Cai You-Qing, Cai Guo-Qiang, Liu Guo-Xiang, Cai Qing, Shi Jia-Hao, Shi Jun, Ma Sun-Kai, Sun Xia, Sheng Zhe-Jin, Mei Zhen-Tong, Cui Dafu, Guo Lihe, Wang Zhugang, Fei Jian
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, SIBS, CAS, Shanghai, China.
J Neurosci Res. 2006 Aug 1;84(2):255-67. doi: 10.1002/jnr.20884.
It is widely accepted that the GABAergic system plays an important role in the action of ethanol in vivo. GABA transporter subtype 1 (GAT1) constructs high affinity reuptake sites in the CNS and regulates GABAergic transmissions. In this study, mice lacking the GAT1 were developed by homologous recombination. Both hetero- and homozygous GAT1 mutant mice were tested for ethanol, saccharin or quinine consumption, ethanol-conditioned place preference, ethanol-conditioned taste aversion, ethanol-simulated motor activity, and ethanol-induced sedation/hypnosis. The GAT1(-/-) mice showed decreased ethanol aversion and ethanol reward, and insensitivity to both the sedative/hypnotic and the motor stimulant effects of ethanol, along with increased avoidance of quinine preference and consumption. GAT1(+/-) mice showed significantly increased consumption of ethanol and saccharin, however, enhanced the rewarding and preference effect of ethanol, increased avoidance of quinine, and higher sensitivity to the motor stimulant effect of ethanol. These results demonstrate that GAT1, perhaps in a bi-directional way, modulates some behavioral effects of ethanol. The GAT1 mutant mice provided us a very useful model to investigate the mechanisms of ethanol action in vivo.
人们普遍认为，γ-氨基丁酸（GABA）能系统在乙醇的体内作用中发挥着重要作用。GABA转运体亚型1（GAT1）在中枢神经系统中构建高亲和力再摄取位点，并调节GABA能传递。在本研究中，通过同源重组培育出缺乏GAT1的小鼠。对杂合和纯合GAT1突变小鼠进行了乙醇、糖精或奎宁消耗、乙醇条件性位置偏爱、乙醇条件性味觉厌恶、乙醇模拟运动活动以及乙醇诱导的镇静/催眠测试。GAT1（-/-）小鼠表现出乙醇厌恶和乙醇奖赏减少，对乙醇的镇静/催眠和运动刺激作用均不敏感，同时对奎宁偏爱和消耗的回避增加。GAT1（+/-）小鼠表现出乙醇和糖精消耗显著增加，然而，增强了乙醇的奖赏和偏爱效应，增加了对奎宁的回避，并且对乙醇的运动刺激作用更敏感。这些结果表明，GAT1可能以双向方式调节乙醇的一些行为效应。GAT1突变小鼠为我们研究乙醇在体内作用的机制提供了一个非常有用的模型。
