The phencyclidine-like discriminative stimulus effects and reinforcing properties of the NR2B-selective N-methyl-D-aspartate antagonist CP-101 606 in rats and rhesus monkeys.

Development of N-methyl-D-aspartate (NMDA) antagonists for a variety of disorders has been hindered by their production of phencyclidine (PCP)-like psychological effects and abuse potential. There is, however, evidence to suggest that this problem might be mitigated by targeting NMDA receptors subtypes, in particular, those containing the NR2B subunit. To further test this hypothesis, the NR2B selective antagonist CP-101 606 (traxoprodil) was evaluated in two animal models: drug discrimination, a model of the subjective effects of drugs in humans, and self-administration, which evaluates the reinforcing properties of the drug. In the first study, CP-101 606(3-300 microg/kg/infusion) was tested for intravenous self-administration in rhesus monkeys experienced in PCP (5.6 microg/kg/infusion, intravenously) self-administration. In the second study, CP-101 606 was tested for production of PCP-like discriminative stimulus effects in rats (3-56 mg/kg, intraperitoneally) and rhesus monkeys (0.3-5.6 mg/kg intravenously). Evidence was obtained for reinforcing effects of at least one dose of CP-101 606 in all four monkeys. In rats, CP-101 606 produced more than 80% mean PCP-lever selection (2.0 mg/kg, intraperitoneally) but, unlike PCP itself, the dose producing the highest level of substitution was accompanied by more than 50% suppression of response rates. In monkeys, CP-101 606 produced more than 90% PCP-lever selection (0.1 mg/kg intramuscularly) in three of four animals at doses that did not significantly decrease rates of responding. The data show that CP-101 606 has some PCP-like discriminative stimulus effects in rats and monkeys and functions as a positive reinforcer in monkeys. These results suggest that inhibition of NR2B subunit containing NMDA receptors plays a role in the production of the subjective effects and abuse potential associated with many subtype-nonselective NMDA receptor antagonists such as PCP.