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Antipsychotic-Like Properties of 5-alpha-Reductase Inhibitors.

Bortolato M, Frau R, Orrù M, Bourov Y, Marrosu F, Mereu G, Devoto P, Gessa GL

[1] 1Department of Neuroscience ‘Bernard B. Brodie’, University of Cagliari, Monserrato, Cagliari, Italy [2] 2Department of Cardiovascular and Neurological Science, University of Cagliari, Monserrato, Cagliari, Italy [3] 4Tourette Syndrome Center, University of Cagliari, Monserrato, Cagliari, Italy.

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.Neuropsychopharmacology advance online publication, 19 March 2008; doi:10.1038/npp.2008.39.

Published 20 March 2008 in Neuropsychopharmacology.
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