The neurosteroid 3α-hydroxy-5α-pregnan-20-one affects dopamine-mediated behavior in rodents

Abstract.

Rationale: The neurosteroid 3α-hydroxy-5α-pregnan-20-one (3α,5α-THP) has been previously shown to induce catalepsy in mice that is modified by GABAergic, dopaminergic, adenosinergic and serotonergic agents. In light of the interaction of this endogenous neurosteroid with GABAergic and dopaminergic transmission, there is potential interest in the possible role of 3α,5α-THP in psychotic disorders. Objective: This study assessed the effect of 3α,5α-THP in certain dopamine-mediated behavioral paradigms that are widely used to predict antipsychotic-like activity. Methods: 3α,5α-THP (1–8 µg per animal, i.c.v.), the classic neuroleptic (dopamine receptor antagonist) haloperidol (0.25 mg/kg, i.p.), and the benzodiazepine diazepam (7 mg/kg, i.p.) were injected into different groups of animals, and their behavior was screened using the following animal tests: conditioned avoidance response, apomorphine-induced climbing, and amphetamine-induced motor hyperactivity. Separate groups of mice that received 3α,5α-THP (1–8 µg per animal, i.c.v.) were screened for catalepsy. Furthermore, the effect of a sub-cataleptic dose (0.1 µg per mouse, i.c.v.) of 3α,5α-THP, either alone or in combination with the GABA_A receptor antagonist picrotoxin (0.8 mg/kg, i.p.) was measured on haloperidol-induced catalepsy. Results: 3α,5α-THP like haloperidol reduced conditioned avoidance, apomorphine-induced cage climbing and amphetamine-induced motor hyperactivity. Diazepam only affected conditioned avoidance. 3α,5α-THP also induced dose-dependent catalepsy. Furthermore, sub-cataleptic doses of 3α,5α-THP potentiated haloperidol-induced catalepsy. This potentiation was blocked by prior treatment with the GABA_A receptor antagonist picrotoxin. Conclusion: These findings suggest that 3α,5α-THP, by its action at the GABA_A receptors, increases GABAergic tone leading to a behavioral profile similar to that of dopamine receptor antagonists.