Prophylactic sodium valproate administration is associated with improved spatial memory in PTZ-kindled rats: involvement of 5-HT1A receptors.

OBJECTIVE: Previous findings on valproate (VPA) and cognitive function are inconsistent. Given the shared signaling pathways between VPA and 5-HT1A receptors, this study examined whether prophylactic VPA administration is associated with improved spatial memory in pentylenetetrazol (PTZ)-kindled rats and whether 5-HT1A receptor blockade reverses this effect. METHODS: Adult male rats were divided into six groups (n = 10). PTZ (37 mg/kg) and VPA (300 mg/kg) were injected intraperitoneally every 48 h for four weeks. VPA was given 30 min before PTZ in combined groups. Seizure severity was scored daily. After kindling, NAD-299 (5 µg/0.5 µl, i.c.v.) was administered before Morris water maze testing. Spatial learning was assessed over four consecutive training days, followed by a probe trial on day five. RESULTS: VPA significantly attenuated seizure severity (P < 0.001). PTZ-kindled rats treated with VPA showed improved spatial learning and memory compared with the PTZ group, as evidenced by reduced escape latency (P < 0.001) and increased time in the target quadrant (P < 0.01). ANCOVA with cumulative seizure score as a covariate confirmed that VPA improved memory even after controlling for seizure burden (P = 0.042), suggesting a direct cognitive effect beyond seizure suppression. Co-administration of NAD-299 abolished these improvements, with performance comparable to the PTZ group (P > 0.05). CONCLUSION: Prophylactic VPA administration is associated with improved spatial memory in PTZ-kindled rats, an effect critically dependent on intact 5-HT1A receptor signaling. These findings highlight a potential dual benefit of VPA-seizure control and cognitive protection-though post-kindling studies are warranted to establish direct causality.