Department of Psychological and Brain Sciences, the Neuroscience Research Institute, Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, California 93106-9660.
Translational Neuroscience Facility, School of Medical Sciences, University of New South Wales, New South Wales 2052, Australia, and.
J Neurosci. 2019 Apr 3;39(14):2745-2761. doi: 10.1523/JNEUROSCI.1909-18.2018. Epub 2019 Feb 8.
The bed nucleus of the stria terminalis (BNST) is part of the limbic-hypothalamic system important for behavioral responses to stress, and glutamate transmission within this region has been implicated in the neurobiology of alcoholism. Herein, we used a combination of immunoblotting, neuropharmacological and transgenic procedures to investigate the role for metabotropic glutamate receptor 5 (mGlu5) signaling within the BNST in excessive drinking. We discovered that mGlu5 signaling in the BNST is linked to excessive alcohol consumption in a manner distinct from behavioral or neuropharmacological endophenotypes that have been previously implicated as triggers for heavy drinking. Our studies demonstrate that, in male mice, a history of chronic binge alcohol-drinking elevates BNST levels of the mGlu5-scaffolding protein Homer2 and activated extracellular signal-regulated kinase (ERK) in an adaptive response to limit alcohol consumption. Male and female transgenic mice expressing a point mutation of mGlu5 that cannot be phosphorylated by ERK exhibit excessive alcohol-drinking, despite greater behavioral signs of alcohol intoxication and reduced anxiety, and are insensitive to local manipulations of signaling in the BNST. These transgenic mice also show selective insensitivity to alcohol-aversion and increased novelty-seeking, which may be relevant to excessive drinking. Further, the insensitivity to alcohol-aversion exhibited by male mice can be mimicked by the local inhibition of ERK signaling within the BNST. Our findings elucidate a novel mGluR5-linked signaling state within BNST that plays a central and unanticipated role in excessive alcohol consumption. The bed nucleus of the stria terminalis (BNST) is part of the limbic-hypothalamic system important for behavioral responses to stress and alcohol, and glutamate transmission within BNST is implicated in the neurobiology of alcoholism. The present study provides evidence that a history of excessive alcohol drinking increases signaling through the metabotropic glutamate receptor 5 (mGlu5) receptor within the BNST in an adaptive response to limit alcohol consumption. In particular, disruption of mGlu5 phosphorylation by extracellular signal-regulated kinase within this brain region induces excessive alcohol-drinking, which reflects a selective insensitivity to the aversive properties of alcohol intoxication. These data indicate that a specific signaling state of mGlu5 within BNST plays a central and unanticipated role in excessive alcohol consumption.
终纹床核（BNST）是边缘下丘脑系统的一部分，对于应激和酒精的行为反应很重要，谷氨酸在该区域的传递与酒精中毒的神经生物学有关。在此，我们使用免疫印迹、神经药理学和转基因程序的组合，研究 BNST 中的代谢型谷氨酸受体 5（mGlu5）信号在过度饮酒中的作用。我们发现，BNST 中的 mGlu5 信号与过度饮酒有关，与先前被认为是引发大量饮酒的行为或神经药理学表型不同。我们的研究表明，在雄性小鼠中，慢性 binge 饮酒史会升高 BNST 中 mGlu5 衔接蛋白 Homer2 的水平，并通过适应性反应激活细胞外信号调节激酶（ERK），以限制酒精摄入量。表达不能被 ERK 磷酸化的 mGlu5 点突变的雄性和雌性转基因小鼠表现出过度饮酒，尽管有更多的酒精中毒行为迹象和焦虑减少，并且对 BNST 中的信号转导局部操作不敏感。这些转基因小鼠还表现出对酒精厌恶的选择性不敏感和对新奇事物的寻求增加，这可能与过度饮酒有关。此外，雄性小鼠对酒精厌恶的不敏感可以通过 BNST 中 ERK 信号的局部抑制来模拟。我们的发现阐明了 BNST 中一种新的 mGluR5 相关信号状态，它在过度饮酒中起着核心和意外的作用。终纹床核（BNST）是边缘下丘脑系统的一部分，对于应激和酒精的行为反应很重要，BNST 中的谷氨酸传递与酒精中毒的神经生物学有关。本研究提供的证据表明，过度饮酒史会增加 BNST 中代谢型谷氨酸受体 5（mGlu5）受体的信号传递，以适应限制酒精摄入的反应。特别是，该脑区中细胞外信号调节激酶对 mGlu5 磷酸化的破坏会导致过度饮酒，这反映了对酒精中毒的厌恶特性的选择性不敏感。这些数据表明，BNST 中 mGlu5 的特定信号状态在过度饮酒中起着核心和意外的作用。
