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OBJECTIVE AQP4 is widely expressed in brain astrocytes, and its function is mainly to maintain the steady-state of brain water.D-serine as an important neurotransmitter secre ted by glial cells is an endogenous co-agonist of NMDA receptor,and is essential for the induction of long-term potentiation.The present study is to explore whether D-serine is mediated the change of synaptic plasticity and cocaine-induced addictive be havior induced by AQP4 knockout.METHODS The effects of D-serine on NAc LTD and behavior of AQP4 knockout mice were investigated by electrophysiologicai recording and behavioral tests.RESULTS 10 μmol· L-1 D-serine significantly reversed NMDA receptor-dependent LTD in AQP4 KO mice NAc shces.D-serine concentration-dependently antagonized the effects of AQP4 knockout on cocaine addiction behavior.500 mg· kg-1 Dserine significandy increased cocaine-induced locomotor activity in AQP4 KO mice.D-serine (500 mg· kg-1) significantly re stored cocaine-induced conditioned place preferences in AQP4KO mice.CONCLUSION AQP4 knockout changed the be havior of cocaine addiction through affecting the release of D-serine in glial cells.