title: Inhibition of 17α-hydroxylase/C17,20 lyase reduces gating deficits consequent to dopaminergic activation.
abstract: Cogent evidence points to the involvement of neurosteroids in the regulation of dopamine (DA) neurotransmission and signaling, yet the neurobiological bases of this link remain poorly understood. We previously showed that inhibition of 5α-reductase (5αR), a key neurosteroidogenic enzyme, attenuates the sensorimotor gating deficits induced by DA receptor activation, as measured by the prepulse inhibition (PPI) of the acoustic startle reflex. To extend these findings, the present study was aimed at the assessment of the role of other key neurosteroidogenic enzymes in PPI, such as 17α-hydroxylase/C17,20 lyase (CYP17A1), 3α- and 3β-hydroxysteroid dehydrogenase (HSD), in Sprague-Dawley rats. The PPI deficits induced by the DAergic non-selective agonist apomorphine (APO, 0.25mg/kg, SC) were dose-dependently attenuated by the selective CYP17A1 inhibitor abiraterone (ABI, 10-50mg/kg, IP) in a fashion akin to that of the 5αR inhibitor finasteride (FIN, 100mg/kg, IP). These systemic effects were reproduced by intracerebroventricular injection of ABI (1 μg/1 μl), suggesting the involvement of brain CYP17A1 in PPI regulation. Conversely, the PPI disruption induced by APO was not significantly affected by the 3α- and 3β-HSD inhibitors indomethacin and trilostane. Given that CYP17A1 catalyzes androgen synthesis, we also tested the impact on PPI of the androgen receptor (AR) antagonist flutamide (10mg/kg, IP). However, this agent failed to reverse APO-induced PPI deficits; furthermore, AR endogenous ligands testosterone and dihydrotestosterone failed to disrupt PPI. Collectively, these data highlight CYP17A1 as a novel target for antipsychotic-like action, and suggest that the DAergic regulation of PPI is modulated by androgenic neurosteroids, through AR-unrelated mechanisms.
authors.affiliation: "Guy Everett" Laboratory, Department of Biomedical Sciences, University of Cagliari, Italy; Tourette Syndrome Center, University of Cagliari, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Frau
authors.affiliation: "Guy Everett" Laboratory, Department of Biomedical Sciences, University of Cagliari, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Bini
authors.affiliation: "Guy Everett" Laboratory, Department of Biomedical Sciences, University of Cagliari, Italy; Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS, USA.
authors.forename: Romina
authors.initials: R
authors.lastname: Pes
authors.affiliation: "Guy Everett" Laboratory, Department of Biomedical Sciences, University of Cagliari, Italy.
authors.forename: Giuliano
authors.initials: G
authors.lastname: Pillolla
authors.affiliation: "Guy Everett" Laboratory, Department of Biomedical Sciences, University of Cagliari, Italy.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Saba
authors.affiliation: "Guy Everett" Laboratory, Department of Biomedical Sciences, University of Cagliari, Italy; Tourette Syndrome Center, University of Cagliari, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Devoto
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS, USA. Electronic address: bortolato@ku.edu.
authors.forename: Marco
authors.initials: M
authors.lastname: Bortolato
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000494:pharmacology; D000736:Androstenes; D000737:Androstenols / Q000494:pharmacology; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D018120:Finasteride / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects*; D055139:Sensory Gating / Q000187:drug effects*; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*
chemical_list: D058891:5-alpha Reductase Inhibitors; D000736:Androstenes; D000737:Androstenols; D018491:Dopamine Agonists; D018120:Finasteride; D013254:Steroid 17-alpha-Hydroxylase; C089740:abiraterone; D001058:Apomorphine
keywords: 17α-Hydroxylase/C17,20 lyase; Androgen receptors; Dopamine; Neurosteroidogenesis; Prepulse inhibition of the startle