Differential Effects of Chronic Ethanol Administration and Withdrawal on γ-Aminobutyric Acid Type A and NMDA Receptor Subunit Proteins in Male and Female Rat Brain

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Abstract
Investigations have shown that chronic ethanol exposure results in selective alterations in levels of gamma-aminobutyric acid (GABA)A and NMDA receptor subunits. We previously reported significant sex differences in these chronic ethanol-induced adaptations. Because we have more recently found important sex differences in timing for the development of and recovery from ethanol dependence, we wanted to ascertain whether there were associations between overt expression of withdrawal and neuroadaptations at the level of GABAA and NMDA receptors. Western blot analysis was used to assay protein levels for several GABAA and NMDA receptor subunits in rat cerebral cortex and hippocampus by using subunit-selective antibodies. Rats were fed 6% ethanol in a liquid diet with pair-fed controls. Feeding, harvesting of tissue, and Western blot experiments were all conducted while maintaining the paired design. Tissue was harvested after 3 days of ethanol exposure, 9 days of ethanol exposure, or 3 days of ethanol withdrawal after 14 days of liquid diet administration. We again found sex-, subunit-, and brain region-selective effects of ethanol administration and withdrawal for GABAA and NMDA receptors. There was a strong association between increased GABAA receptor alpha4 subunit levels and previously determined withdrawal-induced changes in seizure susceptibility, highlighted by the sex differences in ethanol exposure length required to cause withdrawal signs. In addition, results obtained after 9 days of ethanol administration were in general agreement with previous findings after 14 days of ethanol administration. These data further support the suggestion that alterations in subunit assembly of GABAA and NMDA receptors may have some mechanistic role in neuroadaptations underlying ethanol dependence and withdrawal. Furthermore, significant sex differences in these adaptations suggest that multiple types of adaptations may be elicited, depending on innate differences in the actions/effects of ethanol.
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