title: Targeting neurosteroid synthesis as a therapy for schizophrenia-related alterations induced by early psychosocial stress.
abstract: BACKGROUND
  Cogent evidence has shown that schizophrenia vulnerability is enhanced by psychosocial stress in adolescence, yet the underpinnings of this phenomenon remain elusive. One of the animal models that best capture the relationship between juvenile stress and schizophrenia is isolation rearing (IR). This manipulation, which consists in subjecting rats to social isolation from weaning through adulthood, results in neurobehavioral alterations akin to those observed in schizophrenia patients. In particular, IR-subjected rats display a marked reduction of the prepulse inhibition (PPI) of the startle reflex, which are posited to reflect imbalances in dopamine neurotransmission in the nucleus accumbens (NAcc). We recently documented that the key neurosteroidogenic enzyme 5α-reductase (5αR) plays an important role in the dopaminergic regulation of PPI; given that IR leads to a marked down-regulation of this enzyme in the NAcc, the present study was designed to further elucidate the functional role of 5αR in the regulation of PPI of IR-subjected rats.
  
  
  METHODS
  We studied the impact of the prototypical 5αR inhibitor finasteride (FIN) on the PPI deficits and NAcc steroid profile of IR-subjected male rats, in comparison with socially reared (SR) controls.
  
  
  RESULTS
  FIN (25-100 mg/kg, i.p.) dose-dependently countered IR-induced PPI reduction, without affecting gating integrity in SR rats. The NAcc and striatum of IR-subjected rats displayed several changes in neuroactive steroid profile, including a reduction in pregnenolone in both SR and IR-subjected groups, as well as a decrease in allopregnanolone content in the latter group; both effects were significantly opposed by FIN.
  
  
  CONCLUSIONS
  These results show that 5αR inhibition counters the PPI deficits induced by IR, possibly through limbic changes in pregnenolone and/or allopregnanolone concentrations.
authors.affiliation: "Guy Everett" Laboratory, Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy; Tourette Syndrome Center, University of Cagliari, Cagliari, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Frau
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Center of Excellence on Neurodegenerative Diseases, University of Milan, Milan, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Abbiati
authors.affiliation: "Guy Everett" Laboratory, Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy; Department of Pharmacological and Biomolecular Sciences, Center of Excellence on Neurodegenerative Diseases, University of Milan, Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Bini
authors.affiliation: "Guy Everett" Laboratory, Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Casti
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Center of Excellence on Neurodegenerative Diseases, University of Milan, Milan, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Caruso
authors.affiliation: "Guy Everett" Laboratory, Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy; Tourette Syndrome Center, University of Cagliari, Cagliari, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Devoto
authors.affiliation: Tourette Syndrome Center, University of Cagliari, Cagliari, Italy; Department of Pharmacology and Toxicology, School of Pharmacy, 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; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018120:Finasteride / Q000494:pharmacology*; D006220:Haloperidol / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D011284:Pregnenolone / Q000378:metabolism; D065808:Prepulse Inhibition / Q000187:drug effects* / Q000502:physiology; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism; D012934:Social Isolation; D013315:Stress, Psychological / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D058891:5-alpha Reductase Inhibitors; D014150:Antipsychotic Agents; D018120:Finasteride; D011284:Pregnenolone; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D006220:Haloperidol
keywords: 5α-Reductase; Isolation rearing; Neurosteroids; Prepulse inhibition; Schizophrenia; Sensorimotor gating