Morphine-induced inhibition of Ca2+-dependent D-serine release from astrocytes suppresses excitability of GABAergic neurons in the nucleus accumbens

The nucleus accumbens (NAc) plays a critical role in addictive drug-induced behavioral changes. D-serine is present at high levels in the brain and is involved in the regulation of N-methyl-D-aspartate glutamate (NMDA)-dependent synaptic activity. In this study, we aimed to examine the involvement of D-serine in morphine addiction. Morphine decreased the NMDA receptor-mediated excitatory postsynaptic currents and excitability of GABAergic neurons in the NAc, while exogenous D-serine alleviated the effects of morphine. Morphine reduced extracellular D-serine levels in rat NAc or in primary culture of astrocytes through inhibition of intracellular Ca2+ signals and blockade of D-serine release from cell vesicles. Morphine induced robust internalization of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate acid receptor (AMPAR) in primary cultured astrocytes. Moreover, administration of exogenous D-serine to rats inhibited the development of locomotor sensitization to morphine, attenuated the morphine-induced potentiation on conditioned place preference and suppressed the morphine-enhanced expression of p-CREB and Delta FosB in the NAc. Overall, our results showed that morphine inhibited D-serine release from astrocytes through modulation of AMPAR-mediated Ca2+ influx, and led to the inhibition of postsynaptic excitability of GABAergic neurons in the NAc. This work may provide a new insight into the underlying mechanisms of morphine addiction.