l-701324 and 2-3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline

We investigated the role of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor in the induction and expression of an amphetamine-induced conditioned place preference (CPP) in mice. The selective AMPA-receptor antagonist 2, 3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX) failed to prevent the induction of a CPP, except at a dose (30 mg/kg) that also produced a conditioned place aversion. NBQX also failed to affect the expression of a CPP at a dose high enough to reduce activity levels. In contrast, the less selective AMPA receptor antagonist 6-cyano-7-nitroquinoxalone-2,3-dione (CNQX) prevented the expression of a CPP at doses (1-10 mg/kg) that had no effect on activity levels. We therefore tested the possibility that CNQX exerted its effects due to antagonism at the glycine site of the N-methyl-D-aspartate receptor. The glycine-site antagonist 7-chloro-4-hydroxy-3-(2-phenoxy)phenyl-2(1H)-quinolone also prevented the expression of a CPP at doses that had no effect on activity levels (0.1-0.3 mg/kg). These results suggest that neither the induction nor the expression of an amphetamine-induced CPP requires AMPA receptor-mediated transmission and that effects found in previous studies using the less selective AMPA receptor antagonists may be due to the effects of these compounds at the glycine site of the N-methyl-D-aspartate receptor.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Amphetamine; Animals; Central Nervous System Stimulants; Conditioning, Operant; Excitatory Amino Acid Antagonists; Male; Mice; Mice, Inbred C57BL; Motor Activity; Quinolones; Quinoxalines; Receptors, AMPA; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate

The aim of this study was to assess whether a drug which combines an antagonistic action at both NMDA and non-NMDA receptors offers advantages for treatment of epileptic seizures compared to drugs which antagonize only one of these ionotropic glutamate receptors. The novel glutamate receptor antagonist LU 73068 (4,5-dihydro-1-methyl-4-oxo-7-trifluoromethylimidazo[1,2a]quinoxal ine-2-carbonic acid) binds with high affinity to both the glycine site of the NMDA receptor (Ki 185 nM) and to the AMPA receptor (Ki 158 nM). Furthermore, binding experiments with recombinant kainate receptor subunits showed that LU 73068 binds to several of these subunits, particularly to rGluR7 (Ki 104 nM) and rGluR5 (Ki 271 nM). In comparison, the prototype non-NMDA receptor antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo[f]quinoxaline) binds with high affinity to AMPA receptors only. Both NBQX and LU 73068 were about equieffective after i.p. injection in mice to block lethal convulsions induced by AMPA or NMDA. In the rat amygdala kindling model of temporal lobe epilepsy, LU 73068 dose-dependently increased the focal seizure threshold (afterdischarge threshold, ADT). When rats were stimulated with a current 20% above the individual control ADT, LU 73068 completely blocked seizures with an ED50 of 4.9 mg kg(-1). Up to 20 mg kg(-1), only moderate adverse effects, e.g. slight ataxia, were observed. NBQX, 10 mg kg(-1), and the glycine/NMDA site antagonist L-701,324 (7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-quinoline-2(1H)one), 2.5 or 5 mg kg(-1), exerted no anticonvulsant effects in kindled rats when administered alone, but combined treatment with both drugs resulted in a significant ADT increase. The data indicate that combination of glycine/NMDA and non-NMDA receptor antagonism in a single drug is an effective means of developing a potent and effective anticonvulsant agent.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Anticonvulsants; Disease Models, Animal; Dizocilpine Maleate; Drug Synergism; Epilepsy; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Imidazoles; Kindling, Neurologic; Male; Mice; Mice, Inbred Strains; N-Methylaspartate; Quinolones; Quinoxalines; Receptors, AMPA; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Tritium