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Several behavioral traits relevant for alcoholism are controlled by ɣ2 subunit containing GABAA receptors on dopamine neurons in mice.
Neuropsychopharmacology ( IF 7.6 ) Pub Date : 2018-06-01 , DOI: 10.1038/s41386-018-0022-z
Andrea Stojakovic 1 , Magdalena Walczak 2 , Przemysław E Cieślak 3 , Aleksandra Trenk 2 , Johan Sköld 1 , Joanna Zajdel 1 , Elahe Mirrasekhian 1 , Camilla Karlsson 1 , Annika Thorsell 1 , Markus Heilig 1 , Jan Rodriguez Parkitna 3 , Tomasz Błasiak 2 , David Engblom 1
Affiliation  

The risk factors for developing alcohol addiction include impulsivity, high sensitivity to the rewarding action of ethanol, and low sensitivity to its sedative and intoxicating effects. Genetic variation in GABAA receptor subunits, including the ɣ2 subunit (Gabrg2), affects the risk for developing alcoholism. Alcohol directly potentiates GABAA receptors and activates the mesolimbic dopamine system. Here, we deleted Gabrg2 selectively in dopamine cells of adult mice. The deletion resulted in elevated firing of dopamine neurons and made them less sensitive to drugs acting at GABAA receptors. At the behavioral level, the deletion increased exploratory behavior and augmented both correct and incorrect responding in the go/no-go task, a test often used to assay the response inhibition component of impulsivity. In addition, conditioned place preference to alcohol, but not to cocaine or morphine, was increased. Ethanol-induced locomotor activation was enhanced in the mice lacking Gabrg2 on dopaminergic cells, whereas the sedative effect of alcohol was reduced. Finally, the alcohol drinking, but not the alcohol preference, at a high concentration was increased in the mutant mice. In summary, deletion of Gabrg2 on dopamine cells induced several behavioral traits associated with high risk of developing alcoholism. The findings suggest that mice lacking Gabrg2 on dopaminergic cells could be used as models for individuals at high risk for developing alcoholism and that GABAA receptors on dopamine cells are protective against the development of excessive alcohol drinking.

中文翻译:

与酒精中毒相关的几种行为特征由小鼠多巴胺神经元上含有 GABAA 受体的 ɣ2 亚基控制。

发展成酒精成瘾的风险因素包括冲动、对乙醇的奖励作用高度敏感,以及对其镇静和陶醉作用的敏感性低。GABA A受体亚基的遗传变异,包括 ɣ2 亚基 (Gabrg2),会影响发生酒精中毒的风险。酒精直接增强 GABA A受体并激活中脑边缘多巴胺系统。在这里,我们在成年小鼠的多巴胺细胞中选择性地删除了 Gabrg2。缺失导致多巴胺神经元的放电升高,并使它们对作用于 GABA A 的药物不太敏感受体。在行为水平上,删除增加了探索行为,并增加了 go/no-go 任务中正确和不正确的响应,这是一种经常用于检测冲动的反应抑制成分的测试。此外,对酒精而不是可卡因或吗啡的条件性位置偏好增加了。在缺乏 Gabrg2 的多巴胺能细胞上,乙醇诱导的运动激活增强,而酒精的镇静作用降低。最后,在突变小鼠中,高浓度的饮酒而不是酒精偏好增加了。总之,多巴胺细胞上 Gabrg2 的缺失诱导了几种与酒精中毒高风险相关的行为特征。多巴胺细胞上的A受体可防止过度饮酒的发展。
更新日期:2018-02-06
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