A role for *4(non-*6)* nicotinic acetylcholine receptors in motor behavior.
A role for *4(non-*6)* nicotinic acetylcholine receptors in motor behavior.
复制标题
*4(非-*6)*烟碱乙酰胆碱受体在运动行为中的作用。
DOI：
10.1016/j.neuropharm.2013.05.001
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发表时间：
2013
影响因子：
4.7
通讯作者：
Tapper,AndrewR
中科院分区：
文献类型：
--
作者：
Soll,LindseyG;Grady,SharonR;Salminen,Outi;Marks,MichaelJ;Tapper,AndrewR
含有 α4 和/或 α6 亚基的烟碱乙酰胆碱受体 (nAChR) 在背侧纹状体的多巴胺能神经末梢中强烈表达，推测它们通过胆碱能中间神经元的乙酰胆碱 (ACh) 刺激来调节多巴胺 (DA) 的释放。然而，在小鼠中，对 nAChR 进行药物阻断或对单个 nAChR 亚基（包括 α4 和 α6）进行基因删除，对运动行为几乎没有影响。基于含有α4亚基的nAChR在背侧纹状体DA调节中的假定作用，我们假设在α4 nAChR亚基Leu9'Ala中表达单点突变的小鼠，该突变使nAChR对激动剂过敏，与WT小鼠相比，其运动行为会表现出夸大的差异。为了深入了解这些差异，我们用 α4β2 nAChR 拮抗剂二氢-β-赤霉素 (DHβE) 攻击 WT 和 Leu9'Ala 小鼠。有趣的是，在 Leu9'Ala 小鼠中，DHβE 引发了强烈的、可逆的运动损伤，其特征是运动不足、运动不能、僵住、紧握和震颤。而拮抗剂在所有测试剂量下对 WT 小鼠几乎没有作用。预注射尼古丁 (0.1 mg/kg) 可阻断 DHβE 诱导的 Leu9'Ala 小鼠运动障碍，证实该表型是由 nAChR 拮抗作用介导的。此外，SKF82958 (1 mg/kg) 和安非他明 (5 mg/kg) 可预防运动表型。与 WT 动物相比，DHβE 显着激活 Leu9'Ala 小鼠纹状体和黑质网状部内更多的神经元，表明间接运动通路的激活是运动功能障碍的潜在回路。 ACh 诱发的 Leu9'Ala 纹状体突触体释放 DA 显示仅在 α4（非 α6）* nAChR 处具有激动剂超敏性。同样，α4 超敏 nAChR (Leu9'Ala/α6 KO) 背景中的 α6 nAChR 亚基缺失对 DHβE 诱导的表型几乎没有影响，表明存在 α4(非 α6)* nAChR 依赖性机制。总之，这些数据表明 α4(non-α6)* nAChR 对运动输出有影响，并且可能是治疗与运动损伤相关的疾病的潜在分子靶标。
Nicotinic acetylcholine receptors (nAChRs) containing either the α4 and/or α6 subunit are robustly expressed in dopaminergic nerve terminals in dorsal striatum where they are hypothesized to modulate dopamine (DA) release via acetylcholine (ACh) stimulation from cholinergic interneurons. However, pharmacological blockade of nAChRs or genetic deletion of individual nAChR subunits, including α4 and α6, in mice, yields little effect on motor behavior. Based on the putative role of nAChRs containing the α4 subunit in modulation of DA in dorsal striatum, we hypothesized that mice expressing a single point mutation in the α4 nAChR subunit, Leu9′Ala, that renders nAChRs hypersensitive to agonist, would exhibit exaggerated differences in motor behavior compared to WT mice. To gain insight into these differences, we challenged WT and Leu9′Ala mice with the α4β2 nAChR antagonist dihydro-β-erythroidine (DHβE). Interestingly, in Leu9′Ala mice, DHβE elicited a robust, reversible motor impairment characterized by hypolocomotion, akinesia, catalepsy, clasping, and tremor; whereas the antagonist had little effect in WT mice at all doses tested. Pre-injection of nicotine (0.1 mg/kg) blocked DHβE-induced motor impairment in Leu9′Ala mice confirming that the phenotype was mediated by antagonism of nAChRs. In addition, SKF82958 (1 mg/kg) and amphetamine (5 mg/kg) prevented the motor phenotype. DHβE significantly activated more neurons within striatum and substantia nigra pars reticulata in Leu9′Ala mice compared to WT animals, suggesting activation of the indirect motor pathway as the circuit underlying motor dysfunction. ACh evoked DA release from Leu9′Ala striatal synaptosomes revealed agonist hypersensitivity only at α4(non-α6)* nAChRs. Similarly, α6 nAChR subunit deletion in an α4 hypersensitive nAChR (Leu9′Ala/α6 KO) background had little effect on the DHβE-induced phenotype, suggesting an α4(non-α6)* nAChR-dependent mechanism. Together, these data indicate that α4(non-α6)* nAChR have an impact on motor output and may be potential molecular targets for treatment of disorders associated with motor impairment.