Dn. Stephens et L. Turski, KINDLING TO THE BENZODIAZEPINE RECEPTOR INVERSE AGONIST, FG 7142 - EVIDENCE FOR INVOLVEMENT OF NMDA, BUT NOT NON-NMDA, GLUTAMATERGIC RECEPTORS, Neuropharmacology, 32(10), 1993, pp. 1011-1017
Repeated administration of the beta-carboline FG 7142 to mice leads to
the development of kindled convulsions. In order to investigate a rol
e for glutamatergic mechanisms in the processes underlying FG 7142 kin
dling, the N-methyl-D-aspartate (NMDA) antagonist, 2-amino-7-phosphono
heptanoic acid (AP7; 25 nmol), was administered intracerebroventricula
rly (i.c.v.) daily before administration of FG 7142 (40 mg/kg, i.p.).
Under these conditions, kindling to FG 7142 did not occur. Administrat
ion of two antagonists at non-NMDA excitatory amino acid receptors, 6-
cyano-7-nitroquinoxaline-2,3-dione (CNQX) and gamma-D-glutamylaminomet
hylsulphonic acid (gamma-D-GAMS, both 25 nmol) did not prevent the dev
elopment of seizures; these doses were, however, adequate and selectiv
e in protecting against seizures induced by respectively quisqualic an
d 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 si
milar in mice which had shown 5 kindled seizures to that seen in drug-
naive mice; mice which had shown 10 kindled seizures showed a decrease
d sensitivity to NMDA-induced convulsions (ED50 was increased from 0.2
4 to 0.31 nmol). No changes were seen in the convulsant thresholds of
either NMDA or non-NMDA agonists. These observations suggest that alth
ough 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 hav
e convulsed, a decreased sensitivity to NMDA agonists occurs.