The Inhibiting Effect Of D-serine On Morphine-induced Potentiation Of CPP And Its Mechanism

Object: To explore the roles of D-serine in the nucleus accumbens in the morphine addition rat models, and to examine the possibility that exogenous D-serine inhibits the morphine addiction.Methods: The morphine addiction models were replicated by multiple injection of morphine in the adult SD rats. And, the possibility that D-serine alleviates the morphine addiction was examined by the conditioned place preference. The NMDA currents of the middle spiny neurons in nucleus accumbens were recorded; the effect of exogenous D-serine on NMDA channel was also observed. In addition, the level of D-serine in the nucleus accumbens was explored by high pressure liquid chromatography. The expression levels of SR, DAAO, p-CREB, ΔFos B, AMPAR and the concentration of intracellular Ca2+ were also examined.Results: Administration of exogenous D-serine inhibited the development of locomotor sensitization to morphine and reduced morphine-induced CPP. Exogenous D-serine also alleviated morphine-induced decrease in the NMDAR-induced excitatory postsynaptic currents and exogenous morphine-inhibited excitability of GABAergic neurons in NAc. We noted that morphine reduced extracellular D-serine levels in rat NAc or primary culture of astrocytes through inhibition of intracellular Ca2+ signals and blockade of D-serine release from cell vesicles. Moreover, we observed the morphine-induced internalization of AMPAR in primary cultured astrocytes.Conclusion: D-serine administration significantly inhibited morphine CPP. The underlined mechanism may associate with the drug altered NMDA-mediated synaptic plasticity.