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

Rationale and objectives: The ability of progesterone (P4) and its neuroste roid metabolite, 3 alpha-OH-5 beta-pregnan-20-one (pregnanolone) in protect ing against the anxiogenic-like effect of inescapable shock (IS) in male ra ts was examined, as these steroids exert anxiolytic, anticonvulsant, and at axic effects similar to the benzodiazepines (BZ), drugs shown to prevent IS -induced anxiogenesis. Methods: Adult male rats were injected with pregnano lone (8 mg/kg, SC), P-4 (4 mg/rat) or its appropriate vehicle before exposu re to IS. Twenty-four hours later, animals were injected with the steroid o r its vehicle and then tested in the elevated plus-maze. In a control exper iment, animals were injected with chlordiazepoxide (CDP, 15 mg/kg, IP) or v ehicle 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 r esponse seen 24 h after IS, P-4 before IS did not protect against the anxio genic-like effect of IS. The acute anxiolytic-like effect of pregnanolone a nd P-4 was lost in animals that were injected with vehicle before the IS, b ut was observed in animals that were injected with the steroids before IS. Moreover, P-4 injection in non-shocked animals was associated with an anxio genic-like response observed 24 h after steroid administration. Conclusion: The protection against the effect of IS afforded by a GABAergic neurostero id is comparable to that observed with BZs, and thus provides further evide nce of an allosteric relationship between the neurosteroid and BZ binding s ite on the GABA(A) receptor complex.