Chronic nicotine selectively enhances alpha4beta2* nicotinic acetylcholine receptors in the nigrostriatal dopamine pathway.
Chronic nicotine selectively enhances alpha4beta2* nicotinic acetylcholine receptors in the nigrostriatal dopamine pathway.
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DOI：
10.1523/jneurosci.2939-09.2009
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发表时间：
2009-10-07
期刊：
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：
Xiao C;Nashmi R;McKinney S;Cai H;McIntosh JM;Lester HA
这些电生理学实验在切片和完整动物中进行，研究了体内长期接触尼古丁对黑质纹状体多巴胺能 (DA) 通路中功能性 α4β2* nAChR 的影响。在野生型和 α4 烟碱乙酰胆碱受体 (nAChR) 亚基敲除小鼠中进行记录。慢性尼古丁增强了 3 – 1000 μM ACh 在黑质网状部 (SNr) 的 GABA 能神经元中引起的 MLA 抗性、DHβE 敏感烟碱电流，但在黑质致密部 (SNc) 的 DA 神经元中则不然。这种增强导致 SNr GABA 能神经元的放电率更高，从而增加 SNc DA 神经元的 GABA 能抑制。在背侧纹状体中，神经元体细胞上未发现功能性 α4* nAChR；然而，尼古丁通过 DA 末端的 α4β2* nAChR 发挥作用，调节谷氨酸释放到中型多棘神经元 (MSN) 上。慢性尼古丁还会增加这些 α4β2* nAChR 的数量和/或功能。这些数据表明，在黑质纹状体 DA 通路中，α4β2* nAChR 的慢性尼古丁增强在细胞类型、nAChR 亚型以及细胞区室中表现出选择性。这些选择性事件既增强了 SNr GABA 能神经元对 SNc DA 神经元的抑制，又调节了背侧纹状体中谷氨酸的释放。这些作用可能会降低 SNc DA 神经元兴奋性毒性的风险，也可能抵消 DA 系统退化期间皮质纹状体谷氨酸输入的有效性增加。这些过程可能导致烟草使用与帕金森病之间的负相关。
These electrophysiological experiments, in slices and intact animals, study the effects of in vivo chronic exposure to nicotine on functional α4β2* nAChRs in the nigrostriatal dopaminergic (DA) pathway. Recordings were made in wild-type and α4 nicotinic acetylcholine receptor (nAChR) subunit knockout mice. Chronic nicotine enhanced MLA-resistant, DHβE-sensitive nicotinic currents elicited by 3 – 1000 μM ACh in GABAergic neurons of the substantia nigra pars reticulata (SNr), but not in DA neurons of the substantia nigra pars compacta (SNc). This enhancement leads to higher firing rates of SNr GABAergic neurons, and consequently to increased GABAergic inhibition of the SNc DA neurons. In the dorsal striatum, functional α4* nAChRs were not found on the neuronal somata; however nicotine acts via α4β2* nAChRs in the DA terminals to modulate glutamate release onto the medium spiny neurons (MSNs). Chronic nicotine also increased the number and/or function of these α4β2* nAChRs. These data suggest that in nigrostriatal DA pathway, chronic nicotine enhancement of α4β2* nAChRs displays selectivity in cell type, in nAChR subtype, as well as in cellular compartment. These selective events both augment inhibition of SNc DA neurons by SNr GABAergic neurons, and also temper the release of glutamate in the dorsal striatum. The effects may reduce the risk of excitotoxicity in SNc DA neurons, and may also counteract the increased effectiveness of corticostriatal glutamatergic inputs during degeneration of the DA system. These processes may contribute to the inverse correlation between tobacco use and Parkinson’s disease.