Date of Award

2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

College

College of Graduate Studies

First Advisor

Howard C. Becker

Second Advisor

L. Judson Chandler

Third Advisor

Colleen A. Hanlon

Fourth Advisor

Jacqueline F. McGinty

Fifth Advisor

Carmela M. Reichel

Abstract

Alcoholism is a widespread public health concern with limited therapeutic interventions available to help individuals battle relapse, moderate their use, and sustain abstinence. While many variables contribute to relapse vulnerability, stress is considered to play a prominent role in triggering relapse. The neuropeptide oxytocin (OXT) has recently been implicated in a number of neuropsychiatric disorders, including drug and alcohol use disorders. Given that OXT is known to interact with brain reward systems and exert anxiolytic and anti-stress effects in humans and rodents, the main overall hypothesis of this dissertation is that OXT (and OXT receptor signaling) will be effective in reducing alcohol consumption and stress-induced alcohol relapse-like behavior. We demonstrate that systemic administration of OXT reduced binge-like alcohol drinking, operant oral self-administration of alcohol, and stress-induced relapse-like behavior in a dose-related manner in male and female mice. Targeted chemogenetic activation of OXT neurons in the paraventricular nucleus of the hypothalamus (PVN) reduced binge-like alcohol drinking and operant oral self-administration in a similar manner as systemic administration of the neuropeptide and this effect was reversed by pretreatment with the centrally-active OXTR antagonist in males. Finally, administration of an OXTR antagonist systemically and directly into the central amygdala blocked the effects of OXT on stress-induced alcohol relapse-like behavior in male, but not female mice. These data highlight potential sex differences in oxytocin receptor signaling and support the therapeutic potential for OXT in treating alcohol use disorder.

Rights

All rights reserved. Copyright is held by the author.

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