Antipsychotic-Like Properties of 5-alpha-Reductase Inhibitors

Bortolato M;FRAU, ROBERTO;Orrù M;Bourov;MARROSU, FRANCESCO;Mareu G;DEVOTO, PAOLA;Gessa GL

2008-01-01

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Abstract

Recent evidence indicates that neuroactive steroids may participate in the pathogenesis of schizophrenia spectrum disorders, yet the mechanisms of this involvement are elusive. As 5-alpha-reductase (5AR) is the rate-limiting enzyme of one of the two major metabolic pathways in brain steroidogenesis, we investigated the effects of its blockade in several rat models of psychotic-like behavior. The 5AR inhibitor finasteride ( FIN, 60 or 100 mg/kg, intraperitoneal, i.p.) dose- and time-dependently antagonized prepulse inhibition (PPI) deficits induced by apomorphine ( APO, 0.25 mg/kg, subcutaneous, s.c.) and d-amphetamine ( AMPH, 5 mg/kg, s.c.), in a manner analogous to haloperidol ( HAL, 0.1 mg/kg, i.p.) and clozapine ( CLO, 5 mg/kg, i.p.). Similar results were observed with the other 5AR inhibitors dutasteride ( DUT, 40 or 80 mg/kg, i.p.) and SKF 105111 ( 30 mg/kg, i.p.). FIN ( 60 or 100 mg/kg, i.p.) also reduced hyperlocomotion induced by AMPH ( 1 or 3 mg/kg, s.c.) and attenuated stereotyped behaviors induced by APO ( 0.25 mg/kg, s.c.). Nevertheless, FIN ( 100 mg/kg, i.p.) did not reverse the PPI disruption induced by the N-methyl-d-aspartate receptor antagonist dizocilpine ( 0.1 mg/kg, s.c.). FIN (60-300 mg/kg, i.p.) induced no catalepsy in either the bar test or the paw test. Our results suggest that 5AR inhibitors elicit antipsychotic-like effects in animals and may be proposed as a putative novel target in the management of psychotic disorders.