Valproate-induced hormonal and histological alterations in PTZ-kindled female rats with a focus on 5HT1A receptors

Valproic acid (VPA), a widely used antiseizure medication, has been associated with significant reproductive and hormonal side effects that may lead to infertility in both sexes. Although VPA increases serotonin availability, the contribution of specific serotonergic receptors to these alterations remains unclear. This study evaluated the involvement of 5-HT1A receptors in VPA-induced hormonal and ovarian changes in pentylenetetrazol (PTZ)-kindled female rats. Fifty adult female Wistar rats were assigned to five groups (n = 10): Control (saline), PTZ + saline, PTZ + VPA, PTZ + NAD-299 (5-HT1A antagonist), and PTZ + VPA + NAD-299. PTZ kindling was induced by intraperitoneal injections (37 mg/kg, every 48 h). Endpoints included seizure staging, serum estradiol, testosterone, progesterone, and ovarian histology/morphometrics. Data were analyzed by one‑way ANOVA followed by Tukey's test (p < 0.05). PTZ kindling increased testosterone and progesterone levels and reduced estradiol compared with controls. VPA treatment decreased all three hormones, whereas co-administration of NAD-299 with VPA further intensified these hormonal disturbances and ovarian structural changes, including follicular depletion and increased ovarian wall thickness. Behaviorally, VPA limited seizures severity to stages 1-2, whereas 5‑HT1A antagonism heightened seizure intensity. The results indicate that co-administration of the 5-HT1A receptor antagonist with VPA exacerbated the observed hormonal and tissue alterations. The results indicate that co-administration of the 5-HT1A receptor antagonist with VPA exacerbated the observed hormonal and ovarian alterations. These findings suggest that 5-HT1A receptor activity may be involved in modulating VPA-associated endocrine and tissue changes, while receptor blockade is associated with increased reproductive adverse effects.