Discriminative stimulus effects of the NMDA receptor antagonists MK-801 and CGP 37849 in rats

Rats were trained to discriminate MK-801 (0.05 mg/kg, IP), an uncompetitive, or CGP 37849 (3 mg/kg, IP), a competitive NMDA receptor antagonist from saline, using a two-lever, operant drug discrimination paradigm. In generalization tests the role of dopaminergic and serotonergic systems in the discriminative stimulus effects produced by both NMDA receptor antagonists was studied with amphetamine (0.5 mg/kg), cocaine (5.0 and 7.5 mg/kg), and fenfluramine (2.5 and 5.0 mg/kg). Additionally, memantine (5.0, 7.5 and 10.0 mg/kg), an uncompetitive NMDA receptor antagonist, was tested. The discriminative stimuli produced by MK-801 and CGP 37849 were not generalized to each other. Among the tested drugs only memantine generalized to the MK-801 discriminative stimulus. None of the tested drugs showed CGP 37849-like discriminative stimulus properties. The different mechanisms underlying NMDA antagonism by MK-801 and GP 37849 might explain the observed lack of cross-generalization. The results suggest that dopaminergic and serotonergic systems are not of major importance in the discriminative stimulus effects produced by both MK-801 and CGP 37849.