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Ovarian hormones modulate antidepressant-induced hippocampal cell proliferation in the dentate gyrus of adult female rats Foisy, Michelle

Abstract

Major depression is twice as common in women and symptoms are more severe in women than in men. These sex differences are linked to ovarian hormone levels in women. Interestingly, ovarian hormones may modulate antidepressant efficacy, with low ovarian hormone levels in women associated with a poorer antidepressant response. The mechanisms behind antidepressant efficacy have not yet been established, but chronic, and not acute, antidepressant treatment increases hippocampal neurogenesis in rodents and humans and normalizes hypothalamic-pituitary-adrenal axis negative feedback in rodents and humans. The antidepressant-induced increase in neurogenesis is, therefore, one mechanism by which antidepressants may work to alleviate some depressive symptoms. In this experiment we examined the effect of ovarian hormone status on the ability of chronic antidepressant treatment to increase cell proliferation in the dentate gyrus of female rats. Adult female rats were ovariectomized (OVX) or sham ovariectomized (Sham) prior to receiving 21 daily injections with either vehicle, the tricyclic antidepressant imipramine, or the selective serotonin reuptake inhibitor fluoxetine. Animals were then perfused, and brains were immunohistochemically processed for two endogenous markers: Ki67, which labels proliferating cells in the previous 24 hours, and doublecortin, which labels immature neurons aged 1-21 days. Ki67- and doublecortin-labeled cells were counted in two regions of the dentate gyrus: the dorsal region, important for memory, and the ventral region, important for regulating stress/emotion. Chronic imipramine treatment increased cell proliferation (Ki67-labeled cells) in the ventral dentate gyrus of Sham animals only, while chronic fluoxetine treatment increased cell proliferation in the dorsal dentate gyrus of OVX animals only. Furthermore, OVX animals receiving imipramine had an increased number of immature neurons (doublecortin-labeled cells) in the ventral dentate gyrus. OVX/water compared to Sham/water controls had significantly decreased adrenal to body weight ratios that were restored following chronic treatment with imipramine and fluoxetine. Both antidepressants also lengthened the estrous cycle. This study is the first to demonstrate that ovarian hormones modulate antidepressant-induced increases in cell proliferation in females in a drug-specific and region-specific manner, and highlights the importance of considering ovarian hormone status when examining the neurogenic effects of antidepressants.

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