Allopregnanolone mediates the exacerbation of Tourette-like responses by acute stress in mouse models

Abstract Tourette syndrome (TS) is a neuropsychiatric disorder characterized by multiple tics and sensorimotor abnormalities, the severity of which is typically increased by stress. The neurobiological underpinnings of this exacerbation, however, remain elusive. We recently reported that spatial con...

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Autores principales:	Laura J. Mosher, Sean C. Godar, Marianela Nelson, Stephen C. Fowler, Graziano Pinna, Marco Bortolato
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3ab4a6989ba3454dac75b5a92be0ee11
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spelling	oai:doaj.org-article:3ab4a6989ba3454dac75b5a92be0ee112021-12-02T12:30:10ZAllopregnanolone mediates the exacerbation of Tourette-like responses by acute stress in mouse models10.1038/s41598-017-03649-12045-2322https://doaj.org/article/3ab4a6989ba3454dac75b5a92be0ee112017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03649-1https://doaj.org/toc/2045-2322Abstract Tourette syndrome (TS) is a neuropsychiatric disorder characterized by multiple tics and sensorimotor abnormalities, the severity of which is typically increased by stress. The neurobiological underpinnings of this exacerbation, however, remain elusive. We recently reported that spatial confinement (SC), a moderate environmental stressor, increases tic-like responses and elicits TS-like sensorimotor gating deficits in the D1CT-7 mouse, one of the best-validated models of TS. Here, we hypothesized that these adverse effects may be mediated by neurosteroids, given their well-documented role in stress-response orchestration. Indeed, SC increased the levels of progesterone, as well as its derivatives 5α-dihydroprogesterone and allopregnanolone, in the prefrontal cortex (PFC) of D1CT-7 mice. Among these steroids, however, only allopregnanolone (5–15 mg/kg, IP) dose-dependently exacerbated TS-like manifestations in D1CT-7, but not wild-type littermates; these effects were countered by the benchmark anti-tic therapy haloperidol (0.3 mg/kg, IP). Furthermore, the phenotypic effects of spatial confinement in D1CT-7 mice were suppressed by finasteride (25–50 mg/kg, IP), an inhibitor of the main rate-limiting enzyme in allopregnanolone synthesis. These findings collectively suggest that stress may exacerbate TS symptoms by promoting allopregnanolone synthesis in the PFC, and corroborate previous clinical results pointing to finasteride as a novel therapeutic avenue to curb symptom fluctuations in TS.Laura J. MosherSean C. GodarMarianela NelsonStephen C. FowlerGraziano PinnaMarco BortolatoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-9 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Laura J. Mosher Sean C. Godar Marianela Nelson Stephen C. Fowler Graziano Pinna Marco Bortolato Allopregnanolone mediates the exacerbation of Tourette-like responses by acute stress in mouse models
description	Abstract Tourette syndrome (TS) is a neuropsychiatric disorder characterized by multiple tics and sensorimotor abnormalities, the severity of which is typically increased by stress. The neurobiological underpinnings of this exacerbation, however, remain elusive. We recently reported that spatial confinement (SC), a moderate environmental stressor, increases tic-like responses and elicits TS-like sensorimotor gating deficits in the D1CT-7 mouse, one of the best-validated models of TS. Here, we hypothesized that these adverse effects may be mediated by neurosteroids, given their well-documented role in stress-response orchestration. Indeed, SC increased the levels of progesterone, as well as its derivatives 5α-dihydroprogesterone and allopregnanolone, in the prefrontal cortex (PFC) of D1CT-7 mice. Among these steroids, however, only allopregnanolone (5–15 mg/kg, IP) dose-dependently exacerbated TS-like manifestations in D1CT-7, but not wild-type littermates; these effects were countered by the benchmark anti-tic therapy haloperidol (0.3 mg/kg, IP). Furthermore, the phenotypic effects of spatial confinement in D1CT-7 mice were suppressed by finasteride (25–50 mg/kg, IP), an inhibitor of the main rate-limiting enzyme in allopregnanolone synthesis. These findings collectively suggest that stress may exacerbate TS symptoms by promoting allopregnanolone synthesis in the PFC, and corroborate previous clinical results pointing to finasteride as a novel therapeutic avenue to curb symptom fluctuations in TS.
format	article
author	Laura J. Mosher Sean C. Godar Marianela Nelson Stephen C. Fowler Graziano Pinna Marco Bortolato
author_facet	Laura J. Mosher Sean C. Godar Marianela Nelson Stephen C. Fowler Graziano Pinna Marco Bortolato
author_sort	Laura J. Mosher
title	Allopregnanolone mediates the exacerbation of Tourette-like responses by acute stress in mouse models
title_short	Allopregnanolone mediates the exacerbation of Tourette-like responses by acute stress in mouse models
title_full	Allopregnanolone mediates the exacerbation of Tourette-like responses by acute stress in mouse models
title_fullStr	Allopregnanolone mediates the exacerbation of Tourette-like responses by acute stress in mouse models
title_full_unstemmed	Allopregnanolone mediates the exacerbation of Tourette-like responses by acute stress in mouse models
title_sort	allopregnanolone mediates the exacerbation of tourette-like responses by acute stress in mouse models
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/3ab4a6989ba3454dac75b5a92be0ee11
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Allopregnanolone mediates the exacerbation of Tourette-like responses by acute stress in mouse models

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