The neurosteroid pregnanolone prevents the anxiogenic-like effect of inescapable shock in the rat

Rationale and objectives: The ability of progesterone (P4) and its neurosteroid metabolite, 3 alpha-OH-5 beta-pregnan-20-one (pregnanolone) in protecting against the anxiogenic-like effect of inescapable shock (IS) in male rats was examined, as these steroids exert anxiolytic, anticonvulsant, and ataxic effects similar to the benzodiazepines (BZ), drugs shown to prevent IS-induced anxiogenesis. Methods: Adult male rats were injected with pregnanolone (8 mg/kg, SC), P-4 (4 mg/rat) or its appropriate vehicle before exposure to IS. Twenty-four hours later, animals were injected with the steroid or its vehicle and then tested in the elevated plus-maze. In a control experiment, animals were injected with chlordiazepoxide (CDP, 15 mg/kg, IP) or vehicle before IS, and tested in the plus-maze 24 h later. Results: Whereas CDP or pregnanolone before IS resulted in the loss of the anxiogenic-like response seen 24 h after IS, P-4 before IS did not protect against the anxiogenic-like effect of IS. The acute anxiolytic-like effect of pregnanolone and P-4 was lost in animals that were injected with vehicle before the IS, but was observed in animals that were injected with the steroids before IS. Moreover, P-4 injection in non-shocked animals was associated with an anxiogenic-like response observed 24 h after steroid administration. Conclusion: The protection against the effect of IS afforded by a GABAergic neurosteroid is comparable to that observed with BZs, and thus provides further evidence of an allosteric relationship between the neurosteroid and BZ binding site on the GABA(A) receptor complex.