Neuroactive steroid sensitivity in withdrawal seizure-prone and -resistant mice

Withdrawal Seizure-Prone (WSP) and -Resistant (WSR) mice, which were selectively bred for severe (WSP) or mild (WSR) handling-induced convulsions (HICs) following chronic ethanol inhalation, were found to differ in sensitivity to the anticonvulsant effects of the neuroactive steroid 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-P. 3 alpha,5 alpha-P (5 or 10 mg/kg, ip) significantly increased seizure thresholds to pentylenetetrazol in ethanol-native males of both the WSP and WSR lines. In general, WSP mice were more sensitive than WSR mice to the anticonvulsant effect of 3 alpha,5 alpha-P. Subsequent studies in male WSP mice exposed to ethanol vapor or air for 24 hr demonstrated enhanced sensitivity to the anticonvulsant effect of 3 alpha,5 alpha-P (0.5-20 mg/kg, ip) during ethanol withdrawal. Only the highest dose affected HICs in air-exposed animals, whereas both the two highest doses significantly reduced HICs in ethanol-exposed mice. These results provide the first demonstration that 3 alpha,5 alpha-P attenuates ethanol withdrawal convulsions and indicate enhanced sensitivity to the anticonvulsant effect of 3 alpha,5 alpha-P in animals withdrawing from ethanol dependence.