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Variation in dopamine genes influences responsivity of the human reward system.

ABSTRACT: In humans, dopamine neurotransmission is influenced by functional polymorphisms in the dopamine transporter (DAT1) and catechol-O-methyltransferase (COMT) genes. Here, we used event-related functional magnetic resonance imaging to directly investigate the neurofunctional effects of the Val(158)Met COMT and variable number of tandem repeat DAT1 polymorphisms on distinct components of the reward system in humans. The results revealed a main effect of COMT genotype in the ventral striatum and lateral prefrontal cortex during reward anticipation (P < 0.001, uncorrected) and in the orbitofrontal cortex at the time of reward delivery (P < 0.005), met/met individuals exhibiting the highest activation. The main effect of DAT1 genotype was seen in robust blood-oxygen-level-dependent response differences in the caudate nucleus and ventral striatum during reward anticipation (P < 0.001) and in the lateral prefrontal cortex and midbrain at the time of reward delivery, with carriers of the DAT1 9-repeat allele showing the highest activity. Moreover, an interaction between the COMT and DAT1 genes was found in the ventral striatum and lateral prefrontal cortex during reward anticipation and in the lateral prefrontal and orbitofrontal cortices as well as in the midbrain at the time of reward delivery, with carriers of the DAT1 9-repeat allele and COMT met/met allele exhibiting the highest activation, presumably reflecting functional change consequent to higher synaptic dopamine availability. Taken together, these results indicate that genetically influenced variations in dopamine transmission modulate the response of brain regions involved in anticipation and reception of rewards and suggest that these responses may contribute to individual differences in reward-seeking behavior and in predisposition to neuropsychiatric disorders.

SUBMITTER: Dreher JC

PROVIDER: S-EPMC2626752 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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Variation in dopamine genes influences responsivity of the human reward system.

Dreher Jean-Claude JC Kohn Philip P Kolachana Bhaskar B Weinberger Daniel R DR Berman Karen Faith KF

Proceedings of the National Academy of Sciences of the United States of America 20081222 2

In humans, dopamine neurotransmission is influenced by functional polymorphisms in the dopamine transporter (DAT1) and catechol-O-methyltransferase (COMT) genes. Here, we used event-related functional magnetic resonance imaging to directly investigate the neurofunctional effects of the Val(158)Met COMT and variable number of tandem repeat DAT1 polymorphisms on distinct components of the reward system in humans. The results revealed a main effect of COMT genotype in the ventral striatum and later ...[more]

PMID: 19104049

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Project description:Dopamine is important to learning and plasticity. Dopaminergic drugs are the focus of many therapies targeting the motor system, where high inter-individual differences in response are common. The current study examined the hypothesis that genetic variation in the dopamine system is associated with significant differences in motor learning, brain plasticity, and the effects of the dopamine precursor L-Dopa. Skilled motor learning and motor cortex plasticity were assessed using a randomized, double-blind, placebo-controlled, crossover design in 50 healthy adults during two study weeks, one with placebo and one with L-Dopa. The influence of five polymorphisms with established effects on dopamine neurotransmission was summed using a gene score, with higher scores corresponding to higher dopaminergic neurotransmission. Secondary hypotheses examined each polymorphism individually. While training on placebo, higher gene scores were associated with greater motor learning (p = .03). The effect of L-Dopa on learning varied with the gene score (gene score*drug interaction, p = .008): participants with lower gene scores, and thus lower endogenous dopaminergic neurotransmission, showed the largest learning improvement with L-Dopa relative to placebo (p<.0001), while L-Dopa had a detrimental effect in participants with higher gene scores (p = .01). Motor cortex plasticity, assessed via transcranial magnetic stimulation (TMS), also showed a gene score*drug interaction (p = .02). Individually, DRD2/ANKK1 genotype was significantly associated with motor learning (p = .02) and its modulation by L-Dopa (p<.0001), but not with any TMS measures. However, none of the individual polymorphisms explained the full constellation of findings associated with the gene score. These results suggest that genetic variation in the dopamine system influences learning and its modulation by L-Dopa. A polygene score explains differences in L-Dopa effects on learning and plasticity most robustly, thus identifying distinct biological phenotypes with respect to L-Dopa effects on learning and plasticity. These findings may have clinical applications in post-stroke rehabilitation or the treatment of Parkinson's disease.

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Variation in dopamine genes influences responsivity of the human reward system.

Publications

Variation in dopamine genes influences responsivity of the human reward system.

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