Access Type

Open Access Dissertation

Date of Award

January 2014

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry

First Advisor

Tiffany A. Mathews

Abstract

Brain-derived neurotrophic factor (BDNF) is an important neuromodulator that has implicated in regard to several neurological disorders, including alcohol addiction. BDNF is also an important modulator of dopamine (DA), a neurotransmitter that is heavily implicated in addiction with one of the DA rich brain regions being referred to as the reward center of the brain. One of the focuses in alcohol dependence research includes determining risk factors that make an individual more susceptible to becoming dependent. BDNF has been of interest as a risk factor due to its involvement in ethanol consumption and addiction evidenced in a vast number of studies using both human and animal models. The goal of this study was primarily to understand how low endogenous BDNF levels could lead a person to be more susceptible to alcohol dependence/ addiction. This was coupled with the goal of understanding ethanol's alterations on the striatal DA system. Using two different mouse models and both voluntary ethanol consumption along with acute exposure to ethanol via systemic injection several striatal alterations were observed. Seven days of voluntary binge-like ethanol consumption produce a tolerance to ethanol stimulation of DA release, which could be mediated by alterations in adenylyl cyclase (AC) isoforms. BDNF and its receptor (tyrosine kinase B, TrkB) are reduced in WT mice, but not in BDNF-deficient mice following DID. The alterations observed with BDNF and TrkB could have important implications for the continued used of the DID model. Finally using double-knockout animals that lack AC1 and AC8 it was shown that these isoforms are necessary for ethanol-stimulation of DA. Together these findings show how quickly neuroadaptations can occur following ethanol exposure and provide several avenues for future investigations.

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