Selective serotonin reuptake inhibitors (SSRI) are widely used antidepressants and their effect is partly mediated by restoring stress axis dynamics, which may depend on sex and hormonal states. In the present study, we investigate the effect of daily injections of the SSRI paroxetine (5 mg/kg s.c.) on swim stress-induced corticosterone (CORT) response, depressive-like behavior (forced swim test) and anxiety-like behavior (open field test) in nulliparous Sprague Dawley rats. Data were acquired after either 1-3 (acute PXT) or 11-13 (chronic PXT) injections. We found that chronic, but not acute, paroxetine blunted the swim stress-induced CORT response. We observed an increase in depressive-like and anxiety-like behavior following acute PXT, and a normalization after chronic PXT treatment. Intriguingly, our findings of rapid recovery from adverse SSRI effects differ from corresponding studies performed by our group in postpartum rats. Thus, the study emphasizes that mechanisms of action and efficacy of SSRIs differ according to reproductive states, which if translated to humans may inform treatment strategies, beyond SSRIs alone, for hormone transition related depressive states.

Chronic paroxetine blunts stress response and normalizes adverse behavioral effects seen acutely in nulliparous rats