Taar1-mediated modulation of presynaptic dopaminergic neurotransmission: Role of D2 dopamine autoreceptors
Taar1-mediated modulation of presynaptic dopaminergic neurotransmission: Role of D2 dopamine autoreceptors
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DOI：
10.1016/j.neuropharm.2014.02.007
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发表时间：
2014-06-01
影响因子：
4.7
通讯作者：
Gainetdinov, R. R.
中科院分区：
文献类型：
--
作者：
Leo, D.;Mus, L.;Gainetdinov, R. R.
微量胺相关受体 I (TAAR1) 是一种 G 蛋白偶联受体 (GPCR)，在多个哺乳动物大脑区域中表达，并由“微量胺”(TA) 激活。助教的角色未知；然而，它们受体的发现提供了研究它们功能的机会。体内证据表明 TAAR1 对多巴胺 (DA) 神经传递具有抑制作用，可能是通过调节多巴胺转运蛋白 (DAT) 或与 D2 DA 受体相互作用和/或激活内向整流 K+ 通道。为了阐明 TAAR1 依赖性调节的机制，我们在一组神经化学实验中使用 TAAR1 敲除小鼠 (TAAR1-KO)、TAAR1 激动剂 (R05166017) 和 TAAR1 拮抗剂 (EPPTB)。 TAAR1-KO 组织含量分析显示 DA 代谢物高香草酸 (HVA) 水平增加，体内微透析显示 TAAR1-KO 伏核 (NAcc) 细胞外 DA 增加。在快速扫描循环伏安法 (FSCV) 实验中，TAAR1-KO NAcc 中诱发的 DA 释放较高。此外，激动剂 R05166017 会诱导野生型中 DA 释放的减少，这可以通过应用 TAAR1 拮抗剂 EPPTB 来预防。没有观察到由 DAT 介导的 DA 清除率的变化。为了评估 TAAR1 和 D2 自身受体之间的相互作用，我们测试了自身受体介导的动力学。仅在野生型小鼠中，TAAR1 激动剂能够增强喹吡罗诱导的 DA 释放抑制作用。此外，TAAR1-KO 中配对脉冲后 DA 释放的短期可塑性降低，表明 D2 自身受体的自身抑制减少。这些观察结果表明 TAAR1 和 D2 自身受体调节之间存在密切的相互作用。 (C) 2014 Elsevier Ltd. 保留所有权利。
Trace Amine-Associated Receptor I (TAAR1) is a G protein-coupled receptor (GPCR) expressed in several mammalian brain areas and activated by "trace amines" (TAs). TAs role is unknown; however, discovery of their receptors provided an opportunity to investigate their functions. In vivo evidence has indicated an inhibitory influence of TAAR1 on dopamine (DA) neurotransmission, presumably via modulation of dopamine transporter (DAT) or interaction with the D2 DA receptor and/or activation of inwardly rectifying K+ channels. To elucidate the mechanisms of TAAR1-dependent modulation, we used TAAR1 knockout mice (TAAR1-KO), a TAAR1 agonist (R05166017) and a TAAR1 antagonist (EPPTB) in a set of neurochemical experiments. Analysis of the tissue content of TAAR1-KO revealed increased level of the DA metabolite homovanillic acid (HVA), and in vivo microdialysis showed increased extracellular DA in the nucleus accumbens (NAcc) of TAAR1-KO. In fast scan cyclic voltammetry (FSCV) experiments, the evoked DA release was higher in the TAAR1-KO NAcc. Furthermore, the agonist R05166017 induced a decrease in the DA release in wild-type that could be prevented by the application of the TAAR1 antagonist EPPTB. No alterations in DA clearance, which are mediated by the DAT, were observed. To evaluate the interaction between TAAR1 and D2 autoreceptors, we tested the autoreceptor-mediated dynamics. Only in wild type mice, the TAAR1 agonist was able to potentiate quinpirole-induced inhibitory effect on DA release. Furthermore, the short-term plasticity of DA release following paired pulses was decreased in TAAR1-KO, indicating less autoinhibition of D2 autoreceptors. These observations suggest a close interaction between TAAR1 and the D2 autoreceptor regulation. (C) 2014 Elsevier Ltd. All rights reserved.