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. ³Department of Experimental Biology, University of Cagliari, Monserrato, Cagliari, Italy
4. ⁴Tourette Syndrome Center, University of Cagliari, Monserrato, Cagliari, Italy

Correspondence: Dr M Bortolato, Department of Neuroscience 'Bernard B. Brodie', University of Cagliari, Cittadella Universitaria, S.S.554 Km 4,500, Monserrato, CA 09042, Italy. Tel: +39 070 6754342; Fax: +39 070 6754320; E-mail: marco.bortolato@inwind.it

Received 10 September 2007; Revised 17 February 2008; Accepted 17 February 2008; Published online 19 March 2008.

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--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.