Reduced ethanol withdrawal severity and altered withdrawal-induced c-fos expression in various brain regions of mice lacking protein kinase C-epsilon

Withdrawal from chronic ethanol consumption can be accompanied by motor sei zures, which may be a result of altered GABA(A) receptor function. Recently . we have generated and characterized mice lacking the epsilon isoform of p rotein kinase C as being supersensitive to the behavioral and biochemical e ffects of positive GABA(A) receptor allosteric modulators, including ethano l. The aim of the present study was to determine whether protein kinase C-e psilon null mutant mice display altered seizure severity during alcohol wit hdrawal. In addition, we used c-fos immunohistochemistry immediately follow ing seizure assessment to identify potential brain regions involved in any observed differences in withdrawal severity. Mice were allowed to consume a n ethanol-containing or control liquid diet as the sole source of food for 14 days. During the 7-h period following removal of the diet, both ethanol- fed wild-type and protein kinase C-epsilon null mutant mice displayed an ov erall increase in Handling-induced Convulsion score versus control-fed mice . However, at 6 and 7 h following diet removal, the Handling-Induced Convul sion score was reduced in ethanol fed protein kinase C-epsilon null mutant mice compared to ethanol-fed wild-type mice. Ethanol fed protein kinase C-e psilon null mutant mice also exhibited a decrease in the number of Fos-posi tive cells in the lateral septum, and an increase in the number of Fos-posi tive cells in the dentate gyrus. mediodorsal thalamus, paraventricular nucl ei of the thalamus and hypothalamus, and substantia nigra compared to ethan ol-fed wild-type mice. These data demonstrate that deletion of protein kinase C-epsilon results in diminished progression of ethanol withdrawal associated seizure severity, suggesting that selective pharmacological inhibitors of protein kinase C-ep silon may be useful in the treatment of seizures during alcohol withdrawal. These data also provide insight into potential brain regions involved in g eneration or suppression of ethanol withdrawal seizures. (C) 2001 IBRO. Pub lished by Elsevier Science Ltd. All rights reserved.