D-Serine in the nucleus accumbens region modulates behavioral sensitization and extinction of conditioned place preference
D-Serine in the nucleus accumbens region modulates behavioral sensitization and extinction of conditioned place preference
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伏隔核区域的 D-丝氨酸调节行为敏化和条件性位置偏好的消退
DOI：
10.1016/j.pbb.2016.02.002
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发表时间：
2016-04-01
影响因子：
3.6
通讯作者：
Wang, Wei
中科院分区：
文献类型：
--
作者：
Liu, Zhi-Qiang;Gu, Xun-Hu;Wang, Wei
背景：D-丝氨酸是N-甲基-D-天冬氨酸受体（NMDARs）的内源性共激动剂，被认为是学习和记忆所必需的。为系统研究D-丝氨酸在成瘾行为中的作用，采用高效液相色谱法（HPLC）测定了D-丝氨酸在大鼠延髓核（NAc）中的含量。用可卡因诱发的行为敏化和条件性位置偏爱（CPP）模型，研究了中脑背外侧核丝氨酸含量的变化与可卡因诱发的行为效应的关系。Western blot分析丝氨酸消旋酶（SR）、D-氨基酸氧化酶（DAAO）、cAMP反应元件结合蛋白（CREB）及其上游激酶和N-甲基-D-天冬氨酸（NMDA）受体亚单位的表达。结果：行为敏化组大鼠NAc脑片D-丝氨酸浓度明显降低，DAAO表达增加，SR表达下调，且呈剂量依赖性。此外，D-丝氨酸注射到延髓核阻断了行为敏化的发展，并引起CPP的消退。ERIC-CREB-Fos通路和NAc中的NMDA受体NR 2B亚单位参与可卡因诱导的行为敏化。我们还发现，D-丝氨酸是必需的NMDAR依赖性LTD和D-丝氨酸调节LTD的钟形浓度依赖性的方式。被破坏的NMDAR依赖的LTD在NAC可卡因治疗的大鼠被逆转D-serine.Conclusions：我们的研究结果提供了证据D-丝氨酸在可卡因成瘾相关的突触可塑性的关键作用，并表明，D-丝氨酸可能是一种有效的治疗药物可卡因成瘾。(C)2016 Elsevier Inc. All rights reserved.
Background: D-serine, the endogenous co-agonist of N-methyl-D-aspartate receptors (NMDARs), is considered to be essential for learning and memory. The aim of the current investigation was to systematically evaluate the role of D-serine on addiction behaviors considered to be mediated by the nucleus accumbens (NAc).Methods: D-Serine concentration in the NAc was measured by high-performance liquid chromatography (HPLC). Cocaine-induced behavioral sensitization and conditioned place preference (CPP) models were used to evaluate the relation between changes in serine in the nucleus accumbens and cocaine-induced behavioral effects. The expression of serine racemase (SR), D-amino acid oxidase (DAAO), the cAMP response element-binding protein (CREB) and upstream kinases, and N-methyl-D-aspartate (NMDA) receptors subunits were analyzed by western blot. Long-term depression (LTD) in the NAc was investigated by electrophysiological methods.Results: The NAc slices obtained from the behavioral sensitization rats presented significantly reduced D-serine concentrations, increased expression of DAAO, and down-regulated expression of SR in a dose-dependent manner. Furthermore, D-serine injections into the nucleus accumbens blocked the development of behavioral sensitization and caused extinction of CPP. The ERIC-CREB-Fos pathway and the NMDA receptor NR2B subunits in the NAc were involved in the cocaine-induced behavioral sensitization. We also found that D-serine was essential for NMDAR-dependent LTD and D-serine-regulated LTD in a bell-shaped concentration-dependent manner. The disrupted NMDAR-dependent LTD in the NAc of cocaine-treated rats was reversed by D-serine.Conclusions: Our results provide evidence for a critical role of D-serine in synaptic plasticity relevant to cocaine addiction and indicate that D-serine may be an effective therapeutic agent for cocaine addiction. (C) 2016 Elsevier Inc. All rights reserved.