DRD2 promoter methylation and measures of alcohol reward: functional activation of reward circuits and clinical severity

• Published in: Addiction biology Vol. 24; no. 3; pp. 539 - 548
• Main Authors: Bidwell, L. Cinnamon, Karoly, Hollis C., Thayer, Rachel E., Claus, Eric D., Bryan, Angela D., Weiland, Barbara J., YorkWilliams, Sophie, Hutchison, Kent E.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01-05-2019
• Subjects: Adult; alcohol dependence; Alcohol Drinking - physiopathology; Alcohol Drinking - psychology; Alcohol use; Alcoholism - physiopathology; Alcoholism - psychology; Brain - metabolism; Brain mapping; Cues; DNA methylation; DNA Methylation - physiology; Dopamine D2 receptors; DRD2; Drug dependence; Epigenetics; Female; fMRI; Functional magnetic resonance imaging; Functional morphology; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Molecular modelling; Neostriatum; Neuroimaging; Nucleus accumbens; Promoter Regions, Genetic - drug effects; Putamen; Receptors, Dopamine D2 - drug effects; Receptors, Dopamine D2 - metabolism; Reinforcement; Reward; striatum; Substance use; Taste - physiology; Young Adult; DNA methylation; fMRI; striatum; DRD2; alcohol dependence; epigenetics
• ISSN: 1355-6215; 1369-1600
• DOI: 10.1111/adb.12614

Studies have identified strong associations between D2 receptor binding potential and neural responses to rewarding stimuli and substance use. Thus, D2 receptor perturbations are central to theoretical models of the pathophysiology of substance dependence, and epigenetic changes may represent one of the fundamental molecular mechanisms impacting the effects of alcohol exposure on the brain. We hypothesized that epigenetic alterations in the promoter region of the dopamine D2 receptor (DRD2) gene would be associated with cue‐elicited activation of neural reward regions, as well as severity of alcohol use behavior. The current study leveraged functional neuroimaging (fMRI) during an alcohol reward paradigm (n = 383) to test associations among DRD2 promoter methylation in peripheral tissue, signal change in the striatum during the presentation of alcohol cues, and severity of alcohol use disorder (AUD). Controlling for age, DRD2 promoter methylation was positively associated with responses to alcohol cues in the right accumbens (partial r = 0.144, P = 0.005), left putamen (partial r = 0.133, P = 0.009), right putamen (partial r = 0.106, P = 0.039), left caudate (partial r = 0.117, P = 0.022), and right caudate (partial r = 0.133, P = 0.009), suggesting that DRD2 methylation was positively associated with robust activation in the striatum in response to reward cues. DRD2 methylation was also positively associated with clinical metrics of AUD severity. Specifically, controlling for age, DRD2 methylation was associated with Alcohol Use Disorders Identification Test total (partial r = 0.140, P = 0.002); Impaired Control Scale total (partial r = 0.097, P = 0.044) and Alcohol Dependence Scale total (partial r = 0.152, P = 0.001). Thus, DRD2 methylation may be a critical mechanism linking D2 receptors with functional striatal brain changes and clinical severity among alcohol users.
D2 receptor perturbations are central to theoretical models of alcohol use disorder, and D2 receptor gene (DRD2) epigenetic changes may represent one of the fundamental molecular mechanisms impacting the effect of alcohol exposure on the brain. Leveraging functional neuroimaging during an alcohol reward paradigm in a large sample (n = 383), associations were shown among DRD2 promoter methylation, signal change in the striatum during the presentation of alcohol cues, and the severity of alcohol use disorder.