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Summary: Purpose:We determined the antiepileptic profile of tiagabine (TGB), a selective y-aminobutyric acid (GABA) uptake inhibitor, in the rat kindling model of temporal lobe epilepsy (TLE).Methods: The anticonvulsant and adverse effects of TGB were examined in amygdala-or hippocampal-kindled rats and compared with those of other GABA uptake inhibitors (SKF89976A and NNC-7 1 1) and conventional antiepileptic drugs [AEDs: valproate (VPA) and carbamazepine (CBZ)]. In addition, the antiepileptogenic effects of TGB on amygdala kindling development were examined.Results: TGB (2.540 mgkg intraperitoneally, i.p.) had potent and dose-dependent anticonvulsant effects on both amygdala-and hippocampal-kindled seizures. The order of anticonvulsant potency of the three GABA uptake inhibitors tested was: NNC-711 > TGB > SKF-89976A and paralleled the in vitro GABA uptake efficacy. In addition, daily treatment with TGB 10 mgkg for 10 days significantly retarded kindling development. Although adverse effects of TGB on motor systems were significantly less than those of VPA and CBZ, high toxic doses of TGB often caused EEG paroxysm and myoclonus.Conclusions: Our results indicate the clinical usefulness of TGB for treatment of drug-resistant TLE.

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There is an increased incidence of schizophrenia-like psychosis in temporal lobe epilepsy (TLE), and several risk factors have been implicated, including the duration of epilepsy and temporal lobe neuropathology. To investigate the biological mechanism of epileptic psychosis, we examined alterations of central dopaminergic systems in the kainate model of TLE. In adult rats, kainate was microinjected into the left amygdala to induce status epilepticus. An indirect dopamine agonist methamphetamine (MAP, 2 mg/kg, i.p.) was administered before and 1 month after the kainate treatment. MAP-induced locomotor activity was significantly enhanced in the kainate group compared with the baseline (pre-kainate) level, which was antagonized by pretreatment with haloperidol. The enhancement of locomotor activity in the kainate group was significantly correlated with the density of hippocampal CA1 neurons. Although the basal extracellular dopamine concentration was significantly lower in the striatum in the kainate group than in the control group (5.5 vs 39.2 fmol/20-min sample), the maximal concentration following MAP administration did not differ between the two groups. These results clearly demonstrate that hypersensitivity of the dopamine systems develops in the chronic phase of the kainate-induced TLE model, which may be responsible for the mechanism of epileptic psychosis.