Cholinergic modulation of locomotion and striatal dopamine release is mediated by alpha6alpha4* nicotinic acetylcholine receptors.
Cholinergic modulation of locomotion and striatal dopamine release is mediated by alpha6alpha4* nicotinic acetylcholine receptors.
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DOI：
10.1523/jneurosci.2056-10.2010
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发表时间：
2010-07-21
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影响因子：
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通讯作者：
Lester HA
中科院分区：
文献类型：
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作者：
Drenan RM;Grady SR;Steele AD;McKinney S;Patzlaff NE;McIntosh JM;Marks MJ;Miwa JM;Lester HA
纹状体多巴胺（DA）的释放受中脑DA神经元、纹状体胆碱能张力和DA突触前末端烟碱性乙酰胆碱受体（nAChRs）的放电速率控制。DA神经元选择性表达α6* nAChRs，表现出对乙酰胆碱和尼古丁的高敏感性。为了帮助鉴定控制DA传播的nAChR亚型，我们研究了表达超敏α 6l9s *受体的转基因小鼠。α 6l9s小鼠过度活跃，行走距离更远，表现出更多的走动行为，如行走、转身和饲养，减少暂停、悬挂、饮水和梳理。这些作用是由α6α4*五聚体介导的，缺乏α4亚基的α 6l9s小鼠表现出基本正常的行为。在α 6l9s小鼠中，受体数量正常，但α4亚基缺失导致α6*受体数量减少，敏感性降低。功能获得性尼古丁刺激纹状体突触体释放DA需要α4亚基，暗示α6α4β2* nAChRs参与α 6l9s小鼠行为。在脑切片中，我们采用电化学测量方法研究α 6l9s nAChRs对DA释放的控制作用。在α 6l9s中，DA纤维的爆发刺激可选择性地增加DA的释放，而在WT或α4KO/α 6l9s小鼠中则没有。因此，nAChR活性的增加与活性的降低一样，会导致相放电期间细胞外DA释放的增强。爆发可能直接促进α 6l9s突触前末端的DA释放，但纹状体DA受体数量、DA转运体水平和功能在体外无差异。这些结果提示α6α4β2* nAChRs参与胆碱能控制DA传递，并强烈提示这些受体是DA系统疾病的候选药物靶点。
Dopamine (DA) release in striatum is governed by firing rates of midbrain DA neurons, striatal cholinergic tone, and nicotinic ACh receptors (nAChRs) on DA presynaptic terminals. DA neurons selectively express α6* nAChRs, which show high ACh and nicotine sensitivity. To help identify nAChR subtypes that control DA transmission, we studied transgenic mice expressing hypersensitive α6L9′S* receptors. α6L9′S mice are hyperactive, travel greater distance, exhibit increased ambulatory behaviors such as walking, turning, and rearing, and show decreased pausing, hanging, drinking, and grooming. These effects were mediated by α6α4* pentamers, as α6L9′S mice lacking α4 subunits displayed essentially normal behavior. In α6L9′S mice, receptor numbers are normal, but loss of α4 subunits leads to fewer and less sensitive α6* receptors. Gain-of-function nicotine-stimulated DA release from striatal synaptosomes requires α4 subunits, implicating α6α4β2* nAChRs in α6L9′S mouse behaviors. In brain slices, we applied electrochemical measurements to study control of DA release by α6L9′S nAChRs. Burst stimulation of DA fibers elicited increased DA release relative to single action potentials selectively in α6L9′S, but not WT or α4KO/α6L9′S, mice. Thus, increased nAChR activity, like decreased activity, leads to enhanced extracellular DA release during phasic firing. Bursts may directly enhance DA release from α6L9′S presynaptic terminals, as there was no difference in striatal DA receptor numbers or DA transporter levels or function in vitro. These results implicate α6α4β2* nAChRs in cholinergic control of DA transmission, and strongly suggest that these receptors are candidate drug targets for disorders involving the DA system.