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 3α‐hydroxy‐5α‐pregnan‐20‐one (3α,5α‐P). 3α,5α‐P (5 or 10 mg/kg, ip) significantly increased seizure thresholds to pentylenetetrazol in ethanol‐naive males of both the WSP and WSR lines. In general, WSP mice were more sensitive than WSR mice to the anticonvulsant effect of 3α,5α‐P. Subsequent studies in male WSP mice exposed to ethanol vapor or air for 24 hr demonstrated enhanced sensitivity to the anticonvulsant effect of 3α,5α‐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 3α,5α‐P attenuates ethanol withdrawal convulsions and indicate enhanced sensitivity to the anticonvulsant effect of 3α,5α‐P in animals withdrawing from ethanol dependence.