Influence of combined treatment with NMDA and non-NMDA receptor antagonists on electroconvulsions in mice.
alpha-Amino-3-hydroxy-5-methyl-isoxazole-4-propionate/kainate (AMPA/kainate) receptor antagonists (at subthreshold doses against electroconvulsions), 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466 at maximally 5 mg/kg) and 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline (NBQX at maximally 20 mg/kg) enhanced the protective effects of NMDA receptor antagonists, MK-801 (dizocilpine) or 2-(2-carboxypiperazine-4-yl)-1-propenyl-1-phosphonic acid (D-CPP-ene), against electroconvulsions. Similarly, MK-801 or D-CPP-ene reduced the ED50 values of both NBQX and GYKI 52466 against maximal electroshock. The adverse effects of D-CPP-ene, evaluated in the chimney and rotorod tests, were potentiated by both GYKI 52466 (2.5 mg/kg) and NBQX (10 mg/kg). Also, D-CPP-ene (0.1 mg/kg) worsened the motor performance of mice pretreated with GYKI 52466 in the rotorod test. Neither MK-801 (0.025 mg/kg) nor D-CPP-ene (0.1 mg/kg) affected the NBQX-induced impairment of motor coordination. Similarly, GYKI 52466 (2.5 mg/kg) or NBQX (10 mg/kg) did not influence the performance of mice treated with MK-801 (0.2 mg/kg). It may be concluded that the blockade of more than one subtype of glutamate receptors leads to a more pronounced anticonvulsive effect when compared with the effect of blockade of an individual receptor subtype. In some cases more efficient seizure protection was not associated with increased adverse effects.
Department of Pharmacology and Toxicology, Medical University School, Lublin, Poland.
S J
SJ
Czuczwar
K K
KK
Borowicz
Z
Z
Kleinrok
P
P
Tutka
T
T
Zarnowski
W A
WA
Turski
D000818:Animals; D014151:Anti-Anxiety Agents; D000927:Anticonvulsants / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology; D004338:Drug Combinations; D004597:Electroshock; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects; D011810:Quinoxalines / Q000494:pharmacology; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012640:Seizures
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D004338:Drug Combinations; D011810:Quinoxalines; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C061950:GYKI 52466; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D001569:Benzodiazepines