Date of Award

2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Howard C. Becker

Second Advisor

Jacqueline McGinty

Third Advisor

John Woodward

Fourth Advisor

Patrick Mulholland

Fifth Advisor

Colleen Hanlon

Abstract

Alcohol use disorder (AUD) continues to be a burden to society. Currently, few efficacious treatments exist. In addition to behavioral therapy and support groups (e.g. Alcoholics Anonymous), there are only three FDA approved pharmacotherapies. The lack of treatment options for alcohol addiction denotes the need to discover and develop new strategies and pharmacological targets to improve abstinence, prevent relapse, and inhibit the development of alcohol addiction. Chronic alcohol exposure reduces brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex (mPFC). Reductions of BDNF in the mPFC drive alcohol-dependent drinking in mice and conversely, elevating BDNF in this region blocks alcohol dependence-related drinking. Therefore, enhancing TrkB (BDNF primary receptor) activity in the mPFC, by pharmacological activation or increased expression of BDNF via exercise, may provide a new treatment strategy for AUD. To engender alcohol dependence mice are exposed to repeated cycles of chronic intermittent ethanol (CIE) vapor, producing escalated alcohol drinking compared to Baseline and control (Air) mice. Additionally, deficits in Bdnf mRNA and protein are seen in the mPFC after CIE exposure. Exercise (wheel running) noninvasively induces BDNF expression in the dentate gyrus (DG) of rodents and in the blood of humans. This information led to the question of whether exercise could increase BDNF in the mPFC, reduce alcohol dependence-related drinking, and if this effect would occur through a BDNF-TrkB mediated mechanism. Studies tested the hypothesis that: Daily, limited (2-hr) voluntary wheel running would increase BDNF expression in the brain and through BDNF-TrkB signaling, attenuate CIE-induced escalated alcohol drinking. Following the Introduction, Chapter 2 demonstrates mice given limited access to a running wheel every day for several weeks, show increased Bdnf mRNA (qRT-PCR) and BDNF protein (ELISA) expression in the mPFC and DG. Building on these findings, Chapter 3 shows exercise attenuates CIE induced escalated alcohol drinking and mitigates reductions of BDNF mRNA in the mPFC caused by chronic alcohol exposure. Finally, in Chapter 4, using pharmacological inhibition of TrkB receptors, the ability of exercise to attenuate escalated alcohol intake is prevented. Taken together this study demonstrates exercise attenuates escalated alcohol intake in a model of dependence via BDNF-TrkB mediated signaling.

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