title: The Neurosteroidogenic Enzyme 5α-Reductase Mediates Psychotic-Like Complications of Sleep Deprivation.
abstract: Acute sleep deprivation (SD) can trigger or exacerbate psychosis- and mania-related symptoms; the neurobiological basis of these complications, however, remains elusive. Given the extensive involvement of neuroactive steroids in psychopathology, we hypothesized that the behavioral complications of SD may be contributed by 5α-reductase (5αR), the rate-limiting enzyme in the conversion of progesterone into the neurosteroid allopregnanolone. We first tested whether rats exposed to SD may exhibit brain-regional alterations in 5αR isoenzymes and neuroactive steroid levels; then, we assessed whether the behavioral and neuroendocrine alterations induced by SD may be differentially modulated by the administration of the 5αR inhibitor finasteride, as well as progesterone and allopregnanolone. SD selectively enhanced 5αR expression and activity, as well as AP levels, in the prefrontal cortex; furthermore, finasteride (10-100 mg/kg, IP) dose-dependently ameliorated PPI deficits, hyperactivity, and risk-taking behaviors, in a fashion akin to the antipsychotic haloperidol and the mood stabilizer lithium carbonate. Finally, PPI deficits were exacerbated by allopregnanolone (10 mg/kg, IP) and attenuated by progesterone (30 mg/kg, IP) in SD-subjected, but not control rats. Collectively, these results provide the first-ever evidence that 5αR mediates a number of psychosis- and mania-like complications of SD through imbalances in cortical levels of neuroactive steroids.
authors.affiliation: Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, Monserrato, Italy.|Tourette Syndrome Center, Monserrato, Italy.|Sleep Medicine Center; University of Cagliari, Monserrato, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Frau
authors.affiliation: Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, Monserrato, Italy.|Tourette Syndrome Center, Monserrato, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Bini
authors.affiliation: 'L. Spallanzani' Institute, Proteomics Section-Department of Veterinary Sciences and Public Health, University of Milan, Milan, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Soggiu
authors.affiliation: Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.|Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, USA.
authors.forename: Simona
authors.initials: S
authors.lastname: Scheggi
authors.affiliation: Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, Monserrato, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pardu
authors.affiliation: Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, Monserrato, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fanni
authors.affiliation: 'L. Spallanzani' Institute, Proteomics Section-Department of Veterinary Sciences and Public Health, University of Milan, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Roncada
authors.affiliation: Tourette Syndrome Center, Monserrato, Italy.|Sleep Medicine Center; University of Cagliari, Monserrato, Italy.|Department of Public Health, Section of Neurology, Monserrato, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Puligheddu
authors.affiliation: Tourette Syndrome Center, Monserrato, Italy.|Sleep Medicine Center; University of Cagliari, Monserrato, Italy.|Department of Public Health, Section of Neurology, Monserrato, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Marrosu
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Center of Excellence for Neurodegenerative Diseases, University of Milan, Milan, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Caruso
authors.affiliation: Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, Monserrato, Italy.|Tourette Syndrome Center, Monserrato, Italy.|Sleep Medicine Center; University of Cagliari, Monserrato, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Devoto
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Bortolato
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000161:Acoustic Stimulation / Q000009:adverse effects; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D042944:Cholestenone 5 alpha-Reductase / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018120:Finasteride / Q000494:pharmacology / Q000627:therapeutic use; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D008297:Male; D011280:Pregnanolone / Q000494:pharmacology; D011618:Psychotic Disorders / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects; D012892:Sleep Deprivation / Q000150:complications*; D013256:Steroids / Q000378:metabolism*
chemical_list: D058891:5-alpha Reductase Inhibitors; D014150:Antipsychotic Agents; D013256:Steroids; D018120:Finasteride; D011280:Pregnanolone; D042944:Cholestenone 5 alpha-Reductase