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Dopamine Transporter Gene Methylation is Associated with Nucleus Accumbens Activation During Reward Processing in Healthy but not Alcohol‐Dependent Individuals
Author(s) -
Muench Christine,
Wiers Corinde E.,
Cortes Carlos R.,
Momenan Reza,
Lohoff Falk W.
Publication year - 2018
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.13526
Subject(s) - dopamine transporter , nucleus accumbens , methylation , functional magnetic resonance imaging , anticipation (artificial intelligence) , dopamine , striatum , endocrinology , medicine , dna methylation , psychology , biology , neuroscience , gene expression , genetics , gene , dopaminergic , artificial intelligence , computer science
Background Alcohol's reinforcement is mediated by dopamine signaling in the ventral striatum, which is modulated by the dopamine transporter ( DAT ). We hypothesized that methylomic variation in the DAT gene ( DAT1/SLC 6A3 ) affects DAT expression, thus contributing to differences in brain reward circuitry in individuals with alcohol dependence ( ALC ). Methods Blood from 45 recently detoxified ALC and 45 healthy control ( HC ) individuals was used to assess DNA methylation across 5 functional regions of SLC 6A3 . Participants completed the monetary incentive delay task in a 3‐Tesla magnetic resonance imaging (MRI) scanner. Employing regression models, we examined effects of SLC 6A3 methylation on nucleus accumbens ( NA c) blood‐oxygen‐level dependent ( BOLD ) responses during anticipation of high/low reward/loss. Results Results showed that decreased methylation of the promoter region of SLC 6A3 predicted NA c activation during high loss anticipation ( p = 0.028) and low loss anticipation (at trend‐level; p = 0.057) in HC but not in individuals with ALC . Specifically, percentage of methylation at 2 CpG sites, located −1,001 and −993 base pairs from the transcription start site, accounted for significant variability in NA c activation in the HC group during high ( p s ≤ 0.010) and low ( p s ≤ 0.006) loss anticipation. There was no effect on reward anticipation. Furthermore, promoter methylation was positively associated with age, which replicates previous findings. Conclusions Our data suggest that methylation in the promoter region of SLC 6A3 predicts NA c activation during the anticipation of monetary loss in HC s. However, this effect was not present in the ALC group, suggesting that epigenetic regulation of striatal DAT expression might be disrupted in ALC , which may contribute to previously reported differences in sensitivity to reward and punishment in this population. Alternatively, it is possible that a similar relationship in the ALC group remained undetected possibly due to methodological limitations inherent in functional MRI (e.g., poor spatial resolution, low signal‐to‐noise ratio) that generally restrict interpretations regarding mechanisms of epigenetic factors involved in group differences in BOLD responses. Future neuroimaging studies are needed to further elucidate the relationship between SLC 6A3 methylation and NA c activation in ALC .