The competitive N-methyl-D-aspartate (NMDA) antagonist CGS 19755 attenuates the rate-decreasing effects of NMDA in rhesus monkeys without producing ketamine-like discriminative stimulus effects.
The purported competitive excitatory amino acid antagonist CGS 19755 was compared to the non-competitive antagonists ketamine and MK-801 in three rhesus monkeys discriminating between 1.78 mg/kg of ketamine and saline while responding under a fixed-ratio 100 schedule of food presentation. MK-801 substituted completely for the ketamine discriminative stimulus and was 32 times more potent than ketamine as a discriminative stimulus. CGS 19755 was studied using single and cumulative dosing procedures up to a dose of 10.0 mg/kg; for all conditions, CGS 19755 produced responding exclusively on the saline lever and had only modest rate-decreasing effects. N-Methyl-D-aspartate administered alone also did not produce ketamine-appropriate responding but did decrease response rates in a dose-related manner. N-Methyl-D-aspartate eliminated responding in all monkeys at doses of 5.6-10.0 mg/kg. MK-801 and ketamine antagonized the rate-decreasing effects of N-methyl-D-aspartate, however, ketamine was most effective as an antagonist at doses that decreased response rates when administered alone. CGS 19755 also attenuated the rate-decreasing effects of N-methyl-D-aspartate and shifted the N-methyl-D-aspartate dose-effect curve more than 5-fold to the right. The magnitude of antagonism of N-methyl-D-aspartate appeared to be somewhat greater with CGS 19755 than with MK-801 or ketamine. Thus, a competitive (CGS 19755) and some non-competitive (MK-801 and ketamine) excitatory amino acid antagonists can attenuate the rate-decreasing effects of N-methyl-D-aspartate.(ABSTRACT TRUNCATED AT 250 WORDS)
France
C P
CP
Department of Psychology, University of Michigan, Ann Arbor 48109-0626.
Woods
J H
JH
Ornstein
P
P
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D003986:Dibenzocycloheptenes / Q000494:pharmacology; D004192:Discrimination, Psychological / Q000187:drug effects*; D016291:Dizocilpine Maleate; D007649:Ketamine / Q000494:pharmacology*; D008253:Macaca mulatta; D008297:Male; D016202:N-Methylaspartate; D010875:Pipecolic Acids; D010880:Piperidines / Q000494:pharmacology*
D000927:Anticonvulsants; D003986:Dibenzocycloheptenes; D010875:Pipecolic Acids; D010880:Piperidines; D001224:Aspartic Acid; C053672:selfotel; D016202:N-Methylaspartate; D007649:Ketamine; D016291:Dizocilpine Maleate