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Genetic Determinants of Severity of Acute Withdrawal From Diazepam in Mice: Commonality With Ethanol and Pentobarbital

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Abstract

Potentially life-threatening seizures can occur following withdrawal from benzodiazepines, ethanol, or barbiturates. In animals, withdrawal severity has been shown to be partially genetically determined for each drug class. Susceptibility to these drugs is partially determined by common genetic factors, but the evidence is conflicting. We tested the hypothesis that acute benzodiazepine withdrawal convulsions are influenced by at least some genes that also affect withdrawal from ethanol and pentobarbital. Results in inbred mouse strains demonstrate that strain susceptibility is genetically correlated with susceptibility to ethanol and pentobarbital. The proportion of variance accounted for by genetic factors common to diazepam and ethanol was estimated at 69%. Results contrast with previous data obtained in mice that were serially tested for withdrawal severity from ethanol, pentobarbital, and then diazepam, because serial testing of mice significantly affected the previous results for some strains. Diazepam withdrawal severity was also genetically correlated with pentobarbital withdrawal. Together, these results suggest that some genes influence severity of withdrawal from several types of depressant drugs.

Section snippets

Subjects

Adult male mice (52–67-days-old at the time of testing) from 14 of the 15 inbred strains tested in our previous study (50) were used in this experiment. The following inbred strains were available in sufficient numbers for testing: 129/J, A/HeJ, AKR/J, BALB/cJ, C3H/HeJ, C57BL/6J, C57BR/cdJ, C57L/J, CBA/J, DBA/1J, DBA/2J, PL/J, SJL/J, and SWR/J. Mice were purchased from the Jackson Laboratory, Bar Harbor, ME, and housed by strain, three to four animals per polycarbonate cage (28 × 17 × 11.5 cm)

Results

Results are shown in Fig. 1A and B. As we had seen previously, the inbred strains differed significantly in diazepam withdrawal severity (50). The time courses of withdrawal for four representative strains are depicted in Fig. 1A. The inbred strains are known to differ considerably in basal HIC severity 18, 50, and a significant main effect of strain on baseline HIC was detected, F(13, 140) = 31.05, p < 0.01; range of strain mean values: 0–4. As expected, treatment groups within strain did not

Discussion

The results of this study provide strong evidence that there are common genetic determinants of diazepam, ethanol, and pentobarbital withdrawal convulsions. There is substantial evidence to suggest that there should be a common neural mechanism underlying withdrawal from these three types of drugs. One receptor system known to mediate some of the effects of all three of these drugs is the GABA/benzodiazepine receptor/chloride ionophore complex (GRC). Besides distinct binding sites for GABA and

Acknowledgements

This study was supported by National Institute on Alcohol Abuse and Alcoholism Grants AA10760, AA06243, National Institute on Drug Abuse Grant DA05228, and a grant from the Department of Veterans Affairs. Pamela Metten was supported by National Institute on Drug Abuse Training Grant T32 DA 07262. We thank Sue Burkhart-Kasch for superb technical assistance, and Dr. Edward J. Gallaher for the drugs.

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