Relapse-like drinking following stress hormone exposure

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Besheer, J and Jaramillo, AA

Bowles Center for Alcohol Studies, Department of Psychiatry, University of North Carolina-Chapel Hill, United States

Chronic exposure to the stress hormone corticosterone (CORT) in the drinking water results in reduced sensitivity to the interoceptive effects of alcohol and increased alcohol self-administration. We sought to investigate whether a history of CORT exposure would impact relapse-like behavior following an abstinence period. Long Evans rats were trained to self-administer alcohol (15% v/v+2% sucrose (w/v)). Following self-administration training, rats were exposed to CORT in the drinking water (0.3 mg/ml) or water-only for 7 days. During this time self-administration training was withheld. Following the end of CORT exposure, rats remained in the home cage for another 7 days (i.e., 14 day total abstinence period). On the test day, relapse-like behavior (both seeking and reinstatement of drinking) was examined. Rats with a history of CORT, showed increased alcohol-seeking behavior and potentiated reinstatement of self-administration relative to the Water controls. In order to examine potential mechanism underlying this CORT-induced increase in relapse-like behavior, we examined the potential role of Group II metabotropic glutamate receptors (mGluR2/3). Interestingly, mGluR2/3 activation by LY379268 significantly reduced the relapse-like behavior in rats with the history of CORT exposure, but did not alter behavior in the Water controls. To begin to examine brain regional involvement we utilized a chemogenetic approach in which hM4D(Gi) Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) were used to silence the insular cortex. The insular cortex was selected based on its role in integrating sensitivity to cues to affect motivated behavior. Inactivation of the insular cortex following activation of the DREADDs by clozapine-N-oxide, resulted in reduced relapse-like behavior in the rats with a history of CORT exposure. Together, these results suggest that experiencing an episode of heightened stress hormone levels potentiate relapse-like drinking behavior, and identify targets that may be efficacious in reversing these maladaptive alcohol-related behaviors. Supported by: AA019682