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Several lines of evidence suggest that uridine, as a neuromodulator, plays an important role in drug addiction. We previously found that uridine circumvents morphine-induced behavioral sensitization by decreasing the extracellular dopamine levels in the dorsal striatum. In the present study, the effects of uridine on morphine-induced conditioned place preference (CPP) and the possible roles of glutamate and GABA in the stress-induced reinstatement of CPP were investigated. First, the effects of uridine (1, 10 and 100 mg/kg, i.p.) on the four defined phases - acquisition, expression, extinction and reinstatement (drug priming and restraint stress) - of morphine-induced CPP were studied. The results showed that pretreatment with uridine significantly blocked the acquisition and expression phases of CPP. Additionally, uridine also facilitated CPP extinction and inhibited stress-induced CPP reinstatement, although it failed to affect drug-induced CPP reinstatement. Since glutamatergic and GABAergic systems are both involved in CPP reinstatement, the extracellular levels of glutamate and GABA in the mPFC during the stress-induced CPP reinstatement were determined using in vivo microdialysis. The results showed that uridine attenuated the stress-induced glutamate increase in the mPFC without influencing the basal glutamate levels, and increased the levels of extracellular GABA in the mPFC both under normal physiological conditions and after the stress stimulus. Thus, our results indicate that uridine depresses the stress-induced reinstatement of CPP, simultaneously regulating glutamatergic and GABAergic neurotransmission in the mPFC. The present work provides further understanding of the role of uridine in morphine-induced neurobehavioral changes.Uridine blocked the rewarding effects of morphine.Levels of glutamate and GABA in the mPFC may be related to stress-induced relapse.Uridine depressed the glutamate overflow in the stress-induced relapse.Uridine increased the GABA levels in the stress-induced relapse.