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The pathogenesis of<jats:styled-content style=\"fixed-case\">TS<\/jats:styled-content>is considered to reflect dysregulations in the signalling of dopamine (<jats:styled-content style=\"fixed-case\">DA<\/jats:styled-content>) and other neurotransmitters, which lead to excitation\/inhibition imbalances in cortico\u2010striato\u2010thalamocortical circuits. The causes of these deficits may reflect complex gene\u00a0\u00d7\u00a0environment\u00a0\u00d7\u00a0sex (G\u00a0\u00d7\u00a0E\u00a0\u00d7\u00a0S) interactions; indeed, the disorder is markedly predominant in males, with a male\u2010to\u2010female prevalence ratio of approximately 4\u00a0:\u00a01. Converging lines of evidence point to neuroactive steroids as being likely molecular candidates to account for G\u00a0\u00d7\u00a0E\u00a0\u00d7\u00a0S interactions in<jats:styled-content style=\"fixed-case\">TS<\/jats:styled-content>. Building on these premises, our group has begun examining the possibility that alterations in the steroid biosynthetic process may be directly implicated in<jats:styled-content style=\"fixed-case\">TS<\/jats:styled-content>pathophysiology; in particular, our research has focused on 5\u03b1\u2010reductase (5\u03b1R), the enzyme catalysing the key rate\u2010limiting step in the synthesis of pregnane and androstane neurosteroids. In clinical and preclinical studies, we found that 5\u03b1R inhibitors exerted marked anti\u2010<jats:styled-content style=\"fixed-case\">DA<\/jats:styled-content>ergic and tic\u2010suppressing properties, suggesting a central role for this enzyme in<jats:styled-content style=\"fixed-case\">TS<\/jats:styled-content>pathogenesis. Based on these data, we hypothesise that enhancements in 5\u03b1R activity in early developmental stages may lead to an inappropriate activation of the \u2018backdoor\u2019 pathway for androgen synthesis from adrenarche until the end of puberty. We predict that the ensuing imbalances in steroid homeostasis may impair the signalling of<jats:styled-content style=\"fixed-case\">DA<\/jats:styled-content>and other neurotransmitters, ultimately resulting in the facilitation of tics and other behavioural abnormalities in<jats:styled-content style=\"fixed-case\">TS<\/jats:styled-content>.<\/jats:p>","DOI":"10.1111\/jne.12066","type":"journal-article","created":{"date-parts":[[2013,6,25]],"date-time":"2013-06-25T07:52:48Z","timestamp":1372146768000},"page":"1196-1208","source":"Crossref","is-referenced-by-count":32,"title":["The Implication of Neuroactive Steroids in Tourette's Syndrome Pathogenesis: A Role for 5\u03b1\u2010Reductase?"],"prefix":"10.1111","volume":"25","author":[{"given":"M.","family":"Bortolato","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology School of Pharmacy University of Kansas Lawrence KS USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"Frau","sequence":"additional","affiliation":[{"name":"Section of Neuroscience and Clinical Pharmacology Department of Biomedical Sciences University of Cagliari Monserrato Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. 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