Jiangsu Key Laboratory of Translational Research and Therapy for Neuropsychiatric Disorders and The Collaborative Innovation Center for Brain Sciences, College of Pharmaceutical Sciences, Soochow University, China.
College of Medicine, Nantong University, China.
Addict Biol. 2017 Sep;22(5):1289-1303. doi: 10.1111/adb.12417. Epub 2016 May 29.
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 Ca signals and blockade of d-serine release from cell vesicles. Morphine induced robust internalization of α-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 ΔFosB in the NAc. Overall, our results showed that morphine inhibited d-serine release from astrocytes through modulation of AMPAR-mediated Ca 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.
伏隔核（NAc）在成瘾性药物引起的行为改变中起着关键作用。D-丝氨酸在大脑中含量很高，参与调节 N-甲基-D-天冬氨酸谷氨酸（NMDA）依赖性突触活动。在这项研究中，我们旨在研究 D-丝氨酸在吗啡成瘾中的作用。吗啡降低了 NAc 中 GABA 能神经元的 NMDA 受体介导的兴奋性突触后电流和兴奋性，而外源性 D-丝氨酸减轻了吗啡的作用。吗啡通过抑制细胞内 Ca 信号和阻断 D-丝氨酸从细胞囊泡释放来降低大鼠 NAc 或原代培养星形胶质细胞中的细胞外 D-丝氨酸水平。吗啡诱导原代培养星形胶质细胞中α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）的强烈内化。此外，向大鼠给予外源性 D-丝氨酸可抑制对吗啡的运动敏感化的发展，减弱吗啡诱导的条件位置偏好的增强，并抑制 NAc 中 p-CREB 和 ΔFosB 的表达增强。总的来说，我们的结果表明，吗啡通过调节 AMPAR 介导的 Ca 内流抑制星形胶质细胞中 D-丝氨酸的释放，导致 NAc 中 GABA 能神经元的突触后兴奋性抑制。这项工作可能为吗啡成瘾的潜在机制提供新的见解。
