Acute neuroactive steroid withdrawal in withdrawal seizure-prone and withdrawal seizure-resistant mice

Allopregnanolone (3 alpha -hydroxy-5 alpha -pregnan-20-one) is an endogenou sly derived metabolite of progesterone, and a potent positive modulator of gamma -aminobutyric acid(A) (GABA(A)) receptors. A withdrawal syndrome, cha racterized by central nervous system (CNS) hyperexcitability, has been demo nstrated following abrupt discontinuation of high progesterone levels in ra ts, which was due in part to altered levels of allopregnanolone. The purpos e of the present study was to determine if a single administration of pregn anolone or allopregnanolone could produce an acute withdrawal response in m ice selected for susceptibility (Withdrawal Seizure-Prone, WSP) or resistan ce (Withdrawal Seizure-Resistant, WSR) to ethanol withdrawal convulsions. W SP mice administered 75 mg/kg pregnanolone showed a significant increase in handling-induced convulsion (HIC) scores over a 25-h testing period. In co ntrast, HIC scores in WSR mice were negligible after acute administration o f 25, 50, 75, or 100 mg/kg pregnanolone. WSP mice also showed a similar inc rease in HIC after withdrawal from 75 mg/kg allopregnanolone. This effect w as evident at both the 10-h and 25-h overall withdrawal severity assessment . These results demonstrate that neuroactive steroids can elicit an acute w ithdrawal response similar to that of other positive modulators of GABA(A) receptors in WSP mice, supporting the notion that a common set of genes und erlie acute and chronic withdrawal severity from multiple agents with depre ssant effects on the central nervous system. (C) 2001 Elsevier Science Inc. All rights reserved.