Identification of the sites of 2-arachidonoylglycerol synthesis and action imply retrograde endocannabinoid signaling at both GABAergic and glutamatergic synapses in the ventral tegmental area
Identification of the sites of 2-arachidonoylglycerol synthesis and action imply retrograde endocannabinoid signaling at both GABAergic and glutamatergic synapses in the ventral tegmental area
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DOI：
10.1016/j.neuropharm.2007.05.028
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发表时间：
2008-01-01
影响因子：
4.7
通讯作者：
Katona, Istvan
中科院分区：
文献类型：
--
作者：
Matyas, Ferenc;Urban, Gabriella M.;Katona, Istvan
完整的内源性大麻素信号转导涉及药物成瘾的几个方面。最重要的是，内源性大麻素对滥用药物的主要奖励效应产生显著影响，包括外源性大麻本身，通过调节药物诱导的腹侧被盖区（VTA）多巴胺能神经元爆发活动的增加。之前的电生理研究表明，这些多巴胺能神经元可能以活动依赖性的方式释放内源性大麻素来调节其各种突触输入;然而，潜在的分子和解剖学底物迄今为止还难以捉摸。为了促进对药物成瘾中内源性大麻素信号传导的神经生物学机制的理解，我们对腹侧被盖区内源性大麻素系统的分子结构进行了详细的分析。原位杂交的sn-1-二酰基甘油脂肪酶-α（DGL-alpha），最丰富的内源性大麻素，2-花生四烯酸甘油（2-AG）的生物合成酶，揭示了DGL-a的大多数VTA的神经元表达在中等到高水平。DGL-α的免疫染色导致在光镜水平上的广泛点状图案，而高分辨率电子显微镜分析表明，这种图案是由于邻近突触后特化的几种不同形态类型的谷氨酸能和GABA能突触的酶的积累。这些轴突末端类型携带突触前CB1大麻素受体的对侧的DGL-α-含有突触和双重免疫染色证实，DGL-α是存在于质膜上的酪氨酸羟化酶（TH）阳性（多巴胺能）和TH阴性树突。这些发现表明，由2-AG通过CB1介导的逆行突触信号可能会影响腹侧被盖区多种类型突触的药物奖赏回路。(c)2007爱思唯尔有限公司保留所有权利。
Intact endogenous cannabinoid signaling is involved in several aspects of drug addiction. Most importantly, endocannabinoids exert pronounced influence on primary rewarding effects of abused drugs, including exogenous cannabis itself, through the regulation of drug-induced increase in bursting activity of dopaminergic: neurons in the ventral tegmental area (VTA). Previous electrophysiological studies have proposed that these dopaminergic neurons may release endocannabinoids in an activity-dependent manner to regulate their various synaptic inputs; however, the underlying molecular and anatomical substrates have so far been elusive. To facilitate understanding of the neurobiological mechanisms involving endocannabinoid signaling in drug addiction, we carried out detailed analysis of the molecular architecture of the endocannabinoid system in the VTA. In situ hybridization for sn-1-diacylglycerol lipase-alpha (DGL-alpha), the biosynthetic enzyme of the most abundant endocannabinoid, 2-arachidonoylglycerol (2-AG), revealed that DGL-a was expressed at moderate to high levels by most neurons of the VTA. Immunostaining for DGL-a resulted in a widespread punctate pattern at the light microscopic level, whereas high-resolution electron microscopic analysis demonstrated that this pattern is due to accumulation of the enzyme adjacent to postsynaptic specializations of several distinct morphological types of glutamatergic and GABAergic synapses. These axon terminal types carried presynaptic CB1 cannabinoid receptors on the opposite side of DGL-alpha-containing synapses and double immunostaining confirmed that DGL-alpha is present on the plasma membrane of both tyrosine hydroxylase (TH)-positive (dopaminergic) and TH-negative dendrites. These findings indicate that retrograde synaptic signaling mediated by 2-AG via CB1 may influence the drug-reward circuitry at multiple types of synapses in the VTA. (c) 2007 Elsevier Ltd. All rights reserved.