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.
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Acknowledgements
MB designed the research, analyzed the data and wrote the manuscript; RF wrote the first draft of the manuscript, performed the behavioral studies, analyzed the data and managed the literature search; VB, AP, and SF performed the behavioral tests; DC performed the neurochemical assays; PR and AS performed the molecular assays; PD, FM, MP, DC, PR revised the paper. We would like to thank Graziella De Montis and Carla Gambarana for their support in the execution of western-blotting experiments; Pierluigi Saba and Barbara Tuveri for their technical assistance; and Sean Godar for his valuable comments on the manuscript and assistance with the figures. This work was partially supported by grants from the National Institute of Health (R01 MH104603; to MB), Tourette Syndrome Association of America (to MB), Italian Ministry of Health grant PE-2011–02351898 (to MP), Michael J Fox Foundation grant 9969 (to PD), and Regione Autonoma della Sardegna (to PD). None of the institutions had any further role in the decision to submit the paper for publication.
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Frau, R., Bini, V., Soggiu, A. et al. The Neurosteroidogenic Enzyme 5α-Reductase Mediates Psychotic-Like Complications of Sleep Deprivation. Neuropsychopharmacol 42, 2196–2205 (2017). https://doi.org/10.1038/npp.2017.13
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DOI: https://doi.org/10.1038/npp.2017.13
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