Altered serotonin innervation in the rat epileptic brain.

Studies in animal models of epilepsy revealed compromised serotonin (5-HT) transmission between the raphe nuclei and the brain limbic system. The goal of the present study was to evaluate the effects of epilepsy on the structural integrity of the dorsal (DR) and median (MnR) raphe nuclei and on the morphology of serotonergic fiber terminals in the dentate gyrus (DG), infralimbic cortex (IL) and medial septum (MS). The study was performed in adult Wistar rats using the kainate (9.5 mg/kg) status epilepticus (SE) model. Four months post-SE, the brainstem sections of the animals were immunostained for 5-HT, whereas the forebrain sections were immunostained for serotonin transporter (SERT). Stereological analysis revealed that epileptic rats, as compared to controls, had approximately 30% less 5-HT-stained cells in the interfascicular part of the DR, but twice as many 5-HT-stained cells in the MnR. Another finding was the reorganization of the 5-HT fiber network in all target areas analyzed, as indicated by the rightward shift of the density-size distribution histograms of SERT-stained fiber varicosities. Nonlinear regression analysis of these histograms revealed that SERT-stained varicosities were represented by two subpopulations characterized by distinct cross-sectional areas. The areal density of the small-sized varicosities was decreased in the DG (hilus and molecular layer), IL cortex (layers II/III) and MS, while that of the larger-sized varicosities was increased. The present results support the hypothesis that chronic epilepsy can trigger profound structural reorganization of the ascending serotonergic pathways in the rat brain.

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

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: 6.5mg/kg, 9.0mg/kg or 12.5mg/kg. A single dose of 6.5mg/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.