Cozzoli Debra K, Goulding Scott P, Zhang Ping Wu, Xiao Bo, Hu Jia-Hua, Ary Alexis W, Obara Ilona, Rahn Alison, Abou-Ziab Hoda, Tyrrel Burgundy, Marini Christina, Yoneyama Naomi, Metten Pamela, Snelling Christopher, Dehoff Marlin H, Crabbe John C, Finn Deborah A, Klugmann Matthias, Worley Paul F, Szumlinski Karen K
Department of Psychology and the Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, California 93106-9660, USA.
J Neurosci. 2009 Jul 8;29(27):8655-68. doi: 10.1523/JNEUROSCI.5900-08.2009.
The glutamate receptor-associated protein Homer2 regulates alcohol-induced neuroplasticity within the nucleus accumbens (NAC), but the precise intracellular signaling cascades involved are not known. This study examined the role for NAC metabotropic glutamate receptor (mGluR)-Homer2-phosphatidylinositol 3-kinase (PI3K) signaling in regulating excessive alcohol consumption within the context of the scheduled high alcohol consumption (SHAC) model of binge alcohol drinking. Repeated bouts of binge drinking ( approximately 1.5 g/kg per 30 min) elevated NAC Homer2a/b expression and increased PI3K activity in this region. Virus-mediated knockdown of NAC Homer2b expression attenuated alcohol intake, as did an intra-NAC infusion of the mGluR5 antagonist MPEP [2-methyl-6-(phenylethynyl)pyridine hydrochloride] (0.1-1 microg/side) and the PI3K antagonist wortmannin (50 ng/side), supporting necessary roles for mGluR5/Homer2/PI3K in binge alcohol drinking. Moreover, when compared with wild-type littermates, transgenic mice with an F1128R point mutation in mGluR5 that markedly reduces Homer binding exhibited a 50% reduction in binge alcohol drinking, which was related to reduced NAC basal PI3K activity. Consistent with the hypothesis that mGluR5-Homer-PI3K signaling may be a mechanism governing excessive alcohol intake, the "anti-binge" effects of MPEP and wortmannin were not additive, nor were they observed in the mGluR5(F1128R) transgenic mice. Finally, mice genetically selected for a high versus low SHAC phenotype differed in NAC mGluR, Homer2, and PI3K activity, consistent with the hypothesis that augmented NAC mGluR5-Homer2-PI3K signaling predisposes a high binge alcohol-drinking phenotype. Together, these data point to an important role for NAC mGluR5-Homer2-PI3K signaling in regulating binge-like alcohol consumption that has relevance for our understanding of the neurobiology of alcoholism and its pharmacotherapy.
谷氨酸受体相关蛋白Homer2调节伏隔核（NAC）内酒精诱导的神经可塑性，但其中确切的细胞内信号级联尚不清楚。本研究在暴饮酒精的定时高酒精摄入（SHAC）模型背景下，研究了NAC代谢型谷氨酸受体（mGluR）-Homer2-磷脂酰肌醇3激酶（PI3K）信号在调节过量酒精摄入中的作用。反复暴饮（每30分钟约1.5克/千克）可提高NAC中Homer2a/b的表达，并增加该区域的PI3K活性。病毒介导的NAC Homer2b表达敲低可减弱酒精摄入，向NAC内注射mGluR5拮抗剂MPEP [2-甲基-6-（苯乙炔基）吡啶盐酸盐]（0.1-1微克/侧）和PI3K拮抗剂渥曼青霉素（50纳克/侧）也有同样效果，这支持了mGluR5/Homer2/PI3K在暴饮酒精中的必要作用。此外，与野生型同窝小鼠相比，mGluR5中具有明显降低Homer结合能力的F1128R点突变的转基因小鼠，其暴饮酒精量减少了50%，这与NAC基础PI3K活性降低有关。与mGluR5-Homer-PI3K信号可能是控制过量酒精摄入的一种机制这一假设一致，MPEP和渥曼青霉素的“抗暴饮”作用并非相加性，在mGluR5（F1128R）转基因小鼠中也未观察到。最后，根据高与低SHAC表型进行基因选择的小鼠在NAC mGluR、Homer2和PI3K活性方面存在差异，这与增强的NAC mGluR5-Homer2-PI3K信号易导致高暴饮酒精表型的假设一致。总之，这些数据表明NAC mGluR5-Homer2-PI3K信号在调节类似暴饮的酒精摄入中起重要作用，这对于我们理解酒精中毒的神经生物学及其药物治疗具有重要意义。
