The development of alcohol use disorders involves a transition from casual drinking, to inflexible habitual drinking. Habitual alcohol seeking is no longer mediated by the reinforcing properties of alcohol but rather by drug-paired cues. Our preliminary data suggest that chronic intermittent exposure to ethanol results in rapid formation of alcohol habits - that is, mice chronically exposed to alcohol become unable to flexibly regulate alcohol seeking behavior. Considerable research has highlighted the role of the PFC in regulating the development and expression of stimulus-response habits. In particular, the infralimbic PFC (IL) has been shown to be required for habit formation. Recent data suggest that mGluR2 expression in corticolimbic circuits may be dysregulated after chronic exposure to alcohol. The current proposal is designed to test the novel hypothesis that decreased expression of mGluR2 on IL projection neurons mediates the rapid transition to stimulus-response habits induced by chronic alcohol exposure. We believe that reductions in IL mGluR2 expression result in enhanced IL glutamatergic signaling in subcortical targets, therefore promoting premature expression of habitual reward seeking. Our preliminary data suggest that systemic enhancement of mGluR2 signaling can restore goal-directed alcohol seeking after the transition to habitual alcohol seeking.
Aim 1 is designed to confirm the effects of chronic alcohol exposure on habitual ethanol seeking, and to assess the specificity of these effects to alcohol seeking habits. These data are critical for understanding whether chronic alcohol-induced alterations in corticolimbic circuitry promote a general deficit in flexible behavior, or if these effects are specific to alcohol seeking.
Aim 2 is designed characterize the full extent of chronic alcohol induced mGluR2 reduction in IL circuitry using cell tracing and immunohistochemical techniques.
In Aim 3 we will employ pharmacological and optogenetic techniques using a novel photoswitch to demonstrate a causal role for IL mGluR2 signaling in the restoration of goal-directed ethanol seeking. Finally, we will test the hypothesis that loss of mGluR2 signaling is required for the CIE-induced acceleration of the development of alcohol- seeking habits through the use of viral overexpression of mGluR2 in the IL PFC. The results of these studies are expected to provide considerable information about the effects of chronic alcohol exposure on behavioral flexibility, and further, the mechanisms through which this loss can be restored. We believe that the knowledge gained from these experiments will provide insight into the mechanisms of the development of alcohol use disorders that will ultimately inform the development of novel prevention and therapeutic strategies.

Public Health Relevance

The development of alcohol use disorders results in part from the inability to control and regulate alcohol seeking. Though habitual behavior occurs over time and repeated performance, our data suggest that chronic ethanol exposure itself results in premature expression of inflexible, habitual alcohol-seeking behaviors, but the neurobiological mechanism through which this occurs is unclear. The project proposed in the current application will examine alcohol exposure-induced alterations in the limbic corticostriatal circuitry that mediate the expression of flexible, goal-directed reward seeking, specifically focusing on dependence-induced alterations in glutamate signaling.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Postdoctoral Individual National Research Service Award (F32)
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Biomedical Research Review Subcommittee (AA)
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Regunathan, Soundar
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Medical University of South Carolina
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Barker, Jacqueline M; Bryant, Kathleen G; Osborne, Jennifer I et al. (2017) Age and Sex Interact to Mediate the Effects of Intermittent, High-Dose Ethanol Exposure on Behavioral Flexibility. Front Pharmacol 8:450
Barker, Jacqueline M; Taylor, Jane R (2017) Sex differences in incentive motivation and the relationship to the development and maintenance of alcohol use disorders. Physiol Behav :
Barker, Jacqueline M; Lench, Daniel H; Chandler, L Judson (2016) Reversal of alcohol dependence-induced deficits in cue-guided behavior via mGluR2/3 signaling in mice. Psychopharmacology (Berl) 233:235-42
Barker, Jacqueline M; Taylor, Jane R; De Vries, Taco J et al. (2015) Brain-derived neurotrophic factor and addiction: Pathological versus therapeutic effects on drug seeking. Brain Res 1628:68-81
Barker, Jacqueline M; Corbit, Laura H; Robinson, Donita L et al. (2015) Corticostriatal circuitry and habitual ethanol seeking. Alcohol 49:817-24