Reduced d-serine levels in the nucleus accumbens of cocaine-treated rats hinder the induction of NMDA receptor-dependent synaptic plasticity
Reduced d-serine levels in the nucleus accumbens of cocaine-treated rats hinder the induction of NMDA receptor-dependent synaptic plasticity
复制标题
DOI：
10.1093/brain/awt036
复制
发表时间：
2013-04-01
期刊：
影响因子：
14.5
通讯作者：
D'Ascenzo, Marcello
中科院分区：
文献类型：
--
作者：
Curcio, Livia;Podda, Maria V.;D'Ascenzo, Marcello
可卡因寻求行为和复发与伏隔核兴奋性突触的增强和抑制受损有关，但人们对这一过程背后的机制知之甚少。我们发现，在大鼠伏隔核核心中，d-丝氨酸是 N-甲基-d-天冬氨酸受体的内源性共激动剂，它的存在对于 N-甲基-d-天冬氨酸受体依赖性突触传递的增强和抑制至关重要。从可卡因治疗大鼠戒断 1 天后获得的伏核核心切片显示，d-丝氨酸浓度显着降低，d-丝氨酸降解酶、d-氨基酸氧化酶表达增加，丝氨酸消旋酶（负责 d-丝氨酸合成的酶）表达下调。 d-丝氨酸缺乏与谷氨酸能突触传递的增强和抑制有关，通过用外源性 d-丝氨酸进行切片灌注可以恢复这种作用。此外，体内将 d-丝氨酸直接注射到伏隔核核心可阻断对可卡因的行为过敏。这些结果为 d-丝氨酸信号传导在与可卡因成瘾相关的突触可塑性中的关键作用提供了证据。
Cocaine seeking behaviour and relapse have been linked to impaired potentiation and depression at excitatory synapses in the nucleus accumbens, but the mechanism underlying this process is poorly understood. We show that, in the rat nucleus accumbens core, d-serine is the endogenous coagonist of N-methyl-d-aspartate receptors, and its presence is essential for N-methyl-d-aspartate receptor-dependent potentiation and depression of synaptic transmission. Nucleus accumbens core slices obtained from cocaine-treated rats after 1 day of abstinence presented significantly reduced d-serine concentrations, increased expression of the d-serine degrading enzyme, d-amino acid oxidase, and downregulated expression of serine racemase, the enzyme responsible for d-serine synthesis. The d-serine deficit was associated with impairment of potentiation and depression of glutamatergic synaptic transmission, which was restored by slice perfusion with exogenous d-serine. Furthermore, in vivo administration of d-serine directly into the nucleus accumbens core blocked behavioural sensitization to cocaine. These results provide evidence for a critical role of d-serine signalling in synaptic plasticity relevant to cocaine addiction.