Alcohol inhibits NR2B-Containing NMDA receptors in the ventral bed nucleus of the stria terminalis
Alcohol inhibits NR2B-Containing NMDA receptors in the ventral bed nucleus of the stria terminalis
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DOI：
10.1038/sj.npp.1301504
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发表时间：
2008-05-01
影响因子：
7.6
通讯作者：
Winder, Danny G.
中科院分区：
文献类型：
--
作者：
Kash, Thomas L.;Matthews, Robert T.;Winder, Danny G.
中脑边缘多巴胺系统的组成部分，特别是腹侧被盖区（VTA）的多巴胺能细胞，与乙醇的急性增强作用有关。终纹腹侧床核 (vBNST) 有效调节 VTA 中的多巴胺能细胞放电，并与乙醇的行为作用有关。 N-甲基-D-天冬氨酸受体 (NMDAR) 是乙醇的主要分子靶标，然而，目前的证据表明，乙醇对 NMDAR 功能的调节变化很大，并且可能取决于许多因素。因此，研究乙醇对 NMDAR 功能在与乙醇调节行为相关的突触（例如 vBNST 中）的调节至关重要。在这里，我们使用多种技术证明乙醇以突触后方式抑制 vBNST 神经元中的 NMDAR 功能。此外，我们证明了 vBNST 中包含 NR2A 和 NR2B 的 NMDAR 的功能存在。虽然 NR2A 的基因去除不会改变乙醇抑制的程度，但 NR2B 的药理学阻断使突触激活的 NMDAR 对乙醇抑制不敏感。最后，我们证明乙醇抑制 vBNST 细胞中投射到 VTA 的 NMDAR，为 vBNST 中的乙醇调节多巴胺能系统提供了直接方法。
Components of the mesolimbic dopamine system, in particular dopaminergic cells in the ventral tegmental area (VTA), have been implicated in the acute reinforcing actions of ethanol. The ventral bed nucleus of the stria terminalis (vBNST) potently regulates dopaminergic cell firing in the VTA, and has been implicated in the behavioral actions of ethanol. The N-methyl-D-asparate receptor (NMDAR) is a major molecular target of ethanol, however, current evidence suggests that ethanol regulation of NMDAR function is widely variable and likely depends on a number of factors. Thus, it is critical to investigate ethanol regulation of NMDAR function at synapses relevant to ethanol-regulated behaviors, such as in the vBNST. Here we show, using multiple techniques, that ethanol inhibits NMDAR function in vBNST neurons in a postsynaptic fashion. Further, we demonstrate the functional presence of both NR2A and NR2B-containing NMDARs in the vBNST. While genetic removal of NR2A did not alter the magnitude of ethanol inhibition, pharmacological blockade of NR2B rendered synaptically activated NMDARs insensitive to ethanol inhibition. Finally, we demonstrate that ethanol inhibits NMDARs in cells in the vBNST that project to the VTA, providing a direct means by which ethanol in the vBNST can modulate the dopaminergic system.