Behavioral and Neural Manifestations of Reward Memory in Carriers of Low-Expressing versus High-Expressing Genetic Variants of the Dopamine D2 Receptor

Abstract

Dopamine is critically important in the neural manifestation of motivated behavior, and alterations in the human dopaminergic system have been implicated in the etiology of motivation-related psychiatric disorders, most prominently addiction. Patients with chronic addiction exhibit reduced dopamine D2 receptor (DRD2) availability in the striatum, and the DRD2 TaqIA (rs1800497) and C957T (rs6277) genetic polymorphisms have previously been linked to individual differences in striatal dopamine metabolism and clinical risk for alcohol and nicotine dependence. Here, we investigated the hypothesis that the variants of these polymorphisms would show increased reward-related memory formation, which has previously been shown to jointly engage the mesolimbic dopaminergic system and the hippocampus, as a potential intermediate phenotype for addiction memory. To this end, we performed functional magnetic resonance imaging (fMRI) in 62 young, healthy individuals genotyped for DRD2 TaqIA and C957T variants. Participants performed an incentive delay task, followed by a recognition memory task 24 h later. We observed effects of both genotypes on the overall recognition performance with carriers of low-expressing variants, namely TaqIA A1 carriers and C957T C homozygotes, showing better performance than the other genotype groups. In addition to the better memory performance, C957T C homozygotes also exhibited a response bias for cues predicting monetary reward. At the neural level, the C957T polymorphism was associated with a genotype-related modulation of right hippocampal and striatal fMRI responses predictive of subsequent recognition confidence for reward-predicting items. Our results indicate that genetic variations associated with DRD2 expression affect explicit memory, specifically for rewarded stimuli. We suggest that the relatively better memory for rewarded stimuli in carriers of low-expressing DRD2 variants may reflect an intermediate phenotype of addiction memory.

Keywords: C957T; TaqIA; dopamine D2 receptor; episodic memory; fMRI; intermediate phenotype; reward.

FIGURE 1

Effects of the C957T polymorphism on behavioral and fMRI correlates of reward memory. (A) Significant behavioral C957T genotype effects on episodic memory performance. Bar plots depict overall corrected hit rates (left) and familiarity estimates (middle) with standard errors. The C957T C allele is associated with an overall higher recognition performance. The box plot (right) depicts differential confidence rating medians (rewarded vs. neutral) in the monetary reward category. Horizontal lines represent the medians, the box represents the 25th and 75th percentiles, the whiskers indicate the 5th and 95th percentiles, dots mark outliers, and the colored asterisks indicate the extremes. Lower values of the C homozygotes indicate a bias to declare rewarded as compared to neutral items as old, independent of their actual item type. ^∗p < 0.05. (B) Neural manifestations of the interaction between C957T genotype and reward category during encoding. Significant interactions of C957T genotype and reward category in right hippocampus (green) and striatum (blue). Statistical F-map and ROIs for small volume alpha error correction overlaid on a mean anatomical image. L, left; R, right.