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Women are more prone to develop depression and such susceptibility might be related to 5\u2010hydroxytryptaminergic (serotonergic) dysregulation.<\/jats:p><jats:p><jats:bold>EXPERIMENTAL APPROACH<\/jats:bold> We performed tests of depression\u2010related behaviours on female R6\/1 HD mice that had been chronically treated with sertraline or provided with running\u2010wheels. Functional assessments of 5\u2010HT<jats:sub>1A<\/jats:sub> and 5\u2010HT<jats:sub>2A<\/jats:sub> receptors were performed by measuring behavioural and physiological responses following administration of specific agonists, in combination with analysis of hippocampal gene expression. Finally we assessed the effect of exercise on hippocampal cell proliferation.<\/jats:p><jats:p><jats:bold>KEY RESULTS<\/jats:bold> Female HD mice recorded increased immobility time in the forced\u2010swimming test, reduced saccharin preference and a hyperthermic response to stress compared with wild\u2010type animals. These alterations were improved by chronic sertraline treatment. Wheel\u2010running also resulted in similar improvements with the exception of saccharin preference but failed to correct the hippocampal cell proliferation deficits displayed by HD mice. The benefits of sertraline treatment and exercise involved altered 5\u2010HT<jats:sub>1A<\/jats:sub> autoreceptor function, as demonstrated by modulation of the exaggerated 8\u2010OH\u2010DPAT\u2010induced hypothermia exhibited by female HD mice. On the other hand, sertraline treatment was unable to restore the reduced 5\u2010HT<jats:sub>1A<\/jats:sub> and 5\u2010HT<jats:sub>2<\/jats:sub> heteroceptor function observed in HD animals.<\/jats:p><jats:p><jats:bold>CONCLUSIONS AND IMPLICATIONS<\/jats:bold> We report for the first time a crucial role for 5\u2010HT<jats:sub>1A<\/jats:sub> autoreceptor function in mediating the sex\u2010specific depressive\u2010like phenotype of female R6\/1 HD mice. Our data further support a differential effect of chronic sertraline treatment and exercise on hippocampal cell proliferation despite common behavioural benefits.<\/jats:p>","DOI":"10.1111\/j.1476-5381.2011.01567.x","type":"journal-article","created":{"date-parts":[[2011,6,30]],"date-time":"2011-06-30T18:50:28Z","timestamp":1309459828000},"page":"1375-1389","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["Treatment of depressive\u2010like behaviour in Huntington's disease mice by chronic sertraline and exercise"],"prefix":"10.1111","volume":"165","author":[{"given":"Thibault","family":"Renoir","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terence YC","family":"Pang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle 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