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.

Fig. 1.

Main effect of COMT genotype during anticipation of reward with maximal uncertainty. (Left) Statistical maps showing BOLD fMRI responses in the ventral striatum, left superior PFC, and dorsolateral PFC overlaid onto structural MRI coronal and axial planes. (Right) Negative relationship between COMT val allele dosage (0_met/met, 1_val/met, or 2_val/val) and BOLD response in these brain regions during anticipation of reward with maximal uncertainty.

Fig. 2.

Main effect of DAT1 genotype during anticipation of reward with maximal uncertainty. (Top) Statistical maps showing BOLD fMRI responses in the bilateral caudate nuclei. More robust BOLD response was observed in 9-repeat carriers (including DAT1 9-repeat and 9/10) compared to 10-repeat individuals during reward anticipation. (Bottom) Statistical maps showing BOLD fMRI responses in the bilateral ventral striatum. Again, 9-repeat carriers exhibited higher BOLD response than 10-repeat individuals.

Fig. 3.

Interaction between COMT and DAT1 genotypes with COMT Met homozygous and DAT1 9-repeat homozygous subjects showing augmented neural response during anticipation of reward with maximal uncertainty. (Left) Statistical maps of the BOLD signal interaction showing stronger engagement of ventral striatum and anterior lateral PFC. (Right) Interaction between the COMT and DAT1 genotypes in the prefronto-striatal system during anticipation of reward. Combined heritable variation in dopamine neurotransmission associated with the COMT met/met and 9-repeat and 9/10 VNTR DAT1 alleles produces hyperresponsivity of the reward system.

Fig. 4.

Main effect of COMT genotype at the time of reward delivery (Outcome_{$20_All potentially rewarded slots} > Outcome_{$0_Slot_D} where slot_D denotes the slot machine with sure knowledge to get no reward). (Upper) Statistical maps showing BOLD fMRI responses in the OFC. (Lower) Negative relationship between COMT val allele dosage and OFC activation at the time of reward delivery.

Fig. 5.

Main effect of DAT1 genotype at the time of reward delivery. (Top) Statistical maps showing BOLD fMRI responses in the lateral prefrontal cortex. The graphs below show higher prefrontal BOLD signal in DAT1 9-repeat allele dosage compared to 10-repeat carriers at the time of reward delivery. (Bottom Left) Statistical map showing BOLD fMRI responses in the midbrain. (Bottom Right) Graph showing higher midbrain BOLD response in 9-repeat carriers as compared to 10-repeat individuals at the time of reward delivery.

Fig. 6.

Interaction between the COMT and DAT1 genotypes in the lateral PFC, midbrain, and OFC at the time of reward delivery. (Left: Top, Middle, Bottom) Statistical maps showing BOLD fMRI responses in the right lateral prefrontal cortex, midbrain, and right OFC. (Right: Top, Middle, Bottom) Effect of the interaction between COMT and DAT1 genotype on BOLD response in these brain regions at the time of reward delivery.