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.
Highlights
Dopamine (DA) is crucially involved in motivated behavior, and dysfunctional dopaminergic neurotransmission has been implicated in the pathophysiology of neuropsychiatric disorders like schizophrenia and substance dependence (Heinz and Schlagenhauf, 2010)
Among the 62 participants, we identified three A1 homozygotes, 28 heterozygotes, and 31 A2 homozygotes of the TaqIA polymorphism
As TaqIA and C957T are in linkage disequilibrium (LD), a combined analysis was conducted
Summary
Dopamine (DA) is crucially involved in motivated behavior, and dysfunctional dopaminergic neurotransmission has been implicated in the pathophysiology of neuropsychiatric disorders like schizophrenia and substance dependence (Heinz and Schlagenhauf, 2010). The DRD2 gene on Chr 11q23.2, which encodes the dopamine D2 receptor, harbors several genetic variants previously linked to variability of D2 receptor expression as well as individual differences in motivated behavior and risk for psychiatric disorders. A common single nucleotide polymorphism (SNP, rs1800497; minor allele frequency 0.33 in dbSNP) located in the neighboring ANKK1 gene, known as TaqIA polymorphism, has repeatedly been linked to reduced striatal D2 receptor expression in A1 allele carriers in both post mortem expression investigations and in vivo radioligand binding studies using Positron emission tomography (PET; Noble et al, 1991; Thompson et al, 1997; Pohjalainen et al, 1998; Jonsson et al, 1999; Ritchie and Noble, 2003; Hirvonen et al, 2009a). Haplotypes containing both polymorphisms have been associated with impulsivity-related psychiatric disorders, most prominently addiction (Morton et al, 2006; Doehring et al, 2009; Voisey et al, 2012)
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