Rationale and objectives: The ability of progesterone (P4) and its neurosteroid metabolite, 3alpha-OH-5beta-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), P4 (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, P4 before IS did not protect against the anxiogenic-like effect of IS. The acute anxiolytic-like effect of pregnanolone and P4 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, P4 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.