Kindling to the benzodiazepine receptor inverse agonist, FG 7142: evidence for involvement of NMDA, but not non-NMDA, glutamatergic receptors.
Repeated administration of the beta-carboline FG 7142 to mice leads to the development of kindled convulsions. In order to investigate a role for glutamatergic mechanisms in the processes underlying FG 7142 kindling, the N-methyl-D-aspartate (NMDA) antagonist, 2-amino-7-phosphono-heptanoic acid (AP7; 25 nmol), was administered intracerebroventricularly (i.c.v.) daily before administration of FG 7142 (40 mg/kg, i.p.). Under these conditions, kindling to FG 7142 did not occur. Administration of two antagonists at non-NMDA excitatory amino acid receptors, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and gamma-D-glutamylaminomethylsulphonic acid (gamma-D-GAMS; both 25 nmol) did not prevent the development of seizures; these doses were, however, adequate and selective in protecting against seizures induced by respectively quisqualic and kainic acids given by i.c.v. The susceptibility of mice kindled with FG 7142 to seizures induced by NMDA, or kainate or quisqualate was similar in mice which had shown 5 kindled seizures to that seen in drug-naive mice; mice which had shown 10 kindled seizures showed a decreased sensitivity to NMDA-induced convulsions (ED50 was increased from 0.24 to 0.31 nmol). No changes were seen in the convulsant thresholds of either NMDA or non-NMDA agonists. These observations suggest that although NMDA receptors appear to be involved in the processes underlying FG 7142 kindling, such kindling is not necessarily associated with an increased sensitivity of glutamate receptors, and in animals which have convulsed, a decreased sensitivity to NMDA agonists occurs.
Stephens
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Research Laboratories of Schering AG, Berlin, Germany.
Turski
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D000818:Animals; D002243:Carbolines / Q000494:pharmacology*; D005260:Female; D005973:Glutamine / Q000031:analogs & derivatives / Q000494:pharmacology; D007276:Injections, Intraventricular; D007608:Kainic Acid / Q000494:pharmacology; D007696:Kindling, Neurologic / Q000187:drug effects*; D051379:Mice; D016318:Quisqualic Acid / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects*; D017470:Receptors, Glutamate / Q000187:drug effects*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D013238:Stereotaxic Techniques
D002243:Carbolines; D011963:Receptors, GABA-A; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D005973:Glutamine; C035874:FG 7142; D016318:Quisqualic Acid; C042626:gamma-glutamylaminomethylsulfonic acid; D007608:Kainic Acid