Abstract: Many laboratories have reported that co-administration of N-methyl-D-aspartate (NMDA) receptor antagonists such as MK-801 with addictive drugs prevents the development of behavioral sensitization and therefore concluded that NMDA receptor transmission is necessary for sensitization. However, according to “State-dependency” interpretation, NMDA receptor antagonists do not prevent sensitization. Rather, they become a conditioned stimulus for the sensitized response. There is also considerable evidence showing that the circumstances surrounding drug administration play an important role in modulating the development and expression of the sensitization. Thus, 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 develop state-dependency to the effect of MK-801.
42 male Wistar rats were randomly divided into six groups: Saline, MK-801, Morphine (paired group), MK-801 plus Morphine (paired group), Morphine (unpaired group) and MK-801 plus Morphine (unpaired group). During the development period, each rat was administered with MK-801 (0.1mg/kg) or saline by intraperitoneal, 30 minutes later administered with morphine (5mg/kg) or saline for 7 days on end. In the paired group, the administration of morphine was performed with environmental cues (test cage) and the unpaired group received morphine without cues by replacing them into their home cage. The locomotor activities of the rats in paired group were monitored 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 plus 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 groups that have received MK-801 plus morphine during the development period; the sensitized response of animals previously treated with morphine in the MK-801 drug state was expressed only when the animal was tested in the MK-801 drug state.
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 under any other state. The interoceptive MK-801 cues has become one of conditioned stimulus, and it overshadows the environmental cues which serve as another conditioned stimulus. 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

Key words: morphine, MK-801, behavioral sensitization, state-dependency