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) dizocilpine (0.03-3 mg/kg), CGS 19755 (1-10 mg/kg), and 7-chlorokynurenic 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 carbamazepine (5 and 20 mg/kg), two standard anticonvulsants, using the partially-kindled hippocampal model for epileptic seizures in freely moving rats. The anticonvulsant effect of these compounds were assessed by determining (1) the afterdischarge (AD), which is indicative of the severity of the seizure and related to seizure maintenance, and (2) the pulse number threshold (PNT), which is indicative of the seizure threshold or initiation. In addition, ataxia, a measure of CNS dysfunction, 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 (carbamazepine, dizocilpine, CGS 19755 and 7-chlorokynurenic acid); (2) reduction of AD (diazepam and muscimol); and (3) mixed action, i.e., increased PNT and decreased AD (YM90K). Behavioral data indicated that all compounds, except carbamazepine, produced a dose- or concentration-dependent 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.
Katsumori
H
H
Division of Cortical Function Disorder, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
Minabe
Y
Y
Osawa
M
M
Ashby
C R
CR
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001259:Ataxia / Q000139:chemically induced; D002220:Carbamazepine / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000009:adverse effects / Q000494:pharmacology*; D018755:GABA Agonists / Q000009:adverse effects / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects*; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D010875:Pipecolic Acids / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced*
D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists; D010875:Pipecolic Acids; D011810:Quinoxalines; C086162:6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione; D009118:Muscimol; D002220:Carbamazepine; C053672:selfotel; D016291:Dizocilpine Maleate; D007736:Kynurenic Acid; D003975:Diazepam; C057013:7-chlorokynurenic acid