The noncompetitive NMDA antagonist MK-801 fails to block amphetamine-induced place conditioning in rats

The noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 prevents the development of sensitization to the locomotor-activating effects of amphetamine. In the present study, the possibility that the NMDA receptor might also play a role in the rewarding effects of amphetamine (as measured in the conditioned place preference paradigm) was investigated. Male Sprague-Dawley rats received amphetamine (2.0 mg/kg IP) paired with one side of a two-compartment box and saline paired with the other side. During these pairings locomotor activity was measured. On the test day, the amount of time drug-free rats spent in each compartment was determined. Rats trained with amphetamine alone showed a significant increase in time spent on the drug-paired side from pre- to postconditioning, indicating a place preference. When rats were injected with MK-801 (0.03, 0.1, or 0.3 mg/kg SC) prior to amphetamine, no significant effects on amphetamine place conditioning were observed. Rats treated with MK-801 alone showed significant place conditioning, but only at the intermediate dose. On conditioning days, MK-801 produced a dose-dependent enhancement of amphetamine-induced locomotor activity; however, MK-801 alone caused a similar increase in activity. The preferential D2 dopamine receptor antagonist eticlopride (0.01, 0.05, or 0.1 mg/kg SC) significantly reduced amphetamine locomotor activity, and the highest dose blocked place conditioning. These data suggest that the NMDA receptor is not involved in either the rewarding or locomotor-activating effects of amphetamine.