REVERSAL OF BEHAVIORAL-EFFECTS OF PENTYLENETETRAZOL BY THE NEUROACTIVE STEROID GANAXOLONE

Neuroactive steroids are naturally occurring or synthetically derived compounds many of which have anticonvulsant, anesthetic, anxiolytic, a nalgesic or hypnotic properties. The major site of neuronal activity a ppears to be with a specific steroid-sensitive site on the gamma-amino butyric acid(A) receptor/chloride ionophore complex. Ganaxolone (3 alp ha-hydroxy-3 beta-methyl-5 alpha-pregnan-20-one) is a synthetic neuroa ctive steroid protected from metabolic attack of the 3 alpha position. Ganaxolone is an efficacious anticonvulsant agent in a variety-of acu te seizure models, as well as in electrical and chemical kindling mode ls, and is currently under Phase II clinical investigation for epileps y. A prior observation that ganaxolone appeared to reverse the marked behavioral changes induced by the convulsant pentylenetetrazol (PTZ) w as systematically examined in the present study. A model to quantify P TZ-induced behaviors is described and used to evaluate ganaxolone in c omparison with the anticonvulsants valproate, ethosuximide, clonazepam , diazepam and phenobarbital. All compounds were compared using dose e quivalents based on their respective ED50 values in preventing convuls ions induced by 70 mg/kg PTZ. The ED50 and lower doses of ganaxolone p revented the observed behavioral effects of PTZ as well as its depress ant effects on locomotor activity and rearing of mice. In contrast, th e other anticonvulsants, if effective, were much less potent. Striking ly, most of the other anticonvulsants were incapable of preventing all the behavioral effects of PTZ. Only phenobarbital prevented all the b ehavioral effects of PTZ and only at doses 4 to 8 times the anticonvul sant ED50. Rather than normalizing behavior as ganaxolone did, however , phenobarbital resulted in supranormal behavioral responses (e.g., in creases in activity). Repeated administration of PTZ did not decrease the protective efficacy of ganaxolone. The results document the unique pharmacological profile of ganaxolone and suggest additional potentia l benefits from its use as an antiepileptic. Furthermore, because beha vioral effects of PTZ have been used to model anxiety and anxiety asso ciated with withdrawal from drugs of abuse, ganaxolone may find additi onal therapeutic application in those areas.