Positive allosteric modulators of the GABA(A) receptor: differential interaction of benzodiazepines and neuroactive steroids with ethanol

Endogenous pregnane steroids, such as allopregnanolone (3 alpha-hydroxy-5 a lpha-pregnan-20-one; 3 alpha, 5 alpha-P) and pregnanolone (3 alpha-hydroxy- 5 beta-pregnan-20-one; 3 alpha,5 beta-P), allosterically modulate GABA(A) r eceptor function and exhibit behavioral effects similar to benzodiazepines, though acting at a distinct recognition site. Inasmuch as some positive al losteric modulators of GABAA receptor function exhibit profound interaction s with ethanol, the effects of 3 alpha,5 alpha-P and 3 alpha,5 beta-P were compared to those of two benzodiazepines, triazolam and diazepam, on the mo tor function of mice and rats when administered either alone or in combinat ion with ethanol. All four test compounds exhibited dose-related impairment of motor function in the horizontal wire task in mice and the rotorod task in rats. Ethanol caused a marked enhancement of triazolam- and diazepam-in duced motor impairment. In contrast, ethanol enhanced to a lesser extent th e motor impairment induced by both neurosteroids in mice and not at all in rats. All four compounds increased ethanol-induced behavioral sleep time in mice, although the benzodiazepines did so at a much smaller fraction of th eir ataxic doses as compared to the neurosteroids. As one of the undesired side-effects of therapeutic use of benzodiazepines is their interaction wit h ethanol, development of neuroactive steroids as drugs may offer therapeut ic advantages.