title: The neurosteroidogenic enzyme 5α-reductase modulates the role of D1 dopamine receptors in rat sensorimotor gating.
abstract: Neurosteroids exert diverse modulatory actions on dopamine neurotransmission and signaling. We previously documented that the enzyme 5α-reductase, which catalyzes the main rate-limiting step in neurosteroid synthesis, is required for the behavioral responses of Sprague-Dawley rats to non-selective dopaminergic agonists, such as the D1-D2 receptor agonist apomorphine. Specifically, systemic and intra-accumbal administrations of the 5α-reductase inhibitor finasteride countered apomorphine-induced deficits of sensorimotor gating, as measured by the prepulse inhibition (PPI) of the startle reflex; the classes of dopamine receptors involved in these effects, however, remain unknown. Prior rodent studies have revealed that the contributions of dopamine receptors to PPI regulation vary depending on the genetic background; thus, we analyzed the effect of finasteride on the PPI deficits induced by selective dopamine receptor agonists in Long-Evans (a strain exhibiting PPI deficits in response to both D1 and D2 receptor agonists) and Sprague-Dawley rats (which display PPI reductions following treatment with D2, and D3, but not D1 receptor agonists). In Long-Evans rats, finasteride opposed the PPI deficits induced by activation of D1, but not D2 receptors; conversely, in Sprague-Dawley rats, finasteride prevented the reductions in %PPI and accumbal dopamine extracellular levels caused by selective stimulation of D3, but not D2 receptors; however, the effects on %PPI were not confirmed by analyses on absolute PPI values. Our findings suggest that 5α-reductase modulates the effects of D1, but not D2 receptor agonists on sensorimotor gating. These data may help elucidate the role of neurosteroids in neuropsychiatric disorders featuring PPI deficits, including schizophrenia and Tourette syndrome.
authors.affiliation: "Guy Everett" Laboratory, Dept. 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: Dept. of Pharmacology and Toxicology, University of Kansas, Lawrence, KS, USA; Consortium for Translational Research on Aggression and Drug Abuse (ConTRADA), University of Kansas, Lawrence, KS, USA; Problem Gambling Research Studies (ProGResS) Network, University of Kansas, Lawrence, KS, USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Mosher
authors.affiliation: "Guy Everett" Laboratory, Dept. of Biomedical Sciences, University of Cagliari, Italy; Tourette Syndrome Center, University of Cagliari, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Bini
authors.affiliation: "Guy Everett" Laboratory, Dept. of Biomedical Sciences, University of Cagliari, Italy.
authors.forename: Giuliano
authors.initials: G
authors.lastname: Pillolla
authors.affiliation: "Guy Everett" Laboratory, Dept. of Biomedical Sciences, University of Cagliari, Italy; Dept. of Pharmacology and Toxicology, University of Kansas, Lawrence, KS, USA.
authors.forename: Romina
authors.initials: R
authors.lastname: Pes
authors.affiliation: "Guy Everett" Laboratory, Dept. of Biomedical Sciences, University of Cagliari, Italy.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Saba
authors.affiliation: "Guy Everett" Laboratory, Dept. of Biomedical Sciences, University of Cagliari, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fanni
authors.affiliation: "Guy Everett" Laboratory, Dept. 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: Tourette Syndrome Center, University of Cagliari, Italy; Dept. of Pharmacology and Toxicology, University of Kansas, Lawrence, KS, USA; Consortium for Translational Research on Aggression and Drug Abuse (ConTRADA), University of Kansas, Lawrence, KS, USA; Problem Gambling Research Studies (ProGResS) Network, University of Kansas, Lawrence, KS, USA. Electronic address: bortolato@ku.edu.
authors.forename: Marco
authors.initials: M
authors.lastname: Bortolato
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism*; D058891:5-alpha Reductase Inhibitors / Q000494:pharmacology*; D000818:Animals; D018491:Dopamine Agonists / Q000494:pharmacology*; D018120:Finasteride / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D065808:Prepulse Inhibition / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000187:drug effects* / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000187:drug effects* / Q000378:metabolism; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology; D055139:Sensory Gating / Q000187:drug effects / Q000502:physiology
chemical_list: D058891:5-alpha Reductase Inhibitors; D018491:Dopamine Agonists; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D018120:Finasteride; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase
keywords: 5α-Reductase; Dopamine; Finasteride; Neurosteroids; Prepulse inhibition of the startle