Effects of Chronic Paroxetine Exposure and Irisin Treatment on Sexual Motivation, Reproductive Endocrine Profile, and Vaginal Histological and Immune-Inflammatory Outcomes in Adult Female Rats

Selective serotonin reuptake inhibitors (SSRIs), particularly paroxetine, are frequently associated with sexual dysfunction, yet their effects on female reproductive endocrine regulation and the local vaginal tissue environment remain incompletely characterized. Irisin is an exercise-responsive adipomyokine with reported reproductive and immunomodulatory actions, but its influence during chronic paroxetine exposure is unknown. This study evaluated the behavioral, endocrine, histological, and immune-related effects of chronic paroxetine treatment and examined whether irisin changed responses. Forty regularly cycling female Sprague–Dawley rats were allocated to sham control, paroxetine, irisin, or paroxetine + irisin groups (n = 10/group). Paroxetine was administered orally at 20 mg/kg/day for 8 weeks, while irisin was delivered continuously by subcutaneous mini-osmotic pumps at 100 ng/kg/day during the final 4 weeks. Sexual incentive motivation and active investigation behaviors, serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and anti-Müllerian hormone (AMH), vaginal fibroblast and plasma cell numbers, Toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB) immunoreactivity, and periodic acid–Schiff (PAS) reactivity were evaluated. Paroxetine did not significantly affect sexual incentive motivation parameters or circulating reproductive hormone concentrations (p > 0.05), but both paroxetine-treated groups showed a lower duration of investigation directed toward the female and a higher male investigation preference ratio than the sham control (p < 0.05). Irisin alone reduced locomotor activity (p < 0.01). Paroxetine increased vaginal fibroblast counts (p = 0.0001) and NF-κB immunoreactivity (p = 0.003) compared with the sham control, whereas TLR4 immunoreactivity remained unchanged. Plasma cell counts were elevated in all treatment groups compared with the sham control (p < 0.0001). Irisin co-treatment reduced fibroblast counts relative to paroxetine group and reduced plasma cell counts relative to both single-treatment groups (all p < 0.001). Vaginal epithelial PAS reactivity was severe (+++) in sham control, weak (+) after paroxetine, and moderate (++) in both irisin-treated groups. Overall, chronic paroxetine exposure produced selective behavioral and local vaginal stromal, immune-inflammatory, and epithelial alterations without significant changes in the measured reproductive hormonal profile. Irisin influenced several vaginal tissue responses but did not change the paroxetine-associated alterations in active investigation behavior.