ACUTE EFFECTS OF VARIOUS GABA RECEPTOR AGONISTS AND GLUTAMATE ANTAGONISTS ON FOCAL HIPPOCAMPAL SEIZURES IN FREELY MOVING RATS ELICITED BY LOW-FREQUENCY STIMULATION

In this study, we examined the acute anticonvulsant spectrum of (1) di zocilpine (0.03-3 mg/kg), CGS 19755 (1-10 mg/kg), and 7-chlorokynureni c acid (1-100 nmol) (NMDA receptor/ionophore complex antagonists); (2) muscimol (0.1-10 nmol; direct GABA(A) agonist); (3) YM90K (3-10 mg/kg ; AMPA receptor antagonist); and (4) diazepam (2 and 5 mg/kg) and carb amazepine (5 and 20 mg/kg), two standard anticonvulsants, using the pa rtially-kindled hippocampal model for epileptic seizures in freely mov ing rats. The anticonvulsant effect of these compounds were assessed b y determining (1) the afterdischarge (AD), which is indicative of the severity of the seizure and related to seizure maintenance, and (2) th e pulse number threshold (PNT), which is indicative of the seizure thr eshold or initiation. In addition, ataxia, a measure of CNS dysfunctio n, was assessed for each compound. Overall, our results indicated that the anticonvulsant compounds examined could be classified into three categories based on effects on the AD and PNT: (1) elevation of PNT (c arbamazepine, dizocilpine, CGS 19755 and 7-chlorokyurenic acid); (2) r eduction of AD (diazepam and muscimol); and (3) mixed action, i.e., in creased PNT and decreased AD (YM90K). Behavioral data indicated that a ll compounds, except carbamazepine, produced a dose-or concentration-d ependent ataxia. Overall, our results suggest that NMDA receptors play a role in seizure initiation, whereas the GABA(A) receptors appear to be involved in seizure maintenance and AMPA receptors may be involved in both phenomena. (C) 1998 Wiley-Liss, Inc.