Treatment of depressive‐like behaviour in Huntington's disease mice by chronic sertraline and exercise

BACKGROUND AND PURPOSE Depression is the most common psychiatric disorder in Huntington's disease (HD) patients. Women are more prone to develop depression and such susceptibility might be related to 5‐hydroxytryptaminergic (serotonergic) dysregulation. EXPERIMENTAL APPROACH We performed tests of depression‐related behaviours on female R6/1 HD mice that had been chronically treated with sertraline or provided with running‐wheels. Functional assessments of 5‐HT1A and 5‐HT2A 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. KEY RESULTS Female HD mice recorded increased immobility time in the forced‐swimming test, reduced saccharin preference and a hyperthermic response to stress compared with wild‐type animals. These alterations were improved by chronic sertraline treatment. Wheel‐running 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‐HT1A autoreceptor function, as demonstrated by modulation of the exaggerated 8‐OH‐DPAT‐induced hypothermia exhibited by female HD mice. On the other hand, sertraline treatment was unable to restore the reduced 5‐HT1A and 5‐HT2 heteroceptor function observed in HD animals. CONCLUSIONS AND IMPLICATIONS We report for the first time a crucial role for 5‐HT1A autoreceptor function in mediating the sex‐specific depressive‐like 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.