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.

摘要

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.