The discriminative stimulus effects of N-methyl-D-aspartate glycine-site ligands in NMDA antagonist-trained rats.
BACKGROUND
Many N-methyl-D-aspartate (NMDA) antagonists produce phencyclidine (PCP)-like side effects that limit their clinical utility. NMDA glycine-site antagonists may be less likely to produce these effects than other site-selective NMDA antagonists.


OBJECTIVE
The objective of the study is to compare the discriminative stimulus effects of novel NMDA glycine-site drugs to those of channel blocking and competitive NMDA antagonists.


METHODS
Drug discrimination studies were performed in separate groups of rats trained with saline vs. PCP (2 mg/kg i.p.) or the competitive antagonist NPC 17742 (4 mg/kg i.p.) using a standard two-lever operant conditioning procedure under an FR32.


RESULTS
Neither the partial glycine-site agonists aminocyclopropane carboxylic acid methyl ester and (+)-HA-966 nor the antagonists L701,324; MDL 100,458; MDL 100,748; MDL 103,371; MDL 104,472; MDL 105,519; MRZ 2/571; MRZ 2/576; and ACEA 0762 produced >50% PCP-lever selection, though all were tested over a sufficient dose range to produce response rate decreasing effects. All of the antagonists, except MDL 100,458 and MDL 100,748, were also tested for NPC 17742-like effects, producing somewhat more variable results than in PCP-trained rats. ACEA-0762 produced full substitution for NPC 17742, whereas MDL 105,519 produced no substitution. The remaining compounds engendered between 20% and 80% drug-lever selection.


CONCLUSIONS
These results provide evidence that NMDA glycine-site partial agonists and antagonists generally do not produce discriminative stimulus effects similar to those of representative NMDA channel blockers or competitive antagonists. This suggests that these NMDA glycine-site antagonists should be less likely to produce the undesirable behavioral side effects seen in clinical trials with many other NMDA antagonists.
Nicholson
Katherine L
KL
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Box 980613, Richmond, VA 23298-0613, USA. klnichol@vcu.edu
Balster
Robert L
RL
D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001665:Binding Sites; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005998:Glycine / Q000819:agonists / Q000037:antagonists & inhibitors*; D008297:Male; D010622:Phencyclidine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors*
D000596:Amino Acids; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; C060212:NPC 12626; D010622:Phencyclidine; D005998:Glycine