkeys; asenapine treatment reversed this dopamine depletion. A significant decrease in serotonin utilization was observed in the orbitofrontal cortex and nucleus accumbens in PCP monkeys, which may underlie poor reversal learning. In the same brain regions, dopamine utilization was not affected. Asenapine ameliorated this serotonin deficit in a dose-related manner that matched its efficacy for reversing the cognitive deficit. Conclusions In this model of cognitive dysfunction, asenapine produced substantial gains in executive functions that were maintained with long-term administration. The cognition-enhancing effects of asenapine and the neurochemical changes in serotonin and dopamine turnover seen in this study are hypothesized to be primarily related to its potent serotonergic and noradrenergic receptor binding properties, and support the potential for asenapine to reduce cognitive dysfunction in patients with schizophrenia and bipolar disorder. PMID:21875607

Blonanserin Ameliorates Phencyclidine-Induced Visual-Recognition Memory Deficits: the Complex Mechanism of Blonanserin Action Involving D3-5-HT2A and D1-NMDA Receptors in the mPFC

PubMed Central

Hida, Hirotake; Mouri, Akihiro; Mori, Kentaro; Matsumoto, Yurie; Seki, Takeshi; Taniguchi, Masayuki; Yamada, Kiyofumi; Iwamoto, Kunihiro; Ozaki, Norio; Nabeshima, Toshitaka; Noda, Yukihiro

2015-01-01

Blonanserin differs from currently used serotonin 5-HT2A/dopamine-D2 receptor antagonists in that it exhibits higher affinity for dopamine-D2/3 receptors than for serotonin 5-HT2A receptors. We investigated the involvement of dopamine-D3 receptors in the effects of blonanserin on cognitive impairment in an animal model of schizophrenia. We also sought to elucidate the molecular mechanism underlying this involvement. Blonanserin, as well as olanzapine, significantly ameliorated phencyclidine (PCP)-induced impairment of visual-recognition memory, as demonstrated by the novel-object recognition test (NORT) and increased extracellular dopamine levels in the medial prefrontal cortex (mPFC). With blonanserin, both of these effects were antagonized by DOI (a serotonin 5-HT2A receptor agonist) and 7-OH-DPAT (a dopamine-D3 receptor agonist), whereas the effects of olanzapine were antagonized by DOI but not by 7-OH-DPAT. The ameliorating effect was also antagonized by SCH23390 (a dopamine-D1 receptor antagonist) and H-89 (a protein kinase A (PKA) inhibitor). Blonanserin significantly remediated the decrease in phosphorylation levels of PKA at Thr197 and of NR1 (an essential subunit of N-methyl-D-aspartate (NMDA) receptors) at Ser897 by PKA in the mPFC after a NORT training session in the PCP-administered mice. There were no differences in the levels of NR1 phosphorylated at Ser896 by PKC in any group. These results suggest that the ameliorating effect of blonanserin on PCP-induced cognitive impairment is associated with indirect functional stimulation of the dopamine-D1-PKA-NMDA receptor pathway following augmentation of dopaminergic neurotransmission due to inhibition of both dopamine-D3 and serotonin 5-HT2A receptors in the mPFC. PMID:25120077

D1 Receptors Regulate Dendritic Morphology in Normal and Stressed Prelimbic Cortex

PubMed Central

Lin, Grant L.; Borders, Candace B.; Lundewall, Leslie J.; Wellman, Cara L.

2014-01-01

Both stress and dysfunction of prefrontal cortex are linked to psychological disorders, and structure and function of medial prefrontal cortex (mPFC) are altered by stress. Chronic restraint stress causes dendritic retraction in the prelimbic region (PL) of mPFC in rats. Dopamine release in mPFC increases during stress, and chronic administration of dopaminergic agonists results in dendritic remodeling. Thus, stress-induced alterations in dopaminergic transmission in PL may contribute to dendritic remodeling. We examined the effects of dopamine D1 receptor (D1R) blockade in PL during daily restraint stress on dendritic morphology in PL. Rats either underwent daily restraint stress (3 h/day, 10 days) or remained unstressed. In each group, rats received daily infusions of either the D1R antagonist SCH23390 or vehicle into PL prior to restraint; unstressed and stressed rats that had not undergone surgery were also examined. On the final day of restraint, rats were euthanized and brains were processed for Golgi histology. Pyramidal neurons in PL were reconstructed and dendritic morphology was quantified. Vehicle-infused stressed rats demonstrated dendritic retraction compared to unstressed rats, and D1R blockade in PL prevented this effect. Moreover, in unstressed rats, D1R blockade produced dendritic retraction. These effects were not due to attenuation of the HPA axis response to acute stress: plasma corticosterone levels in a separate group of rats that underwent acute restraint stress with or without D1R blockade were not significantly different. These findings indicate that dopaminergic transmission in mPFC during stress contributes directly to the stress-induced retraction of apical dendrites, while dopamine transmission in the absence of stress is important in maintaining normal dendritic morphology. PMID:25305546

D1 receptors regulate dendritic morphology in normal and stressed prelimbic cortex.

PubMed

Lin, Grant L; Borders, Candace B; Lundewall, Leslie J; Wellman, Cara L

2015-01-01

Both stress and dysfunction of prefrontal cortex are linked to psychological disorders, and structure and function of medial prefrontal cortex (mPFC) are altered by stress. Chronic restraint stress causes dendritic retraction in the prelimbic region (PL) of mPFC in rats. Dopamine release in mPFC increases during stress, and chronic administration of dopaminergic agonists results in dendritic remodeling. Thus, stress-induced alterations in dopaminergic transmission in PL may contribute to dendritic remodeling. We examined the effects of dopamine D1 receptor (D1R) blockade in PL during daily restraint stress on dendritic morphology in PL. Rats either underwent daily restraint stress (3h/day, 10 days) or remained unstressed. In each group, rats received daily infusions of either the D1R antagonist SCH23390 or vehicle into PL prior to restraint; unstressed and stressed rats that had not undergone surgery were also examined. On the final day of restraint, rats were euthanized and brains were processed for Golgi histology. Pyramidal neurons in PL were reconstructed and dendritic morphology was quantified. Vehicle-infused stressed rats demonstrated dendritic retraction compared to unstressed rats, and D1R blockade in PL prevented this effect. Moreover, in unstressed rats, D1R blockade produced dendritic retraction. These effects were not due to attenuation of the HPA axis response to acute stress: plasma corticosterone levels in a separate group of rats that underwent acute restraint stress with or without D1R blockade were not significantly different. These findings indicate that dopaminergic transmission in mPFC during stress contributes directly to the stress-induced retraction of apical dendrites, while dopamine transmission in the absence of stress is important in maintaining normal dendritic morphology. Copyright © 2014 Elsevier Ltd. All rights reserved.

CHANGES IN APICAL DENDRITIC STRUCTURE CORRELATE WITH SUSTAINED ERK1/2 PHOSPHORYLATION IN MEDIAL PREFRONTAL CORTEX OF A RAT MODEL OF DOPAMINE D1 RECEPTOR AGONIST SENSITIZATION

PubMed Central

Papadeas, Sophia T.; Halloran, Christopher; McCown, Thomas J.; Breese, George R.; Blake, Bonita L.

2008-01-01

Rats lesioned with 6-hydroxydopamine (6-OHDA) as neonates exhibit behavioral and neurochemical abnormalities in adulthood that mimic Lesch-Nyhan disease, schizophrenia and other developmental disorders of frontostriatal circuit dysfunction. In these animals, a latent sensitivity to D1 agonists is maximally exposed by repeated administration of dopamine agonists in the post-pubertal period (D1 priming). In neonate-lesioned, adult rats primed with SKF-38393, we found selective, persistent alterations in the morphology of pyramidal neuron apical dendrites in the prelimbic area of the medial prefrontal cortex (mPFC). In these animals, dendrite bundling patterns and the typically straight trajectories of primary dendritic shafts were disrupted, whereas the diameter of higher-order oblique branches was increased. Although not present in neonate-lesioned rats treated with saline, these morphological changes persisted at least 21 days after repeated dosing with SKF-38393, and were not accompanied by markers of neurodegenerative change. A sustained increase in phospho-ERK immunoreactivity in wavy dendritic shafts over the same period suggested a relationship between prolonged ERK phosphorylation and dendritic remodeling in D1-primed rats. In support of this hypothesis, pretreatment with the MEK1/2-ERK1/2 pathway inhibitors PD98059 or SL327, prior to each priming dose of SKF-38393, prevented the morphological changes associated with D1 priming. Together, these findings demonstrate that repeated stimulation of D1 receptors in adulthood interacts with the developmental loss of dopamine to profoundly and persistently modify neuronal signaling and dendrite morphology in the mature prefrontal cortex. Furthermore, sustained elevation of ERK activity in mPFC pyramidal neurons may play a role in guiding these morphological changes in vivo. PMID:18785628

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.

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

PubMed

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

2015-03-15

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

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.

Schizotypal Traits are Linked to Dopamine-Induced Striato-Cortical Decoupling: A Randomized Double-Blind Placebo-Controlled Study.

PubMed

Rössler, Julian; Unterassner, Lui; Wyss, Thomas; Haker, Helene; Brugger, Peter; Rössler, Wulf; Wotruba, Diana

2018-06-07

The dopamine hypothesis of schizophrenia implies that alterations in the dopamine system cause functional abnormalities in the brain that may converge to aberrant salience attribution and eventually lead to psychosis. Indeed, widespread brain disconnectivity across the psychotic spectrum has been revealed by resting-state functional magnetic resonance imaging (rs-fMRI). However, the dopaminergic involvement in intrinsic functional connectivity (iFC) and its putative relationship to the development of psychotic spectrum disorders remains partly unclear-in particular at the low-end of the psychosis continuum. Therefore, we investigated dopamine-induced changes in striatal iFC and their modulation by psychometrically assessed schizotypy. Our randomized, double-blind placebo-controlled study design included 54 healthy, right-handed male participants. Each participant was assessed with the Schizotypal Personality Questionnaire (SPQ) and underwent 10 minutes of rs-fMRI scanning. Participants then received either a placebo or 200 mg of L-DOPA, a dopamine precursor. We analyzed iFC of 6 striatal seeds that are known to evoke modulation of dopamine-related networks. The main effect of L-DOPA was a significant functional decoupling from the right ventral caudate to both occipital fusiform gyri. This dopamine-induced decoupling emerged primarily in participants with low SPQ scores, while participants with high positive SPQ scores showed decoupling indifferently of the L-DOPA challenge. Taken together, these findings demonstrate that schizotypal traits may be the result of dopamine-induced striato-occipital decoupling.

Therapeutic potential of silymarin in chronic unpredictable mild stress induced depressive-like behavior in mice.

PubMed

Thakare, Vishnu N; Patil, Rajesh R; Oswal, Rajesh J; Dhakane, Valmik D; Aswar, Manoj K; Patel, Bhoomika M

2018-02-01

Silymarin, a plant-derived polyphenolic flavonoid of Silybum marianum, elicited significant antidepressant-like activity in an acute restraint stress model of depression. It improved monoamines, mainly 5-hydroxytryptamine (5-HT) levels in the cortex, dopamine (DA) and norepinephrine (NE) in the cerebellum in mice. The present study was undertaken to explore the antidepressant potential of silymarin in chronic unpredictable mild stress (CUMS) induced depressive-like behavior in mice, and to find out its probable mechanism(s) of action, mainly neurogenesis, neuroinflammation, and/or oxidative stress. The mice were subjected to CUMS for 28 days (4 weeks) and administered with silymarin (100 mg/kg and 200 mg/kg), or fluoxetine or vehicle from days 8 to 28 (3 weeks simultaneously). Animals were evaluated for behavioral changes, such as anhedonia by sucrose preference test, behavioral despair by forced swim test, and exploratory behaviors by an open field test. In addition, neurobiochemical alterations, mainly monoamines, 5-HT, NE, DA, neurotrophic factor BDNF, and cytokines, IL-6, TNF-α, oxidant-antioxidant parameters by determining the malondialdehyde formation (an index of lipid peroxidation process), superoxide dismutase (SOD) and catalase (CAT) activity in hippocampus and cerebral cortex along with serum corticosterone were investigated. Our findings reveal that mice subjected to CUMS exhibited lower sucrose preference, increase immobility time without affecting general locomotion of the animals, and reduce BDNF, 5-HT, NE, and DA level, increased serum corticosterone, IL-6 and TNF-α along with an oxidant-antioxidant imbalance in the hippocampus and cerebral cortex. Silymarin significantly reversed the CUMS-induced changes in the hippocampus and cerebral cortex in mice. Thus, the possible mechanism involved in the antidepressant-like activity of silymarin is correlated to the alleviation of monoaminergic, neurogenesis (enhancing 5-HT, NE, and BDNF levels), and attenuation of inflammatory cytokines system and oxidative stress by modulation of corticosterone response, restoration of antioxidant defense system in cerebral cortex and hippocampus.

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

The Roles of Orbital Frontal Cortex in the Modulation of Antisocial Behavior

ERIC Educational Resources Information Center

Blair, R. J. R.

2004-01-01

This article considers potential roles of orbital frontal cortex in the modulation of antisocial behavior. Two forms of aggression are distinguished: reactive aggression elicited in response to frustration/threat and goal directed, instrumental aggression. It is suggested that orbital frontal cortex is directly involved in the modulation of…

Heterogeneity of D2 dopamine receptors in different brain regions.

PubMed Central

Leonard, M N; Macey, C A; Strange, P G

1987-01-01

The binding of [3H]spiperone has been examined in membranes derived from different regions of bovine brain. In caudate nucleus, nucleus accumbens, olfactory tubercle and putamen binding is to D2 dopamine and 5HT2 serotonin receptors, whereas in cingulate cortex only serotonin 5HT2 receptor binding can be detected. D2 dopamine receptors were examined in detail in caudate nucleus, olfactory tubercle and putamen using [3H]spiperone binding in the presence of 0.3 microM-mianserin (to block 5HT2 serotonin receptors). No evidence for heterogeneity among D2 dopamine receptors either between brain regions or within a brain region was found from the displacements of [3H]spiperone binding by a range of antagonists, including dibenzazepines and substituted benzamides. Regulation of agonist binding by guanine nucleotides did, however, differ between regions. In caudate nucleus a population of agonist binding sites appeared resistant to guanine nucleotide regulation, whereas this was not the case in olfactory tubercle and putamen. PMID:2963621

Protective Effects Induced by Microwave-Assisted Aqueous Harpagophytum Extract on Rat Cortex Synaptosomes Challenged with Amyloid β-Peptide.

PubMed

Ferrante, Claudio; Recinella, Lucia; Locatelli, Marcello; Guglielmi, Paolo; Secci, Daniela; Leporini, Lidia; Chiavaroli, Annalisa; Leone, Sheila; Martinotti, Sara; Brunetti, Luigi; Vacca, Michele; Menghini, Luigi; Orlando, Giustino

2017-08-01

Harpagophytum procumbens is a plant species that displays anti-inflammatory properties in multiple tissues. The iridoid glycosides arpagoside, harpagide, and procumbide appear to be the most therapeutically important constituents. In addition, harpagoside treatment exerted neuroprotective effects both in vitro and in vivo. Considering these findings, the aim of the present work is to explore the possible protective role of the previously described microwave-assisted aqueous extract of H. procumbens on rat hypothalamic (Hypo-E22) cells, and in rat cortex challenged with amyloid β-peptide (1-40). In this context, we assayed the protective effects induced by H. procumbens by measuring the levels of malondialdehyde, 3-hydroxykynurenine (3-HK), brain-derived neurotrophic factor, and tumor necrosis factor-α, 3-HK. Finally, we evaluated the effects of H. procumbens treatment on cortex levels of dopamine, norepinephrine, and serotonin. H. procumbens extract was well tolerated by Hypo-E22 cells and upregulated brain-derived neurotrophic factor gene expression but down-regulated tumor necrosis factor-α gene expression. In addition, the extract reduced amyloid β-peptide stimulation of malondialdehyde and 3-HK and blunted the decrease of dopamine, norepinephrine, and serotonin, in the cortex. In this context, our work supports further studies for the evaluation and confirmation of Harpagophytum in the management of the clinical symptoms related to Alzheimer's disease. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Dopamine modulates acute responses to cocaine, nicotine and ethanol in Drosophila.

PubMed

Bainton, R J; Tsai, L T; Singh, C M; Moore, M S; Neckameyer, W S; Heberlein, U

2000-02-24

Drugs of abuse have a common property in mammals, which is their ability to facilitate the release of the neurotransmitter and neuromodulator dopamine in specific brain regions involved in reward and motivation. This increase in synaptic dopamine levels is believed to act as a positive reinforcer and to mediate some of the acute responses to drugs. The mechanisms by which dopamine regulates acute drug responses and addiction remain unknown. We present evidence that dopamine plays a role in the responses of Drosophila to cocaine, nicotine or ethanol. We used a startle-induced negative geotaxis assay and a locomotor tracking system to measure the effect of psychostimulants on fly behavior. Using these assays, we show that acute responses to cocaine and nicotine are blunted by pharmacologically induced reductions in dopamine levels. Cocaine and nicotine showed a high degree of synergy in their effects, which is consistent with an action through convergent pathways. In addition, we found that dopamine is involved in the acute locomotor-activating effect, but not the sedating effect, of ethanol. We show that in Drosophila, as in mammals, dopaminergic pathways play a role in modulating specific behavioral responses to cocaine, nicotine or ethanol. We therefore suggest that Drosophila can be used as a genetically tractable model system in which to study the mechanisms underlying behavioral responses to multiple drugs of abuse.

Coordinated Recruitment of Cortical-Subcortical Circuits and Ascending Dopamine and Serotonin Neurons During Inhibitory Control of Cocaine Seeking in Rats.

PubMed

Navailles, Sylvia; Guillem, Karine; Vouillac-Mendoza, Caroline; Ahmed, Serge H

2015-09-01

People with cocaine addiction retain some degree of prefrontal cortex (PFC) inhibitory control of cocaine craving, a brain capacity that may underlie the efficacy of cognitive behavioral therapy for addiction. Similar findings were recently found in rats after extended access to and escalation of cocaine self-administration. Rats' inhibitory control of cocaine seeking was flexible, sufficiently strong to suppress cocaine-primed reinstatement and depended, at least in part, on neuronal activity within the prelimbic (PL) PFC. Here, we used a large-scale and high-resolution Fos mapping approach to identify, beyond the PL PFC, how top-down and/or bottom-up PFC-subcortical circuits are recruited during inhibition of cocaine seeking. Overall, we found that effective inhibitory control of cocaine seeking is associated with the coordinated recruitment of different top-down cortical-striatal circuits originating from different PFC territories, and of different bottom-up dopamine (DA) and serotonin (5-HT) midbrain subsystems that normally modulate activity in these circuits. This integrated brain response suggests that rats concomitantly engage and experience intricate cognitive and affective processes when they have to inhibit intense cocaine seeking. Thus, even after extended drug use, rats can be successfully trained to engage whole-brain inhibitory control mechanisms to suppress cocaine seeking. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Effects of feedback delay on learning from positive and negative feedback in patients with Parkinson's disease off medication.

PubMed

Weismüller, Benjamin; Ghio, Marta; Logmin, Kazimierz; Hartmann, Christian; Schnitzler, Alfons; Pollok, Bettina; Südmeyer, Martin; Bellebaum, Christian

2018-05-11

Phasic dopamine (DA) signals conveyed from the substantia nigra to the striatum and the prefrontal cortex crucially affect learning from feedback, with DA bursts facilitating learning from positive feedback and DA dips facilitating learning from negative feedback. Consequently, diminished nigro-striatal dopamine levels as in unmedicated patients suffering from Parkinson's Disease (PD) have been shown to lead to a negative learning bias. Recent studies suggested a diminished striatal contribution to feedback processing when the outcome of an action is temporally delayed. This study investigated whether the bias towards negative feedback learning induced by a lack of DA in PD patients OFF medication is modulated by feedback delay. To this end, PD patients OFF medication and healthy controls completed a probabilistic selection task, in which feedback was given immediately (after 800 ms) or delayed (after 6800 ms). PD patients were impaired in immediate but not delayed feedback learning. However, differences in the preference for positive/negative learning between patients and controls were seen for both learning from immediate and delayed feedback, with evidence of stronger negative learning in patients than controls. A Bayesian analysis of the data supports the conclusion that feedback timing did not affect the learning bias in the patients. These results hint at reduced, but still relevant nigro-striatal contribution to feedback learning, when feedback is delayed. Copyright © 2018 Elsevier Ltd. All rights reserved.

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.

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.

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 = .004). The brains of autistic individuals have abnormalities in both serotonin transporter and dopamine transporter binding. The present findings indicate that the gross abnormalities in these neurotransmitter systems may underpin the neurophysiologic mechanism of autism. Our sample was not characteristic or representative of a typical sample of adults with autism in the community.

Genotype status of the dopamine-related catechol-O-methyltransferase (COMT) gene corresponds with desirability of “unhealthy” foods

PubMed Central

Wallace, Deanna L.; Aarts, Esther; Uquillas, Federico d’Oleire; Dang, Linh C.; Greer, Stephanie M.; Jagust, William J.; D’Esposito, Mark

2015-01-01

The role of dopamine is extensively documented in weight regulation and food intake in both animal models and humans. Yet the role of dopamine has not been well studied in individual differences for food desirability. Genotype status of the dopamine-related catechol-O-methyltransferase (COMT) gene has been shown to influence dopamine levels, with greater COMT enzymatic activity in val/val individuals corresponding to greater degradation of dopamine. Decreased dopamine has been associated with poorer cognitive control and diminished goal-directed behavior in various behavioral paradigms. Additionally, dopaminergic-rich regions such as the frontal cortex and dorsal striatum have been shown to be important for supporting food-related decision-making. However, the role of dopamine, as assessed by COMT genotype status, in food desirability has not been fully explored. Therefore, we utilized an individual’s COMT genotype status (n=61) and investigated food desirability based on self-rated “healthy” and “unhealthy” food perceptions. Here we found val/val individuals (n=19) have greater desirability for self-rated “unhealthy” food items, but not self-rated “healthy” food items, as compared to val/met (n=24) and met/met (n=18) individuals (p<0.005). Utilizing an objective health measure for the food items, we also found val/val and val/met individuals have greater desirability for objectively defined “unhealthy” food items, as compared to met/met individuals (p<0.01). This work further substantiates a role of dopamine in food-related behaviors and more specifically in relationship to food desirability for “unhealthy” food items. PMID:25963102

Dopamine negatively modulates the NCA ion channels in C. elegans

PubMed Central

Topalidou, Irini; Pereira, Laura

2017-01-01

The NALCN/NCA ion channel is a cation channel related to voltage-gated sodium and calcium channels. NALCN has been reported to be a sodium leak channel with a conserved role in establishing neuronal resting membrane potential, but its precise cellular role and regulation are unclear. The Caenorhabditis elegans orthologs of NALCN, NCA-1 and NCA-2, act in premotor interneurons to regulate motor circuit activity that sustains locomotion. Recently we found that NCA-1 and NCA-2 are activated by a signal transduction pathway acting downstream of the heterotrimeric G protein Gq and the small GTPase Rho. Through a forward genetic screen, here we identify the GPCR kinase GRK-2 as a new player affecting signaling through the Gq-Rho-NCA pathway. Using structure-function analysis, we find that the GPCR phosphorylation and membrane association domains of GRK-2 are required for its function. Genetic epistasis experiments suggest that GRK-2 acts on the D2-like dopamine receptor DOP-3 to inhibit Go signaling and positively modulate NCA-1 and NCA-2 activity. Through cell-specific rescuing experiments, we find that GRK-2 and DOP-3 act in premotor interneurons to modulate NCA channel function. Finally, we demonstrate that dopamine, through DOP-3, negatively regulates NCA activity. Thus, this study identifies a pathway by which dopamine modulates the activity of the NCA channels. PMID:28968387

Dopamine negatively modulates the NCA ion channels in C. elegans.

PubMed

Topalidou, Irini; Cooper, Kirsten; Pereira, Laura; Ailion, Michael

2017-10-01

The NALCN/NCA ion channel is a cation channel related to voltage-gated sodium and calcium channels. NALCN has been reported to be a sodium leak channel with a conserved role in establishing neuronal resting membrane potential, but its precise cellular role and regulation are unclear. The Caenorhabditis elegans orthologs of NALCN, NCA-1 and NCA-2, act in premotor interneurons to regulate motor circuit activity that sustains locomotion. Recently we found that NCA-1 and NCA-2 are activated by a signal transduction pathway acting downstream of the heterotrimeric G protein Gq and the small GTPase Rho. Through a forward genetic screen, here we identify the GPCR kinase GRK-2 as a new player affecting signaling through the Gq-Rho-NCA pathway. Using structure-function analysis, we find that the GPCR phosphorylation and membrane association domains of GRK-2 are required for its function. Genetic epistasis experiments suggest that GRK-2 acts on the D2-like dopamine receptor DOP-3 to inhibit Go signaling and positively modulate NCA-1 and NCA-2 activity. Through cell-specific rescuing experiments, we find that GRK-2 and DOP-3 act in premotor interneurons to modulate NCA channel function. Finally, we demonstrate that dopamine, through DOP-3, negatively regulates NCA activity. Thus, this study identifies a pathway by which dopamine modulates the activity of the NCA channels.

Dopamine, Noradrenaline and Differences in Sexual Behavior between Roman High and Low Avoidance Male Rats: A Microdialysis Study in the Medial Prefrontal Cortex.

PubMed

Sanna, Fabrizio; Bratzu, Jessica; Piludu, Maria A; Corda, Maria G; Melis, Maria R; Giorgi, Osvaldo; Argiolas, Antonio

2017-01-01

Roman High- (RHA) and Low-Avoidance (RLA) outbred rats, which differ for a respectively rapid vs. poor acquisition of the active avoidance response in the shuttle-box, display differences in sexual activity when put in the presence of a sexually receptive female rat. Indeed RHA rats show higher levels of sexual motivation and copulatory performance than RLA rats, which persist also after repeated sexual activity. These differences have been correlated to a higher tone of the mesolimbic dopaminergic system of RHA rats vs. RLA rats, revealed by the higher increase of dopamine found in the dialysate obtained from the nucleus accumbens of RHA than RLA rats during sexual activity. This work shows that extracellular dopamine and noradrenaline (NA) also, increase in the dialysate from the medial prefrontal cortex (mPFC) of male RHA and RLA rats put in the presence of an inaccessible female rat and more markedly during direct sexual interaction. Such increases in dopamine (and its main metabolite 3,4-dihydroxyphenylacetic acid, DOPAC) and NA were found in both sexually naïve and experienced animals, but they were higher: (i) in RHA than in RLA rats; and (ii) in sexually experienced RHA and RLA rats than in their naïve counterparts. Finally, the differences in dopamine and NA in the mPFC occurred concomitantly to those in sexual activity, as RHA rats displayed higher levels of sexual motivation and copulatory performance than RLA rats in both the sexually naïve and experienced conditions. These results suggest that a higher dopaminergic tone also occurs in the mPFC, together with an increased noradrenergic tone, which may be involved in the different copulatory patterns found in RHA and RLA rats, as suggested for the mesolimbic dopaminergic system.

Dopamine, Noradrenaline and Differences in Sexual Behavior between Roman High and Low Avoidance Male Rats: A Microdialysis Study in the Medial Prefrontal Cortex

PubMed Central

Sanna, Fabrizio; Bratzu, Jessica; Piludu, Maria A.; Corda, Maria G.; Melis, Maria R.; Giorgi, Osvaldo; Argiolas, Antonio

2017-01-01

Roman High- (RHA) and Low-Avoidance (RLA) outbred rats, which differ for a respectively rapid vs. poor acquisition of the active avoidance response in the shuttle-box, display differences in sexual activity when put in the presence of a sexually receptive female rat. Indeed RHA rats show higher levels of sexual motivation and copulatory performance than RLA rats, which persist also after repeated sexual activity. These differences have been correlated to a higher tone of the mesolimbic dopaminergic system of RHA rats vs. RLA rats, revealed by the higher increase of dopamine found in the dialysate obtained from the nucleus accumbens of RHA than RLA rats during sexual activity. This work shows that extracellular dopamine and noradrenaline (NA) also, increase in the dialysate from the medial prefrontal cortex (mPFC) of male RHA and RLA rats put in the presence of an inaccessible female rat and more markedly during direct sexual interaction. Such increases in dopamine (and its main metabolite 3,4-dihydroxyphenylacetic acid, DOPAC) and NA were found in both sexually naïve and experienced animals, but they were higher: (i) in RHA than in RLA rats; and (ii) in sexually experienced RHA and RLA rats than in their naïve counterparts. Finally, the differences in dopamine and NA in the mPFC occurred concomitantly to those in sexual activity, as RHA rats displayed higher levels of sexual motivation and copulatory performance than RLA rats in both the sexually naïve and experienced conditions. These results suggest that a higher dopaminergic tone also occurs in the mPFC, together with an increased noradrenergic tone, which may be involved in the different copulatory patterns found in RHA and RLA rats, as suggested for the mesolimbic dopaminergic system. PMID:28638325

Down-regulation of tryptamine binding sites following chronic molindone administration. A comparison with responses of dopamine and 5-hydroxytryptamine receptors.

PubMed

Nguyen, T V; Juorio, A V

1989-10-01

The present study assessed changes of tryptamine, dopamine D2, 5-HT1 and 5-HT2 binding sites in rat brain following chronic treatment with low (5 mg/kg/day) and high (40 mg/kg/day) doses of molindone, a clinically effective psychotropic drug. The high-dose molindone treatment produced a decrease in the number of tryptamine binding sites while both high and low doses caused an increase in the number of dopamine D2 binding sites in the striatum. No significant changes were observed in either 5-HT1 or 5-HT2 binding sites in the cerebral cortex. Competition binding experiments showed that molindone was a potent inhibitor at dopamine D2 but less effective at tryptamine, 5-HT1 and 5-HT2 binding sites. The inhibition activity of molindone towards type A monoamine oxidase produced a significant increase in endogenous tryptamine accumulation rate which was much higher than that of dopamine and 5-HT. These findings suggest that the reduction in the number of tryptamine binding sites produced by chronic molindone administration is related to monoamine oxidase inhibition and that the increase in the number of dopamine D2 binding sites is correlated to receptor blocking activity of the drug.

Maternal high-fat diet and obesity impact palatable food intake and dopamine signaling in nonhuman primate offspring.

PubMed

Rivera, Heidi M; Kievit, Paul; Kirigiti, Melissa A; Bauman, Leigh Ann; Baquero, Karalee; Blundell, Peter; Dean, Tyler A; Valleau, Jeanette C; Takahashi, Diana L; Frazee, Tim; Douville, Luke; Majer, Jordan; Smith, M Susan; Grove, Kevin L; Sullivan, Elinor L

2015-11-01

To utilize a nonhuman primate model to examine the impact of maternal high-fat diet (HFD) consumption and pre-pregnancy obesity on offspring intake of palatable food and to examine whether maternal HFD consumption impaired development of the dopamine system, critical for the regulation of hedonic feeding. The impact of exposure to maternal HFD and obesity on offspring consumption of diets of varying composition was assessed after weaning. The influence of maternal HFD consumption on the development of the prefrontal cortex-dopaminergic system at 13 months of age was also examined. During a preference test, offspring exposed to maternal HFD consumption and obesity displayed increased intake of food high in fat and sugar content relative to offspring from lean control mothers. Maternal HFD consumption suppressed offspring dopamine signaling (as assessed by immunohistochemistry) relative to control offspring. Specifically, there was decreased abundance of dopamine fibers and of dopamine receptor 1 and 2 proteins. This study reveals that offspring exposed to both maternal HFD consumption and maternal obesity during early development are at increased risk for obesity due to overconsumption of palatable energy-dense food, a behavior that may be related to reduced central dopamine signaling. © 2015 The Obesity Society.

Dopamine D2 Receptor Levels in Striatum, Thalamus, Substantia Nigra, Limbic Regions, and Cortex in Schizophrenic Subjects

PubMed Central

Kessler, Robert M; Woodward, Neil D; Riccardi, Patrizia; Li, Rui; Ansari, M Sib; Anderson, Sharlett; Dawant, Benoit; Zald, David; Meltzer, Herbert Y

2009-01-01

Background Studies in schizophrenics have reported dopaminergic abnormalities in striatum, substantia nigra, thalamus, anterior cingulate, hippocampus and cortex which have been related to positive symptoms and cognitive impairments. Methods [18F]fallypride PET studies were performed in off medication or never medicated schizophrenic subjects [N = 11, 6 M, 5 F; mean age of 30.5 ± 8.0 (S.D.); 4 drug naive] and age matched healthy subjects [N = 11, 5M, 6F, mean age of 31.6 ± 9.2 (S.D.)] to examine dopamine D2 receptor (DA D2r) levels in the caudate, putamen, ventral striatum, medial thalamus, posterior thalamus, substantia nigra, amygdala, temporal cortex, anterior cingulate, and hippocampus. Results In schizophrenic subjects increased DA D2r levels were seen in the substantia nigra bilaterally; decreased levels were seen in the left medial thalamus. Correlations of symptoms with region of interest data demonstrated a significant correlation of disorganized thinking/nonparanoid delusions with the right temporal cortex region of interest (r = 0.94, P = 0.0001) which remained significant after correction for multiple comparisons (P<0.03). Correlations of symptoms with parametric images of DA D2r levels revealed no significant clusters of correlations with negative symptoms, but significant clusters of positive correlations of total positive symptoms, delusions and bizarre behavior with the lateral and anterior temporal cortex, and hallucinations with the left ventral striatum. Conclusions The results of this study demonstrate abnormal DA D2r mediated neurotransmission in the substantia nigra consistent with nigral dysfunction in schizophrenia and suggest that both temporal cortical and ventral striatal DA D2r mediate positive symptoms. PMID:19251247

Effect of neonatal nociceptin or nocistatin imprinting on the brain concentration of biogenic amines and their metabolites.

PubMed

Tekes, Kornélia; Gyenge, Melinda; Sótonyi, Péter; Csaba, György

2009-04-01

Noradrenaline (NA), dopamine (DA), homovanillic acid (HA), serotonin (5HT) and 5-hydroxyindole acetic acid (5HIAA) content of five brain regions (hypothalamus, hippocampus, brainstem, striatum and frontal cortex) and the cerebrospinal fluid (CSF) was measured in adult (three months old) male and female rats treated neonatally with a single dose of 10 microg nociceptin (NC) or 10 microg nocistatin (NS) for hormonal imprinting. The biogenic amine and metabolite content of cerebrospinal fluid was also determined. In NC treated animals the serotonergic, dopaminergic as well as noradrenergic systems were influenced by the imprinting. The 5HT level increased in hypothalamus, the 5HIAA tissue levels were found increased in hypothalamus. Hippocampus and striatum and the HVA levels increased highly significantly in brainstem. Dopamine level decreased significantly in striatum, however in frontal cortex both noradrenalin and 5HIAA level decreased. Nevertheless, in NS-treated rats decreased NA tissue levels were found in hypothalamus, brainstem and frontal cortex. Decreased DA levels were found in the hypothalamus, brainstem and striatum. NS imprinting resulted in decreased HVA level, but increased one in the brainstem. The 5HT levels decreased in the hypothalamus, brainstem, striatum and frontal cortex, while 5HIAA content of CSF, and frontal cortex decreased, and that of hypothalamus, hippocampus and striatum increased. There was no significant difference between genders except in the 5HT tissue levels of NC treated rats. Data presented show that neonatal imprinting both by NC and NS have long-lasting and brain area specific effects. In earlier experiments endorphin imprinting also influenced the serotonergic system suggesting that during labour release of pain-related substances may durably affect the serotonergic (dopaminergic, adrenergic) system which can impress the animals' later behavior.

Simultaneous quantification of monoamine neurotransmitters and their biogenic metabolites intracellularly and extracellularly in primary neuronal cell cultures and in sub-regions of guinea pig brain.

PubMed

Schou-Pedersen, Anne Marie V; Hansen, Stine N; Tveden-Nyborg, Pernille; Lykkesfeldt, Jens

2016-08-15

In the present paper, we describe a validated chromatographic method for the simultaneous quantification of monoamine neurotransmitters and their biogenic metabolites intracellularly and extracellularly in primary neuronal cell culture and in sub-regions of the guinea pig brain. Electrochemical detection provided limits of quantifications (LOQs) between 3.6 and 12nM. Within the linear range, obtained recoveries were from 90.9±9.9 to 120±14% and intra-day and inter-day precisions found to be less than 5.5% and 12%, respectively. The analytical method was applicable for quantification of intracellular and extracellular amounts of monoamine neurotransmitters and their metabolites in guinea pig frontal cortex and hippocampal primary neuronal cell cultures. Noradrenaline, dopamine and serotonin were found to be in a range from 0.31 to 1.7pmol per 2 million cells intracellularly, but only the biogenic metabolites could be detected extracellularly. Distinct differences in monoamine concentrations were observed when comparing concentrations in guinea pig frontal cortex and cerebellum tissue with higher amounts of dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid in frontal cortex, as compared to cerebellum. The chemical turnover in frontal cortex tissue of guinea pig was for serotonin successfully predicted from the turnover observed in the frontal cortex cell culture. In conclusion, the present analytical method shows high precision, accuracy and sensitivity and is broadly applicable to monoamine measurements in cell cultures as well as brain biopsies from animal models used in preclinical neurochemistry. Copyright © 2016 Elsevier B.V. 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.

Protective role of Kv7 channels in oxygen and glucose deprivation-induced damage in rat caudate brain slices

PubMed Central

Barrese, Vincenzo; Taglialatela, Maurizio; Greenwood, Iain A; Davidson, Colin

2015-01-01

Ischemic stroke can cause striatal dopamine efflux that contributes to cell death. Since Kv7 potassium channels regulate dopamine release, we investigated the effects of their pharmacological modulation on dopamine efflux, measured by fast cyclic voltammetry (FCV), and neurotoxicity, in Wistar rat caudate brain slices undergoing oxygen and glucose deprivation (OGD). The Kv7 activators retigabine and ICA27243 delayed the onset, and decreased the peak level of dopamine efflux induced by OGD; and also decreased OGD-induced damage measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Retigabine also reduced OGD-induced necrotic cell death evaluated by lactate dehydrogenase activity assay. The Kv7 blocker linopirdine increased OGD-evoked dopamine efflux and OGD-induced damage, and attenuated the effects of retigabine. Quantitative-PCR experiments showed that OGD caused an ~6-fold decrease in Kv7.2 transcript, while levels of mRNAs encoding for other Kv7 subunits were unaffected; western blot experiments showed a parallel reduction in Kv7.2 protein levels. Retigabine also decreased the peak level of dopamine efflux induced by L-glutamate, and attenuated the loss of TTC staining induced by the excitotoxin. These results suggest a role for Kv7.2 in modulating ischemia-evoked caudate damage. PMID:25966943

Dopaminergic Balance between Reward Maximization and Policy Complexity

PubMed Central

Parush, Naama; Tishby, Naftali; Bergman, Hagai

2011-01-01

Previous reinforcement-learning models of the basal ganglia network have highlighted the role of dopamine in encoding the mismatch between prediction and reality. Far less attention has been paid to the computational goals and algorithms of the main-axis (actor). Here, we construct a top-down model of the basal ganglia with emphasis on the role of dopamine as both a reinforcement learning signal and as a pseudo-temperature signal controlling the general level of basal ganglia excitability and motor vigilance of the acting agent. We argue that the basal ganglia endow the thalamic-cortical networks with the optimal dynamic tradeoff between two constraints: minimizing the policy complexity (cost) and maximizing the expected future reward (gain). We show that this multi-dimensional optimization processes results in an experience-modulated version of the softmax behavioral policy. Thus, as in classical softmax behavioral policies, probability of actions are selected according to their estimated values and the pseudo-temperature, but in addition also vary according to the frequency of previous choices of these actions. We conclude that the computational goal of the basal ganglia is not to maximize cumulative (positive and negative) reward. Rather, the basal ganglia aim at optimization of independent gain and cost functions. Unlike previously suggested single-variable maximization processes, this multi-dimensional optimization process leads naturally to a softmax-like behavioral policy. We suggest that beyond its role in the modulation of the efficacy of the cortico-striatal synapses, dopamine directly affects striatal excitability and thus provides a pseudo-temperature signal that modulates the tradeoff between gain and cost. The resulting experience and dopamine modulated softmax policy can then serve as a theoretical framework to account for the broad range of behaviors and clinical states governed by the basal ganglia and dopamine systems. PMID:21603228

The First Negative Allosteric Modulator for Dopamine D2 and D3 Receptors, SB269652 May Lead to a New Generation of Antipsychotic Drugs.

PubMed

Rossi, Mario; Fasciani, Irene; Marampon, Francesco; Maggio, Roberto; Scarselli, Marco

2017-06-01

D 2 and D 3 dopamine receptors belong to the largest family of cell surface proteins in eukaryotes, the G protein-coupled receptors (GPCRs). Considering their crucial physiologic functions and their relatively accessible cellular locations, GPCRs represent one of the most important classes of therapeutic targets. Until recently, the only strategy to develop drugs regulating GPCR activity was through the identification of compounds that directly acted on the orthosteric sites for endogenous ligands. However, many efforts have recently been made to identify small molecules that are able to interact with allosteric sites. These sites are less well-conserved, therefore allosteric ligands have greater selectivity on the specific receptor. Strikingly, the use of allosteric modulators can provide specific advantages, such as an increased selectivity for GPCR subunits and the ability to introduce specific beneficial therapeutic effects without disrupting the integrity of complex physiologically regulated networks. In 2010, our group unexpectedly found that N -[(1r,4r)-4-[2-(7-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-1H-indole-2-carboxamide (SB269652), a compound supposed to interact with the orthosteric binding site of dopamine receptors, was actually a negative allosteric modulator of D 2 - and D 3 -receptor dimers, thus identifying the first allosteric small molecule acting on these important therapeutic targets. This review addresses the progress in understanding the molecular mechanisms of interaction between the negative modulator SB269652 and D 2 and D 3 dopamine receptor monomers and dimers, and surveys the prospects for developing new dopamine receptor allosteric drugs with SB269652 as the leading compound. U.S. Government work not protected by U.S. copyright.

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

Affective neuroscience of pleasure: reward in humans and animals

PubMed Central

2010-01-01

Introduction Pleasure and reward are generated by brain circuits that are largely shared between humans and other animals. Discussion Here, we survey some fundamental topics regarding pleasure mechanisms and explicitly compare humans and animals. Conclusion Topics surveyed include liking, wanting, and learning components of reward; brain coding versus brain causing of reward; subjective pleasure versus objective hedonic reactions; roles of orbitofrontal cortex and related cortex regions; subcortical hedonic hotspots for pleasure generation; reappraisals of dopamine and pleasure-electrode controversies; and the relation of pleasure to happiness. PMID:18311558

Dopamine Modulates the Efficiency of Sensory Evidence Accumulation During Perceptual Decision Making.

PubMed

Beste, Christian; Adelhöfer, Nico; Gohil, Krutika; Passow, Susanne; Roessner, Veit; Li, Shu-Chen

2018-04-02

Perceptual decision making is the process through which available sensory information is gathered and processed to guide our choices. However, the neuropsychopharmacological basis of this important cognitive function is largely elusive. Yet, theoretical considerations suggest that the dopaminergic system may play an important role. In a double-blind, randomized, placebo-controlled study design, we examined the effect of methylphenidate in 2 dosages (0.25 mg/kg and 0.5 mg/kg body weight) in separate groups of healthy young adults. We used a moving dots task in which the coherency of the direction of moving dots stimuli was manipulated in 3 levels (5%, 15%, and 35%). Drift diffusion modelling was applied to behavioral data to capture subprocesses of perceptual decision making. The findings show that only the drift rate (v), reflecting the efficiency of sensory evidence accumulation, but not the decision criterion threshold (a) or the duration of nondecisional processes (Ter), is affected by methylphenidate vs placebo administration. Compared with placebo, administering 0.25 mg/kg methylphenidate increased v, but only in the 35% coherence condition. Administering 0.5 mg/kg methylphenidate did not induce modulations. The data suggest that dopamine selectively modulates the efficacy of evidence accumulation during perceptual decision making. This modulation depends on 2 factors: (1) the degree to which the dopaminergic system is modulated using methylphenidate (i.e., methylphenidate dosage) and (2) the signal-to-noise ratio of the visual information. Dopamine affects sensory evidence accumulation only when dopamine concentration is not shifted beyond an optimal level and the incoming information is less noisy.

Deficient reinforcement learning in medial frontal cortex as a model of dopamine-related motivational deficits in ADHD.

PubMed

Silvetti, Massimo; Wiersema, Jan R; Sonuga-Barke, Edmund; Verguts, Tom

2013-10-01

Attention Deficit/Hyperactivity Disorder (ADHD) is a pathophysiologically complex and heterogeneous condition with both cognitive and motivational components. We propose a novel computational hypothesis of motivational deficits in ADHD, drawing together recent evidence on the role of anterior cingulate cortex (ACC) and associated mesolimbic dopamine circuits in both reinforcement learning and ADHD. Based on findings of dopamine dysregulation and ACC involvement in ADHD we simulated a lesion in a previously validated computational model of ACC (Reward Value and Prediction Model, RVPM). We explored the effects of the lesion on the processing of reinforcement signals. We tested specific behavioral predictions about the profile of reinforcement-related deficits in ADHD in three experimental contexts; probability tracking task, partial and continuous reward schedules, and immediate versus delayed rewards. In addition, predictions were made at the neurophysiological level. Behavioral and neurophysiological predictions from the RVPM-based lesion-model of motivational dysfunction in ADHD were confirmed by data from previously published studies. RVPM represents a promising model of ADHD reinforcement learning suggesting that ACC dysregulation might play a role in the pathogenesis of motivational deficits in ADHD. However, more behavioral and neurophysiological studies are required to test core predictions of the model. In addition, the interaction with different brain networks underpinning other aspects of ADHD neuropathology (i.e., executive function) needs to be better understood. Copyright © 2013 Elsevier Ltd. All rights reserved.

Dopamine D1 receptor density in the mPFC responds to cognitive demands and receptor turnover contributes to general cognitive ability in mice.

PubMed

Wass, Christopher; Sauce, Bruno; Pizzo, Alessandro; Matzel, Louis D

2018-03-14

In both humans and mice, performance on tests of intelligence or general cognitive ability (GCA) is related to dopamine D1 receptor-mediated activity in the prelimbic cortex, and levels of DRD1 mRNA predict the GCA of mice. Here we assessed the turnover rate of D1 receptors as well as the expression level of the D1 chaperone protein (DRiP78) in the medial PPC (mPFC) of mice to determine whether rate of receptor turnover was associated with variations in the GCA of genetically heterogeneous mice. Following assessment of GCA (aggregate performance on four diverse learning tests) mice were administered an irreversible dopamine receptor antagonist (EEDQ), after which the density of new D1 receptors were quantified. GCA was positively correlated with both the rate of D1 receptor recovery and levels of DRiP78. Additionally, the density of D1 receptors was observed to increase within 60 min (or less) in response to intense demands on working memory, suggesting that a pool of immature receptors was available to accommodate high cognitive loads. These results provide evidence that innate general cognitive abilities are related to D1 receptor turnover rates in the prefrontal cortex, and that an intracellular pool of immature D1 receptors are available to accommodate cognitive demands.

Reward Contingencies Improve Goal-Directed Behavior by Enhancing Posterior Brain Attentional Regions and Increasing Corticostriatal Connectivity in Cocaine Addicts.

PubMed

Rosell-Negre, Patricia; Bustamante, Juan-Carlos; Fuentes-Claramonte, Paola; Costumero, Víctor; Llopis-Llacer, Juan-José; Barrós-Loscertales, Alfonso

2016-01-01

The dopaminergic system provides the basis for the interaction between motivation and cognition. It is triggered by the possibility of obtaining rewards to initiate the neurobehavioral adaptations necessary to achieve them by directing the information from motivational circuits to cognitive and action circuits. In drug addiction, the altered dopamine (DA) modulation of the meso-cortico-limbic reward circuitry, such as the prefrontal cortex (PFC), underlies the disproportionate motivational value of drug use at the expense of other non-drug reinforcers and the user's loss of control over his/her drug intake. We examine how the magnitude of the reward affects goal-directed processes in healthy control (HC) subjects and abstinent cocaine dependent (ACD) patients by using functional magnetic resonance imaging (fMRI) during a counting Stroop task with blocked levels of monetary incentives of different magnitudes (€0, €0.01, €0.5, €1 or €1.5). Our results showed that increasing reward magnitude enhances (1) performance facilitation in both groups; (2) left dorsolateral prefrontal cortex (DLPFC) activity in HC and left superior occipital cortex activity in ACD; and (3) left DLPFC and left putamen connectivity in ACD compared to HC. Moreover, we observed that (4) dorsal striatal and pallidum activity was associated with craving and addiction severity during the parametric increases in the monetary reward. In conclusion, the brain response to gradients in monetary value was different in HC and ACD, but both groups showed improved task performance due to the possibility of obtaining greater monetary rewards.

Reward Contingencies Improve Goal-Directed Behavior by Enhancing Posterior Brain Attentional Regions and Increasing Corticostriatal Connectivity in Cocaine Addicts

PubMed Central

Rosell-Negre, Patricia; Bustamante, Juan-Carlos; Fuentes-Claramonte, Paola; Costumero, Víctor; Llopis-Llacer, Juan-José; Barrós-Loscertales, Alfonso

2016-01-01

The dopaminergic system provides the basis for the interaction between motivation and cognition. It is triggered by the possibility of obtaining rewards to initiate the neurobehavioral adaptations necessary to achieve them by directing the information from motivational circuits to cognitive and action circuits. In drug addiction, the altered dopamine (DA) modulation of the meso-cortico-limbic reward circuitry, such as the prefrontal cortex (PFC), underlies the disproportionate motivational value of drug use at the expense of other non-drug reinforcers and the user’s loss of control over his/her drug intake. We examine how the magnitude of the reward affects goal-directed processes in healthy control (HC) subjects and abstinent cocaine dependent (ACD) patients by using functional magnetic resonance imaging (fMRI) during a counting Stroop task with blocked levels of monetary incentives of different magnitudes (€0, €0.01, €0.5, €1 or €1.5). Our results showed that increasing reward magnitude enhances (1) performance facilitation in both groups; (2) left dorsolateral prefrontal cortex (DLPFC) activity in HC and left superior occipital cortex activity in ACD; and (3) left DLPFC and left putamen connectivity in ACD compared to HC. Moreover, we observed that (4) dorsal striatal and pallidum activity was associated with craving and addiction severity during the parametric increases in the monetary reward. In conclusion, the brain response to gradients in monetary value was different in HC and ACD, but both groups showed improved task performance due to the possibility of obtaining greater monetary rewards. PMID:27907134

Pleasure junkies all around! Why it matters and why ‘the arts’ might be the answer: a biopsychological perspective

PubMed Central

2017-01-01

Today's society is pleasure seeking. We expect to obtain pleasurable experiences fast and easily. We are used to hyper-palatable foods and drinks, and we can get pornography, games and gadgets whenever we want them. The problem: with this type of pleasure-maximizing choice behaviour we may be turning ourselves into mindless pleasure junkies, handing over our free will for the next dopamine shoot. Pleasure-only activities are fun. In excess, however, such activities might have negative effects on our biopsychological health: they provoke a change in the neural mechanisms underlying choice behaviour. Choice behaviour becomes biased towards short-term pleasure-maximizing goals, just as in the addicted brain (modulated by the amygdala, posterior ventromedial prefrontal cortex' (VMPFC), striatum, nucleus accumbens; ‘A-system’) and away from long-term prosperity and general well-being maximizing objectives (normally ensured by the insula, anterior VMPFC, hippocampus, dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC); ‘I-system‘). This paper outlines, first, what ‘pleasure’ is and what ‘pleasure-only’ activities are (e.g. social media engagement, hyper-palatable eating). Second, an account is given of the type of action that might aid to maintain the neural systems underlying choice behaviour balanced. Finally, it is proposed that engagement with the arts might be an activity with the potential to foster healthy choice behaviour—and not be just for pleasure. The evidence in this rather new field of research is still piecemeal and inconclusive. This review aims to motivate targeted research in this domain. PMID:28469018

Neural activation in the "reward circuit" shows a nonlinear response to facial attractiveness.

PubMed

Liang, Xiaoyun; Zebrowitz, Leslie A; Zhang, Yi

2010-01-01

Positive behavioral responses to attractive faces have led neuroscientists to investigate underlying neural mechanisms in a "reward circuit" that includes brain regions innervated by dopamine pathways. Using male faces ranging from attractive to extremely unattractive, disfigured ones, this study is the first to demonstrate heightened responses to both rewarding and aversive faces in numerous areas of this putative reward circuit. Parametric analyses employing orthogonal linear and nonlinear regressors revealed positive nonlinear effects in anterior cingulate cortex, lateral orbital frontal cortex (LOFC), striatum (nucleus accumbens, caudate, putamen), and ventral tegmental area, in addition to replicating previously documented linear effects in medial orbital frontal cortex (MOFC) and LOFC and nonlinear effects in amygdala and MOFC. The widespread nonlinear responses are consistent with single cell recordings in animals showing responses to both rewarding and aversive stimuli, and with some human fMRI investigations of non-face stimuli. They indicate that the reward circuit does not process face valence with any simple dissociation of function across structures. Perceiver gender modulated some responses to our male faces: Women showed stronger linear effects, and men showed stronger nonlinear effects, which may have functional implications. Our discovery of nonlinear responses to attractiveness throughout the reward circuit echoes the history of amygdala research: Early work indicated a linear response to threatening stimuli, including faces; later work also revealed a nonlinear response with heightened activation to affectively salient stimuli regardless of valence. The challenge remains to determine how such dual coding influences feelings, such as pleasure and pain, and guides goal-related behavioral responses, such as approach and avoidance.

Response disengagement on a spatial self-ordered sequencing task: effects of regionally selective excitotoxic lesions and serotonin depletion within the prefrontal cortex.

PubMed

Walker, Susannah C; Robbins, Trevor W; Roberts, Angela C

2009-05-06

Prefrontal cortex (PFC) is critical for self-ordered response sequencing. Patients with frontal lobe damage are impaired on response sequencing tasks, and increased blood flow has been reported in ventrolateral and dorsolateral PFC in subjects performing such tasks. Previously, we have shown that large excitotoxic lesions of the lateral PFC (LPFC) and orbitofrontal cortex FC (OFC), but not global prefrontal dopamine depletion, markedly impaired marmoset performance on a spatial self-ordered sequencing task (SSOST). To determine whether LPFC or OFC was responsible for the previously observed impairments and whether the underlying neural mechanism was modulated by serotonin, the present study compared the effects of selective LPFC and OFC excitotoxic lesions and 5,7-DHT-induced PFC serotonin depletions in marmosets on SSOST performance. Severe and long-lasting impairments in SSOST performance, including robust perseverative responding, followed LPFC but not OFC lesions. The deficit was ameliorated by task manipulations that precluded perseveration. Depletions of serotonin within LPFC and OFC had no effect, despite impairing performance on a visual discrimination reversal task, thus providing further evidence for differential monaminergic regulation of prefrontal function. In the light of the proposed attentional control functions of ventrolateral PFC and the failure of LPFC-lesioned animals to disengage from the immediately preceding response, it is proposed that this deficit may be due to a failure to attend to and register that a response has been made and thus should not be repeated. However, 5-HT does not appear to be implicated in this response inhibitory capacity.

Late Reduction of Cocaine Cravings in a Randomized, Double-Blind Trial of Aripiprazole vs Perphenazine in Schizophrenia and Comorbid Cocaine Dependence.

PubMed

Beresford, Thomas; Buchanan, Jennifer; Thumm, Elizabeth Brie; Emrick, Chad; Weitzenkamp, David; Ronan, Patrick J

2017-12-01

Co-occurring schizophrenia spectrum disorder and International Statistical Classification of Diseases, 10th Revision cocaine dependence present a particularly destructive constellation that is often difficult to treat. Both conditions raise dopamine transmission effects in the brain. Traditional neuroleptics block dopamine receptors, whereas aripiprazole modulates dopamine activity as an agonist/antagonist. We tested whether dopamine modulation is superior to dopamine blocking in dual-diagnosis patients. In a randomized, double-blind, comparison design, cocaine-dependent schizophrenic subjects actively using cocaine received either aripiprazole or perphenazine in an 8-week trial. Primary outcome targeted cocaine-free urine sample proportions, whereas cocaine craving scores were a secondary variable. Subjects (N = 44) randomized (n = 22 per group) did not differ at baseline. The proportion of cocaine-free urine samples did not differ by medication group. Contrasting weeks 3 to 5 vs 6 to 8 revealed significant late reductions in craving with aripiprazole. On the respective 5-point subscales, craving intensity decreased by 1.53 ± 0.43 (P < 0.0005) points, craving frequency by 1.4 ± 0.40 (P > 0.0004) points, and craving duration by 1.76 ± 0.44 (P > 0.0001) points. A drug effect of aripiprazole on craving items appeared at week 6 of treatment, on average, and was not seen before that length of drug exposure. The data suggest that dopamine modulation reduces cocaine cravings but requires an acclimation period. To understand the mechanism of action better, a trial of depot aripiprazole may be useful. Clinically, a reduction in craving potentially offers a clearer focus for ongoing behavioral treatment. It may also offer a longer-term treatment effect with respect to the severity of relapse.

Neurotensin enhances glutamatergic EPSCs in VTA neurons by acting on different neurotensin receptors.

PubMed

Bose, Poulomee; Rompré, Pierre-Paul; Warren, Richard A

2015-11-01

Neurotensin (NT) is an endogenous neuropeptide that modulates dopamine and glutamate neurotransmission in several limbic regions innervated by neurons located in the ventral tegmental area (VTA). While several studies showed that NT exerted a direct modulation on VTA dopamine neurons less is known about its role in the modulation of glutamatergic neurotransmission in this region. The present study was aimed at characterising the effects of NT on glutamate-mediated responses in different populations of VTA neurons. Using whole cell patch clamp recording technique in horizontal rat brain slices, we measured the amplitude of glutamatergic excitatory post-synaptic currents (EPSCs) evoked by electrical stimulation of VTA afferents before and after application of different concentrations of NT1-13 or its C-terminal fragment, NT8-13. Neurons were classified as either Ih(+) or Ih(-) based on the presence or absence of a hyperpolarisation activated cationic current (Ih). We found that NT1-13 and NT8-13 produced comparable concentration dependent increase in the amplitude of EPSCs in both Ih(+) and Ih(-) neurons. In Ih(+) neurons, the enhancement effect of NT8-13 was blocked by both antagonists, while in Ih(-) neurons it was blocked by the NTS1/NTS2 antagonist, SR142948A, but not the preferred NTS1 antagonist, SR48692. In as much as Ih(-) neurons are non-dopaminergic neurons and Ih(+) neurons represent both dopamine and non-dopamine neurons, we can conclude that NT enhances glutamatergic mediated responses in dopamine, and in a subset of non-dopamine, neurons by acting respectively on NTS1 and an NT receptor other than NTS1. Copyright © 2015 Elsevier Inc. All rights reserved.

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.

Effects of dopaminergic genes, prenatal adversities, and their interaction on attention-deficit/hyperactivity disorder and neural correlates of response inhibition

PubMed Central

van der Meer, Dennis; Hartman, Catharina A.; van Rooij, Daan; Franke, Barbara; Heslenfeld, Dirk J.; Oosterlaan, Jaap; Faraone, Stephen V.; Buitelaar, Jan K.; Hoekstra, Pieter J.

2017-01-01

Background Attention-deficit/hyperactivity disorder (ADHD) is often accompanied by impaired response inhibition; both have been associated with aberrant dopamine signalling. Given that prenatal exposure to alcohol or smoking is known to affect dopamine-rich brain regions, we hypothesized that individuals carrying the ADHD risk alleles of the dopamine receptor D4 (DRD4) and dopamine transporter (DAT1) genes may be especially sensitive to their effects. Methods Functional MRI data, information on prenatal adversities and genetic data were available for 239 adolescents and young adults participating in the multicentre ADHD cohort study NeuroIMAGE (average age 17.3 yr). We analyzed the effects of DRD4 and DAT1, prenatal exposure to alcohol and smoking and their interactions on ADHD severity, response inhibition and neural activity. Results We found no significant gene × environment interaction effects. We did find that the DRD4 7-repeat allele was associated with less superior frontal and parietal brain activity and with greater activity in the frontal pole and occipital cortex. Prenatal exposure to smoking was also associated with lower superior frontal activity, but with greater activity in the parietal lobe. Further, those exposed to alcohol had more activity in the lateral orbitofrontal cortex, and the DAT1 risk variant was associated with lower cerebellar activity. Limitations Retrospective reports of maternal substance use and the cross-sectional study design restrict causal inference. Conclusion While we found no evidence of gene × environment interactions, the risk factors under investigation influenced activity of brain regions associated with response inhibition, suggesting they may add to problems with inhibiting behaviour. PMID:28234207

Neuroprotective potential of Bacopa monnieri and Bacoside A against dopamine receptor dysfunction in the cerebral cortex of neonatal hypoglycaemic rats.

PubMed

Thomas, Roshni Baby; Joy, Shilpa; Ajayan, M S; Paulose, C S

2013-11-01

Neonatal hypoglycaemia initiates a series of events leading to neuronal death, even if glucose and glycogen stores return to normal. Disturbances in the cortical dopaminergic function affect memory and cognition. We recommend Bacopa monnieri extract or Bacoside A to treat neonatal hypoglycaemia. We investigated the alterations in dopaminergic functions by studying the Dopamine D1 and D2 receptor subtypes. Receptor-binding studies revealed a significant decrease (p < 0.001) in dopamine D1 receptor number in the hypoglycaemic condition, suggesting cognitive dysfunction. cAMP content was significantly (p < 0.001) downregulated in hypoglycaemic neonatal rats indicating the reduction in cell signalling of the dopamine D1 receptors. It is attributed to the deficits in spatial learning and memory. Hypoglycaemic neonatal rats treated with Bacopa extract alone and Bacoside A ameliorated the dopaminergic and cAMP imbalance as effectively as the glucose therapy. The upregulated Bax expression in the present study indicates the high cell death in hypoglycaemic neonatal rats. Enzyme assay of SOD confirmed cortical cell death due to free radical accumulation. The gene expression of SOD in the cortex was significantly downregulated (p < 0.001). Bacopa treatment showed a significant reversal in the altered gene expression parameters (p < 0.001) of Bax and SOD. Our results suggest that in the rat experimental model of neonatal hypoglycaemia, Bacopa extract improved alterations in D1, D2 receptor expression, cAMP signalling and cell death resulting from oxidative stress. This is an important area of study given the significant motor and cognitive impairment that may arise from neonatal hypoglycaemia if proper treatment is not implemented.

Effect of novel atypical antipsychotic, blonanserin, on extracellular neurotransmitter level in rat prefrontal cortex.

PubMed

Ohoyama, Keiko; Yamamura, Satoshi; Hamaguchi, Tatsuya; Nakagawa, Masanori; Motomura, Eishi; Shiroyama, Takashi; Tanii, Hisashi; Okada, Motohiro

2011-02-25

To clarify the mechanisms of action of blonanserin, an atypical antipsychotic drug, we studied the effects of systemic administration of blonanserin and risperidone on extracellular levels of norepinephrine, dopamine, serotonin, GABA and glutamate in the medial prefrontal cortex using microdialysis, and neuronal firing in the ventral tegmental area, locus coeruleus, dorsal raphe nucleus and mediodorsal thalamic nucleus using radiotelemetry. The binding affinities of blonanserin to D(2) and 5-HT(2A) receptors in the rat brain were confirmed and found to be similar. Blonanserin transiently increased neuronal firing in locus coeruleus and ventral tegmental area but not in dorsal raphe nucleus or mediodorsal thalamic nucleus, whereas risperidone increased the firing in locus coeruleus, ventral tegmental area and dorsal raphe nucleus but not in mediodorsal thalamic nucleus. Blonanserin persistently increased frontal extracellular levels of norepinephrine and dopamine but not serotonin, GABA or glutamate, whereas risperidone persistently increased those of norepinephrine, dopamine and serotonin but not GABA or glutamate. These results suggest a pharmacological correlation between the stimulatory effects of these antipsychotics on frontal monoamine release and neuronal activity in monoaminergic nuclei. Inhibition of the α(2) adrenoceptor increased extracellular monoamine levels and enhanced blonanserin-induced increase in extracellular serotonin level. These results indicated that the combination of antagonism of D(2) and 5-HT(2A) receptors contribute to the rise in extracellular levels of norepinephrine and dopamine, and that α(2) adrenoceptors play important roles in frontal serotonin release. They also suggest that blonanserin-induced activation of monoaminergic transmission could be, at least partially, involved in atypical antipsychotic properties of blonanserin. Copyright © 2010 Elsevier B.V. All rights reserved.

Frontal D2/3 Receptor Availability in Schizophrenia Patients Before and After Their First Antipsychotic Treatment: Relation to Cognitive Functions and Psychopathology.

PubMed

Nørbak-Emig, Henrik; Ebdrup, Bjørn H; Fagerlund, Birgitte; Svarer, Claus; Rasmussen, Hans; Friberg, Lars; Allerup, Peter N; Rostrup, Egill; Pinborg, Lars H; Glenthøj, Birte Y

2016-05-01

We have previously reported associations between frontal D2/3 receptor binding potential positive symptoms and cognitive deficits in antipsychotic-naïve schizophrenia patients. Here, we examined the effect of dopamine D2/3 receptor blockade on cognition. Additionally, we explored the relation between frontal D2/3 receptor availability and treatment effect on positive symptoms. Twenty-five antipsychotic-naïve first-episode schizophrenia patients were examined with the Positive and Negative Syndrome Scale, tested with the cognitive test battery Cambridge Neuropsychological Test Automated Battery, scanned with single-photon emission computerized tomography using the dopamine D2/3 receptor ligand [(123)I]epidepride, and scanned with MRI. After 3 months of treatment with either risperidone (n=13) or zuclopenthixol (n=9), 22 patients were reexamined. Blockade of extrastriatal dopamine D2/3 receptors was correlated with decreased attentional focus (r = -0.615, P=.003) and planning time (r = -0.436, P=.048). Moreover, baseline frontal dopamine D2/3 binding potential and positive symptom reduction correlated positively (D2/3 receptor binding potential left frontal cortex rho = 0.56, P=.003; D2/3 receptor binding potential right frontal cortex rho = 0.48, P=.016). Our data support the hypothesis of a negative influence of D2/3 receptor blockade on specific cognitive functions in schizophrenia. This is highly clinically relevant given the well-established association between severity of cognitive disturbances and a poor functional outcome in schizophrenia. Additionally, the findings support associations between frontal D2/3 receptor binding potential at baseline and the effect of antipsychotic treatment on positive symptoms. © The Author 2016. Published by Oxford University Press on behalf of CINP.

The Effects of Medium Spiny Neuron Morphologcial Changes on Basal Ganglia Network under External Electric Field: A Computational Modeling Study

PubMed Central

Zhang, Xiaohan; Liu, Shenquan; Zhan, Feibiao; Wang, Jing; Jiang, Xiaofang

2017-01-01

The damage of dopaminergic neurons that innervate the striatum has been considered to be the proximate cause of Parkinson's disease (PD). In the dopamine-denervated state, the loss of dendritic spines and the decrease of dendritic length may prevent medium spiny neuron (MSN) from receiving too much excitatory stimuli from the cortex, thereby reducing the symptom of Parkinson's disease. However, the reduction in dendritic spine density obtained by different experiments is significantly different. We developed a biological-based network computational model to quantify the effect of dendritic spine loss and dendrites tree degeneration on basal ganglia (BG) signal regulation. Through the introduction of error index (EI), which was used to measure the attenuation of the signal, we explored the amount of dendritic spine loss and dendritic trees degradation required to restore the normal regulatory function of the network, and found that there were two ranges of dendritic spine loss that could reduce EI to normal levels in the case of dopamine at a certain level, this was also true for dendritic trees. However, although these effects were the same, the mechanisms of these two cases were significant difference. Using the method of phase diagram analysis, we gained insight into the mechanism of signal degradation. Furthermore, we explored the role of cortex in MSN morphology changes dopamine depletion-induced and found that proper adjustments to cortical activity do stop the loss in dendritic spines induced by dopamine depleted. These results suggested that modifying cortical drive onto MSN might provide a new idea on clinical therapeutic strategies for Parkinson's disease. PMID:29123477

Neuromodulation of Prefrontal Cortex in Non-Human Primates by Dopaminergic Receptors during Rule-Guided Flexible Behavior and Cognitive Control

PubMed Central

Vijayraghavan, Susheel; Major, Alex J.; Everling, Stefan

2017-01-01

The prefrontal cortex (PFC) is indispensable for several higher-order cognitive and executive capacities of primates, including representation of salient stimuli in working memory (WM), maintenance of cognitive task set, inhibition of inappropriate responses and rule-guided flexible behavior. PFC networks are subject to robust neuromodulation from ascending catecholaminergic systems. Disruption of these systems in PFC has been implicated in cognitive deficits associated with several neuropsychiatric disorders. Over the past four decades, a considerable body of work has examined the influence of dopamine on macaque PFC activity representing spatial WM. There has also been burgeoning interest in neuromodulation of PFC circuits involved in other cognitive functions of PFC, including representation of rules to guide flexible behavior. Here, we review recent neuropharmacological investigations conducted in our laboratory and others of the role of PFC dopamine receptors in regulating rule-guided behavior in non-human primates. Employing iontophoresis, we examined the effects of local manipulation of dopaminergic subtypes on neuronal activity during performance of rule-guided pro- and antisaccades, an experimental paradigm sensitive to PFC integrity, wherein deficits in performance are reliably observed in many neuropsychiatric disorders. We found dissociable effects of dopamine receptors on neuronal activity for rule representation and oculomotor responses and discuss these findings in the context of prior studies that have examined the role of dopamine in spatial delayed response tasks, attention, target selection, abstract rules, visuomotor learning and reward. The findings we describe here highlight the common features, as well as heterogeneity and context dependence of dopaminergic neuromodulation in regulating the efficacy of cognitive functions of PFC in health and disease. PMID:29259545

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.

Opposite roles of dopamine and orexin in quinpirole-induced excessive drinking: a rat model of psychotic polydipsia.

PubMed

Milella, Michele S; Passarelli, Francesca; De Carolis, Lorenza; Schepisi, Chiara; Nativio, Paola; Scaccianoce, Sergio; Nencini, Paolo

2010-08-01

Repeated administration of the dopamine D2/D3 agonist quinpirole (QNP) progressively increases non-regulatory water intake. This effect may model psychotic polydipsia, a potentially fatal but poorly understood condition. The growing evidence for a role of orexin in mediating arousal and cognition has linked this peptide to schizophrenia, hence we examined whether manipulations of dopaminergic and orexinergic systems, as well as of setting, would further characterize the model. Water intake was measured in rats sequentially tested in home and then operant conditioning setting, with chronic administration of D2 antagonist haloperidol (Hal) prior to QNP treatment. A group of rats similarly treated was also assessed for orexin A (OxA) expression in the cortex. Finally, the effect of the orexin-1 receptor antagonist SB-334867 on QNP-induced polydipsia was evaluated. In rats made polydipsic by QNP the amount of water drank during the first 4 h was strongly correlated with the degree of dissociation between appetitive and consummatory components of drinking behavior in the following hour of operant access to water. Hal 0.2 mg/kg prevented both polydipsia and the dissociation, while 0.1 mg/kg only blocked the dissociation. Chronic QNP treatment increased, in a Hal-reversible way, OxA expression in the somatosensory cortex (SI). Moreover, pretreatment with SB-334867 sped up and potentiated QNP-induced polydipsia. Results disclose compulsive components in QNP-induced polydipsia that are mediated by dopamine D2 receptors. QNP also regulates OxA expression in the SI, while the block of orexin-1 receptors enhances QNP-induced polydipsia. We suggest that dopamine and OxA play opposite roles in QNP-induced polydipsia.

Adolescent social defeat alters N-methyl-D-aspartic acid receptor expression and impairs fear learning in adulthood.

PubMed

Novick, Andrew M; Mears, Mackenzie; Forster, Gina L; Lei, Yanlin; Tejani-Butt, Shanaz M; Watt, Michael J

2016-05-01

Repeated social defeat of adolescent male rats results in adult mesocortical dopamine hypofunction, impaired working memory, and increased contextual anxiety-like behavior. Given the role of glutamate in dopamine regulation, cognition, and fear and anxiety, we investigated potential changes to N-methyl-D-aspartic acid (NMDA) receptors following adolescent social defeat. As both NMDA receptors and mesocortical dopamine are implicated in the expression and extinction of conditioned fear, a separate cohort of rats was challenged with a classical fear conditioning paradigm to investigate whether fear learning is altered by adolescent defeat. Quantitative autoradiography was used to measure 3H-MK-801 binding to NMDA receptors in regions of the medial prefrontal cortex, caudate putamen, nucleus accumbens, amygdala and hippocampus. Assessment of fear learning was achieved using an auditory fear conditioning paradigm, with freezing toward the auditory tone used as a measure of conditioned fear. Compared to controls, adolescent social defeat decreased adult NMDA receptor expression in the infralimbic region of the prefrontal cortex and central amygdala, while increasing expression in the CA3 region of the hippocampus. Previously defeated rats also displayed decreased conditioned freezing during the recall and first extinction periods, which may be related to the observed decreases and increases in NMDA receptors within the central amygdala and CA3, respectively. The alteration in NMDA receptors seen following adolescent social defeat suggests that dysfunction of glutamatergic systems, combined with mesocortical dopamine deficits, likely plays a role in the some of the long-term behavioral consequences of social stressors in adolescence seen in both preclinical and clinical studies. Copyright © 2016 Elsevier B.V. All rights reserved.

The roles of the anterior cingulate cortex and its dopamine receptors in self-paced cost-benefit decision making in rats.

PubMed

Wang, Shuai; Hu, Shan-Hu; Shi, Yi; Li, Bao-Ming

2017-03-01

It has been shown that the anterior cingulate cortex (ACC) and its dopamine system are crucial for decision making that requires physical/emotional effort, but not for all forms of cost-benefit decision making. Previous studies had mostly employed behavioral tasks with two competing cost-reward options that were preset by the experimenters. However, few studies have been conducted using scenarios in which the subjects have full control over the energy/time expenditure required to obtain a proportional reward. Here, we assessed the roles of the ACC and its dopamine system in cost-benefit decision making by utilizing a "do more get more" (DMGM) task and a time-reward trade-off (TRTO) task, wherein the animals were able to self-determine how much effort or time to expend at a nosepoke operandum for a proportional reward. Our results showed that (1) ACC inactivation severely impaired DMGM task performance, with a reduction in the rate of correct responses and a decrease in the effort expended, but did not affect the TRTO task; and (2) blocking ACC D2 receptors had no impact on DMGM task performance in the baseline cost-benefit scenario, but it significantly reduced the attempts to invest increased effort for a large reward when the benefit-cost ratio was reduced by half. In contrast, blocking ACC D1 receptors had no effect on DMGM task performance. These findings suggest that the ACC is required for self-paced effort-based but not for time-reward trade-off decision making. Furthermore, ACC dopamine D2 but not D1 receptors are involved in DMGM decision making.

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.

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

Dopamine modulates reward system activity during subconscious processing of sexual stimuli.

PubMed

Oei, Nicole Y L; Rombouts, Serge Arb; Soeter, Roelof P; van Gerven, Joop M; Both, Stephanie

2012-06-01

Dopaminergic medication influences conscious processing of rewarding stimuli, and is associated with impulsive-compulsive behaviors, such as hypersexuality. Previous studies have shown that subconscious subliminal presentation of sexual stimuli activates brain areas known to be part of the 'reward system'. In this study, it was hypothesized that dopamine modulates activation in key areas of the reward system, such as the nucleus accumbens, during subconscious processing of sexual stimuli. Young healthy males (n=53) were randomly assigned to two experimental groups or a control group, and were administered a dopamine antagonist (haloperidol), a dopamine agonist (levodopa), or placebo. Brain activation was assessed during a backward-masking task with subliminally presented sexual stimuli. Results showed that levodopa significantly enhanced the activation in the nucleus accumbens and dorsal anterior cingulate when subliminal sexual stimuli were shown, whereas haloperidol decreased activations in those areas. Dopamine thus enhances activations in regions thought to regulate 'wanting' in response to potentially rewarding sexual stimuli that are not consciously perceived. This running start of the reward system might explain the pull of rewards in individuals with compulsive reward-seeking behaviors such as hypersexuality and patients who receive dopaminergic medication.

Stochastic Simulation of Dopamine Neuromodulation for Implementation of Fluorescent Neurochemical Probes in the Striatal Extracellular Space.

PubMed

Beyene, Abraham G; McFarlane, Ian R; Pinals, Rebecca L; Landry, Markita P

2017-10-18

Imaging the dynamic behavior of neuromodulatory neurotransmitters in the extracelluar space that arise from individual quantal release events would constitute a major advance in neurochemical imaging. Spatial and temporal resolution of these highly stochastic neuromodulatory events requires concurrent advances in the chemical development of optical nanosensors selective for neuromodulators in concert with advances in imaging methodologies to capture millisecond neurotransmitter release. Herein, we develop and implement a stochastic model to describe dopamine dynamics in the extracellular space (ECS) of the brain dorsal striatum to guide the design and implementation of fluorescent neurochemical probes that record neurotransmitter dynamics in the ECS. Our model is developed from first-principles and simulates release, diffusion, and reuptake of dopamine in a 3D simulation volume of striatal tissue. We find that in vivo imaging of neuromodulation requires simultaneous optimization of dopamine nanosensor reversibility and sensitivity: dopamine imaging in the striatum or nucleus accumbens requires nanosensors with an optimal dopamine dissociation constant (K d ) of 1 μM, whereas K d s above 10 μM are required for dopamine imaging in the prefrontal cortex. Furthermore, as a result of the probabilistic nature of dopamine terminal activity in the striatum, our model reveals that imaging frame rates of 20 Hz are optimal for recording temporally resolved dopamine release events. Our work provides a modeling platform to probe how complex neuromodulatory processes can be studied with fluorescent nanosensors and enables direct evaluation of nanosensor chemistry and imaging hardware parameters. Our stochastic model is generic for evaluating fluorescent neurotransmission probes, and is broadly applicable to the design of other neurotransmitter fluorophores and their optimization for implementation in vivo.

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

Opposing effects of dopamine antagonism in a motor sequence task—tiapride increases cortical excitability and impairs motor learning

PubMed Central

Lissek, Silke; Vallana, Guido S.; Schlaffke, Lara; Lenz, Melanie; Dinse, Hubert R.; Tegenthoff, Martin

2014-01-01

The dopaminergic system is involved in learning and participates in the modulation of cortical excitability (CE). CE has been suggested as a marker of learning and use-dependent plasticity. However, results from separate studies on either motor CE or motor learning challenge this notion, suggesting opposing effects of dopaminergic modulation upon these parameters: while agonists decrease and antagonists increase CE, motor learning is enhanced by agonists and disturbed by antagonists. To examine whether this discrepancy persists when complex motor learning and motor CE are measured in the same experimental setup, we investigated the effects of dopaminergic (DA) antagonism upon both parameters and upon task-associated brain activation. Our results demonstrate that DA-antagonism has opposing effects upon motor CE and motor sequence learning. Tiapride did not alter baseline CE, but increased CE post training of a complex motor sequence while simultaneously impairing motor learning. Moreover, tiapride reduced activation in several brain regions associated with motor sequence performance, i.e., dorsolateral PFC (dlPFC), supplementary motor area (SMA), Broca's area, cingulate and caudate body. Blood-oxygenation-level-dependent (BOLD) intensity in anterior cingulate and caudate body, but not CE, correlated with performance across groups. In summary, our results do not support a concept of CE as a general marker of motor learning, since they demonstrate that a straightforward relation of increased CE and higher learning success does not apply to all instances of motor learning. At least for complex motor tasks that recruit a network of brain regions outside motor cortex, CE in primary motor cortex is probably no central determinant for learning success. PMID:24994972

Conflict processing in juvenile patients with neurofibromatosis type 1 (NF1) and healthy controls - Two pathways to success.

PubMed

Bluschke, Annet; von der Hagen, Maja; Papenhagen, Katharina; Roessner, Veit; Beste, Christian

2017-01-01

Neurofibromatosis Type 1 (NF1) is a monogenetic autosomal-dominant disorder with a broad spectrum of clinical symptoms and is commonly associated with cognitive deficits. Patients with NF1 frequently exhibit cognitive impairments like attention problems, working memory deficits and dysfunctional inhibitory control. The latter is also relevant for the resolution of cognitive conflicts. However, it is unclear how conflict monitoring processes are modulated in NF1. To examine this question in more detail, we used a system neurophysiological approach combining high-density ERP recordings with source localisation analyses in juvenile patients with NF1 and controls during a flanker task. Behaviourally, patients with NF1 perform significantly slower than controls. Specifically on trials with incompatible flanker-target pairings, however, the patients with NF1 made significantly fewer errors than healthy controls. Yet, importantly, this overall successful conflict resolution was reached via two different routes in the two groups. The healthy controls seem to arrive at a successful conflict monitoring performance through a developing conflict recognition via the N2 accompanied by a selectively enhanced N450 activation in the case of perceived flanker-target conflicts. The presumed dopamine deficiency in the patients with NF1 seems to result in a reduced ability to process conflicts via the N2. However, NF1 patients show an increased N450 irrespective of cognitive conflict. Activation differences in the orbitofrontal cortex (BA11) and anterior cingulate cortex (BA24) underlie these modulations. Taken together, juvenile patients with NF1 and juvenile healthy controls seem to accomplish conflict monitoring via two different cognitive neurophysiological pathways.

Selective post-training time window for memory consolidation interference of cannabidiol into the prefrontal cortex: Reduced dopaminergic modulation and immediate gene expression in limbic circuits.

PubMed

Rossignoli, Matheus Teixeira; Lopes-Aguiar, Cleiton; Ruggiero, Rafael Naime; Do Val da Silva, Raquel Araujo; Bueno-Junior, Lezio Soares; Kandratavicius, Ludmyla; Peixoto-Santos, José Eduardo; Crippa, José Alexandre; Cecilio Hallak, Jaime Eduardo; Zuardi, Antonio Waldo; Szawka, Raphael Escorsim; Anselmo-Franci, Janete; Leite, João Pereira; Romcy-Pereira, Rodrigo Neves

2017-05-14

The prefrontal cortex (PFC), amygdala and hippocampus display a coordinated activity during acquisition of associative fear memories. Evidence indicates that PFC engagement in aversive memory formation does not progress linearly as previously thought. Instead, it seems to be recruited at specific time windows after memory acquisition, which has implications for the treatment of post-traumatic stress disorders. Cannabidiol (CBD), the major non-psychotomimetic phytocannabinoid of the Cannabis sativa plant, is known to modulate contextual fear memory acquisition in rodents. However, it is still not clear how CBD interferes with PFC-dependent processes during post-training memory consolidation. Here, we tested whether intra-PFC infusions of CBD immediately after or 5h following contextual fear conditioning was able to interfere with memory consolidation. Neurochemical and cellular correlates of the CBD treatment were evaluated by the quantification of extracellular levels of dopamine (DA), serotonin, and their metabolites in the PFC and by measuring the cellular expression of activity-dependent transcription factors in cortical and limbic regions. Our results indicate that bilateral intra-PFC CBD infusion impaired contextual fear memory consolidation when applied 5h after conditioning, but had no effect when applied immediately after it. This effect was associated with a reduction in DA turnover in the PFC following retrieval 5days after training. We also observed that post-conditioning infusion of CBD reduced c-fos and zif-268 protein expression in the hippocampus, PFC, and thalamus. Our findings support that CBD interferes with contextual fear memory consolidation by reducing PFC influence on cortico-limbic circuits. Copyright © 2017 IBRO. 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 and extinction: a convergence of theory with fear and reward circuitry.

PubMed

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

2014-02-01

Research on dopamine lies at the intersection of sophisticated theoretical and neurobiological approaches to learning and memory. Dopamine has been shown to be critical for many processes that drive learning and memory, including motivation, prediction error, incentive salience, memory consolidation, and response output. Theories of dopamine's function in these processes have, for the most part, been developed from behavioral approaches that examine learning mechanisms in reward-related tasks. A parallel and growing literature indicates that dopamine is involved in fear conditioning and extinction. These studies are consistent with long-standing ideas about appetitive-aversive interactions in learning theory and they speak to the general nature of cellular and molecular processes that underlie behavior. We review the behavioral and neurobiological literature showing a role for dopamine in fear conditioning and extinction. At a cellular level, we review dopamine signaling and receptor pharmacology, cellular and molecular events that follow dopamine receptor activation, and brain systems in which dopamine functions. At a behavioral level, we describe theories of learning and dopamine function that could describe the fundamental rules underlying how dopamine modulates different aspects of learning and memory processes. Copyright © 2013 Elsevier Inc. All rights reserved.

Olfactory modulation by dopamine in the context of aversive learning

PubMed Central

Riffell, Jeffrey A.; Martin, Joshua P.; Gage, Stephanie L.; Nighorn, Alan J.

2012-01-01

The need to detect and process sensory cues varies in different behavioral contexts. Plasticity in sensory coding can be achieved by the context-specific release of neuromodulators in restricted brain areas. The context of aversion triggers the release of dopamine in the insect brain, yet the effects of dopamine on sensory coding are unknown. In this study, we characterize the morphology of dopaminergic neurons that innervate each of the antennal lobes (ALs; the first synaptic neuropils of the olfactory system) of the moth Manduca sexta and demonstrate with electrophysiology that dopamine enhances odor-evoked responses of the majority of AL neurons while reducing the responses of a small minority. Because dopamine release in higher brain areas mediates aversive learning we developed a naturalistic, ecologically inspired aversive learning paradigm in which an innately appetitive host plant floral odor is paired with a mimic of the aversive nectar of herbivorized host plants. This pairing resulted in a decrease in feeding behavior that was blocked when dopamine receptor antagonists were injected directly into the ALs. These results suggest that a transient dopaminergic enhancement of sensory output from the AL contributes to the formation of aversive memories. We propose a model of olfactory modulation in which specific contexts trigger the release of different neuromodulators in the AL to increase olfactory output to downstream areas of processing. PMID:22552185

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

Functional Polymorphisms in Dopaminergic Genes Modulate Neurobehavioral and Neurophysiological Consequences of Sleep Deprivation.

PubMed

Holst, Sebastian C; Müller, Thomas; Valomon, Amandine; Seebauer, Britta; Berger, Wolfgang; Landolt, Hans-Peter

2017-04-10

Sleep deprivation impairs cognitive performance and reliably alters brain activation in wakefulness and sleep. Nevertheless, the molecular regulators of prolonged wakefulness remain poorly understood. Evidence from genetic, behavioral, pharmacologic and imaging studies suggest that dopaminergic signaling contributes to the behavioral and electroencephalographic (EEG) consequences of sleep loss, although direct human evidence thereof is missing. We tested whether dopamine neurotransmission regulate sustained attention and evolution of EEG power during prolonged wakefulness. Here, we studied the effects of functional genetic variation in the dopamine transporter (DAT1) and the dopamine D 2 receptor (DRD2) genes, on psychomotor performance and standardized waking EEG oscillations during 40 hours of wakefulness in 64 to 82 healthy volunteers. Sleep deprivation consistently enhanced sleepiness, lapses of attention and the theta-to-alpha power ratio (TAR) in the waking EEG. Importantly, DAT1 and DRD2 genotypes distinctly modulated sleep loss-induced changes in subjective sleepiness, PVT lapses and TAR, according to inverted U-shaped relationships. Together, the data suggest that genetically determined differences in DAT1 and DRD2 expression modulate functional consequences of sleep deprivation, supporting the hypothesis that striato-thalamo-cortical dopaminergic pathways modulate the neurobehavioral and neurophysiological consequences of sleep loss in humans.

[Effects of psychological stress on performances in open-field test of rats and tyrosine's modulation].

PubMed

Chen, Wei-Qiang; Cheng, Yi-Yong; Li, Shu-Tian; Hong, Yan; Wang, Dong-Lan; Hou, Yue

2009-02-01

To explore the effects of different doses of tyrosine modulation on behavioral performances in open field test of psychological stress rats. The animal model of psychological stress was developed by restraint stress for 21 days. Wistar rats were randomly assigned to five groups (n = 10) as follows: control group (CT), stress control group (SCT), low, medium and high-doses of tyrosine modulation stress groups (SLT, SMT and SIT). The changes of behavioral performances were examined by open-field test. Serum levels of cortisol, norepinephrine and dopamine were also detected. The levels of serum cortisol were all increased obviously in the four stress groups, and their bodyweight gainings were diminished. The behavioral performances of SCT rats in open-field test were changed significantly in contrast to that of CT rats. However, The behavioral performances of SMT and SHT rats were not different from that of CT rats. In addition, the serum levels of norepinephrine and dopamine were downregulated obviously in SCT and SLT groups, and no differences were observed in other groups. Psychological stress can impair body behavioral performances, and moderate tyrosine modulation may improve these abnormal changes. The related mechanisms may be involved with the changes of norepinephrine and dopamine.

Citicoline Affects Appetite and Cortico-Limbic Responses to Images of High Calorie Foods

PubMed Central

Killgore, William D. S.; Ross, Amy J.; Kamiya, Toshi; Kawada, Yoko; Renshaw, Perry F.; Yurgelun-Todd, Deborah A.

2011-01-01

Cytidine-5’-diphosphocholine (citicoline) has a variety of cognitive enhancing, neuroprotective, and neuroregenerative properties. In cocaine-addicted individuals, citicoline has been shown to increase brain dopamine levels and reduce cravings. The effects of this compound on appetite, food cravings, and brain responses to food are unknown. We compared the effects of treatment with citicoline (500 mg/day versus 2000 mg/day) for six weeks on changes in appetite ratings, weight, and cortico-limbic responses to images of high calorie foods using functional magnetic resonance imaging (fMRI). After six weeks, there was no significant change in weight status, although significant declines in appetite ratings were observed for the 2000 mg/day group. The higher dose group also showed significant increases in functional brain responses to food stimuli within the amygdala, insula, and lateral orbitofrontal cortex. Increased activation in these regions correlated with declines in appetite ratings. These preliminary findings suggest a potential usefulness of citicoline in modulating appetite, but further research is warranted. PMID:19260039

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.

Elevation of D4 dopamine receptor mRNA in postmortem schizophrenic brain.

PubMed

Stefanis, N C; Bresnick, J N; Kerwin, R W; Schofield, W N; McAllister, G

1998-01-01

The D4 dopamine (DA) receptor has been proposed to be a target for the development of a novel antipsychotic drug based on its pharmacological and distribution profile. There is much interest in whether D4 DA receptor levels are altered in schizophrenia, but the lack of an available receptor subtype-specific radioligand made this difficult to quantitate. In this study, we examined whether D4 mRNA levels are altered in different brain regions of schizophrenics compared to controls. Ribonuclease protection assays were carried out on total RNA samples isolated postmortem from frontal cortex and caudate brain regions of schizophrenics and matched controls. 32P-labelled RNA probes to the D4 DA receptor and to the housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase (G3PDH), were hybridised with the RNA samples, digested with ribonucleases to remove unhybridised probe, and separated on 6% sequencing gels. Densitometer analysis on the subsequent autoradiogams was used to calculate the relative optical density of D4 mRNA compared to G3PDH mRNA. Statistical analysis of the data revealed a 3-fold higher level (P<0.011) of D4 mRNA in the frontal cortex of schizophrenics compared to controls. No increase was seen in caudate. D4 receptors could play a role in mediating dopaminergic activity in frontal cortex, an activity which may be malfunctioning in schizophrenia.

Methylphenidate and Atomoxetine Enhance Prefrontal Function through alpha[subscript 2]-Adrenergic and Dopamine D[subscript 1] Receptors

ERIC Educational Resources Information Center

Gamo, Nao J.; Wang, Min; Arnsten, Amy F. T.

2010-01-01

Objective: This study examined the effects of the attention-deficit/hyperactivity disorder treatments, methylphenidate (MPH) and atomoxetine (ATM), on prefrontal cortex (PFC) function in monkeys and explored the receptor mechanisms underlying enhancement of PFC function at the behavioral and cellular levels. Method: Monkeys performed a working…

Context, Cortex, and Dopamine: A Connectionist Approach to Behavior and Biology in Schizophrenia.

ERIC Educational Resources Information Center

Cohen, Jonathan D.; Servan-Schreiber, David

1992-01-01

Using a connectionist framework, it is possible to develop models exploring effects of biologically relevant variables on behavior. The ability of such models to explain schizophrenic behavior in terms of biological disturbances is considered, and computer models are presented that simulate normal and schizophrenic behavior in an attentional task.…

Visuomotor Binding in Older Adults

ERIC Educational Resources Information Center

Bloesch, Emily K.; Abrams, Richard A.

2010-01-01

Action integration is the process through which actions performed on a stimulus and perceptual aspects of the stimulus become bound as a unitary object. This process appears to be controlled by the dopaminergic system in the prefrontal cortex, an area that is known to decrease in volume and dopamine functioning in older adults. Although the…

Single dose of l-dopa makes extinction memories context-independent and prevents the return of fear

PubMed Central

Haaker, Jan; Gaburro, Stefano; Sah, Anupam; Gartmann, Nina; Lonsdorf, Tina B.; Meier, Kolja; Singewald, Nicolas; Pape, Hans-Christian; Morellini, Fabio; Kalisch, Raffael

2013-01-01

Traumatic events can engender persistent excessive fear responses to trauma reminders that may return even after successful treatment. Extinction, the laboratory analog of behavior therapy, does not erase conditioned fear memories but generates competing, fear-inhibitory “extinction memories” that, however, are tied to the context in which extinction occurred. Accordingly, a dominance of fear over extinction memory expression—and, thus, return of fear—is often observed if extinguished fear stimuli are encountered outside the extinction (therapy) context. We show that postextinction administration of the dopamine precursor l-dopa makes extinction memories context-independent, thus strongly reducing the return of fear in both mice and humans. Reduced fear is accompanied by decreased amygdala and enhanced ventromedial prefrontal cortex activation in both species. In humans, ventromedial prefrontal cortex activity is predicted by enhanced resting-state functional coupling of the area with the dopaminergic midbrain during the postextinction consolidation phase. Our data suggest that dopamine-dependent boosting of extinction memory consolidation is a promising avenue to improving anxiety therapy. PMID:23754384

Behavioral Abnormalities and Circuit Defects in the Basal Ganglia of a Mouse Model of 16p11.2 Deletion Syndrome

PubMed Central

Portmann, Thomas; Ellegood, Jacob; Dolen, Gul; Bader, Patrick L.; Grueter, Brad A.; Goold, Carleton; Fisher, Elaine; Clifford, Katherine; Rengarajan, Pavitra; Kalikhman, David; Loureiro, Darren; Saw, Nay L.; Zhengqui, Zhou; Miller, Michael A.; Lerch, Jason P.; Henkelman, Mark; Shamloo, Mehrdad; Malenka, Robert C.; Crawley, Jacqueline N.; Dolmetsch, Ricardo E.

2014-01-01

Summary A deletion on human chromosome 16p11.2 is associated with autism spectrum disorders. We deleted the syntenic region on mouse chromosome 7F3. MRI and high-throughput single-cell transcriptomics revealed anatomical and cellular abnormalities, particularly in cortex and striatum of juvenile mutant mice (16p11+/−). We found elevated numbers of striatal medium spiny neurons (MSNs) expressing the dopamine D2 receptor (Drd2+) and fewer dopamine-sensitive (Drd1+) neurons in deep layers of cortex. Electrophysiological recordings of Drd2+ MSN revealed synaptic defects, suggesting abnormal basal ganglia circuitry function in 16p11+/− mice. This is further supported by behavioral experiments showing hyperactivity, circling, and deficits in movement control. Strikingly, 16p11+/− mice showed a complete lack of habituation reminiscent of what is observed in some autistic individuals. Our findings unveil a fundamental role of genes affected by the 16p11.2 deletion in establishing the basal ganglia circuitry and provide insights in the pathophysiology of autism. PMID:24794428

Monoaminergic Modulation of Motor Cortex Function

PubMed Central

Vitrac, Clément; Benoit-Marand, Marianne

2017-01-01

Elaboration of appropriate responses to behavioral situations rests on the ability of selecting appropriate motor outcomes in accordance to specific environmental inputs. To this end, the primary motor cortex (M1) is a key structure for the control of voluntary movements and motor skills learning. Subcortical loops regulate the activity of the motor cortex and thus contribute to the selection of appropriate motor plans. Monoamines are key mediators of arousal, attention and motivation. Their firing pattern enables a direct encoding of different states thus promoting or repressing the selection of actions adapted to the behavioral context. Monoaminergic modulation of motor systems has been extensively studied in subcortical circuits. Despite evidence of converging projections of multiple neurotransmitters systems in the motor cortex pointing to a direct modulation of local circuits, their contribution to the execution and learning of motor skills is still poorly understood. Monoaminergic dysregulation leads to impaired plasticity and motor function in several neurological and psychiatric conditions, thus it is critical to better understand how monoamines modulate neural activity in the motor cortex. This review aims to provide an update of our current understanding on the monoaminergic modulation of the motor cortex with an emphasis on motor skill learning and execution under physiological conditions. PMID:29062274

Rapid decreases in preoptic aromatase activity and brain monoamine concentrations after engaging in male sexual behavior.

PubMed

Cornil, C A; Dalla, C; Papadopoulou-Daifoti, Z; Baillien, M; Dejace, C; Ball, G F; Balthazart, J

2005-09-01

In Japanese quail, as in rats, the expression of male sexual behavior over relatively long time periods (days to weeks) is dependent on the local production of estradiol in the preoptic area via the aromatization of testosterone. On a short-term basis (minutes to hours), central actions of dopamine as well as locally produced estrogens modulate behavioral expression. In rats, a view of and sexual interaction with a female increase dopamine release in the preoptic area. In quail, in vitro brain aromatase activity (AA) is rapidly modulated by calcium-dependent phosphorylations that are likely to occur in vivo as a result of changes in neurotransmitter activity. Furthermore, an acute estradiol injection rapidly stimulates copulation in quail, whereas a single injection of the aromatase inhibitor vorozole rapidly inhibits this behavior. We hypothesized that brain aromatase and dopaminergic activities are regulated in quail in association with the expression of male sexual behavior. Visual access as well as sexual interactions with a female produced a significant decrease in brain AA, which was maximal after 5 min. This expression of sexual behavior also resulted in a significant decrease in dopaminergic as well as serotonergic activity after 1 min, which returned to basal levels after 5 min. These results demonstrate for the first time that AA is rapidly modulated in vivo in parallel with changes in dopamine activity. Sexual interactions with the female decreased aromatase and dopamine activities. These data challenge established views about the causal relationships among dopamine, estrogen action, and male sexual behavior.

Rapid decreases in preoptic aromatase activity and brain monoamine concentrations after engaging in male sexual behavior

PubMed Central

Cornil, C. A.; Dalla, C.; Papadopoulou-Daifoti, Z.; Baillien, M.; Dejace, C.; Ball, G.F.; Balthazart, J.

2014-01-01

In Japanese quail as in rats, the expression of male sexual behavior over relatively long time periods (days to weeks) is dependent on the local production of estradiol in the preoptic area via the aromatization of testosterone. On a short-term basis (minutes to hours), central actions of dopamine as well as locally produced estrogens modulate behavioral expression. In rats, a view of and sexual interaction with a female increases dopamine release in the preoptic area. In quail, in vitro brain aromatase activity is rapidly modulated by calcium-dependent phosphorylations that are likely to occur in vivo as a result of changes in neurotransmitter activity. Furthermore, an acute estradiol injection rapidly stimulates copulation in quail, while a single injection of the aromatase inhibitor Vorozole™ rapidly inhibits this behavior. We hypothesized that brain aromatase and dopaminergic activities are regulated in quail in association with the expression of male sexual behavior. Visual access as well as sexual interactions with a female produced a significant decrease in brain aromatase activity that was maximal after 5 min. This expression of sexual behavior also resulted in a significant decrease in dopaminergic as well as serotonergic activity after 1 min, which returned to basal levels after 5 min. These results demonstrate for the first time that aromatase activity is rapidly modulated in vivo in parallel with changes in dopamine activity. Sexual interactions with the female decreased aromatase and dopamine activity. These data challenges established views about the causal relationships among dopamine, estrogen action and male sexual behavior. PMID:15932925

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

PubMed Central

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

2014-01-01

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

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.

Chronic CRH depletion from GABAergic, long-range projection neurons in the extended amygdala reduces dopamine release and increases anxiety.

PubMed

Dedic, Nina; Kühne, Claudia; Jakovcevski, Mira; Hartmann, Jakob; Genewsky, Andreas J; Gomes, Karina S; Anderzhanova, Elmira; Pöhlmann, Max L; Chang, Simon; Kolarz, Adam; Vogl, Annette M; Dine, Julien; Metzger, Michael W; Schmid, Bianca; Almada, Rafael C; Ressler, Kerry J; Wotjak, Carsten T; Grinevich, Valery; Chen, Alon; Schmidt, Mathias V; Wurst, Wolfgang; Refojo, Damian; Deussing, Jan M

2018-06-01

The interplay between corticotropin-releasing hormone (CRH) and the dopaminergic system has predominantly been studied in addiction and reward, while CRH-dopamine interactions in anxiety are scarcely understood. We describe a new population of CRH-expressing, GABAergic, long-range-projecting neurons in the extended amygdala that innervate the ventral tegmental area and alter anxiety following chronic CRH depletion. These neurons are part of a distinct CRH circuit that acts anxiolytically by positively modulating dopamine release.

Impact of gasoline inhalation on some neurobehavioural characteristics of male rats.

PubMed

Kinawy, Amal A

2009-11-24

This paper examines closely and compares the potential hazards of inhalation of two types of gasoline (car fuel). The first type is the commonly use leaded gasoline and the second is the unleaded type enriched with oxygenate additives as lead substituent in order to raise the octane number. The impacts of gasoline exposure on Na+, K+-ATPase, superoxide dismutase (SOD), acetylcholinesterase (AChE), total protein, reduced glutathione (GSH), and lipid peroxidation (TBARS) in the cerebral cortex, and monoamine neurotransmitters dopamine (DA), norepinephrine (NE) and serotonin (5-HT) in the cerebral cortex, hippocampus, cerebellum and hypothalamus were evaluated. The effect of gasoline exposure on the aggressive behaviour tests was also studied. The present results revealed that gasoline inhalation induced significant fluctuations in the levels of the monoamine neurotransmitters in the studied brain regions. This was concomitant with a decrease in Na+, K+-ATPase activity and total protein content. Moreover, the group exposed to the unleaded gasoline exhibited an increase in lipid peroxidation and a decrease in AChE and superoxide dismutase activities. These physiological impairments were accompanied with a higher tendency towards aggressive behaviour as a consequence to gasoline inhalation. It is concluded from the present work that chronic exposure to either the leaded or the unleaded gasoline vapours impaired the levels of monoamine neurotransmitters and other biochemical parameters in different brain areas and modulated several behavioural aspects related to aggression in rats.

A top-down perspective on dopamine, motivation and memory.

PubMed

Phillips, Anthony G; Vacca, Giada; Ahn, Soyon

2008-08-01

Dopamine (DA) activity, in the form of increased neural firing or enhanced release of transmitter from nerve terminals and varicosities, is linked to a number of important psychological processes including: movement; hedonic reactions to positive reward; provision of an error detection signal during the acquisition of new learning; response to novel stimuli; provision of reinforcement signals essential for acquisition of new action patterns; and incentive motivation. This review focuses primarily on our research linking dynamic changes in DA efflux on the timescale of minutes, with incentive motivation, as revealed by brain dialysis experiments in behaving animals. Recent experiments on sensory-specific satiety and successive positive and negative contrast are discussed along with the distinction between preparatory behaviors that precede contact with biologically significant stimuli and subsequent consummatory behaviors. The relationship between DA efflux in the medial prefrontal cortex (mPFC) and foraging for food based on working memory is also discussed in support of the conjecture that DA may serve as a link between motivation and memory functions. Evidence in support of 'top-down' regulation of dopaminergic activity in the mesocorticolimbic DA pathways is reviewed briefly to introduce a mechanism by which activation of ascending DA projections in this manner might optimize dopaminergic modulation of executive function within regions such as the mPFC. Collectively, these processes could ensure coordination between cognitive processes that assess current opportunities and the motivational systems that select and engage patterns of approach behavior that bring organisms into contact with the essentials for survival.

Abnormal response to methylphenidate across multiple fMRI procedures in cocaine use disorder: feasibility study.

PubMed

Moeller, Scott J; Konova, Anna B; Tomasi, Dardo; Parvaz, Muhammad A; Goldstein, Rita Z

2016-07-01

The indirect dopamine agonist methylphenidate remediates cognitive deficits in psychopathology, but the individual characteristics that determine its effects on the brain are not known. We aimed to determine whether targeted dopaminergically modulated traits and individual differences could predict neural response to methylphenidate across multiple functional magnetic resonance imaging (fMRI) procedures. We combined neural measures from three separate procedures (two inhibitory control tasks differing in their degree of emotional salience and resting-state functional connectivity) during methylphenidate (20 mg oral, versus randomized and counterbalanced placebo) and correlated these aggregated responses with cocaine use disorder diagnosis (22 cocaine abusers, 21 controls), symptoms of attention deficit hyperactivity disorder, and working memory capacity. Cocaine abusers, relative to controls, had a lower response in the dorsolateral prefrontal cortex to methylphenidate across all three procedures, driven by responses to the two inhibitory control tasks; reduced methylphenidate fMRI response in this region further correlated with more frequent cocaine use. Cocaine abuse (and its frequency), associated with lower tonic dopamine levels, correlated with a reduction in activation to methylphenidate (versus placebo). These initial results provide feasibility to the idea that multimodal fMRI tasks can be meaningfully aggregated, and that these aggregated procedures show a common disruption in addiction in a highly anticipated region relevant to cognitive control. Results also suggest that drug use frequency may represent an important modulatory variable in interpreting the efficacy of pharmacologically enhanced cognitive interventions in addiction.

Genetic association between the dopamine D1-receptor gene and paranoid schizophrenia in a northern Han Chinese population.

PubMed

Yao, Jun; Ding, Mei; Xing, Jiaxin; Xuan, Jinfeng; Pang, Hao; Pan, Yuqing; Wang, Baojie

2014-01-01

Dysregulation of dopaminergic neurotransmission at the D1 receptor in the prefrontal cortex has been implicated in the pathogenesis of schizophrenia. Genetic polymorphisms of the dopamine D1-receptor gene have a plausible role in modulating the risk of schizophrenia. To determine the role of DRD1 genetic polymorphisms as a risk factor for schizophrenia, we undertook a case-control study to look for an association between the DRD1 gene and schizophrenia. We genotyped eleven single-nucleotide polymorphisms within the DRD1 gene by deoxyribonucleic acid sequencing involving 173 paranoid schizophrenia patients and 213 unrelated healthy individuals. Statistical analysis was performed to identify the difference of genotype, allele, or haplotype distribution between cases and controls. A significantly lower risk of paranoid schizophrenia was associated with the AG + GG genotype of rs5326 and the AG + GG genotype of rs4532 compared to the AA genotype and the AA genotype, respectively. Distribution of haplotypes was no different between controls and paranoid schizophrenia patients. In the males, the genotype distribution of rs5326 was statistically different between cases and controls. In the females, the genotype distribution of rs4532 was statistically different between cases and controls. However, the aforementioned statistical significances were lost after Bonferroni correction. It is unlikely that DRD1 accounts for a substantial proportion of the genetic risk for schizophrenia. As an important dopaminergic gene, DRD1 may contribute to schizophrenia by interacting with other genes, and further relevant studies are warranted.

Cholinergic Axons in the Rat Ventral Tegmental Area Synapse Preferentially onto Mesoaccumbens Dopamine Neurons

PubMed Central

Omelchenko, Natalia; Sesack, Susan R.

2008-01-01

Cholinergic afferents to the ventral tegmental area (VTA) contribute substantially to the regulation of motivated behaviors and the rewarding properties of nicotine. These actions are believed to involve connections with dopamine (DA) neurons projecting to the nucleus accumbens (NAc). However, this direct synaptic link has never been investigated, nor is it known whether cholinergic inputs innervate other populations of DA and GABA neurons, including those projecting to the prefrontal cortex (PFC). We addressed these questions using electron microscopic analysis of retrograde tract-tracing and immunocytochemistry for the vesicular acetylcholine transporter (VAChT) and for tyrosine hydroxylase (TH) and GABA. In tissue labeled for TH, VAChT+ terminals frequently synapsed onto DA mesoaccumbens neurons but only seldom contacted DA mesoprefrontal cells. In tissue labeled for GABA, one third of VAChT+ terminals innervated GABA-labeled dendrites, including both mesoaccumbens and mesoprefrontal populations. VAChT+ synapses onto DA and mesoaccumbens neurons were more commonly of the asymmetric (presumed excitatory) morphological type, whereas VAChT+ synapses onto GABA cells were more frequently symmetric (presumed inhibitory or modulatory). These findings suggest that cholinergic inputs to the VTA mediate complex synaptic actions, with a major portion of this effect likely to involve an excitatory influence on DA mesoaccumbens neurons. As such, the results suggest that natural and drug rewards operating through cholinergic afferents to the VTA have a direct synaptic link to the mesoaccumbens DA neurons that modulate approach behaviors. PMID:16385486

Widespread Increases in Malondialdehyde Immunoreactivity in Dopamine-Rich and Dopamine-Poor Regions of Rat Brain Following Multiple, High Doses of Methamphetamine

PubMed Central

Horner, Kristen A.; Gilbert, Yamiece E.; Cline, Susan D.

2011-01-01

Treatment with multiple high doses of methamphetamine (METH) can induce oxidative damage, including dopamine (DA)-mediated reactive oxygen species (ROS) formation, which may contribute to the neurotoxic damage of monoamine neurons and long-term depletion of DA in the caudate putamen (CPu) and substantia nigra pars compacta (SNpc). Malondialdehyde (MDA), a product of lipid peroxidation by ROS, is commonly used as a marker of oxidative damage and treatment with multiple high doses of METH increases MDA reactivity in the CPu of humans and experimental animals. Recent data indicate that MDA itself may contribute to the destruction of DA neurons, as MDA causes the accumulation of toxic intermediates of DA metabolism via its chemical modification of the enzymes necessary for the breakdown of DA. However, it has been shown that in human METH abusers there is also increased MDA reactivity in the frontal cortex, which receives relatively fewer DA afferents than the CPu. These data suggest that METH may induce neuronal damage regardless of the regional density of DA or origin of DA input. The goal of the current study was to examine the modification of proteins by MDA in the DA-rich nigrostriatal and mesoaccumbal systems, as well as the less DA-dense cortex and hippocampus following a neurotoxic regimen of METH treatment. Animals were treated with METH (10 mg/kg) every 2 h for 6 h, sacrificed 1 week later, and examined using immunocytochemistry for changes in MDA-adducted proteins. Multiple, high doses of METH significantly increased MDA immunoreactivity (MDA-ir) in the CPu, SNpc, cortex, and hippocampus. Multiple METH administration also increased MDA-ir in the ventral tegmental area and nucleus accumbens. Our data indicate that multiple METH treatment can induce persistent and widespread neuronal damage that may not necessarily be limited to the nigrostriatal DA system. PMID:21602916

Fear Memory Recall Potentiates Opiate Reward Sensitivity through Dissociable Dopamine D1 versus D4 Receptor-Dependent Memory Mechanisms in the Prefrontal Cortex.

PubMed

Jing Li, Jing; Szkudlarek, Hanna; Renard, Justine; Hudson, Roger; Rushlow, Walter; Laviolette, Steven R

2018-05-09

Disturbances in prefrontal cortical (PFC) dopamine (DA) transmission are well established features of psychiatric disorders involving pathological memory processing, such as post-traumatic stress disorder and opioid addiction. Transmission through PFC DA D4 receptors (D4Rs) has been shown to potentiate the emotional salience of normally nonsalient emotional memories, whereas transmission through PFC DA D1 receptors (D1Rs) has been demonstrated to selectively block recall of reward- or aversion-related associative memories. In the present study, using a combination of fear conditioning and opiate reward conditioning in male rats, we examined the role of PFC D4/D1R signaling during the processing of fear-related memory acquisition and recall and subsequent sensitivity to opiate reward memory formation. We report that PFC D4R activation potentiates the salience of normally subthreshold fear conditioning memory cues and simultaneously potentiates the rewarding effects of systemic or intra-ventral tegmental area (VTA) morphine conditioning cues. In contrast, blocking the recall of salient fear memories with intra-PFC D1R activation, blocks the ability of fear memory recall to potentiate systemic or intra-VTA morphine place preference. These effects were dependent upon dissociable PFC phosphorylation states involving calcium-calmodulin-kinase II or extracellular signal-related kinase 1-2, following intra-PFC D4 or D1R activation, respectively. Together, these findings reveal new insights into how aberrant PFC DAergic transmission and associated downstream molecular signaling pathways may modulate fear-related emotional memory processing and concomitantly increase opioid addiction vulnerability. SIGNIFICANCE STATEMENT Post-traumatic stress disorder is highly comorbid with addiction. In this study, we use a translational model of fear memory conditioning to examine how transmission through dopamine D1 or D4 receptors, in the prefrontal cortex (PFC), may differentially control acquisition or recall of fear memories and how these mechanisms might regulate sensitivity to the rewarding effects of opioids. We demonstrate that PFC D4 activation not only controls the salience of fear memory acquisition, but potentiates the rewarding effects of opioids. In contrast, PFC D1 receptor activation blocks recall of fear memories and prevents potentiation of opioid reward effects. Together, these findings demonstrate novel PFC mechanisms that may account for how emotional memory disturbances might increase the addictive liability of opioid-class drugs. Copyright © 2018 the authors 0270-6474/18/384543-13$15.00/0.

Prefrontocortical dopamine loss in rats delays long-term extinction of contextual conditioned fear, and reduces social interaction without affecting short-term social interaction memory.

PubMed

Fernandez Espejo, Emilio

2003-03-01

Prefrontal dopamine loss delays extinction of cued fear conditioning responses, but its role in contextual fear conditioning has not been explored. Medial prefrontal lesions also enhance social interaction in rats, but the role of prefrontal dopamine loss on social interaction memory is not known. Besides, a role for subcortical accumbal dopamine on mnesic changes after prefrontal dopamine manipulation has been proposed but not explored. The objective was to study the involvement of dopaminergic neurotransmission in the medial prefrontal cortex (mPFC) and nucleus accumbens in two mnesic tasks: contextual fear conditioning and social interaction memory. For contextual fear conditioning, short- and long-term freezing responses after an electric shock were studied, as well as extinction retention. Regarding social interaction memory, the recognition of a juvenile, a very sensitive short-term memory test, was used. Dopamine loss was carried out by injection of 6-hydroxydopamine, and postmortem catecholamine levels were analyzed by high-performance liquid chromatography. Prefrontocortical dopamine loss (>76%) led to a reactive enhancement of accumbal dopamine content (p<0.01), supporting the hypothesis that a hyperdopaminergic tone emerges in the nucleus accumbens after prefrontocortical dopamine loss. In lesioned rats, long-term extinction of contextual fear conditioning was significantly delayed and extinction retention was impaired without changes in acquisition and short-term contextual fear conditioning and, on the other hand, acquisition and short-term social interaction memory were not affected, although time spent on social interaction was significantly reduced. Added dopamine loss in the nucleus accumbens (>76%) did not alter these behavioral changes. In summary, the results of the present study indicate that the dopaminergic network in the mPFC (but not in the nucleus accumbens) coordinates the normal long-term extinction of contextual fear conditioning responses without affecting their acquisition, and it is involved in time spent on social interaction, but not acquisition and short-term social interaction memory.

Ca2+ channel blockade prevents lysergic acid diethylamide-induced changes in dopamine and serotonin metabolism.

PubMed

Antkiewicz-Michaluk, L; Románska, I; Vetulani, J

1997-07-30

To investigate the effect of a single and multiple administration of lysergic acid diethylamide (LSD) on cerebral metabolism of dopamine and serotonin, male Wistar rats were treated with low and high doses (0.1 and 2.0 mg/kg i.p.) of LSD and the levels of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, 3-methoxytyramine, serotonin and 5-hydroxyindoleacetic acid were assayed by HPLC in the nucleus accumbens, striatum and frontal cortex. Some rats received nifedipine, 5 mg/kg i.p., before each injection of LSD to assess the effect of a Ca2+ channel blockade. High-dose LSD treatment (8 x 2 mg/kg per day) caused a strong stimulation of dopamine metabolism in the nucleus accumbens and striatum, and serotonin metabolism in the nucleus accumbens: the changes were observed 24 (but not 1 h) after the last dose. The changes induced by the low-dose treatment (8 x 0.1 mg/kg per day) had a different pattern, suggesting the release of dopamine from vesicles to cytoplasm. Co-administration of nifedipine completely prevented the LSD-induced biochemical changes. The results suggest that Ca2+ channel blocking agents may prevent development of some behavioral consequences of chronically used LSD.

Blonanserin ameliorates phencyclidine-induced visual-recognition memory deficits: the complex mechanism of blonanserin action involving D₃-5-HT₂A and D₁-NMDA receptors in the mPFC.

PubMed

Hida, Hirotake; Mouri, Akihiro; Mori, Kentaro; Matsumoto, Yurie; Seki, Takeshi; Taniguchi, Masayuki; Yamada, Kiyofumi; Iwamoto, Kunihiro; Ozaki, Norio; Nabeshima, Toshitaka; Noda, Yukihiro

2015-02-01

Blonanserin differs from currently used serotonin 5-HT₂A/dopamine-D₂ receptor antagonists in that it exhibits higher affinity for dopamine-D₂/₃ receptors than for serotonin 5-HT₂A receptors. We investigated the involvement of dopamine-D₃ receptors in the effects of blonanserin on cognitive impairment in an animal model of schizophrenia. We also sought to elucidate the molecular mechanism underlying this involvement. Blonanserin, as well as olanzapine, significantly ameliorated phencyclidine (PCP)-induced impairment of visual-recognition memory, as demonstrated by the novel-object recognition test (NORT) and increased extracellular dopamine levels in the medial prefrontal cortex (mPFC). With blonanserin, both of these effects were antagonized by DOI (a serotonin 5-HT₂A receptor agonist) and 7-OH-DPAT (a dopamine-D₃ receptor agonist), whereas the effects of olanzapine were antagonized by DOI but not by 7-OH-DPAT. The ameliorating effect was also antagonized by SCH23390 (a dopamine-D₁ receptor antagonist) and H-89 (a protein kinase A (PKA) inhibitor). Blonanserin significantly remediated the decrease in phosphorylation levels of PKA at Thr(197) and of NR1 (an essential subunit of N-methyl-D-aspartate (NMDA) receptors) at Ser(897) by PKA in the mPFC after a NORT training session in the PCP-administered mice. There were no differences in the levels of NR1 phosphorylated at Ser(896) by PKC in any group. These results suggest that the ameliorating effect of blonanserin on PCP-induced cognitive impairment is associated with indirect functional stimulation of the dopamine-D₁-PKA-NMDA receptor pathway following augmentation of dopaminergic neurotransmission due to inhibition of both dopamine-D₃ and serotonin 5-HT₂A receptors in the mPFC.

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.

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

Short-term dopaminergic regulation of GABA release in dopamine deafferented caudate-putamen is not directly associated with glutamic acid decarboxylase gene expression.

PubMed

O'Connor, W T; Lindefors, N; Brené, S; Herrera-Marschitz, M; Persson, H; Ungerstedt, U

1991-07-08

In vivo microdialysis and in situ hybridization were combined to study dopaminergic regulation of gamma-amino butyric acid (GABA) neurons in rat caudate-putamen (CPu). Potassium-stimulated GABA release in CPu was elevated following a dopamine deafferentation. Local perfusion with exogenous dopamine (50 microM) for 3 h via the microdialysis probe attenuated the potassium-stimulated increase in extracellular GABA in CPu. Expression of glutamic acid decarboxylase (GAD) mRNA was also increased in the dopamine deafferented CPu. However, local perfusion with dopamine had no significant attenuating effect on the increased GAD mRNA expression. These findings indicate that dopaminergic regulation of GABA neurons in the dopamine deafferented CPu includes both a short-term effect at the level of GABA release independent of changes in GAD mRNA expression and a long-term modulation at the level of GAD gene expression.

Dopamine: a parallel pathway for the modulation of spinal locomotor networks

PubMed Central

Sharples, Simon A.; Koblinger, Kathrin; Humphreys, Jennifer M.; Whelan, Patrick J.

2014-01-01

The spinal cord contains networks of neurons that can produce locomotor patterns. To readily respond to environmental conditions, these networks must be flexible yet at the same time robust. Neuromodulators play a key role in contributing to network flexibility in a variety of invertebrate and vertebrate networks. For example, neuromodulators contribute to altering intrinsic properties and synaptic weights that, in extreme cases, can lead to neurons switching between networks. Here we focus on the role of dopamine in the control of stepping networks in the spinal cord. We first review the role of dopamine in modulating rhythmic activity in the stomatogastric ganglion (STG) and the leech, since work from these preparations provides a foundation to understand its role in vertebrate systems. We then move to a discussion of dopamine’s role in modulation of swimming in aquatic species such as the larval xenopus, lamprey and zebrafish. The control of terrestrial walking in vertebrates by dopamine is less studied and we review current evidence in mammals with a focus on rodent species. We discuss data suggesting that the source of dopamine within the spinal cord is mainly from the A11 area of the diencephalon, and then turn to a discussion of dopamine’s role in modulating walking patterns from both in vivo and in vitro preparations. Similar to the descending serotonergic system, the dopaminergic system may serve as a potential target to promote recovery of locomotor function following spinal cord injury (SCI); evidence suggests that dopaminergic agonists can promote recovery of function following SCI. We discuss pharmacogenetic and optogenetic approaches that could be deployed in SCI and their potential tractability. Throughout the review we draw parallels with both noradrenergic and serotonergic modulatory effects on spinal cord networks. In all likelihood, a complementary monoaminergic enhancement strategy should be deployed following SCI. PMID:24982614

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

Dilts, R.P. Jr.

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

Dopamine modulates hemocyte phagocytosis via a D1-like receptor in the rice stem borer, Chilo suppressalis

USDA-ARS?s Scientific Manuscript database

Dopamine (DA) is a signal moiety bridging the nervous and immune systems. DA dysregulation is linked to serious human diseases, including addiction, schizophrenia, and Parkinson's disease. However, DA actions in the immune system remain incompletely understood. In this study, we found that DA modula...

Ethanolic extracts of Alstonia Scholaris and Bacopa Monniera possess neuroleptic activity due to anti-dopaminergic effect

PubMed Central

Jash, Rajiv; Chowdary, K. Appana

2014-01-01

Background: An increased inclination has been observed for the use of herbal drugs in chronic and incurable diseases. Treatment of psychiatric diseases like schizophrenia is largely palliative and more importantly, a prominent adverse effect prevails with the majority of anti-psychotic drugs, which are the extrapyramidal motor disorders. Existing anti-psychotic drug therapy is not so promising, and their adverse effect is a matter of concern for continuing the therapy for long duration. Objective: This experimental study was done to evaluate the neuroleptic activity of the ethanolic extracts of two plants Alstonia Scholaris and Bacopa Monnieri with different anti-psychotic animal models with a view that these plant extracts shall have no or at least reduced adverse effect so that it can be used for long duration. Materials and Methods: Two doses of both the extracts (100 and 200 mg/kg) and also standard drug haloperidol (0.2 mg/kg) were administered to their respective groups once daily with 5 different animal models. After that, the concentration of the dopamine neurotransmitter was estimated in two different regions of the brain viz. frontal cortex and striatum. Results: The result of the study indicated a significant reduction of amphetamine-induced stereotype and conditioned avoidance response for both the extracts compared with the control group, but both did not have any significant effect in phencyclidine-induced locomotor activity and social interaction activity. However, both the extracts showed minor signs of catalepsy compared to the control group. The study also revealed that the neuroleptic effect was due to the reduction of the dopamine concentration in the frontal cortex region of the rat brain. The results largely pointed out the fact that both the extract may be having the property to alleviate the positive symptoms of schizophrenia by reducing the dopamine levels of dopaminergic neurons of the brain. Conclusion: The estimation of dopamine in the two major regions of brain indicated the alteration of dopamine levels was the reason for the anti-psychotic activity as demonstrated by the different animal models. PMID:24497742

Cerebellum in Levodopa-Induced Dyskinesias: The Unusual Suspect in the Motor Network

PubMed Central

Kishore, Asha; Popa, Traian

2014-01-01

The exact mechanisms that generate levodopa-induced dyskinesias (LID) during chronic levodopa therapy for Parkinson’s disease (PD) are not yet fully established. The most widely accepted theories incriminate the non-physiological synthesis, release and reuptake of dopamine generated by exogenously administered levodopa in the striatum, and the aberrant plasticity in the cortico-striatal loops. However, normal motor performance requires the correct recruitment of motor maps. This depends on a high level of synergy within the primary motor cortex (M1) as well as between M1 and other cortical and subcortical areas, for which dopamine is necessary. The plastic mechanisms within M1, which are crucial for the maintenance of this synergy, are disrupted both during “OFF” and dyskinetic states in PD. When tested without levodopa, dyskinetic patients show loss of treatment benefits on long-term potentiation and long-term depression-like plasticity of the intracortical circuits. When tested with the regular pulsatile levodopa doses, they show further impairment of the M1 plasticity, such as inability to depotentiate an already facilitated synapse and paradoxical facilitation in response to afferent input aimed at synaptic inhibition. Dyskinetic patients have also severe impairment of the associative, sensorimotor plasticity of M1 attributed to deficient cerebellar modulation of sensory afferents to M1. Here, we review the anatomical and functional studies, including the recently described bidirectional connections between the cerebellum and the basal ganglia that support a key role of the cerebellum in the generation of LID. This model stipulates that aberrant neuronal synchrony in PD with LID may propagate from the subthalamic nucleus to the cerebellum and “lock” the cerebellar cortex in a hyperactive state. This could affect critical cerebellar functions such as the dynamic and discrete modulation of M1 plasticity and the matching of motor commands with sensory information from the environment during motor performance. We propose that in dyskinesias, M1 neurons have lost the ability to depotentiate an activated synapse when exposed to acute pulsatile, non-physiological, dopaminergic surges and become abnormally receptive to unfiltered, aberrant, and non-salient afferent inputs from the environment. The motor program selection in response to such non-salient and behaviorally irrelevant afferent inputs would be abnormal and involuntary. The motor responses are worsened by the lack of normal subcortico–cortical inputs from cerebellum and basal ganglia, because of the aberrant plasticity at their own synapses. Artificial cerebellar stimulation might help re-establish the cerebellar and basal ganglia control over the non-salient inputs to the motor areas during synaptic dopaminergic surges. PMID:25183959

Ethanol-induced dopamine elevation in the rat--modulatory effects by subchronic treatment with nicotinic drugs.

PubMed

Löf, Elin; Chau, Pei Pei; Stomberg, Rosita; Söderpalm, Bo

2007-01-26

Chronic nicotine administration is associated with increased ethanol consumption in laboratory animals and in humans. Some smokers report less sedation during acute ethanol intoxication after nicotine administration and the sedative effects from ethanol are mediated by inhibitory GABA(A)-receptors. In a series of in vivo microdialysis experiments we investigated whether subchronic pre-treatment with nicotinic drugs known to enhance ethanol consumption in the rat (nicotine or the peripheral nicotinic antagonist hexamethonium) could modulate the alterations in extracellular dopamine observed in response to administration of ethanol or the sedative GABA(A)-agonist diazepam. In the nucleus accumbens and the dorsal striatum, systemic and/or local ethanol administration resulted in transient increases in extracellular dopamine levels that returned to baseline before the local levels of ethanol started to decline. In hexamethonium pre-treated rats, however, the nucleus accumbens dopamine levels were time-locked to the ethanol levels in the same area after systemic or local ethanol administration. Perfusion of diazepam into the nucleus accumbens produced a significant reduction in nucleus accumbens dopamine in controls. Prior subchronic treatment with nicotine or hexamethonium abolished this effect. The present results suggest that subchronic treatment with the nicotinic acetylcholine receptor antagonist hexamethonium reduces a GABA(A)-R mediated counteraction of the nucleus accumbens dopamine response to ethanol. Additionally, we demonstrate that modulation of nicotinic receptors may reduce the sensitivity of GABA(A) receptors to benzodiazepines. These phenomena may offer a novel explanation to why nicotine and alcohol are often co-abused.

Catechol-O-methyltransferase genotype modifies executive functioning and prefrontal functional connectivity in women with anorexia nervosa.

PubMed

Favaro, Angela; Clementi, Maurizio; Manara, Renzo; Bosello, Romina; Forzan, Monica; Bruson, Alice; Tenconi, Elena; Degortes, Daniela; Titton, Francesca; Di Salle, Francesco; Santonastaso, Paolo

2013-07-01

Anorexia nervosa is characterized by high levels of perseveration and inflexibility, which interfere with successful treatments. Dopamine (DA) signalling seems to play a key role in modulating the prefrontal cortex, since both DA deficiency and excess nega tively influence the efficiency of cognitive functions. The present study explores the effect of a functional polymorphism (Val158Met) in the catechol-O-methyltransferase (COMT) gene on the set-shifting abilities and prefrontal functional connectivity of patients with anorexia nervosa. All participants performed the Wisconsin Card Sorting Task, and a subsample underwent resting-state functional magnetic resonance imaging. We included 166 patients with DSM-IV lifetime anorexia nervosa and 140 healthy women in our study. Both underweight and weight-recovered patients with anorexia nervosa showed high levels of perseveration, but only in the underweight group did the Val158Met polymorphism affect cognitive performance, showing the U-shaped curve characteristic of increased DA signalling in the prefrontal cortex. Underweight patients with anorexia nervosa who are Met homozygotes had significantly higher levels of perseveration and increased prefrontal functional connectivity than underweight patients in the other genotype groups, indicating abnormal regional cortical processing. Although our data show that grey matter reduction in starving patients with anorexia nervosa did not explain our findings, the cross-sectional design of the present study did not allow us to distinguish between the effects of starvation and those of low estrogen levels. Starvation affects DA release in the prefrontal cortex of patients with anorexia nervosa with different effects on executive functioning and prefrontal functional connectivity according to the COMT genotype. This observation has several therapeutic implications that need to be addressed by future studies.

Catechol-O-methyltransferase genotype modifies executive functioning and prefrontal functional connectivity in women with anorexia nervosa

PubMed Central

Favaro, Angela; Clementi, Maurizio; Manara, Renzo; Bosello, Romina; Forzan, Monica; Bruson, Alice; Tenconi, Elena; Degortes, Daniela; Titton, Francesca; Di Salle, Francesco; Santonastaso, Paolo

2013-01-01

Background Anorexia nervosa is characterized by high levels of perseveration and inflexibility, which interfere with successful treatments. Dopamine (DA) signalling seems to play a key role in modulating the prefrontal cortex, since both DA deficiency and excess negatively influence the efficiency of cognitive functions. The present study explores the effect of a functional polymorphism (Val158Met) in the catechol-O-methyltransferase (COMT) gene on the set-shifting abilities and prefrontal functional connectivity of patients with anorexia nervosa. Methods All participants performed the Wisconsin Card Sorting Task, and a subsample underwent resting-state functional magnetic resonance imaging. Results We included 166 patients with DSM-IV lifetime anorexia nervosa and 140 healthy women in our study. Both underweight and weight-recovered patients with anorexia nervosa showed high levels of perseveration, but only in the underweight group did the Val158Met polymorphism affect cognitive performance, showing the U-shaped curve characteristic of increased DA signalling in the prefrontal cortex. Underweight patients with anorexia nervosa who are Met homozygotes had significantly higher levels of perseveration and increased prefrontal functional connectivity than underweight patients in the other genotype groups, indicating abnormal regional cortical processing. Limitations Although our data show that grey matter reduction in starving patients with anorexia nervosa did not explain our findings, the cross-sectional design of the present study did not allow us to distinguish between the effects of starvation and those of low estrogen levels. Conclusion Starvation affects DA release in the prefrontal cortex of patients with anorexia nervosa with different effects on executive functioning and prefrontal functional connectivity according to the COMT genotype. This observation has several therapeutic implications that need to be addressed by future studies. PMID:23046831

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. PMID:27038339

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. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

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.

Effects of phenylethanolamine N-methyltransferase inhibitors on uptake and release of norepinephrine and dopamine from rat brain

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

Liang, N.Y.; Hower, J.A.; Borchardt, R.T.

1985-09-01

Inhibitors of phenylethanolamine N-methyltransferase (PNMT) and amphetamine were evaluated for their effects on the uptake of (TH)-norepinephrine (TH-NE) and the release of endogenous NE and dopamine (DA) from chopped rat brain tissues. Unlike amphetamine, all of PNMT inhibitors tested produced only slight inhibition of (TH)-NE uptake into chopped cerebral cortex. 2,3-Dichloro-alpha-methylbenzylamine (DCMB) and 7,8-dichloro-1,2,3,4-tetrahydroisoquinoline (SKF64139), but not 2-cyclooctyl-2-hydroxyethylamine (CONH) and 1-aminomethylcycloundecanol (CUNH) produced slight release of endogenous NE and DA from chopped hypothalami, but their effects were less pronounced than those produced by amphetamine.

Dysfunctions of the basal ganglia-cerebellar-thalamo-cortical system produce motor tics in Tourette syndrome

PubMed Central

Arbib, Michael A.; Baldassarre, Gianluca

2017-01-01

Motor tics are a cardinal feature of Tourette syndrome and are traditionally associated with an excess of striatal dopamine in the basal ganglia. Recent evidence increasingly supports a more articulated view where cerebellum and cortex, working closely in concert with basal ganglia, are also involved in tic production. Building on such evidence, this article proposes a computational model of the basal ganglia-cerebellar-thalamo-cortical system to study how motor tics are generated in Tourette syndrome. In particular, the model: (i) reproduces the main results of recent experiments about the involvement of the basal ganglia-cerebellar-thalamo-cortical system in tic generation; (ii) suggests an explanation of the system-level mechanisms underlying motor tic production: in this respect, the model predicts that the interplay between dopaminergic signal and cortical activity contributes to triggering the tic event and that the recently discovered basal ganglia-cerebellar anatomical pathway may support the involvement of the cerebellum in tic production; (iii) furnishes predictions on the amount of tics generated when striatal dopamine increases and when the cortex is externally stimulated. These predictions could be important in identifying new brain target areas for future therapies. Finally, the model represents the first computational attempt to study the role of the recently discovered basal ganglia-cerebellar anatomical links. Studying this non-cortex-mediated basal ganglia-cerebellar interaction could radically change our perspective about how these areas interact with each other and with the cortex. Overall, the model also shows the utility of casting Tourette syndrome within a system-level perspective rather than viewing it as related to the dysfunction of a single brain area. PMID:28358814

Dysfunctions of the basal ganglia-cerebellar-thalamo-cortical system produce motor tics in Tourette syndrome.

PubMed

Caligiore, Daniele; Mannella, Francesco; Arbib, Michael A; Baldassarre, Gianluca

2017-03-01

Motor tics are a cardinal feature of Tourette syndrome and are traditionally associated with an excess of striatal dopamine in the basal ganglia. Recent evidence increasingly supports a more articulated view where cerebellum and cortex, working closely in concert with basal ganglia, are also involved in tic production. Building on such evidence, this article proposes a computational model of the basal ganglia-cerebellar-thalamo-cortical system to study how motor tics are generated in Tourette syndrome. In particular, the model: (i) reproduces the main results of recent experiments about the involvement of the basal ganglia-cerebellar-thalamo-cortical system in tic generation; (ii) suggests an explanation of the system-level mechanisms underlying motor tic production: in this respect, the model predicts that the interplay between dopaminergic signal and cortical activity contributes to triggering the tic event and that the recently discovered basal ganglia-cerebellar anatomical pathway may support the involvement of the cerebellum in tic production; (iii) furnishes predictions on the amount of tics generated when striatal dopamine increases and when the cortex is externally stimulated. These predictions could be important in identifying new brain target areas for future therapies. Finally, the model represents the first computational attempt to study the role of the recently discovered basal ganglia-cerebellar anatomical links. Studying this non-cortex-mediated basal ganglia-cerebellar interaction could radically change our perspective about how these areas interact with each other and with the cortex. Overall, the model also shows the utility of casting Tourette syndrome within a system-level perspective rather than viewing it as related to the dysfunction of a single brain area.

Pre-weaning Mn exposure leads to prolonged astrocyte activation and lasting effects on the dopaminergic system in adult male rats

PubMed Central

Kern, Cynthia; Smith, Donald R.

2010-01-01

Little is known about the effects of manganese (Mn) exposure over neurodevelopment and whether these early insults result in effects lasting into adulthood. To determine if early Mn exposure produces lasting neurobehavioral and neurochemical effects, we treated neonate rats with oral Mn (0, 25, or 50 mg Mn/kg/d over PND 1–21) and evaluated 1) behavioral performance in the open arena in the absence (PND 97) and presence (PND 98) of a d-amphetamine challenge, 2) brain dopamine D1 and D2-like receptors and dopamine transporter densities in the prefrontal cortex, striatum, and nucleus accumbens (PND 107), and 3) astrocyte marker glial fibrillary acidic protein (GFAP) levels in these same brain regions (PND 24 and 107). We found that pre-weaning Mn exposure did not alter locomotor activity or behavior disinhibition in adult rats, though Mn-exposed animals did exhibit an enhanced locomotor response to d-amphetamine challenge. Pre-weaning Mn exposure led to increased D1 and D2 receptor levels in the nucleus accumbens and prefrontal cortex, respectively, compared to controls. We also found increased GFAP expression in the prefrontal cortex in Mn-exposed PND 24 weanlings, and increased GFAP levels in prefrontal cortex, medial striatum and nucleus accumbens of adult (PND 107) rats exposed to pre-weaning Mn, indicating an effect of Mn exposure on astrogliosis that persisted and/or progressed to other brain regions in adult animals. These data show that pre-weaning Mn exposure leads to lasting molecular and functional impacts in multiple brain regions of adult animals, long after brain Mn levels returned to normal. PMID:20963817

Effects of VMAT2 inhibitors lobeline and GZ-793A on methamphetamine-induced changes in dopamine release, metabolism and synthesis in vivo.

PubMed

Meyer, Andrew C; Neugebauer, Nichole M; Zheng, Guangrong; Crooks, Peter A; Dwoskin, Linda P; Bardo, Michael T

2013-10-01

Vesicular monoamine transporter-2 (VMAT2) inhibitors reduce methamphetamine (METH) reward in rats. The current study determined the effects of VMAT2 inhibitors lobeline (LOB; 1 or 3 mg/kg) and N-(1,2R-dihydroxylpropyl)-2,6-cis-di(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A; 15 or 30 mg/kg) on METH-induced (0.5 mg/kg, SC) changes in extracellular dopamine (DA) and its metabolite dihydroxyphenylacetic acid (DOPAC) in the reward-relevant nucleus accumbens (NAc) shell using in vivo microdialysis. The effect of GZ-793A (15 mg/kg) on DA synthesis in tissue also was investigated in NAc, striatum, medial prefrontal cortex and orbitofrontal cortex. In NAc shell, METH produced a time-dependent increase in extracellular DA and decrease in DOPAC. Neither LOB nor GZ-793A alone altered extracellular DA; however, both drugs increased extracellular DOPAC. In combination with METH, LOB did not alter the effects of METH on DA; however, GZ-793A, which has greater selectivity than LOB for inhibiting VMAT2, reduced the duration of the METH-induced increase in extracellular DA. Both LOB and GZ-793A enhanced the duration of the METH-induced decrease in extracellular DOPAC. METH also increased tissue DA synthesis in NAc and striatum, whereas GZ-793A decreased synthesis; no effect of METH or GZ-793A on DA synthesis was found in medial prefrontal cortex or orbitofrontal cortex. These results suggest that selective inhibition of VMAT2 produces a time-dependent decrease in DA release in NAc shell as a result of alterations in tyrosine hydroxylase activity, which may play a role in the ability of GZ-793A to decrease METH reward. © 2013 International Society for Neurochemistry.

A Role for Prefrontal Calcium-Sensitive Protein Phosphatase and Kinase Activities in Working Memory

ERIC Educational Resources Information Center

Runyan, Jason D.; Moore, Anthony N.; Dash, Pramod K.

2005-01-01

The prefrontal cortex is involved in the integration and interpretation of information for directing thoughts and planning action. Working memory is defined as the active maintenance of information in mind and is thought to lie at the core of many prefrontal functions. Although dopamine and other neurotransmitters have been implicated, the…

5-HT2C Agonists Modulate Schizophrenia-Like Behaviors in Mice.

PubMed

Pogorelov, Vladimir M; Rodriguiz, Ramona M; Cheng, Jianjun; Huang, Mei; Schmerberg, Claire M; Meltzer, Herbert Y; Roth, Bryan L; Kozikowski, Alan P; Wetsel, William C

2017-10-01

All FDA-approved antipsychotic drugs (APDs) target primarily dopamine D 2 or serotonin (5-HT 2A ) receptors, or both; however, these medications are not universally effective, they may produce undesirable side effects, and provide only partial amelioration of negative and cognitive symptoms. The heterogeneity of pharmacological responses in schizophrenic patients suggests that additional drug targets may be effective in improving aspects of this syndrome. Recent evidence suggests that 5-HT 2C receptors may be a promising target for schizophrenia since their activation reduces mesolimbic nigrostriatal dopamine release (which conveys antipsychotic action), they are expressed almost exclusively in CNS, and have weight-loss-promoting capabilities. A difficulty in developing 5-HT 2C agonists is that most ligands also possess 5-HT 2B and/or 5-HT 2A activities. We have developed selective 5-HT 2C ligands and herein describe their preclinical effectiveness for treating schizophrenia-like behaviors. JJ-3-45, JJ-3-42, and JJ-5-34 reduced amphetamine-stimulated hyperlocomotion, restored amphetamine-disrupted prepulse inhibition, improved social behavior, and novel object recognition memory in NMDA receptor hypofunctioning NR1-knockdown mice, and were essentially devoid of catalepsy. However, they decreased motivation in a breakpoint assay and did not promote reversal learning in MK-801-treated mice. Somewhat similar effects were observed with lorcaserin, a 5-HT 2C agonist with potent 5-HT 2B and 5-HT 2A agonist activities, which is approved for treating obesity. Microdialysis studies revealed that both JJ-3-42 and lorcaserin reduced dopamine efflux in the infralimbic cortex, while only JJ-3-42 decreased it in striatum. Collectively, these results provide additional evidence that 5-HT 2C receptors are suitable drug targets with fewer side effects, greater therapeutic selectivity, and enhanced efficacy for treating schizophrenia and related disorders than current APDs.

Agmatine attenuates reserpine-induced oral dyskinesia in mice: Role of oxidative stress, nitric oxide and glutamate NMDA receptors.

PubMed

Cunha, Andréia S; Matheus, Filipe C; Moretti, Morgana; Sampaio, Tuane B; Poli, Anicleto; Santos, Danúbia B; Colle, Dirleise; Cunha, Mauricio P; Blum-Silva, Carlos H; Sandjo, Louis P; Reginatto, Flávio H; Rodrigues, Ana Lúcia S; Farina, Marcelo; Prediger, Rui D

2016-10-01

Dyskinesia consists in a series of trunk, limbs and orofacial involuntary movements that can be observed following long-term pharmacological treatment in some psychotic and neurological disorders such as schizophrenia and Parkinson's disease, respectively. Agmatine is an endogenous arginine metabolite that emerges as neuromodulator and a promising agent to manage diverse central nervous system disorders by modulating nitric oxide (NO) pathway, glutamate NMDA receptors and oxidative stress. Herein, we investigated the effects of a single intraperitoneal (i.p.) administration of different agmatine doses (10, 30 or 100mg/kg) against the orofacial dyskinesia induced by reserpine (1mg/kg,s.c.) in mice by measuring the vacuous chewing movements and tongue protusion frequencies, and the duration of facial twitching. The results showed an orofacial antidyskinetic effect of agmatine (30mg/kg, i.p.) or the combined administration of sub-effective doses of agmatine (10mg/kg, i.p.) with the NMDA receptor antagonists amantadine (1mg/kg, i.p.) and MK801 (0.01mg/kg, i.p.) or the neuronal nitric oxide synthase (NOS) inhibitor 7-nitroindazole (7-NI; 0.1mg/kg, i.p.). Reserpine-treated mice displayed locomotor activity deficits in the open field and agmatine had no effect on this response. Reserpine increased nitrite and nitrate levels in cerebral cortex, but agmatine did not reverse it. Remarkably, agmatine reversed the decrease of dopamine and non-protein thiols (NPSH) levels caused by reserpine in the striatum. However, no changes were observed in striatal immunocontent of proteins related to the dopaminergic system including tyrosine hydroxylase, dopamine transporter, vesicular monoamine transporter type 2, pDARPP-32[Thr75], dopamine D1 and D2 receptors. These results indicate that the blockade of NO pathway, NMDAR and oxidative stress are possible mechanisms associated with the protective effects of agmatine against the orofacial dyskinesia induced by reserpine in mice. Copyright © 2016 Elsevier B.V. All rights reserved.

Brief exposure to obesogenic diet disrupts brain dopamine networks

PubMed Central

Williams, Jason M.; Siuta, Michael A.; Tantawy, Mohammed N.; Speed, Nicole K.; Saunders, Christine; Galli, Aurelio; Niswender, Kevin D.; Avison, Malcolm J.

2018-01-01

Objective We have previously demonstrated that insulin signaling, through the downstream signaling kinase Akt, is a potent modulator of dopamine transporter (DAT) activity, which fine-tunes dopamine (DA) signaling at the synapse. This suggests a mechanism by which impaired neuronal insulin receptor signaling, a hallmark of diet-induced obesity, may contribute to impaired DA transmission. We tested whether a short-term (two-week) obesogenic high-fat (HF) diet could reduce striatal Akt activity, a marker of central insulin, receptor signaling and blunt striatal and dopaminergic network responsiveness to amphetamine (AMPH). Methods We examined the effects of a two-week HF diet on striatal DAT activity in rats, using AMPH as a probe in a functional magnetic resonance imaging (fMRI) assay, and mapped the disruption in AMPH-evoked functional connectivity between key dopaminergic targets and their projection areas using correlation and permutation analyses. We used phosphorylation of the Akt substrate GSK3α in striatal extracts as a measure of insulin receptor signaling. Finally, we confirmed the impact of HF diet on striatal DA D2 receptor (D2R) availability using [18F]fallypride positron emission tomography (PET). Results We found that rats fed a HF diet for only two weeks have reductions in striatal Akt activity, a marker of decreased striatal insulin receptor signaling and blunted striatal responsiveness to AMPH. HF feeding also reduced interactions between elements of the mesolimbic (nucleus accumbens–anterior cingulate) and sensorimotor circuits (caudate/putamen–thalamus–sensorimotor cortex) implicated in hedonic feeding. D2R availability was reduced in HF-fed animals. Conclusion These studies support the hypothesis that central insulin signaling and dopaminergic neurotransmission are already altered after short-term HF feeding. Because AMPH induces DA efflux and brain activation, in large part via DAT, these findings suggest that blunted central nervous system insulin receptor signaling through a HF diet can impair DA homeostasis, thereby disrupting cognitive and reward circuitry involved in the regulation of hedonic feeding. PMID:29698491

Signals from the ventrolateral thalamus to the motor cortex during locomotion

PubMed Central

Marlinski, Vladimir; Nilaweera, Wijitha U.; Zelenin, Pavel V.; Sirota, Mikhail G.

2012-01-01

The activity of the motor cortex during locomotion is profoundly modulated in the rhythm of strides. The source of modulation is not known. In this study we examined the activity of one of the major sources of afferent input to the motor cortex, the ventrolateral thalamus (VL). Experiments were conducted in chronically implanted cats with an extracellular single-neuron recording technique. VL neurons projecting to the motor cortex were identified by antidromic responses. During locomotion, the activity of 92% of neurons was modulated in the rhythm of strides; 67% of cells discharged one activity burst per stride, a pattern typical for the motor cortex. The characteristics of these discharges in most VL neurons appeared to be well suited to contribute to the locomotion-related activity of the motor cortex. In addition to simple locomotion, we examined VL activity during walking on a horizontal ladder, a task that requires vision for correct foot placement. Upon transition from simple to ladder locomotion, the activity of most VL neurons exhibited the same changes that have been reported for the motor cortex, i.e., an increase in the strength of stride-related modulation and shortening of the discharge duration. Five modes of integration of simple and ladder locomotion-related information were recognized in the VL. We suggest that, in addition to contributing to the locomotion-related activity in the motor cortex during simple locomotion, the VL integrates and transmits signals needed for correct foot placement on a complex terrain to the motor cortex. PMID:21994259

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.

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

PubMed Central

Richter, Anni; Richter, Sylvia; Barman, Adriana; Soch, Joram; Klein, Marieke; Assmann, Anne; Libeau, Catherine; Behnisch, Gusalija; Wüstenberg, Torsten; Seidenbecher, Constanze I.; Schott, Björn H.

2013-01-01

Dopamine has been implicated in the fine-tuning of complex cognitive and motor function and also in the anticipation of future rewards. This dual function of dopamine suggests that dopamine might be involved in the generation of active motivated behavior. The DRD2 TaqIA polymorphism of the dopamine D2 receptor gene (rs1800497) has previously been suggested to affect striatal function with carriers of the less common A1 allele exhibiting reduced striatal D2 receptor density and increased risk for addiction. Here we aimed to investigate the influences of DRD2 TaqIA genotype on the modulation of interference processing by reward and punishment. Forty-six young, healthy volunteers participated in a behavioral experiment, and 32 underwent functional magnetic resonance imaging (fMRI). Participants performed a flanker task with a motivation manipulation (monetary reward, monetary loss, neither, or both). Reaction times (RTs) were shorter in motivated flanker trials, irrespective of congruency. In the fMRI experiment motivation was associated with reduced prefrontal activation during incongruent vs. congruent flanker trials, possibly reflecting increased processing efficiency. DRD2 TaqIA genotype did not affect overall RTs, but interacted with motivation on the congruency-related RT differences, with A1 carriers showing smaller interference effects to reward alone and A2 homozygotes exhibiting a specific interference reduction during combined reward (REW) and punishment trials (PUN). In fMRI, anterior cingulate activity showed a similar pattern of genotype-related modulation. Additionally, A1 carriers showed increased anterior insula activation relative to A2 homozygotes. Our results point to a role for genetic variations of the dopaminergic system in individual differences of cognition-motivation interaction. PMID:23760450

Histamine H3 Receptors Decrease Dopamine Release in the Ventral Striatum by Reducing the Activity of Striatal Cholinergic Interneurons.

PubMed

Varaschin, Rafael Koerich; Osterstock, Guillaume; Ducrot, Charles; Leino, Sakari; Bourque, Marie-Josée; Prado, Marco A M; Prado, Vania Ferreira; Salminen, Outi; Rannanpää Née Nuutinen, Saara; Trudeau, Louis-Eric

2018-04-15

Histamine H 3 receptors are widely distributed G i -coupled receptors whose activation reduces neuronal activity and inhibits release of numerous neurotransmitters. Although these receptors are abundantly expressed in the striatum, their modulatory role on activity-dependent dopamine release is not well understood. Here, we observed that histamine H 3 receptor activation indirectly diminishes dopamine overflow in the ventral striatum by reducing cholinergic interneuron activity. Acute brain slices from C57BL/6 or channelrhodopsin-2-transfected DAT-cre mice were obtained, and dopamine transients evoked either electrically or optogenetically were measured by fast-scan cyclic voltammetry. The H 3 agonist α-methylhistamine significantly reduced electrically- evoked dopamine overflow, an effect blocked by the nicotinic acetylcholine receptor antagonist dihydro-β-erythroidine, suggesting involvement of cholinergic interneurons. None of the drug treatments targeting H 3 receptors affected optogenetically evoked dopamine overflow, indicating that direct H 3 -modulation of dopaminergic axons is unlikely. Next, we used qPCR and confirmed the expression of histamine H 3 receptor mRNA in cholinergic interneurons, both in ventral and dorsal striatum. Activation of H 3 receptors by α-methylhistamine reduced spontaneous firing of cholinergic interneurons in the ventral, but not in the dorsal striatum. Resting membrane potential and number of spontaneous action potentials in ventral-striatal cholinergic interneurons were significantly reduced by α-methylhistamine. Acetylcholine release from isolated striatal synaptosomes, however, was not altered by α-methylhistamine. Together, these results indicate that histamine H 3 receptors are important modulators of dopamine release, specifically in the ventral striatum, and that they do so by decreasing the firing rate of cholinergic neurons and, consequently, reducing cholinergic tone on dopaminergic axons. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

Contrasting Roles of Dopamine and Noradrenaline in the Motivational Properties of Social Play Behavior in Rats.

PubMed

Achterberg, E J Marijke; van Kerkhof, Linda W M; Servadio, Michela; van Swieten, Maaike M H; Houwing, Danielle J; Aalderink, Mandy; Driel, Nina V; Trezza, Viviana; Vanderschuren, Louk J M J

2016-02-01

Social play behavior, abundant in the young of most mammalian species, is thought to be important for social and cognitive development. Social play is highly rewarding, and as such, the expression of social play depends on its pleasurable and motivational properties. Since the motivational properties of social play have only sporadically been investigated, we developed a setup in which rats responded for social play under a progressive ratio schedule of reinforcement. Dopaminergic neurotransmission plays a key role in incentive motivational processes, and both dopamine and noradrenaline have been implicated in the modulation of social play behavior. Therefore, we investigated the role of dopamine and noradrenaline in the motivation for social play. Treatment with the psychostimulant drugs methylphenidate and cocaine increased responding for social play, but suppressed its expression during reinforced play periods. The dopamine reuptake inhibitor GBR-12909 increased responding for social play, but did not affect its expression, whereas the noradrenaline reuptake inhibitor atomoxetine decreased responding for social play as well as its expression. The effects of methylphenidate and cocaine on responding for social play, but not their play-suppressant effects, were blocked by pretreatment with the dopamine receptor antagonist α-flupenthixol. In contrast, pretreatment with the α2-adrenoceptor antagonist RX821002 prevented the play-suppressant effect of methylphenidate, but left its effect on responding for social play unaltered. In sum, the present study introduces a novel method to study the incentive motivational properties of social play behavior in rats. Using this paradigm, we demonstrate dissociable roles for dopamine and noradrenaline in social play behavior: dopamine stimulates the motivation for social play, whereas noradrenaline negatively modulates the motivation for social play behavior and its expression.

Antipsychotic-like Effects of M4 Positive Allosteric Modulators Are Mediated by CB2 Receptor-Dependent Inhibition of Dopamine Release.

PubMed

Foster, Daniel J; Wilson, Jermaine M; Remke, Daniel H; Mahmood, M Suhaib; Uddin, M Jashim; Wess, Jürgen; Patel, Sachin; Marnett, Lawrence J; Niswender, Colleen M; Jones, Carrie K; Xiang, Zixiu; Lindsley, Craig W; Rook, Jerri M; Conn, P Jeffrey

2016-09-21

Muscarinic receptors represent a promising therapeutic target for schizophrenia, but the mechanisms underlying the antipsychotic efficacy of muscarinic modulators are not well understood. Here, we report that activation of M4 receptors on striatal spiny projection neurons results in a novel form of dopaminergic regulation resulting in a sustained depression of striatal dopamine release that is observed more than 30 min after removal of the muscarinic receptor agonist. Furthermore, both the M4-mediated sustained inhibition of dopamine release and the antipsychotic-like efficacy of M4 activators were found to require intact signaling through CB2 cannabinoid receptors. These findings highlight a novel mechanism by which striatal cholinergic and cannabinoid signaling leads to sustained reductions in dopaminergic transmission and concurrent behavioral effects predictive of antipsychotic efficacy. Copyright © 2016 Elsevier Inc. All rights reserved.

Modulation of Memory Consolidation by the Basolateral Amygdala or Nucleus Accumbens Shell Requires Concurrent Dopamine Receptor Activation in Both Brain Regions

ERIC Educational Resources Information Center

LaLumiere, Ryan T.; Nawar, Erene M.; McGaugh, James L.

2005-01-01

Previous findings indicate that the basolateral amygdala (BLA) and the nucleus accumbens (NAc) interact in influencing memory consolidation. The current study investigated whether this interaction requires concurrent dopamine (DA) receptor activation in both brain regions. Unilateral, right-side cannulae were implanted into the BLA and the…

Dopamine Regulation of Human Speech and Bird Song: A Critical Review

ERIC Educational Resources Information Center

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…

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.