Alcohol Dependence and the Epigenetic Mediation of Dopaminergic Striatal CIrcuits

Alcohol cue reactivity, demonstrated by ventral and dorsal striatum activation, is an established marker of alcohol dependence (AD) and can be predictive of treatment outcomes. These divisions of the striatum serve separate functions underlying an individual\u27s response to alcohol cues: the ventral striatum is part of the reward circuit, while the dorsal striatum is part of the habit circuit. Neuroadaptations in response to alcohol consumption in both circuits occur via changes in Dopamine D2 receptors (D2Rs). We hypothesized that dorsal striatal activation during anticipation of the taste of alcohol would differentiate 30 AD cases from 30 controls. No differences in ventral or dorsal striatal activation were found. However, a significant difference between AD cases and controls was found in the activation of the dorsal Anterior Cingulate Cortex (dACC), such that AD cases had much more activation in this area when anticipating the taste of alcohol than controls. A psycho-physiological interaction (PPI) functional connectivity analysis was performed to determine if this dACC activation difference was driven by reward or habit circuit activation (i.e., ventral or dorsal striatal activity). With the dACC as the seed region, no connectivity differences within either division of the striatum were found between the AD cases and controls. Next, a linear analysis was performed in 266 heavy drinkers to see if (1) individual differences in anticipation-related connectivity would be related to AD severity, and (2) to test the hypothesis that individual differences in dACC- striatal connectivity are mediated by methylation of the dopamine D2 receptor gene (DRD2). Methylation is one cellular mechanism that can affect D2R down regulation in the reward and habit circuits. No relationship between AD symptomology, DRD2 gene methylation levels, and dACC-striatal connectivity were found. These results suggest further study of the unique role of the dACC as both (1) a task-positive reward and habit circuit modulator and (2) as a node of the dorsal default mode network (dDMN). Also, dACC dopaminergic activity could be supplemented pharmacologically by indirect dopamine agonists, such as lisdexfetamine. Increased DA in the dACC when faced with salient alcohol cues could assist in recovery from AD