The development of alcohol addiction is increasingly viewed as involving transition from controlled and regulated consumption to uncontrolled drinking characterized as compulsive and habitual. Recent studies in human alcoholics and animal models have suggested that chronic alcohol exposure may induce neurobiological changes in corticostriatal circuits. These changes may underlie deficits in the ability to engage goal-directed processes that normally function to suppress habitual actions. Consistent with this, evidence also indicates that addiction is associated with an inability of the prefrontal cortex (PFC) to exert appropriate inhibitory control over drug-taking and drug-seeking behaviors. Support for this comes from human imaging studies that reveal alterations in prefrontal cortex and striatal brain regions in individuals with alcohol use disorder (AUD) as compared to controls. Published and unpublished preliminary data further demonstrate that chronic intermittent ethanol (CIE) exposure can facilitate the transition from flexible goal-directed drinking to inflexible habitual drinking. Our preliminary data in mice demonstrates that CIE-induced facilitation of habitual responding for alcohol can be reversed by chemogenetic inactivation of the infralimbic (IfL) cortex, a sub-region of the mPFC that is roughly equivalent to the ventromedial PFC of humans. The overarching hypothesis of this ARC research project is that repeated cycles of CIE exposure facilitates the expression of habitual responding for alcohol, and that changes in activity of specific ensembles of neurons in the mPFC plays a critical role in this process. It is further hypothesized that compromised dopamine (DA) modulation of prefrontal function contributes to this CIE-induced transition to habitual drinking. The following three specific aims will test this overarching hypothesis in the ARC mouse model of dependence-induced excessive, habit- like drinking:
Aim 1 will test the hypothesis that dependence-induced facilitation of habitual responding for alcohol is associated with changes in population activity and network organization in the IfL cortex.
Aim 2 will test the hypothesis that DA D1 and D2 receptor-expressing neurons in the IfL cortex modulate dependence- induced facilitation of the expression of habitual responding for alcohol.
Aim 3 will test the hypothesis that dependence-induced facilitation of habitual responding for alcohol is associated with alterations in the biophysical properties of DA D1 and D2 receptor-expressing neurons in the IfL cortex. Together, these studies will address the gap in our knowledge concerning the differential role of PFC-striatal subcircuits in the transition from flexible goal-directed to inflexible habitual drinking, and will identify novel therapeutic targets for more effective treatment of AUD.

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National Institute on Alcohol Abuse and Alcoholism (NIAAA)
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Medical University of South Carolina
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