Genetic determinants of severity of acute withdrawal from diazepam in mice: commonality with ethanol and pentobarbital.
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.
Portland Alcohol Research Center, Department of Behavioral Neuroscience, Oregon Health Sciences University, and Department of Veterans Affairs Medical Center, (R&D 12), 97201, USA.
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Metten
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Crabbe
D000818:Animals; D014151:Anti-Anxiety Agents / Q000009:adverse effects*; D002492:Central Nervous System Depressants / Q000009:adverse effects*; D003975:Diazepam / Q000009:adverse effects*; D000431:Ethanol / Q000009:adverse effects*; D006993:Hypnotics and Sedatives / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010424:Pentobarbital / Q000009:adverse effects*; D015203:Reproducibility of Results; D012640:Seizures / Q000503:physiopathology / Q000523:psychology; D013045:Species Specificity; D013375:Substance Withdrawal Syndrome / Q000235:genetics* / Q000523:psychology
D014151:Anti-Anxiety Agents; D002492:Central Nervous System Depressants; D006993:Hypnotics and Sedatives; D000431:Ethanol; D010424:Pentobarbital; D003975:Diazepam