Abstract

The purpose of this thesis project was to examine the effects of chronic alcohol on the excitability and molecular adaptation of GABA neurons of the ventral tegmental area (VTA). GABA neurons are of interest with regards to ethanol intoxication, reinforcement, and dependence due to their widespread distribution and connectivity to mesocorticolimbic dopamine (DA) neurons implicated in alcohol reward and addiction. Since we have previously shown adaptation of VTA GABA neuron firing rate to chronic ethanol (Gallegos, Criado et al. 1999) and suppression of gap-junction (GJ) mediated coupling between these neurons by acute ethanol (Stobbs, Ohran et al. 2004), we wanted to further characterize the effects of chronic ethanol on VTA GABA neuron excitability, electrical coupling and molecular adaptation. In particular, we analyzed the GJ mediated coupling and protein regulation of VTA GABA neurons following a three week period of continuous ethanol exposure via liquid diet. Although some animals showed tolerance, there was no significant tolerance to ethanol inhibition of GJ-mediated electrical coupling. In addition, we were able to characterize differences in mRNA expression levels for the DA synthesizing enzyme tyrosine hydroxylase (TH), the DA D2 receptor and the NMDAR2B receptor subunit in DA versus GABA neurons, all three of which were expressed at higher levels in DA neurons. We also determined the effects of chronic ethanol on mRNA levels of these same proteins as well as μ-opioid receptors (μORs) and connexin-36 (Cx36) GJs. Most significantly, we found a down-regulation of the DA D2 receptor, confirming that molecular modification occurs in these VTA GABA neurons with chronic alcohol. While we reject our hypothesis that acute ethanol inhibition of VTA GABA neuron electrical coupling would undergo tolerance to chronic ethanol in these non-dependent rats, which was the focus of this thesis, it remains to be determined if tolerance to chronic ethanol might be obtained in ethanol-dependent rats.

Degree

College and Department

Life Sciences; Neuroscience

Rights

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