Ventral Striatum Reactivity Research Articles

Blunted ventral striatal reactivity to social reward is associated with more severe motivation and pleasure deficits in psychosis.

Among individuals living with psychotic disorders, social impairment is common, debilitating, and challenging to treat. While the roots of this impairment are undoubtedly complex, converging lines of evidence suggest that social motivation and pleasure (MAP) deficits play a key role. Yet most neuroimaging studies have focused on monetary rewards, precluding decisive inferences. Here we leveraged parallel social and monetary incentive delay fMRI paradigms to test whether blunted reactivity to social incentives in the ventral striatum-a key component of the distributed neural circuit mediating appetitive motivation and hedonic pleasure-is associated with more severe MAP symptoms in a transdiagnostic sample enriched for psychosis. To maximize ecological validity and translational relevance, we capitalized on naturalistic audiovisual clips of an established social partner expressing positive feedback. Although both paradigms robustly engaged the ventral striatum, only reactivity to social incentives was associated with clinician-rated MAP deficits. This association remained significant when controlling for other symptoms, binary diagnostic status, or ventral striatum reactivity to monetary incentives. Follow-up analyses suggested that this association predominantly reflects diminished striatal activation during the receipt of social reward. These observations provide a neurobiologically grounded framework for conceptualizing the social-anhedonia symptoms and social impairments that characterize many individuals living with psychotic disorders and underscore the need to establish targeted intervention strategies.

385. Transdiagnostic Motivation and Pleasure Deficits Are Associated With Reduced Ventral Striatum Reactivity to Social, Not Monetary, Reward

385. Transdiagnostic Motivation and Pleasure Deficits Are Associated With Reduced Ventral Striatum Reactivity to Social, Not Monetary, Reward

Neural Reactivity to Social Punishment Predicts Future Engagement in Nonsuicidal Self-injury Among Peer-Rejected Adolescents

BackgroundRates of nonsuicidal self-injury (NSSI) increase dramatically in adolescence. Affective reactivity and adverse social experiences have been linked to NSSI, but less is known about whether these factors may separately or interactively predict NSSI, especially longitudinally. This study combined functional magnetic resonance imaging and a sociometric measure to test whether a combination of neural (e.g., amygdala) reactivity to social punishment and peer-nominated peer acceptance/rejection predicts NSSI longitudinally in adolescence. Amygdala reactivity was examined as a potential neural marker of affective reactivity to social punishment, which may heighten NSSI risk in contexts of social adversity. MethodsOne hundred twenty-five adolescents (63 female) completed a social incentive delay task during neuroimaging and school-based peer nominations to measure peer acceptance/rejection. NSSI engagement was assessed at baseline and 1-year follow-up. ResultsGreater amygdala reactivity to social punishment predicted greater NSSI engagement 1 year later among adolescents with high peer rejection. This effect for the amygdala was specific to social punishment (vs. reward) and held when controlling for biological sex and pubertal development. Exploratory analyses found that ventral striatum reactivity to social reward and punishment similarly interacted with peer rejection to predict NSSI but that amygdala connectivity with salience network regions did not. ConclusionsAmygdala reactivity to social punishment, in combination with high peer rejection, may increase NSSI risk in adolescence, possibly via heightened affective reactivity to adverse social experiences. Objective measures of neurobiological and social risk factors may improve prediction of NSSI, while therapeutic approaches that target affective reactivity and increase prosocial skills may protect against NSSI in adolescence.

Genome-wide association studies of alcohol dependence, DSM-IV criterion count and individual criteria.

Genome-wide association studies (GWAS) of alcohol dependence (AD) have reliably identified variation within alcohol metabolizing genes (eg, ADH1B) but have inconsistently located other signals, which may be partially attributable to symptom heterogeneity underlying the disorder. We conducted GWAS of DSM-IV AD (primary analysis), DSM-IV AD criterion count (secondary analysis), and individual dependence criteria (tertiary analysis) among 7418 (1121 families) European American (EA) individuals from the Collaborative Study on the Genetics of Alcoholism (COGA). Trans-ancestral meta-analyses combined these results with data from 3175 (585 families) African-American (AA) individuals from COGA. In the EA GWAS, three loci were genome-wide significant: rs1229984 in ADH1B for AD criterion count (P = 4.16E-11) and Desire to cut drinking (P = 1.21E-11); rs188227250 (chromosome 8, Drinking more than intended, P = 6.72E-09); rs1912461 (chromosome 15, Time spent drinking, P = 1.77E-08). In the trans-ancestral meta-analysis, rs1229984 was associated with multiple phenotypes and two additional loci were genome-wide significant: rs61826952 (chromosome 1, DSM-IV AD, P = 8.42E-11); rs7597960 (chromosome 2, Time spent drinking, P = 1.22E-08). Associations with rs1229984 and rs18822750 were replicated in independent datasets. Polygenic risk scores derived from the EA GWAS of AD predicted AD in two EA datasets (P < .01; 0.61%-1.82% of variance). Identified novel variants (ie, rs1912461, rs61826952) were associated with differential central evoked theta power (loss - gain; P = .0037) and reward-related ventral striatum reactivity (P = .008), respectively. This study suggests that studying individual criteria may unveil new insights into the genetic etiology of AD liability.

Accelerated alcohol use across adolescence predicts early adult symptoms of alcohol use disorder via reward-related neural function.

Alcohol use is commonly initiated during adolescence, with earlier onset known to increase the risk for alcohol use disorder (AUD). Altered function in neural reward circuitry is thought to increase the risk for AUD. To test the hypothesis that adolescent alcohol misuse primes the brain for alcohol-related psychopathology in early adulthood, we examined whether adolescent alcohol consumption rates predicted reward responsivity in the ventral striatum (VS), and in turn, AUD symptoms in adulthood. A total of 139 low income, racially diverse urban males reported on their alcohol use at ages 11, 12, 15, and 17; completed self-reports of personality, psychiatric interviews, and a functional magnetic resonance imaging (fMRI) scan at age 20; and completed a psychiatric interview at age 22. We measured adolescent alcohol use trajectories using latent growth curve modeling and measured neural responses to monetary reward using a VS region of interest. We tested indirect effects of adolescent alcohol use on AUD symptoms at age 22 via VS reward-related reactivity at age 20. Greater acceleration in adolescent alcohol use predicted increased VS response during reward anticipation at age 20. VS reactivity to reward anticipation at age 20 predicted AUD symptoms at age 22, over and above concurrent symptoms. Accelerated adolescent alcohol use predicted AUD symptoms in early adulthood via greater VS reactivity to reward anticipation. Prospective findings support a pathway through which adolescent alcohol use increases the risk for AUD in early adulthood by impacting reward-related neural functioning. These results highlight increased VS reward-related reactivity as a biomarker for AUD vulnerability.

Deflections from adolescent trajectories of antisocial behavior: contextual and neural moderators of antisocial behavior stability into emerging adulthood.

Early adulthood is a critical period when young men involved in antisocial behavior (AB) may desist. Factors including marriage and employment have been shown to predict desistance, but little work has examined whether biological factors (e.g. neural reactivity) predict deflections from lifelong AB trajectories. We examined the continuity of, or desistance from, AB in early adulthood using group-based trajectories of AB across adolescence in a sample of 242 men from low-income, urban families. We examined contextual factors (romantic relationship quality, employment, neighborhood danger) and neural factors (amygdala reactivity to fearful faces, ventral striatum reactivity to reward) as moderators of the continuity of AB from adolescence (age 10-17) into early adulthood (age 22-23), and whether these pathways differed by race. High relationship satisfaction and employment at age 20 predicted decreased AB at age 22-23, but only among men with adolescent-onset/moderate AB trajectories. Ventral striatum reactivity predicted continued AB, but only among African-American men with early-starting AB. Amygdala reactivity to fearful faces was related to later AB for those in the early-starting group, but in divergent directions depending on race: amygdala reactivity to fearful faces was positively related to AB in European-Americans and negatively related to AB among African-Americans. Contextual factors only predicted deflections of AB in those engaged in late-starting, moderate levels of AB, whereas neural factors predicted continued AB only in those with early-starting, severe AB, and in divergent ways based on participant race. Though there is limited power to infer causality from this observational design, research on desistance broadly can contribute to informing personalized interventions for those engaged in serious adolescence AB.

PER1 rs3027172 Genotype Interacts with Early Life Stress to Predict Problematic Alcohol Use, but Not Reward-Related Ventral Striatum Activity.

Increasing evidence suggests that the circadian and stress regulatory systems contribute to alcohol use disorder (AUD) risk, which may partially arise through effects on reward-related neural function. The C allele of the PER1 rs3027172 single nucleotide polymorphism (SNP) reduces PER1 expression in cells incubated with cortisol and has been associated with increased risk for adult AUD and problematic drinking among adolescents exposed to high levels of familial psychosocial adversity. Using data from undergraduate students who completed the ongoing Duke Neurogenetics Study (DNS) (n = 665), we tested whether exposure to early life stress (ELS; Childhood Trauma Questionnaire) moderates the association between rs3027172 genotype and later problematic alcohol use (Alcohol Use Disorders Identification Test) as well as ventral striatum (VS) reactivity to reward (card-guessing task while functional magnetic resonance imaging data were acquired). Initial analyses found that PER1 rs3027172 genotype interacted with ELS to predict both problematic drinking and VS reactivity; minor C allele carriers, who were also exposed to elevated ELS reported greater problematic drinking and exhibited greater ventral striatum reactivity to reward-related stimuli. When gene × covariate and environment × covariate interactions were controlled for, the interaction predicting problematic alcohol use remained significant (p < 0.05, corrected) while the interaction predicting VS reactivity was no longer significant. These results extend our understanding of relationships between PER1 genotype, ELS, and problematic alcohol use, and serve as a cautionary tale on the importance of controlling for potential confounders in studies of moderation including gene × environment interactions.

A neuroscience perspective on sexual risk behavior in adolescence and emerging adulthood.

Late adolescence and emerging adulthood (specifically ages 15-24) represent a period of heightened sexual risk taking resulting in the greatest annual rates of sexually transmitted infections and unplanned pregnancies in the US population. Ongoing efforts to prevent such negative consequences are likely to benefit from a deepening of our understanding of biological mechanisms through which sexual risk taking emerges and biases decision making during this critical window. Here we present a neuroscience framework from which a mechanistic examination of sexual risk taking can be advanced. Specifically, we adapt the neurodevelopmental triadic model, which outlines how motivated behavior is governed by three systems: approach, avoidance, and regulation, to sexual decision making and subsequent risk behavior. We further propose a testable hypothesis of the triadic model, wherein relatively decreased threat-related amygdala reactivity and increased reward-related ventral striatum reactivity leads to sexual risk taking, which is particularly exaggerated during adolescence and young adulthood when there is an overexpression of dopaminergic neurons coupled with immature top-down prefrontal cortex regulation. We conclude by discussing how future research based on our adapted triadic model can inform ongoing efforts to improve intervention and prevention efforts.

Neural and Behavioral Correlates of Alcohol-Induced Aggression Under Provocation.

Although alcohol consumption is linked to increased aggression, its neural correlates have not directly been studied in humans so far. Based on a comprehensive neurobiological model of alcohol-induced aggression, we hypothesized that alcohol-induced aggression would go along with increased amygdala and ventral striatum reactivity and impaired functioning of the prefrontal cortex (PFC) under alcohol. We measured neural and behavioral correlates of alcohol-induced aggression in a provoking vs non-provoking condition with a variant of the Taylor aggression paradigm (TAP) allowing to differentiate between reactive (provoked) and proactive (unprovoked) aggression. In a placebo-controlled cross-over design with moderate alcohol intoxication (~0.6 g/kg), 35 young healthy adults performed the TAP during functional magnetic resonance imaging (fMRI). Analyses revealed that provoking vs non-provoking conditions and alcohol vs placebo increased aggression and decreased brain responses in the anterior cingulate cortex/dorso-medial PFC (provoking<non-provoking) and the ventral striatum (alcohol<placebo) across our healthy sample. Interestingly, alcohol specifically increased proactive (unprovoked) but not reactive (provoked) aggression (alcohol × provocation interaction). However, investigation of inter-individual differences revealed (1) that pronounced alcohol-induced proactive aggression was linked to higher levels of aggression under placebo, and (2) that pronounced alcohol-induced reactive aggression was related to increased amygdala and ventral striatum reactivity under alcohol, providing evidence for their role in human alcohol-induced reactive aggression. Our findings suggest that in healthy young adults a liability for alcohol-induced aggression in a non-provoking context might depend on overall high levels of aggression, but on alcohol-induced increased striatal and amygdala reactivity when triggered by provocation.

Stress-related anhedonia is associated with ventral striatum reactivity to reward and transdiagnostic psychiatric symptomatology.

Early life stress (ELS) is consistently associated with increased risk for subsequent psychopathology. Individual differences in neural response to reward may confer vulnerability to stress-related psychopathology. Using data from the ongoing Duke Neurogenetics Study, the present study examined whether reward-related ventral striatum (VS) reactivity moderates the relationship between retrospectively reported ELS and anhedonic symptomatology. We further assessed whether individual differences in reward-related VS reactivity were associated with other depressive symptoms and problematic alcohol use via stress-related anhedonic symptoms and substance use-associated coping. Blood oxygen level-dependent functional magnetic resonance imaging (fMRI) was collected while participants (n = 906) completed a card-guessing task, which robustly elicits VS reactivity. ELS, anhedonic symptoms, other depressive symptoms, coping behavior, and alcohol use behavior were assessed with self-report questionnaires. Linear regressions were run to examine whether VS reactivity moderated the relationship between ELS and anhedonic symptoms. Structural equation models examined whether this moderation was indirectly associated with other depression symptoms and problematic alcohol use through its association with anhedonia. Analyses of data from 820 participants passing quality control procedures revealed that the VS × ELS interaction was associated with anhedonic symptoms (p = 0.011). Moreover, structural equation models indirectly linked this interaction to non-anhedonic depression symptoms and problematic alcohol use through anhedonic symptoms and substance-related coping. These findings suggest that reduced VS reactivity to reward is associated with increased risk for anhedonia in individuals exposed to ELS. Such stress-related anhedonia is further associated with other depressive symptoms and problematic alcohol use through substance-related coping.

Increased default mode network activity in socially anxious individuals during reward processing.

BackgroundSocial anxiety has been associated with potentiated negative affect and, more recently, with diminished positive affect. It is unclear how these alterations in negative and positive affect are represented neurally in socially anxious individuals and, further, whether they generalize to non-social stimuli. To explore this, we used a monetary incentive paradigm to explore the association between social anxiety and both the anticipation and consumption of non-social incentives. Eighty-four individuals from a longitudinal community sample underwent functional magnetic resonance imaging (fMRI) while participating in a monetary incentive delay (MID) task. The MID task consisted of alternating cues indicating the potential to win or prevent losing varying amounts of money based on the speed of the participant’s response. We examined whether self-reported levels of social anxiety, averaged across approximately 7 years of data, moderated brain activity when contrasting gain or loss cues with neutral cues during the anticipation and outcome phases of incentive processing. Whole brain analyses and analyses restricted to the ventral striatum for the anticipation phase and the medial prefrontal cortex for the outcome phase were conducted.ResultsSocial anxiety did not associate with differences in hit rates or reaction times when responding to cues. Further, socially anxious individuals did not exhibit decreased ventral striatum activity during anticipation of gains or decreased MPFC activity during the outcome of gain trials, contrary to expectations based on literature indicating blunted positive affect in social anxiety. Instead, social anxiety showed positive associations with extensive regions implicated in default mode network activity (for example, precuneus, posterior cingulate cortex, and parietal lobe) during anticipation and receipt of monetary gain. Social anxiety was further linked with decreased activity in the ventral striatum during anticipation of monetary loss.ConclusionsSocially anxious individuals may increase default mode network activity during reward processing, suggesting high self-focused attention even in relation to potentially rewarding stimuli lacking explicit social connotations. Additionally, social anxiety may relate to decreased ventral striatum reactivity when anticipating potential losses.

An altered neural response to reward may contribute to alcohol problems among late adolescents with an evening chronotype

Evening chronotypes not only differ from morning-types in their sleep and circadian timing, but they are prone to problematic outcomes involving reward function, including affective disturbance, sensation seeking, and substance involvement. We explored the neural mechanisms underlying these chronotype differences by comparing the neural response to reward in morning- and evening-types. Using a monetary reward fMRI paradigm, we compared the neural response to reward in 13 morning-types and 21 evening-types (all 20 y/o males). Region-of-interest (ROI) analyses focused on the medial prefrontal cortex (mPFC) and ventral striatum (VS), comparing the chronotype groups in these ROIs during anticipation and outcome conditions, and adjusting for time of scan. Chronotype groups were also compared on measures of sensation-seeking, substance involvement, and sleep quality. Evening-types reported significantly greater levels of alcohol dependence and worse sleep quality. Furthermore, evening-types showed an altered neural response to reward relative to morning-types, specifically, reduced mPFC reactivity during reward anticipation and increased VS reactivity during win outcome. In turn, less activation in the mPFC region in response to reward was associated with greater alcohol consumption, while increased activation in the VS in response to reward was associated with more symptoms of alcohol dependence. Increased reward-related problems among evening-types may be accompanied by altered neural responses to reward.

Reward‐related ventral striatum reactivity mediates gender‐specific effects of a galanin remote enhancer haplotype on problem drinking

The neuropeptide galanin has been implicated in the regulation of appetitive and consummatory behaviors. Prior studies have shown that direct injection of galanin into the hypothalamus results in increased release of dopamine (DA) in the nucleus accumbens (NAcc), and parallel increases in food and alcohol consumption. These studies are consistent with a role of hypothalamic galanin in regulating reward system reactivity. In humans, a common functional haplotype (GAL5.1) within a remote enhancer region upstream of the galanin gene (GAL) affects promoter activity and galanin expression in hypothalamic neurons in vitro. Given the effects of hypothalamic galanin on NAcc DA release and the effects of the GAL5.1 haplotype on GAL expression, we examined the impact of this functional genetic variation on human reward-related ventral striatum (VS) reactivity. Using an imaging genetics strategy in Caucasian individuals (N = 138, 72 women) participating in the ongoing Duke Neurogenetics Study, we report a significant gender-by-genotype interaction (right hemisphere: F1,134 = 8.08, P = 0.005; left hemisphere: F1,134 = 5.39, P = 0.022), such that homozygosity for the GG haplotype, which predicts greater GAL expression, is associated with relatively increased VS reactivity in women (n = 50, right hemisphere: P = 0.015; left hemisphere: P = 0.060), but not in men (N = 49, P-values > 0.10). Furthermore, these differences in VS reactivity correlated positively with differences in alcohol use, such that VS reactivity mediated a gender-specific association between GAL5.1 haplotype and problem drinking. Our current results support those in animal models implicating galanin signaling in neural pathways associated with appetitive and consummatory behaviors of relevance for understanding risk for substance use and abuse.

Neural responses to threat and reward interact to predict stress-related problem drinking: A novel protective role of the amygdala

BackgroundResearch into neural mechanisms of drug abuse risk has focused on the role of dysfunction in neural circuits for reward. In contrast, few studies have examined the role of dysfunction in neural circuits of threat in mediating drug abuse risk. Although typically regarded as a risk factor for mood and anxiety disorders, threat-related amygdala reactivity may serve as a protective factor against substance use disorders, particularly in individuals with exaggerated responsiveness to reward.FindingsWe used well-established neuroimaging paradigms to probe threat-related amygdala and reward-related ventral striatum reactivity in a sample of 200 young adult students from the ongoing Duke Neurogenetics Study. Recent life stress and problem drinking were assessed using self-report. We found a significant three-way interaction between threat-related amygdala reactivity, reward-related ventral striatum reactivity, and recent stress, wherein individuals with higher reward-related ventral striatum reactivity exhibit higher levels of problem drinking in the context of stress, but only if they also have lower threat-related amygdala reactivity. This three-way interaction predicted both contemporaneous problem drinking and problem drinking reported three-months later in a subset of participants.ConclusionsThese findings suggest complex interactions between stress and neural responsiveness to both threat and reward mediate problem drinking. Furthermore, they highlight a novel protective role for threat-related amygdala reactivity against drug use in individuals with high neural reactivity to reward.

The neural signatures of distinct psychopathic traits

Recent studies suggest that psychopathy may be associated with dysfunction in the neural circuitry supporting both threat- and reward-related processes. However, these studies have involved small samples and often focused on extreme groups. Thus, it is unclear to what extent current findings may generalize to psychopathic traits in the general population. Furthermore, no studies have systematically and simultaneously assessed associations between distinct psychopathy facets and both threat- and reward-related brain function in the same sample of participants. Here, we examined the relationship between threat-related amygdala reactivity and reward-related ventral striatum (VS) reactivity and variation in four facets of self-reported psychopathy in a sample of 200 young adults. Path models indicated that amygdala reactivity to fearful facial expressions is negatively associated with the interpersonal facet of psychopathy, whereas amygdala reactivity to angry facial expressions is positively associated with the lifestyle facet. Furthermore, these models revealed that differential VS reactivity to positive versus negative feedback is negatively associated with the lifestyle facet. There was suggestive evidence for gender-specific patterns of association between brain function and psychopathy facets. Our findings are the first to document differential associations between both threat- and reward-related neural processes and distinct facets of psychopathy and thus provide a more comprehensive picture of the pattern of neural vulnerabilities that may predispose to maladaptive outcomes associated with psychopathy.

Ventral Striatum Reactivity to Reward and Recent Life Stress Interact to Predict Positive Affect

Stressful life events are among the most reliable precipitants of major depressive disorder; yet, not everyone exposed to stress develops depression. It has been hypothesized that robust neural reactivity to reward and associated stable levels of positive affect (PA) may protect against major depressive disorder in the context of environmental adversity. However, little empirical data exist to confirm this postulation. Here, we test the hypothesis that individuals with relatively low ventral striatum (VS) reactivity to reward will show low PA levels in the context of recent life stress, while those with relatively high VS reactivity will be protected against these potentially depressogenic effects. Differential VS reactivity to positive feedback was assessed using blood oxygen level-dependent functional magnetic resonance imaging in a sample of 200 nonpatient young adults. Recent life stress, current depressive symptoms, and PA were assessed via self-report. Linear regression models were used to investigate the moderating effects of VS reactivity on the relationship between recent stress and state PA across participants. Recent life stress interacted with VS reactivity to predict self-reported state PA, such that higher levels of life stress were associated with lower PA for participants with relatively low, but not for those with high, VS reactivity. These effects were independent of age, gender, race/ethnicity, trait PA, and early childhood trauma. The current results provide empirical evidence for the potentially protective role of robust reward-related neural responsiveness against reductions in PA that may occur in the wake of life stress and possibly vulnerability to depression precipitated by stressful life events.

Multilocus Genetic Profile for Dopamine Signaling Predicts Ventral Striatum Reactivity

Research integrating neuroimaging and molecular genetics has yielded important insights into how variability in brain chemistry predicts individual differences in brain function, behavior and related risk for psychopathology. However, existing studies have been limited by their focus on the independent effects of single polymorphisms with modest impact on brain chemistry. Here, we explored the effects of five functional polymorphisms affecting dopamine (DA) signaling on reward-related ventral striatum (VS) reactivity, measured with BOLD fMRI, in a sample of 69 Caucasians. We also compiled individual multilocus genetic profile scores reflecting the additive effects of alleles conferring relatively increased DA signaling across the five polymorphic loci: DAT1 9-repeat, DRD4 7-repeat, DRD2 -141C Del, DRD2 Taq1A C (A2), and COMT (158)Met. These multilocus DA profile scores accounted for 10.9% of the inter-individual variability in reward-related VS reactivity. In contrast, none of the individual polymorphisms accounted for significant variability. Our results show that biologically informed multilocus genetic profiles have unique promise as indices of variability in brain chemistry that may yield advances in mapping individual differences in behaviorally relevant brain function. In turn, such genetic profiles may fuel gene-environment interactions research establishing trajectories of risk for psychopathology.

Association between reward‐related activation in the ventral striatum and trait reward sensitivity is moderated by dopamine transporter genotype

The impact of individual differences on human reward processing has been a focus of research in recent years, particularly, as they are associated with a variety of neuropsychiatric diseases including addiction and attention-deficit/hyperactivity disorder. Studies exploring the neural basis of individual differences in reward sensitivity have consistently implicated the ventral striatum (VS) as a core component of the human reward system. However, the mechanisms of dopaminergic neurotransmission underlying ventral striatal activation as well as trait reward sensitivity remain speculative. We addressed this issue by investigating the triadic interplay between VS reactivity during reward anticipation using functional magnetic resonance imaging, trait reward sensitivity, and dopamine (DA) transporter genotype (40-bp 3'VNTR of DAT, SLC6A3) affecting synaptic DA neurotransmission. Our results show that DAT variation moderates the association between VS-reactivity and trait reward sensitivity. Specifically, homozygote carriers of the DAT 10-repeat allele exhibit a strong positive correlation between reward sensitivity and reward-related VS activity whereas this relationship is absent in the DAT 9-repeat allele carriers. We discuss the possibility that this moderation of VS-trait relation might arise from DAT-dependent differences in DA availability affecting synaptic plasticity within the VS. Generally, studying the impact of dopaminergic gene variations on the relation between reward-related brain activity and trait reward sensitivity might facilitate the investigation of complex mechanisms underlying disorders linked to dysregulation of DA neurotransmission.

Genetic variation in components of dopamine neurotransmission impacts ventral striatal reactivity associated with impulsivity

Individual differences in traits such as impulsivity involve high reward sensitivity and are associated with risk for substance use disorders. The ventral striatum (VS) has been widely implicated in reward processing, and individual differences in its function are linked to these disorders. Dopamine (DA) plays a critical role in reward processing and is a potent neuromodulator of VS reactivity. Moreover, altered DA signaling has been associated with normal and pathological reward-related behaviors. Functional polymorphisms in DA-related genes represent an important source of variability in DA function that may subsequently impact VS reactivity and associated reward-related behaviors. Using an imaging genetics approach, we examined the modulatory effects of common, putatively functional DA-related polymorphisms on reward-related VS reactivity associated with self-reported impulsivity. Genetic variants associated with relatively increased striatal DA release (DRD2 -141C deletion) and availability (DAT1 9-repeat), as well as diminished inhibitory postsynaptic DA effects (DRD2 -141C deletion and DRD4 7-repeat), predicted 9-12% of the interindividual variability in reward-related VS reactivity. In contrast, genetic variation directly affecting DA signaling only in the prefrontal cortex (COMT Val158Met) was not associated with variability in VS reactivity. Our results highlight an important role for genetic polymorphisms affecting striatal DA neurotransmission in mediating interindividual differences in reward-related VS reactivity. They further suggest that altered VS reactivity may represent a key neurobiological pathway through which these polymorphisms contribute to variability in behavioral impulsivity and related risk for substance use disorders.