Abstract

Alcohol represents the third leading cause of preventable death in the United States. Yet, despite its prevalent role in impeding human health, there is much to understand about how it elicits its effects on the body and how the body and brain change when an individual becomes physiologically dependent upon alcohol. The work presented herein represents an effort to elucidate the acute and chronic effects of alcohol on the nervous system. We investigate two specific protein pathways and their role in alcohol's effects on the body. The first begins with brain-derived neurotrophic factor (BDNF), which acts on TrkB, and ends with KCC2. We demonstrate that BDNF expression is increased in the VTA during withdrawal from chronic but not acute alcohol exposure and that this increase persists for at least seven days. Concomitantly, we demonstrate that the activation of GABAA channels on produces less inhibition of VTA GABA neurons in mice treated with chronic intermittent ethanol exposure than in alcohol naïve mice. This effect likewise persisted for at least seven days. We illustrate that BDNF has no apparent direct effect on VTA GABA neuron firing rate. The second pathway begins with the T cell marker CD5 and ends with the anti-inflammatory cytokine, IL-10. We demonstrate that in a genetic CD5 knockout (CD5 KO) mouse model both alcohol consumption as well as the sedative properties of alcohol are reduced. Since CD+ B cells secrete more IL-10 than CD5- B cells, we also demonstrate the effects of IL-10 on VTA neurons. We show that IL-10 has direct effects on VTA dopamine (DA) neurons by increasing their firing activity. We relatedly illustrate that IL-10 produces an increase in DA release in the nucleus accumbens (NAc). However, contrary to our hypotheses, we show that IL-10 produces conditioned place aversion rather than conditioned place preference in a place conditioning paradigm, suggesting that IL-10 might mediate pain-induced secretions of DA. Collectively, these results suggest two potential therapeutic targets to reduce alcohol consumption that need further validation. They also suggest a novel mechanism for the sedative effects of alcohol at moderate and high doses.

Degree

PhD

College and Department

Family, Home, and Social Sciences

Rights

https://lib.byu.edu/about/copyright/

Date Submitted

2020-08-07

Document Type

Dissertation

Handle

http://hdl.lib.byu.edu/1877/etd11417

Keywords

alcohol, ethanol, addiction, dependence, BDNF, TrkB, KCC2, CD5, IL-10, cytokine, VTA, GABA, NAc

Language

English

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