Serotonin depletion increases seizure susceptibility and worsens neuropathological outcomes in kainate model of epilepsy

Abstract Serotonin is implicated in the regulation of seizures, but whether or not it can potentiate the effects of epileptogenic factors is not fully established. Using the kainic acid model of epilepsy in rats, we tested the effects of serotonin depletion on (1) susceptibility to acute seizures, (2) development of spontaneous recurrent seizures and (3) behavioral and neuroanatomical sequelae of kainic acid treatment. Serotonin was depleted by pretreating rats with p -chlorophenylalanine. In different groups, kainic acid was injected at 3 different doses: 6.5 mg/kg, 9.0 mg/kg or 12.5 mg/kg. A single dose of 6.5 mg/kg of kainic acid reliably induced status epilepticus in p -chlorophenylalanine-pretreated rats, but not in saline-pretreated rats. The neuroexcitatory effects of kainic acid in the p -chlorophenylalanine-pretreated rats, but not in saline-pretreated rats, were associated with the presence of tonic-clonic convulsions and high lethality. Compared to controls, a greater portion of serotonin-depleted rats showed spontaneous recurrent seizures after kainic acid injections. Loss of hippocampal neurons and spatial memory deficits associated with kainic acid treatment were exacerbated by prior depletion of serotonin. The present findings are of particular importance because they suggest that low serotonin activity may represent one of the major risk factors for epilepsy and, thus, offer potentially relevant targets for prevention of epileptogenesis.