Evaluation of the discriminative stimulus effects of the low-affinity N-methyl-D-aspartate channel blockers AR-R 13950AA and AR-R 16283AA in rats and rhesus monkeys.
Low-affinity channel-blocking -methyl-D-aspartate (NMDA) antagonists have been of interest for clinical development because they are purported to produce few phencyclidine (PCP)-like side-effects, particularly at therapeutic doses. In the current study, two low-affinity NMDA channel blockers, AR-R 13950AA and AR-R 16283AA, were evaluated for NMDA antagonist-associated behavioral effects. The drugs were tested in rats and rhesus monkeys trained to discriminate PCP from saline, using a standard two-lever drug discrimination paradigm, under a fixed-ratio (FR) schedule of food reinforcement. Both drugs were also tested in rats trained to discriminate NPC 17742, a competitive NMDA antagonist, from saline in a similar experimental procedure. In rats, both AR-R 13950AA and AR-R 16283AA resulted in intermediate levels of PCP-lever selection (up to 60%). Testing in NPC 17742-trained rats produced at most 30% NPC 17742-lever responding. In rhesus monkeys, AR-R 13950AA produced virtually no PCP-lever responding at any dose, while AR-R 16283AA produced a dose-dependent substitution for PCP in all four subjects. The results with AR-R 16283AA in monkeys suggest that, at doses above therapeutic levels, it may produce PCP-like intoxication in humans. Overall, the results suggest that, while there is some overlap of the discriminative stimulus effects produced by the AR-R compounds with those of PCP, there are also important differences.
Nicholson
K L
KL
Department of Pharmacology and Toxicology, Medical College of Virginia Commonwealth University, Richmond, Virginia 23298-0613, USA. klnichol@hsc.vcu.edu
Balster
R L
RL
D000081:Acetamides / Q000494:pharmacology*; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects; D004193:Discrimination Learning / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005502:Food; D008253:Macaca mulatta; D008297:Male; D010622:Phencyclidine / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012055:Reinforcement Schedule
C473252:AR-R 16283AA; D000081:Acetamides; D000596:Amino Acids; D018691:Excitatory Amino Acid Antagonists; D011719:Pyrazines; D016194:Receptors, N-Methyl-D-Aspartate; C060212:NPC 12626; C094194:FPL 13950; D010622:Phencyclidine