Serotonergic receptor mechanisms underlying antidepressant-like action in the progesterone withdrawal model of hormonally induced depression in rats

Hormonally induced mood disorders such as premenstrual dysphoric disorder (PMDD) are characterized by a range of physical and affective symptoms including anxiety, irritability, anhedonia, social withdrawal and depression. Studies demonstrated rodent models of progesterone withdrawal (PWD) have a high level of constructive and descriptive validity to model hormonally-induced mood disorders in women. Here we evaluate the effects of several classes of antidepressants in PWD female Long-Evans rats using the forced swim test (FST) as a measure of antidepressant activity. The study included fluoxetine, duloxetine, amitriptyline and an investigational multimodal antidepressant, vortioxetine (5-HT₃, 5-HT₇ and 5-HT_1D receptor antagonist; 5-HT_1B receptor partial agonist; 5-HT_1A receptor agonist; inhibitor of the serotonin transporter (SERT)). After 14 days of administration, amitriptyline and vortioxetine significantly reduced immobility in the FST whereas fluoxetine and duloxetine were ineffective. After 3 injections over 48h, neither fluoxetine nor duloxetine reduced immobility, whereas amitriptyline and vortioxetine significantly reduced FST immobility during PWD. When administered acutely during PWD, the 5-HT_1A receptor agonist, flesinoxan, significantly reduced immobility, whereas the 5-HT_1A receptor antagonist, WAY-100635, increased immobility. The 5-HT₃ receptor antagonist, ondansetron, significantly reduced immobility, whereas the 5-HT₃ receptor agonist, SR-57227, increased immobility. The 5-HT₇ receptor antagonist, SB-269970, was inactive, although the 5-HT₇ receptor agonist, AS-19, significantly increased PWD-induced immobility. None of the compounds investigated (ondansetron, flesinoxan and SB-269970) improved the effect of fluoxetine during PWD. These data indicate that modulation of specific 5-HT receptor subtypes is critical for manipulating FST immobility in this model of hormone-induced depression.