Effect of the non-NMDA receptor antagonist, 2,3-dihydro-6-nitro-7-sulfamoylbenzo(f)quinoxaline, on local cerebral glucose uptake in the limbic forebrain.
The present investigation examined the effect of in vivo antagonism of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor by 2,3-dihydro-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX) on local cerebral glucose utilization (LCGU) using the quantitative autoradiographic 2-deoxy[14C]-glucose method in conscious rats. NBQX, at doses of 10, 30, and 60 mg/kg i.p. or three injections of 30 mg/kg i.p., did not increase LCGU in limbic areas such as the primary olfactory cortex, olfactory tubercle, hippocampus, dentate gyrus, posterior cingulate cortex, mamillary body, caudate nucleus, anterior thalamic nucleus, and nucleus accumbens. NBQX, at doses of > or = 60 mg/kg i.p., decreased LCGU in these brain areas. These data demonstrate that in vivo antagonism of the AMPA receptors by NBQX produces a pattern of alterations in metabolic activity, different from that produced by noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) receptor, e.g., phencyclidine and MK-801. Combined with a lack of "phencyclidine-like" behavior produced by NBQX, these data suggest that antagonism of the AMPA receptor represents a novel mechanism to block excitatory amino acids in the CNS, which may be devoid of unwanted behavioral side effects associated with noncompetitive antagonism of the NMDA receptor.
Department of Receptor Neurochemistry, Pharmaceuticals Division, Novo Nordisk A/S, Måløv, Denmark.
P D
PD
Suzdak
M J
MJ
Sheardown
D000818:Animals; D001345:Autoradiography; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists; D005947:Glucose / Q000378:metabolism*; D008032:Limbic System / Q000378:metabolism*; D008297:Male; D016548:Prosencephalon / Q000378:metabolism*; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA
D018691:Excitatory Amino Acid Antagonists; D011810:Quinoxalines; D018091:Receptors, AMPA; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D005947:Glucose