| 1 objectiveDrug addiction is long-term adaptation in brain elicited by repeated exposure to abusive drug. Past investigations indicated that rewarding effect of abusive drugs is considered as the major reason, which results in addiction especially psychological dependence. Recently more researches focus on the N-methyl-D-aspartate (NMDA) receptor, which involves in development of addiction through interaction with dopamine receptor. NMDA receptor complex belongs to the family of ligand-gated ion channels, with multi-regulatory sites including glycine, Mg2+, Zn2+, polyamine, protons and redox active reagent. And its activation requires the simultaneous binding of two agonists: glutamate and glycine. Both competitive and uncompetitive NMDA receptor antagonists have been found to block conditioned place preference (CPP) induced by morphine, amphetamine and cocaine, suggesting a possible role in the treatment of drug addiction. On the contrary, most of both classes of NMDA receptor antagonists have been reported to produce severe psycho-stimulant and psychotomimetic-like effects in animal and clinical experiments, even evoking death of animal. Moreover, CPP paradigms have established that both classes of NMDA antagonist have rewarding properties, implying that they would have abusive potential. In contrast, substantial studies showed that glycine-binding site NMDA receptor antagonists neither have psychotomimetic effects, nor have rewarding properties inCPP experiments.MRZ2/576 synthesized by MERZ Pharmaceutical GmbH is potent glycine-binding site NMDA receptor antagonist with about 20min of half-life and 366.81 of molecule weigh, which had been proved to produce anticonvulsant and neuroprotective effects. In addition, Mrz2/576 not only prolonged suppression of morphine withdrawal precipitated by naltrexone in mice, but also retarded morphine tolerance development in mice. There is no report about MRZ2/576 on the psychological dependence of morphine. So, the current study was designed to assess the effect of Glycine site/NMDA receptor antagonist MRZ2/576 on the rewarding effect and locomotor activity in mice.2 Materials and methods2.1 AnimalsMale adult ICR mice, weigh 18~22g.2.2 DrugsMRZ2/576: 8-chloro-4-hydroxy-l-oxo-l,2-dihydropyridaliono(4,5-b)quinoline -5-oxide choline salt, morphine hydrochloride injection2.3 CPP apparatusThe computer-based video-tracking CPP apparatus is composed of shuttle boxes that were divided into a gray and a black chamber of equal size, a soundproof container, video system and a computer.MiceTrack software was used to analyze the video that recorded mice.2.4 Conditioning procedureThe procedure included conditioning and test phases.(1)Conditioning phase: On days 1, 3, 5, 7, mice treated with drugs were confined to the gray chamber for 50min. On days 2, 4, 6, 8, mice were injected only with saline before confined in the black chamber for 50min.(2)Testing phase: On day 9, after the separator was raised 7cm above the floor, the mice were placed in the shuttle box to freely access to each chamber with or without treatment according to study requirement and capture the video mice spent inthe shuttle boxes.2.5 Rewarding effect and locomotor activity in miceExperiment 1. Effect of MRZ2/576 aloneTo investigate whether MRZ2/576(1.25, 2.5 and 5mg/kg, i.p.) alone can establish conditioned place preference, MRZ2/576 used as conditioning drug was given to mice before conditioning trial in the gray chamber of the apparatus on days 1, 3, 5 and 7. On day2, 4, 6 and 8, mice were injected with saline before the conditioning trial in the black chamber of the apparatus. Conditioning trials (8 consecutive days) lasted for 50 min. Experiment 2. Effect of MRZ2/576 on the acquisition of morphine-induced CPPTo investigate whether NMDA receptor antagonist could block acquisition of conditioned place preference induced by morphine. On days 1, 3, 5 and 7, mice were injected with various doses of NMDA receptor antagonist MRZ2/576(1.25, 2.5 and 5mg/kg...
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