N-methyl-D-aspartic acid-induced lethality in mice: selective antagonism by phencyclidine-like drugs.
N-Methyl-D-aspartic acid (NMDA) produced a dose-related increase in lethality in mice, with 200 mg/kg (i.p.) effecting 100% lethality. Upon daily dosing, acutely sublethal doses of NMDA produced deaths. This NMDA-induced lethality was stereoselective; N-methyl-L-aspartic acid had no effects at doses as high as 400 mg/kg. Moderate doses of phencyclidine (PCP) and drugs having PCP-like behavioral effects blocked the NMDA-induced lethality. Other classes of psychoactive drugs, including opioids, anticonvulsants and antipsychotics, were ineffective in preventing NMDA-induced lethality. The potency of PCP-like drugs to block the NMDA-induced lethality correlates highly with the dose necessary to produce PCP-like catalepsy and PCP-like discrimination in pigeons. These data support the hypothesis that PCP-like drugs produce many of their effects by impairing the normal functioning of the NMDA-defined excitatory neurotransmitter receptor in the central nervous system.
Leander
J D
JD
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.
Lawson
R R
RR
Ornstein
P L
PL
Zimmerman
D M
DM
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D016202:N-Methylaspartate; D010622:Phencyclidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D001224:Aspartic Acid; D016202:N-Methylaspartate; D010622:Phencyclidine