Common genetic determinants of severity of acute withdrawal from ethanol, pentobarbital and diazepam in inbred mice.

Abstract

Severity of drug withdrawal is in part genetically mediated, and can be indexed by exacerbation of the handling-induced convulsion in mice. Acute withdrawal has been reported following single injections of hypnotic doses of ethanol and pento-barbital, and can be precipitated by injection of flumazenil following a single dose of diazepam. Results with Swiss-Webster mice indicate that the magnitude of ethanol and diazepam withdrawal severity did not differ across a range of doses in the acute paradigm. We characterized 15 inbred mouse strains for handling-induced convulsion severity following administration of standard doses of each of these drugs. Significant strain differences in withdrawal severity were found for each drug. Two of the strains showed a tendency toward more pronounced withdrawal from all drugs, while six strains showed low withdrawal from all drugs. The correlations among strain mean withdrawal responses were analyzed to estimate common genetic influences. Ethanol and pentobarbital withdrawal severities were positively genetically correlated, indicating influence of some genes on both responses. A positive genetic correlation was also found between the severity of the withdrawal from pentobarbital and diazepam; however, diazepam and ethanol withdrawal severities were not found to be genetically related. These experiments suggest that some genes influence severity of withdrawal from more than one subclass of depressant drugs.