The GABAergic system of the piriform cortex in a rat model of chronic ethanol consumption

This thesis examined the effects of chronic exposure to ethanol on GABA A-receptor mediated function in rat piriform cortex. I tested the hypothesis that chronic exposure to ethanol alters GABAA-receptor mediated function in layer II pyramidal neurons. A parallel hypothesis is that the epigenetic properties of GABAA receptors will also be altered in a way the can account for the changes in the functional properties of GABA A receptors. Adult rats were exposed to ethanol for 30 days by including 5% ethanol in their diet. Control rats were pair-fed the identical diet except that isocaloric sucrose-maltose was substituted for ethanol. Whole-cell patch clamp electrophysiology was used to study layer II pyramidal neurons in the piriform cortical slice. Spontaneous GABAA-receptor mediated synaptic currents (IPSC) were analyzed first. Acute ethanol inhibited IPSC amplitudes in neurons in the control-fed group. IPSC amplitudes in neurons from the ethanol-fed group were significantly higher than in the control group, and were further potentiated during exposure to acute ethanol. Analysis of concentration-response relationships revealed decreased apparent efficacy and increased apparent potency of GABA after chronic exposure to ethanol. GABA-induced current responses were potentiated by acute ethanol only in the ethanol-fed group. Diazepam-induced positive allosteric modulation of the GABAA receptor was unaltered after chronic exposure to ethanol. The expression of GABAA receptor subunit mRNAs was analyzed in the piriform cortex. Real time quantitative PCR revealed an increase in α3 and α4 mRNA. No changes were found in the α1,2, β1,2,3 or γ1,2L,2S,3 GABAA receptor subunit mRNAs. These results suggest that, in contrast to studies in other brain regions, chronic exposure to ethanol results in a sensitization of GABA A receptor-meditated actions in layer II pyramidal neurons of the piriform cortex. This sensitization is not accompanied by cross-sensitization or cross-tolerance to diazepam.