Antipsychotic-like properties of 5-alpha-reductase inhibitors.
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.
Bortolato
Marco
M
Department of Neuroscience 'Bernard B. Brodie', University of Cagliari, Monserrato, Cagliari, Italy. marco.bortolato@inwind.it
Frau
Roberto
R
Orrù
Marco
M
Bourov
Youri
Y
Marrosu
Francesco
F
Mereu
Giampaolo
G
Devoto
Paola
P
Gessa
Gian L
GL
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism; D058891:5-alpha Reductase Inhibitors; D000731:Androstanes / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001378:Azasteroids / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects* / Q000201:enzymology*; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology; D000068538:Dutasteride; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018120:Finasteride / Q000494:pharmacology* / Q000627:therapeutic use; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D006948:Hyperkinesis / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D011618:Psychotic Disorders / Q000188:drug therapy* / Q000201:enzymology* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D055139:Sensory Gating / Q000187:drug effects / Q000502:physiology; D013239:Stereotyped Behavior / Q000187:drug effects / Q000502:physiology; D013739:Testosterone / Q000096:biosynthesis; D016896:Treatment Outcome
D058891:5-alpha Reductase Inhibitors; D000731:Androstanes; D014150:Antipsychotic Agents; D001378:Azasteroids; D018491:Dopamine Agonists; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D012739:Gonadal Steroid Hormones; D016194:Receptors, N-Methyl-D-Aspartate; C473295:SKF 105111; D013739:Testosterone; D018120:Finasteride; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D000068538:Dutasteride