Protein Kinase C Epsilon Activity in the Nucleus Accumbens and Central Nucleus of the Amygdala Mediates Binge Alcohol Consumption.
Protein Kinase C Epsilon Activity in the Nucleus Accumbens and Central Nucleus of the Amygdala Mediates Binge Alcohol Consumption.
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DOI：
10.1016/j.biopsych.2015.01.019
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发表时间：
2016-03-15
影响因子：
10.6
通讯作者：
Szumlinski KK
中科院分区：
文献类型：
--
作者：
Cozzoli DK;Courson J;Rostock C;Campbell RR;Wroten MG;McGregor H;Caruana AL;Miller BW;Hu JH;Wu Zhang P;Xiao B;Worley PF;Crabbe JC;Finn DA;Szumlinski KK
蛋白激酶C ε（PKCε）正成为开发药物治疗酒精使用障碍的潜在靶点，然而关于高度流行的饮酒形式的历史，酗酒摄入如何影响酶启动或激酶活性与过量饮酒的功能相关性知之甚少。采用免疫印迹法检测自发性和酗酒诱导的PKCε启动的变化。采用神经药理学方法，在黑暗中饮酒（DID）和计划性高酒精摄入（SHAC）这两种不同的酗酒程序的背景下，研究了PKCε易位与酗酒的功能相关性，并确定了潜在的上游信号通路。酗酒可使NAC和杏仁中央核（CeA）中p（Ser 729）-PKCε水平升高。此外，选择性繁殖和转基因小鼠品系的免疫印迹研究显示，NAC和CeA中的组成性p（Ser 729）-PKCε水平与酗酒倾向呈正相关。最后，神经药理学抑制两个区域内的PKCε易位以需要完整的第1组代谢型谷氨酸受体、Homer 2、磷脂酶C（PLC）和/或磷脂酰肌醇-3激酶（PI 3 K）功能的方式减少了酗酒。综上所述，这些数据表明NAC和CeA中的PKCε信号传导是酗酒和消耗过量酒精的遗传倾向的主要贡献者。
Protein kinase C epsilon (PKCε) is emerging as a potential target for the development of pharmacotherapies to treat alcohol use disorders, yet little is known regarding how a history of a highly prevalent form of drinking, binge alcohol intake, influences enzyme priming or the functional relevance of kinase activity for excessive alcohol intake. Immunoblotting was employed on tissue from subregions of the nucleus accumbens (NAC) and the amygdala to examine both idiopathic and binge drinking-induced changes in constitutive PKCε priming. The functional relevance of PKCε translocation for binge drinking and determination of potential upstream signaling pathways involved were investigated using neuropharmacological approaches within the context of 2 distinct binge drinking procedures, Drinking in the Dark (DID) and Scheduled High Alcohol Consumption (SHAC). Binge alcohol drinking elevated p(Ser729)-PKCε levels in both the NAC and the central nucleus of the amygdala (CeA). Moreover, immunoblotting studies of selectively bred and transgenic mouse lines revealed a positive correlation between the propensity to binge drink alcohol and constitutive p(Ser729)-PKCε levels in the NAC and CeA. Finally, neuropharmacological inhibition of PKCε translocation within both regions reduced binge alcohol consumption in a manner requiring intact Group1 metabotropic glutamate receptors, Homer2, phospholipase C (PLC) and/or phosphotidylinositide-3 kinase (PI3K) function. Taken together, these data indicate that PKCε signaling in both the NAC and CeA is a major contributor to binge alcohol drinking and to the genetic propensity to consume excessive amounts of alcohol.