Interactions Of MK-801 And Environmental Cues On The Behavioral Sensitization Induced By Morphine

Many laboratories have reported that coadministration of N-methyl-D-aspartate (NMDA) receptor antagonists with addictive drugs prevent the development of behavioral sensitization and therefore concluded that NMDA receptor transmission is necessary for sensitization. According to an alternative "State-dependency" interpretation, NMDA receptor antagonists do not prevent sensitization. Rather, they become a conditioned stimulus for the sensitized response. We attempted to investigate the interactions of MK-801 and environmental cues on the behavioral sensitization induced by morphine, and determine whether the rats that receive MK-801+morphine combination will development state-dependency to the effect of MK-801. In this experiment, 42 male Wistar rats were randomly divided into six groups. During the development period, each rat was administered intraperitoneal of MK-801 (0.1mg/kg) or saline followed 30 minutes later by morphine (5mg/kg) or saline for 7 days, and the locomotor activities of the rats in paired group were measured daily immediately after the second injection by using computer-interfaced monitoring system. During the expression period, all the rats were received challenge injection for three times by morphine (day15), MK-801 (day18) and MK-801+morphine (day21) each. The distance traveled (cm) during the development period was analyzed by two-way ANOVA with treatment day as the repeated measure. The data from the three challenge tests were separately analyzed by one-way ANOVA. Post hoc analyses (LSD test) were performed for assessing specific group comparison. MK-801 did not block but rather enhanced the day-to-day increase in morphine-induced locomotion. When, following initial sensitization, morphine was given in the absence of MK-801, there was no expression of sensitization of the rats in both paired and unpaired group that received MK-801 plus morphine before; the sensitized response of animals previously treated in the MK-801 drug state was expressed only when the animal was tested in the MK-801 drug state. These finding suggested that the development of behavioral sensitization to morphine is not prevented by MK-801. Rather, the co-administration of MK-801 has made the sensitization of morphine state dependent; the sensitization can be better expressed in the same state under which it developed than underany other state. The interoceptive MK-801 cues has become one of conditioned stimulus, and it overshadow the environmental cues which serve as another conditioned stimulus weaker than MK-801. These findings illustrate the state-dependent effects of MK-801 may not only restricted to atypical stimulants such as bromocriptine, and the role of NMDA receptor in behavioral sensitization could benefit from further examination with some other NMDA receptor antagonists which are less discriminative.