Accumbens Homer2-mediated signaling: a factor contributing to mouse strain differences in alcohol drinking?
Accumbens Homer2-mediated signaling: a factor contributing to mouse strain differences in alcohol drinking?
复制标题
DOI：
10.1111/j.1601-183x.2010.00647.x
复制
发表时间：
2011-02
期刊：
影响因子：
--
通讯作者：
Szumlinski KK
中科院分区：
文献类型：
--
作者：
Goulding SP;Obara I;Lominac KD;Gould AT;Miller BW;Klugmann M;Szumlinski KK
酒精诱导的伏隔核谷氨酸增加积极调节酒精摄入，并且皮质 - 伏隔核谷氨酸系统对酒精的反应性与酒精奖赏的遗传变异有关。在此，我们通过检测近交系C57BL/6J和DBA2/J小鼠之间谷氨酸相关信号分子在纹状体表达的基础水平以及酒精诱导的变化差异，扩展了先前关于近交系小鼠伏隔核谷氨酸差异的数据。反复酒精处理（8×2 g/kg）增加了第1组代谢型谷氨酸受体、N - 甲基 - D - 天冬氨酸受体的NR2a/b亚单位、Homer2a/b以及蛋白激酶C ε和磷酸肌醇 - 3 - 激酶的活化形式在腹侧纹状体（而非背侧纹状体）中的表达。无论先前是否有酒精摄入经历，与DBA2/J小鼠相比，C57BL/6J小鼠表现出伏隔核中mGluR1/5、Homer2a/b、NR2a和活化激酶水平更高，而仅在C57BL/6J小鼠中观察到酒精诱导的背侧纹状体mGluR1/5表达升高。接下来，我们采用病毒介导的基因转移方法来确定所观察到的伏隔核Homer2表达的品系差异对酒精诱导的谷氨酸致敏以及酒精偏好/摄入量方面B6/D2差异的功能相关性。调节伏隔核壳部Homer2b表达积极调节了C57BL/6J小鼠的这些指标，而DBA2/J小鼠对病毒介导的Homer2表达变化的神经化学和行为效应相对不敏感。这些数据支持一个总体假设，即增强的伏隔核Homer2介导的谷氨酸信号可能是一种与酒精摄入遗传变异相关的内表型。如果与人类相关，此类数据表明影响谷氨酸受体/Homer2信号的多态性在酗酒的病因学中起作用。
Alcohol-induced increases in nucleus accumbens glutamate actively regulate alcohol consumption and the alcohol responsiveness of corticoaccumbens glutamate systems relates to genetic variance in alcohol reward. Here, we extend earlier data for inbred mouse strain differences in accumbens glutamate by examining for differences in basal and alcohol-induced changes in the striatal expression of glutamate-related signaling molecules between inbred C57BL/6J and DBA2/J mice. Repeated alcohol treatment (8 × 2 g/kg) increased the expression of Group1 metabotropic glutamate receptors, the NR2a/b subunits of the N-methyl-D-aspartate receptor, Homer2a/b, as well as the activated forms of protein kinase C epsilon and phosphoinositol-3-kinase within ventral, but not dorsal, striatum. Regardless of prior alcohol experience, C57BL/6J mice exhibited higher accumbens levels of mGluR1/5, Homer2a/b, NR2a and activated kinases versus DBA2/J mice, while an alcohol-induced rise in dorsal striatum mGluR1/5 expression was observed only in C57BL/6J mice. We next employed virus-mediated gene transfer approaches to ascertain the functional relevance of the observed strain difference in accumbens Homer2 expression for B6/D2 differences in alcohol-induced glutamate sensitization, as well as alcohol preference/intake. Manipulating NAC shell Homer2b expression actively regulated these measures in C57BL/6J mice, while DBA2/J mice were relatively insensitive to the neurochemical and behavioral effects of virus-mediated changes in Homer2 expression. These data support the over-arching hypothesis that augmented accumbens Homer2-mediated glutamate signaling may be an endophenotype related to genetic variance in alcohol consumption. If relevant to humans, such data pose polymorphisms affecting glutamate receptor/Homer2 signaling in the etiology of alcoholism.