Glutamate and Dopamine Transmission from Midbrain Dopamine Neurons Share Similar Release Properties But Are Differentially Affected by Cocaine
Glutamate and Dopamine Transmission from Midbrain Dopamine Neurons Share Similar Release Properties But Are Differentially Affected by Cocaine
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DOI：
10.1523/jneurosci.4958-13.2014
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发表时间：
2014-02-26
影响因子：
5.3
通讯作者：
Alvarez, Veronica A.
中科院分区：
文献类型：
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作者：
Adrover, Martin F.;Shin, Jung Hoon;Alvarez, Veronica A.
腹侧被盖区和中脑核之间的突触传递与奖赏动机行为密切相关，并被认为在成瘾中发生改变。除了多巴胺（DA），谷氨酸被包装和释放的中脑边缘DA神经元的一个子集，引发EPSC到中等多刺神经元在NAc。关于DA中脑末梢谷氨酸释放的性质和调节以及可卡因的作用知之甚少。使用光遗传学方法选择性地激活中脑DA纤维，我们比较了使用快速扫描循环伏安法和全细胞记录在小鼠脑切片中测量的DA瞬变和EPSC的性质和调制。DA受体D2R激动剂抑制DA瞬变和EPSC，并显示出明显的成对脉冲抑制，需要2分钟才能完全恢复。多巴胺使EPSC的振幅降低了50%，但增强了中脑DA神经元的整体DA传递。AMPA和NMDA受体介导的EPSCs同样受到可卡因的抑制，这表明了突触前的作用机制。DA神经元D2R的药理学阻断和基因缺失阻止了可卡因对EPSC的抑制，并引起DA瞬时峰的较大增加，证实了突触前D2R的参与。这些研究结果表明，急性可卡因抑制DA和谷氨酸释放中脑DA神经元通过突触前D2R，但有差异的整体影响，其在NAc的传输。我们推测，可卡因，通过阻断DA再摄取，抑制DA瞬变和促进DA和谷氨酸从这些终端释放的反馈抑制。
Synaptic transmission between ventral tegmental area and nucleus accumbens (NAc) is critically involved in reward-motivated behaviors and thought to be altered in addiction. In addition to dopamine (DA), glutamate is packaged and released by a subset of mesolimbic DA neurons, eliciting EPSCs onto medium spiny neurons in NAc. Little is known about the properties and modulation of glutamate release from DA midbrain terminals and the effect of cocaine. Using an optogenetic approach to selectively activate midbrain DA fibers, we compared the properties and modulation of DA transients and EPSCs measured using fast-scan cyclic voltammetry and whole-cell recordings in mouse brain slices. DA transients and EPSCs were inhibited by DA receptor D2R agonist and showed a marked paired-pulse depression that required 2 min for full recovery. Cocaine depressed EPSCs amplitude by 50% but enhanced the overall DA transmission from midbrain DA neurons. AMPA and NMDA receptor-mediated EPSCs were equally inhibited by cocaine, suggesting a presynaptic mechanism of action. Pharmacological blockage and genetic deletion of D2R in DA neurons prevented the cocaine-induced inhibition of EPSCs and caused a larger increase in DA transient peak, confirming the involvement of presynaptic D2R. These findings demonstrate that acute cocaine inhibits DA and glutamate release from midbrain DA neurons via presynaptic D2R but has differential overall effects on their transmissions in the NAc. We postulate that cocaine, by blocking DA reuptake, prolongs DA transients and facilitates the feedback inhibition of DA and glutamate release from these terminals.