Excitatory amino acid-induced convulsions in neonatal rats mediated by distinct receptor subtypes.
We found that N-methyl-D-aspartate (NMDA) was a very potent, systematically active convulsant in the rat in the early period of postnatal development (7-11 days of age). Other receptor subtype-selective excitatory amino acid agonists were then examined for their convulsant effects following i.p. administration to neonatal rats. alpha-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) was the most potent convulsant (ED50 0.6 mg/kg), followed by kainate (ED50 1.5 mg/kg), N-methyl-D-aspartate (NMDA) (ED50 3.1 mg/kg), then quisqualate (ED50 5.1 mg/kg). NMDA-induced convulsions were antagonized in a dose-related manner by prior administration of the NMDA antagonists cis-(+/- )-4-phosphonomethyl-2-piperidine carboxylic acid (CGS19755), cis-(+/- )-4-(2H-tetrazol-5-yl)methyl-piperidine-2-carboxylic acid (LY233053), (+/- )3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), D,L-2-amino-5-phosphonovalerate (D,L-AP5) and MK801. NMDA antagonists did not protect against AMPA- or kainate-induced convulsions. 6,7-Dinitroquinoxaline-2,3-dione (DNQX) selectively prevented the effect of AMPA at doses which had no effect on NMDA or kainate convulsions. Quisqualate-induced convulsions were antagonized by NMDA antagonists or DNQX. The greater sensitivity of neonatal rats to systemically administered excitatory amino acid agonists appears useful for evaluating the selectivity of antagonists acting at ionotropic excitatory amino acid receptors in the central nervous system. Using neonatal rats three pharmacologically distinct excitatory amino acid receptor effects were demonstrated following administration of NMDA, AMPA or kainate.
Schoepp
D D
DD
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285.
Gamble
A Y
AY
Salhoff
C R
CR
Johnson
B G
BG
Ornstein
P L
PL
D000375:Aging / Q000502:physiology; D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D000927:Anticonvulsants; D003292:Convulsants; D005260:Female; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D017459:Receptors, Amino Acid; D011956:Receptors, Cell Surface / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology
D000596:Amino Acids; D000927:Anticonvulsants; D003292:Convulsants; D017459:Receptors, Amino Acid; D011956:Receptors, Cell Surface; D016202:N-Methylaspartate