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.
Finn
D A
DA
Research Service (151C), Department of Veterans Affairs Medical Center, Hospital Road, Portland, OR 97201, USA.
Roberts
A J
AJ
Crabbe
J C
JC
D000430:Alcohol Withdrawal Delirium / Q000503:physiopathology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects*; D008297:Male; D051379:Mice; D010433:Pentylenetetrazole / Q000494:pharmacology; D011280:Pregnanolone / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology*
D000927:Anticonvulsants; D011280:Pregnanolone; D010433:Pentylenetetrazole