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

Molecular Psychiatry, Sep 2007

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.

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

Abstract 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. Introduction Interindividual variability in overlapping psychological constructs, such as self-regulation, impulse control, delay of gratification and intertemporal choice,1 has been associated with the likelihood of engaging in addictive behaviors (for example, cigarette smoking) and of developing related psychopathologies, such as pathological gambling, and drug and alcohol abuse.2, 3, 4, 5 Thus, such individual tendencies represent important intermediate behavioral phenotypes of predictive utility which offer traction in the search for pathways mediating risk for addiction and related disorders. Explication of the underlying neural processes that give rise to such interindividual variability will similarly allow for a more comprehensive understanding of the mechanisms leading to not only normal variability in such behaviors but also the pathophysiology of addiction. Through reciprocal cortical and subcortical connections, the nucleus accumbens and, more broadly, the ventral striatum (VS) contribute to the motivational salience of stimuli and abet appetitive or reward-dependent behaviors.6 The magnitude of VS reactivity predicts individual differences in simple laboratory indices of preference for immediate over delayed rewards7 as well as more complex measures of incentive-based decision-making.8 Moreover, dysregulation of the VS contributes to addiction, perhaps by affecting impulsive decision-making.9 Therefore, interindividual variability in VS reactivity to reward-related stimuli likely contributes to the emergence of differences in the intermediate behavioral risk factors for, as well as the clinical expression of, addictions. Dopamine (DA) modulation of neuronal activity, especially in the VS (that is, the mesolimbic system), serves as a nexus for the expression of DA signaling at the level of reward-related behaviors.10, 11 Functioning of the DA system has been linked to normal individual differences in reward-related traits,12 and disorders involving enhanced reward-seeking, such as addiction, have been hypothesized to reflect maladaptive alterations of this mesolimbic reward system.13, 14 As such, identifying factors that determine interindividual variability in DA signaling and its related impact on the reactivity of the VS will facilitate our understanding of the neurobiological mechanisms governing reward-related behaviors and augment efforts to improve the treatment and even prevention of pathological behaviors such as drug abuse and addiction. In the current study, we used imaging genetics15 to explore the role of altered DA signaling, resulting from DA-related genetic polymorphisms, in determining interindividual variability in reward-related VS reactivity and correlated variability in behavioral impulsivity. Reward-related VS reactivity was determined via blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) while subjects completed a simple number-guessing game resulting in positive and negative feedback in the context of monetary reward. Importantly, we have successfully employed this challenge paradigm to explore the relationship between interindividual variability in VS reactivity and delay dis (...truncated)


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E E Forbes, S M Brown, M Kimak, R E Ferrell, S B Manuck, A R Hariri. Genetic variation in components of dopamine neurotransmission impacts ventral striatal reactivity associated with impulsivity, Molecular Psychiatry, 2007, pp. 60-70, Issue: 14, DOI: 10.1038/sj.mp.4002086