Behavioral interactions caused by combined administration of morphine and MK-801 in rats

Rationale: The NMDA antagonist MK-801 reportedly blocks experience-dependen t changes in sensitivity to morphine, including tolerance to its analgesic actions and sensitization to its locomotor-stimulating effects. However, ev idence in the existing literature suggests that some of MK-801's effects ar e additive (or synergistic) with those of morphine. Objectives: Experiments were conducted to characterize the effects of acute and repeated administr ation of the combination of MK-801 and morphine on analgesia, locomotor act ivity, and drug discrimination in rats. Methods: In each experiment, rats w ere first tested repeatedly after treatment with the combination of MK-801 and morphine, and then after treatment with either drug alone. Results: The analgesic effects of MK-801 combined with morphine were greater than those of morphine alone, but tolerance to the combination of drugs developed at a similar rate as to morphine alone. The locomotor-stimulating effects of M K-801. combined with morphine were also greater than those of either drug a lone, and locomotor sensitization developed to the combination of drugs but not to either drug alone at the low doses used. Rats learned to discrimina te a combination of MK-801 and morphine from vehicle as quickly as they lea rned to discriminate morphine alone from vehicle, but those trained with th e combination of MK-801. and morphine responded primarily at the vehicle-ap propriate lever when given either drug alone. Conclusions: Since behavioral adaptations readily occur in the presence of MK-801, it appears that NMDA antagonists fail to invariably block the cellular plasticity that underlies such adaptations. Rather, the expression of adaptations in drug sensitivit y appears related, at least in part, to the continued presence of the discr iminative stimulus cues that are present during conditioning. Although NMDA receptors are important for some forms of cellular plasticity, the present studies illustrate the difficulty in interpreting behavioral studies in wh ich MK-801 is given with morphine.