Striatal Dopamine D2 Receptor Research Articles

Aerobic exercise improves motor dysfunction in Parkinson's model mice via differential regulation of striatal medium spiny neuron.

The striatum plays a crucial role in providing input to the basal ganglia circuit and is implicated in the pathological process of Parkinson's disease (PD). Disruption of the dynamic equilibrium in the basal ganglia loop can be attributed to the abnormal functioning of the medium spiny neurons (MSNs) within the striatum, potentially acting as a trigger for PD. Exercise has been shown to mitigate striatal neuronal dysfunction through neuroprotective and neurorestorative effects and to improve behavioral deficits in PD model mice. In addition, this effect is offset by the activation of MSNs expressing dopamine D2 receptors (D2-MSNs). In the current study, we investigated the underlying neurobiological mechanisms of this effect. Our findings indicated that exercise reduces the power spectral density of the beta-band in the striatum and decreases the overall firing frequency of MSNs, particularly in the case of striatal D2-MSNs. These observations were consistent with the results of molecular biology experiments, which revealed that aerobic training specifically enhanced the expression of striatal dopamineD2 receptors (D2R). Taken together, our results suggest that aerobic training aimed at upregulating striatal D2R expression to inhibit the functional activity of D2-MSNs represents a potential therapeutic strategy for the amelioration of motor dysfunction in PD.

Post-transcriptional regulation and subcellular localization of G-protein γ7 subunit: implications for striatal function and behavioral responses to cocaine.

The striatal D1 dopamine receptor (D1R) and A2a adenosine receptor (A2aR) signaling pathways play important roles in drug-related behaviors. These receptors activate the Golf protein comprised of a specific combination of αolfβ2γ7 subunits. During assembly, the γ7 subunit sets the cellular level of the Golf protein. In turn, the amount of Golf protein determines the collective output from both D1R and A2aR signaling pathways. This study shows the Gng7 gene encodes multiple γ7 transcripts differing only in their non-coding regions. In striatum, Transcript 1 is the predominant isoform. Preferentially expressed in the neuropil, Transcript 1 is localized in dendrites where it undergoes post-transcriptional regulation mediated by regulatory elements in its 3' untranslated region that contribute to translational suppression of the γ7 protein. Earlier studies on gene-targeted mice demonstrated loss of γ7 protein disrupts assembly of the Golf protein. In the current study, morphological analysis reveals the loss of the Golf protein is associated with altered dendritic morphology of medium spiny neurons. Finally, behavioral analysis of conditional knockout mice with cell-specific deletion of the γ7 protein in distinct populations of medium spiny neurons reveals differential roles of the Golf protein in mediating behavioral responses to cocaine. Altogether, these findings provide a better understanding of the regulation of γ7 protein expression, its impact on Golf function, and point to a new potential target and mechanisms for treating addiction and related disorders.

Leucine-rich repeat kinase 2 limits dopamine D1 receptor signaling in striatum and biases against heavy persistent alcohol drinking

The transition from hedonic alcohol drinking to problematic drinking is a hallmark of alcohol use disorder that occurs only in a subset of drinkers. This transition requires long-lasting changes in the synaptic drive and the activity of striatal neurons expressing dopamine D1 receptor (D1R). The molecular mechanisms that generate vulnerability in some individuals to undergo the transition are less understood. Here, we report that the Parkinson’s-related protein leucine-rich repeat kinase 2 (LRRK2) modulates striatal D1R function to affect the behavioral response to alcohol and the likelihood that mice transition to heavy, persistent alcohol drinking. Constitutive deletion of the Lrrk2 gene specifically from D1R-expressing neurons potentiated D1R signaling at the cellular and synaptic level and enhanced alcohol-related behaviors and drinking. Mice with cell-specific deletion of Lrrk2 were more prone to heavy alcohol drinking, and consumption was insensitive to punishment. These findings identify a potential novel role for LRRK2 function in the striatum in promoting resilience against heavy and persistent alcohol drinking.

Translational findings linking poor inhibitory control and heightened drug reward sensitivity.

Poor inhibitory control and heightened sensitivity to drug reward are two well-established risk factors for substance use disorders. Although these risk factors have traditionally been studied independently, there is reason to expect they may be related at the neurobiological level. Here, translational studies investigating the association between poor inhibition and greater drug reward sensitivity in both laboratory animals and humans are reviewed. Findings show that in animals, inhibitory deficits are associated with greater self-administration of cocaine, nicotine, 3,4-methylenedioxy-methamphetamine (MDMA), and alcohol, but not heroin. Likewise, in healthy human volunteers, poor inhibitory control and less brain engagement in right frontal regions during inhibition are associated with greater and more positive subjective responses to amphetamine and alcohol. The potential neurobiological mechanisms underlying this association are discussed, including the number or function of striatal dopamine D₂ receptors, as well as the implications of the findings and directions for future research. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Chronic H3R activation reduces L-Dopa-induced dyskinesia, normalizes cortical GABA and glutamate levels, and increases striatal dopamine D1R mRNA expression in 6-hydroxydopamine-lesioned malerats.

Dyskinesias induced by L-3,4-dihydroxyphenylalanine, L-Dopa (LIDs), are the major complication in the pharmacological treatment of Parkinson's disease. LIDs induce overactivity of the glutamatergic cortico-striatal projections, and drugs that reduce glutamatergic overactivity exert antidyskinetic actions. Chronic administration of immepip, agonist at histamine H3 receptors (H3R), reduces LIDs and diminishes GABA and glutamate content in striatal dialysates (Avila-Luna et al., Psychopharmacology 236: 1937-1948, 2019). In rats unilaterally lesioned with 6-hydroxydopamine in the substantia nigra pars compacta (SNc), we examined whether the chronic administration of immepip and their withdrawal modify LIDs, the effect of L-Dopa on glutamate and GABA content, and mRNA levels of dopamine D1 receptors (D1Rs) and H3Rs in the cerebral cortex and striatum. The administration of L-Dopa for 21 days induced LIDs. This effect was accompanied by increased GABA and glutamate levels in the cerebral cortex ipsi and contralateral to the lesioned SNc, and immepip administration prevented (GABA) or reduced (glutamate) these actions. In the striatum, GABA content increased in the ipsilateral nucleus, an effect prevented by immepip. L-Dopa administration had no significant effects on striatal glutamate levels. In lesioned and L-Dopa-treated animals, D1R mRNA decreased in the ipsilateral striatum, an effect prevented by immepip administration. Our results indicate that chronic H3R activation reduces LIDs and the overactivity of glutamatergic cortico-striatal projections, providing further evidence for an interaction between D1Rs and H3Rs in the cortex and striatum under normal and pathological conditions.

The Addiction-Susceptibility TaqIA/Ankk1 Controls Reward and Metabolism Through D2 Receptor-Expressing Neurons

BackgroundA large body of evidence highlights the importance of genetic variants in the development of psychiatric and metabolic conditions. Among these, the TaqIA polymorphism is one of the most commonly studied in psychiatry. TaqIA is located in the gene that codes for the ankyrin repeat and kinase domain containing 1 kinase (Ankk1) near the dopamine D2 receptor (D2R) gene. Homozygous expression of the A1 allele correlates with a 30% to 40% reduction of striatal D2R, a typical feature of addiction, overeating, and other psychiatric pathologies. The mechanisms by which the variant influences dopamine signaling and behavior are unknown. MethodsHere, we used transgenic and viral-mediated strategies to reveal the role of Ankk1 in the regulation of activity and functions of the striatum. ResultsWe found that Ankk1 is preferentially enriched in striatal D2R-expressing neurons and that Ankk1 loss of function in the dorsal and ventral striatum leads to alteration in learning, impulsivity, and flexibility resembling endophenotypes described in A1 carriers. We also observed an unsuspected role of Ankk1 in striatal D2R-expressing neurons of the ventral striatum in the regulation of energy homeostasis and documented differential nutrient partitioning in humans with or without the A1 allele. ConclusionsOverall, our data demonstrate that the Ankk1 gene is necessary for the integrity of striatal functions and reveal a new role for Ankk1 in the regulation of body metabolism.

Striatal dopamine D2 receptor availability as a predictor of subsequent alcohol use in social drinkers.

Whereas striatal dopamine D2 receptor (D2R) availability has shown to be altered in individuals with alcohol use disorder (AUD) and in healthy individuals with a family history of AUD, the role of D2R in the development of AUD is unknown. In this positron emission tomography (PET) study, we measured whether D2R availability is associated with subsequent alcohol use and alcohol-related factors, at a follow-up 8 to 16 years post-PET scan, in social drinkers. Longitudinal study investigating the association between PET data and later self-report measures in healthy individuals. Academic research imaging centre in Stockholm, Sweden. There were 71 individuals (68 of whom had evaluable PET data, 5 females, 42.0 years mean age) from a series of previous PET studies. One PET examination with the D2R antagonist radioligand [11 C]raclopride at baseline and self-report measures assessing alcohol use, drug use, impulsivity, reward sensitivity and family history of alcohol or substance use disorder at follow-up. We found no evidence for an association between D2R availability and later alcohol use (B = -0.019, B 95% CI = -0.043 to -0.006, P = 0.147) nor for the majority of the alcohol-related factors (B 95% CI = -0.034 to 0.004, P = 0.273-0.288). A negative association with a small effect size was found between D2R availability and later impulsivity (B = -0.017, B 95% CI = -0.034 to -0.001, P = 0.046). Low striatal dopamine D2 receptor availability may not be a strong predictor in the development of alcohol use disorder.

Unique effect of clozapine on adenosine A2A-dopamine D2 receptor heteromerization

The striatal dopamine D2 receptor (D2R) is generally accepted to be involved in positive symptoms of schizophrenia and is a main target for clinically used antipsychotics. D2R are highly expressed in the striatum, where they form heteromers with the adenosine A2A receptor (A2AR). Changes in the density of A2AR-D2R heteromers have been reported in postmortem tissue from patients with schizophrenia, but the degree to which A2R are involved in schizophrenia and the effect of antipsychotic drugs is unknown. Here, we examine the effect of exposure to three prototypical antipsychotic drugs on A2AR-D2R heteromerization in mammalian cells using a NanoBiT assay. After 16 h of exposure, a significant increase in the density of A2AR-D2R heteromers was found with haloperidol and aripiprazole, but not with clozapine. On the other hand, clozapine, but not haloperidol or aripiprazole, was associated with a significant decrease in A2AR-D2R heteromerization after 2 h of treatment. Computational binding models of these compounds revealed distinctive molecular signatures that explain their different influence on heteromerization. The bulky tricyclic moiety of clozapine displaces TM 5 of D2R, inducing a clash with A2AR, while the extended binding mode of haloperidol and aripiprazole stabilizes a specific conformation of the second extracellular loop of D2R that enhances the interaction with A2AR. It is proposed that an increase in A2AR-D2R heteromerization is involved in the extrapyramidal side effects (EPS) of antipsychotics and that the specific clozapine-mediated destabilization of A2AR-D2R heteromerization can explain its low EPS liability.

Age-related differences in striatal dopamine D1 receptors mediate subjective drug effects.

Age-related differences in striatal dopamine D1 receptors mediate subjective drug effects.

SUVN‐I7016031: A Novel M1‐receptor Positive Allosteric Modulator (M1‐PAM) for the treatment of Parkinson's Disease Associated Dementia

AbstractBackgroundParkinson's disease (PD) patients experience progressive cognitive decline over the time and as the disease progresses. Drug‐induced Parkinsonism (DIP) is the second‐most‐common etiology of parkinsonism in the elderly after Parkinson's disease. DIP is indistinguishable from pathological PD as the symptoms are similar for both conditions. Haloperidol is a classical antipsychotic, known for its propensity to cause parkinsonism, which can be accompanied with the cognitive impairment, due to the blockade of striatal dopamine D2 receptors and further the downstream antagonism of M1 receptors in the signaling cascade. Therapeutic potential of SUVN‐I7016031 was evaluated in an animal model reflecting PD associated dementia.MethodHaloperidol was supplied in water feeder bottles at 2 mg/kg, p.o. to induce PD associated dementia. Following one week of haloperidol supplementation, treatment with either SUVN‐I7016031 (0.3, 1, 3 and 10 mg/kg, p.o.) or rivastigmine (0.3 mg/kg, s.c.) was began and the treatments were continued up to 37 days. Social recognition task (SRT) was conducted on day‐13 and day‐37. In SRT, familiarization and recognition trials were conducted with a trial delay of 30 min. Social investigation time by adult rat with either familiar or novel juvenile rat was assessed during recognition trial and compared, along with discriminative index. Statistical analysis is carried out using GraphPad Prism software (Version 7.02).ResultAnimals treated with haloperidol did not discriminate the novel juvenile from the familiar juvenile and showed cognitive impairment on day‐13 and day‐37. Rivastigmine reversed haloperidol‐induced PD dementia on day‐13 and day‐37. SUVN‐I7016031 at 10 mg/kg, p.o., reversed haloperidol‐induced PD dementia on day‐13 of testing. However, on day‐37, SUVN‐I7016031 reversed haloperidol‐induced PD dementia at 1, 3 and 10 mg/kg, p.o. which resulted in dose‐dependent positive efficacy. Further, rivastigmine and SUVN‐I7016031 treatment also resulted in significant improvement of discriminative index relative to haloperidol control on day‐37. Effects observed with SUVN‐I7016031 are more prominent on day‐37 relative to day‐13.ConclusionSUVN‐I7016031 showed positive efficacy in an animal model reflecting PD associated dementia, which could be a future promising therapeutic strategy in improving health related quality of life (hQOL) in PD patients.

The effect of selective nigrostriatal dopamine excess on behaviors linked to the cognitive and negative symptoms of schizophrenia.

Excess dopamine release in the dorsal striatum (DS) is linked to psychosis. Antipsychotics are thought to work by blocking striatal D2 dopamine receptors, but they lack efficacy for the negative and cognitive symptoms of schizophrenia. These observations and the fact that increasing brain-wide dopamine improves cognition have fueled the dogma that excess dopamine is not involved in negative and cognitive symptoms. However, this idea has never been explicitly tested with DS-pathway specificity. To determine if excess DS dopamine is involved in cognitive and negative symptoms, we selectively re-expressed excitatory TRPV1 receptors in DS-projecting dopamine neurons of Trpv1 knockout mice. We treated these mice with capsaicin (TRPV1 agonist) to selectively activate these neurons, validated this approach with fiber photometry, and assessed its effects on social interaction and working memory, behavioral constructs related to negative and cognitive symptoms. We combined this manipulation with antipsychotic treatment (haloperidol) and compared it to brain-wide dopamine release via amphetamine treatment. We found that selectively activating DS-projecting dopamine neurons increased DS (but not cortical) dopamine release and increased locomotor activity. Surprisingly, this manipulation also impaired social interaction and working memory. Haloperidol normalized locomotion, but only partially rescued working memory and had no effect on social interaction. By contrast, amphetamine increased locomotion but did not impair social interaction or working memory. These results suggest that excess dopamine release, when restricted to the DS, causes behavioral deficits linked to negative and cognitive symptoms. Future therapies should address this disregarded role for excess striatal dopamine in thetreatment-resistant symptoms of psychosis.

Dopamine D2 receptors bidirectionally regulate striatal enkephalin expression: Implications for cocaine reward.

Low dopamine D2 receptor (D2R) availability in the striatum can predispose for cocaine abuse; though how low striatal D2Rs facilitate cocaine reward is unclear. Overexpression of D2Rs in striatal neurons or activation of D2Rs by acute cocaine suppresses striatal Penk mRNA. Conversely, low D2Rs in D2-striatal neurons increases striatal Penk mRNA and enkephalin peptide tone, an endogenous mu-opioid agonist. In brain slices, met-enkephalin and inhibition of enkephalin catabolism suppresses intra-striatal GABA transmission. Pairing cocaine with intra-accumbens met-enkephalin during place conditioning facilitates acquisition of preference, while mu-opioid receptor antagonist blocks preference in wild-type mice. We propose that heightened striatal enkephalin potentiates cocaine reward by suppressing intra-striatal GABA to enhance striatal output. Surprisingly, a mu-opioid receptor antagonist does not block cocaine preference in mice with low striatal D2Rs, implicating other opioid receptors. The bidirectional regulation of enkephalin by D2R activity and cocaine offers insights into mechanisms underlying the vulnerability for cocaine abuse.

Lower Vitamin C Levels Are Associated With Less Improvement in Negative Symptoms in Initially Antipsychotic-Naïve Patients With First-Episode Psychosis.

Low levels of vitamin C have been observed in patients with schizophrenia and psychosis, and vitamin C may affect the dopaminergic system. Likewise, antipsychotic medication modulates striatal dopamine D2 receptors. We measured vitamin C levels in 52 patients with first-episode psychoses (24 females, age 23.1 ± 5.2 years) and 57 matched HCs (20 females, age 22.7 ± 4.3 years) before and after 6 weeks where patients received aripiprazole monotherapy (mean dose 10.4 mg ± 4.8 mg). At baseline, patients displayed lower levels of vitamin C (57.4 ± 25.9 µM) than controls (72.7 ± 21.4 µM) (t = 3.4, P = .001). Baseline symptoms and vitamin C levels were not correlated. Higher baseline vitamin C levels were associated with more improvement in negative symptoms (n = 39, R2 = 0.20, F = 8.2, P = .007), but not with age, sex, or p-aripiprazole. Because negative symptoms are generally considered challenging to alleviate, a potential adjunctive effect of vitamin C on treatment response should be tested in future randomized clinical trials.

Imaging extra-striatal dopamine D2 receptors in a maternal immune activation rat model

Maternal immune activation (MIA) is a risk factor for schizophrenia in the offspring. MIA in pregnant rodents can be induced by injection of synthetic polyriboinosinic-polyribocytidilic acid (Poly I:C), which causes decreased striatal dopamine D2 receptor (D2R) expression and behavioral dysfunction mediated by the dopaminergic system in the offspring. However, previous studies did not determine whether Poly I:C induced cortical dopamine D2R abnormality in an MIA rat model. In this study, we performed micro-positron emission tomography (micro-PET) in vivo imaging and ex vivo neurochemical analyses of cortical D2Rs in MIA. In the micro-PET analyses, the anterior cingulate cortex (ACC) region in the offspring showed significantly reduced binding potential for [11C]FLB457, a high affinity radio-ligand toward D2Rs. Neurochemical analysis showed reduction of D2Rs and augmentation of dopamine turnover in the ACC of the rat offspring. Thus, MIA induces dopaminergic dysfunction in the ACC of offspring, similar to the neuronal pathology reported in patients with schizophrenia.

Altered Pain Processing Associated with Administration of Dopamine Agonist and Antagonist in Healthy Volunteers.

Striatal dopamine dysfunction is associated with the altered top-down modulation of pain processing. The dopamine D2-like receptor family is a potential substrate for such effects due to its primary expression in the striatum, but evidence for this is currently lacking. Here, we investigated the effect of pharmacologically manipulating striatal dopamine D2 receptor activity on the anticipation and perception of acute pain stimuli in humans. Participants received visual cues that induced either certain or uncertain anticipation of two pain intensity levels delivered via a CO2 laser. Rating of the pain intensity and unpleasantness was recorded. Brain activity was recorded with EEG and analysed via source localisation to investigate neural activity during the anticipation and receipt of pain. Participants completed the experiment under three conditions, control (Sodium Chloride), D2 receptor agonist (Cabergoline), and D2 receptor antagonist (Amisulpride), in a repeated-measures, triple-crossover, double-blind study. The antagonist reduced an individuals’ ability to distinguish between low and high pain following uncertain anticipation. The EEG source localisation showed that the agonist and antagonist reduced neural activations in specific brain regions associated with the sensory integration of salient stimuli during the anticipation and receipt of pain. During anticipation, the agonist reduced activity in the right mid-temporal region and the right angular gyrus, whilst the antagonist reduced activity within the right postcentral, right mid-temporal, and right inferior parietal regions. In comparison to control, the antagonist reduced activity within the insula during the receipt of pain, a key structure involved in the integration of the sensory and affective aspects of pain. Pain sensitivity and unpleasantness were not changed by D2R modulation. Our results support the notion that D2 receptor neurotransmission has a role in the top-down modulation of pain.

Striatal neurons expressing dopamine D1 receptor promote wakefulness in mice

Patients with Parkinson's disease (PD) suffer from severe sleep disorders. Pathophysiology of the basal ganglia (BG) underlies PD, and the dorsal striatum represents the major input pathway of the BG. However, the roles and mechanisms of the dorsal striatum in controlling sleep-wake cycles remain unknown. To demonstrate the contribution of dopamine D1 receptor (D1R)-positive neurons within the dorsal striatum in promoting wakefulness, we combined optogenetic manipulations and fiber photometry with electroencephalography/electromyography recording in D1R-Cre mice. As a result, optogenetic activation of striatal D1R neurons induced immediate transitions from non-rapid eye movement (NREM) sleep to wakefulness, whereas inhibition of striatal D1R neurons attenuated wakefulness by chemogenetics. Multi-channel fiber photometry recordings revealed that the activity of striatal D1R neurons synchronized with that of BG upstreams, namely the prefrontal cortex and mediodorsal thalamus, in terms of immediate increase in activity during NREM-to-wake transitions and rapid decease during wake-to-NREM transitions. Further optogenetic manipulations revealed a prominent contribution of striatal D1R neurons in control of wakefulness by upstream, corticostriatal, thalamostriatal, and nigrostriatal projections and via downstream, striato-entopeduncular, or striatonigral pathways. Taken together, our findings revealed a circuit regulating wakefulness through striatal D1R neurons. Striatal D1R neurons play an important role in controlling wakefulness by integrating the corticostriatal, thalamostriatal, and nigrostriatal projections and innervation of striato-entopeduncular or striatonigral pathways.

Fine-tuning role of L-DOPA and its receptor GPR143 for dopamine D2 receptor in the striatal indirect pathway

Levodopa (L-DOPA) therapy is the gold standard for the treatment with Parkinson's disease. The pharmacological actions of L-DOPA have been believed to be mediated through its conversion to dopamine. On the contrary, we propose that L-DOPA is a neurotransmitter. We identified G-protein coupled receptor (GPCR) GPR143, a gene product of ocular albinism-1, as a receptor for L-DOPA. In the course of our phenotypic analysis of Gpr143 gene-deficient (Gpr143-/y) mice, we found that behavioral response to quinpirole, a dopamine D2 receptor (D2R) agonist, was attenuated in Gpr143-/y mice when compared to wild type (WT) mice. This phenotype was also observed in the striatal indirect pathway specific Gpr143 gene-deficient (A2A-cre;Gpr143flox/y) mice. To investigate the physiological role of GPR143, we performed anxiety behavior using zero maze test. The anxiety behavior was attenuated in Gpr143-/y and A2A-cre;Gpr143flox/y mice when compared to corresponding control animals, as was reported in the striatal indirect pathway specific D2R deficient mice. These results suggest that L-DOPA-GPR143 fine-tunes the dopamine D2R in the striatal indirect pathway.

How changes in dopamine D2 receptor levels alter striatal circuit function and motivation.

It was first posited, more than five decades ago, that the etiology of schizophrenia involves overstimulation of dopamine receptors. Since then, advanced clinical research methods, including brain imaging, have refined our understanding of the relationship between striatal dopamine and clinical phenotypes as well as disease trajectory. These studies point to striatal dopamine D2 receptors, the main target for all current antipsychotic medications, as being involved in both positive and negative symptoms. Simultaneously, animal models have been central to investigating causal relationships between striatal dopamine D2 receptors and behavioral phenotypes relevant to schizophrenia. We begin this article by reviewing the circuit, cell-type and subcellular locations of dopamine D2 receptors and their downstream signaling pathways. We then summarize results from several mouse models in which D2 receptor levels were altered in various brain regions, cell-types and developmental periods. Behavioral, electrophysiological and anatomical consequences of these D2 receptor perturbations are reviewed with a selective focus on striatal circuit function and alterations in motivated behavior, a core negative symptom of schizophrenia. These studies show that D2 receptors serve distinct physiological roles in different cell types and at different developmental time points, regulating motivated behaviors in sometimes opposing ways. We conclude by considering the clinical implications of this complex regulation of striatal circuit function by D2 receptors.

Motivational learning biases are differentially modulated by genetic determinants of striatal and prefrontal dopamine function

Dopaminergic neurotransmission plays a pivotal role in appetitively motivated behavior in mammals, including humans. Notably, action and valence are not independent in motivated tasks, and it is particularly difficult for humans to learn the inhibition of an action to obtain a reward. We have previously observed that the carriers of the DRD2/ANKK1 TaqIA A1 allele, that has been associated with reduced striatal dopamine D2 receptor expression, showed a diminished learning performance when required to learn response inhibition to obtain rewards, a finding that was replicated in two independent cohorts. With our present study, we followed two aims: first, we aimed to replicate our finding on the DRD2/ANKK1 TaqIA polymorphism in a third independent cohort (N = 99) and to investigate the nature of the genetic effects more closely using trial-by-trial behavioral analysis and computational modeling in the combined dataset (N = 281). Second, we aimed to assess a potentially modulatory role of prefrontal dopamine availability, using the widely studied COMT Val108/158Met polymorphism as a proxy. We first report a replication of the above mentioned finding. Interestingly, after combining all three cohorts, exploratory analyses regarding the COMT Val108/158Met polymorphism suggest that homozygotes for the Met allele, which has been linked to higher prefrontal dopaminergic tone, show a lower learning bias. Our results corroborate the importance of genetic variability of the dopaminergic system in individual learning differences of action–valence interaction and, furthermore, suggest that motivational learning biases are differentially modulated by genetic determinants of striatal and prefrontal dopamine function.

Relationship between regional gray matter volumes and dopamine D2 receptor and transporter in living human brains.

Although striatal dopamine neurotransmission is believed to be functionally linked to the formation of the corticostriatal network, there has been little evidence for this regulatory process in the human brain and its disruptions in neuropsychiatric disorders. Here, we aimed to investigate associations of striatal dopamine transporter (DAT) and D2 receptor availabilities with gray matter (GM) volumes in healthy humans. Positron emission tomography images of D2 receptor (n = 34) and DAT (n = 17) captured with the specific radioligands [11C]raclopride and [18F]FE‐PE2I, respectively, were acquired along with T1‐weighted magnetic resonance imaging data in our previous studies, and were re‐analyzed in this work. We quantified the binding potentials (BP ND) of these radioligands in the limbic, executive, and sensorimotor functional subregions of the striatum. Correlations between the radioligand BP ND and regional GM volume were then examined by voxel‐based morphometry. In line with the functional and anatomical connectivity, [11C]raclopride BP ND in the limbic striatum was positively correlated with volumes of the uncal/parahippocampal gyrus and adjacent temporal areas. Similarly, we found positive correlations between the BP ND of this radioligand in the executive striatum and volumes of the prefrontal cortices and their adjacent areas as well as between the BP ND in the sensorimotor striatum and volumes of the somatosensory and supplementary motor areas. By contrast, no significant correlation was found between [18F]FE‐PE2I BP ND and regional GM volumes. Our results suggest unique structural and functional corticostriatal associations involving D2 receptor in healthy humans, which might be partially independent of the nigrostriatal pathway reflected by striatal DAT.