Neurotensin inhibits glutamate-mediated synaptic inputs onto ventral tegmental area dopamine neurons through the release of the endocannabinoid 2-AG
Neurotensin inhibits glutamate-mediated synaptic inputs onto ventral tegmental area dopamine neurons through the release of the endocannabinoid 2-AG
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DOI：
10.1016/j.neuropharm.2012.07.037
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发表时间：
2012-11-01
影响因子：
4.7
通讯作者：
Trudeau, Louis-Eric
中科院分区：
文献类型：
--
作者：
Kortleven, Christian;Bruneau, Laura Charlotte;Trudeau, Louis-Eric
神经降压素（NT）是中脑腹侧丰富的一种神经肽，起源于腹侧被盖区（VTA），是中脑边缘多巴胺（DA）系统的关键调节因子。NT激活与Gq异源三聚体G蛋白偶联的代谢型受体，这是一种经常触发大脑中内源性大麻素（EC）产生的信号传导途径。由于内皮细胞作为许多谷氨酸突触的负调节因子，最近也被证明门控LTP诱导的腹侧被盖区，我们研究的假设，NT调节谷氨酸介导的突触输入腹侧被盖区DA神经元。我们在TH-EGFP转基因小鼠脑切片中的VTA DA神经元中进行了全细胞膜片钳记录，发现NT诱导由1型NT受体介导的EPSC振幅的长期持续降低。CB 1 EC受体的拮抗剂阻断了这种减少。NT的这种作用不依赖于细胞内钙，但需要G蛋白激活和磷脂酶C。阻断CB 1受体诱导后EPSC抑郁逆转突触抑制，效果不模仿阻断NT受体，从而表明EC的生产和释放延长的发生。负责突触抑制的EC被鉴定为2-花生四烯酰甘油，与已知在VIA DA神经元中门控LTP诱导的EC相同。然而，在LTP诱导过程中阻断NT受体并不能促进LTP诱导，这表明内源性释放的NT不是LIP诱导刺激过程中EC产生的主要来源。(C)2012爱思唯尔有限公司保留所有权利。
Neurotensin (NT), a neuropeptide abundant in the ventral midbrain, is known to act as a key regulator of the mesolimbic dopamine (DA) system, originating in the ventral tegmental area (VTA). NT activates metabotropic receptors coupled to Gq heterotrimeric G proteins, a signaling pathway often triggering endocannabinoid (EC) production in the brain. Because ECs act as negative regulators of many glutamate synapses and have also been shown recently to gate LTP induction in the VTA, we examined the hypothesis that NT regulates glutamate-mediated synaptic inputs to VTA DA neurons. We performed whole cell patch-clamp recordings in VTA DA neurons in TH-EGFP transgenic mouse brain slices and found that NT induces a long-lasting decrease of the EPSC amplitude that was mediated by the type 1 NT receptor. An antagonist of the CB1 EC receptor blocked this decrease. This effect of NT was not dependent on intracellular calcium, but required G-protein activation and phospholipase C. Blockade of the CB1 receptor after the induction of EPSC depression reversed synaptic depression, an effect not mimicked by blocking NT receptors, thus suggesting the occurrence of prolonged EC production and release. The EC responsible for synaptic depression was identified as 2-arachidonoylglycerol, the same EC known to gate LTP induction in VIA DA neurons. However, blocking NT receptors during LTP induction did not facilitate LTP induction, suggesting that endogenously released NT is not a major source of EC production during LIP inducing stimulations. (C) 2012 Elsevier Ltd. All rights reserved.