A key issue in the alcohol field is identification of the neuronal circuits responsible for the loss of control over alcohol drinking in dependence. Loss of control has long been hypothesized to result from dysfunction of the frontal lobes and subsequent disinhibition (or activation) of subcortical systems that underlie stress, anxiety, reward, pain, and habits. Recent work has also causally implicated an ensemble in the central nucleus of the amygdala as required for excessive drinking and anxiety-like behavior during abstinence. The goal of the Neurocircuitry Component is to integrate these views by identifying the cortical pathways upstream (cortico- amygdalar) and downstream (amygdalo-cortical) of the CeA that contribute to the compulsivity of alcohol- drinking and negative emotional behavior. The first hypothesis in this proposal is that reduced infralimbic and greater anterior insula glutamatergic outflow to the amygdala promotes more compulsive drinking, with greater anxiety- and irritability-like behavior in abstinence. Reciprocally, the second hypothesis is that dysregulation of the prefrontal cortex partially results from activation of a neuronal ensemble in the CeA that promotes compulsive alcohol drinking and abstinence symptoms via recruitment of direct and indirect amygdalo-cortical projections to the infralimbic cortex and anterior insula. The third hypothesis is that dysregulated activation in cortico-amygdalo-cortical loops can be normalized by a selective glucocorticoid receptor antagonist or microtubule-associated protein-type 2 (MAP-2) ligand. This project may have a sustained and powerful impact on the field by (1) causally implicating specific cortico-amygdalo-cortico loops in the compulsivity of alcohol drinking and emergence of negative emotional states during abstinence and 2) identifying a circuit mechanism for the efficacy of glucocorticoid receptor antagonists and MAP-2 ligands to reduce drinking and negative emotional symptoms.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Comprehensive Center (P60)
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Special Emphasis Panel (ZAA1)
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Scripps Research Institute
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