Characterizing the Access of Cholinergic Antagonists to Efferent Synapses in the Inner Ear.
Characterizing the Access of Cholinergic Antagonists to Efferent Synapses in the Inner Ear.
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DOI：
10.3389/fnins.2021.754585
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发表时间：
2021
影响因子：
4.3
通讯作者：
Holt JC
中科院分区：
文献类型：
--
作者：
Lee C;Sinha AK;Henry K;Walbaum AW;Crooks PA;Holt JC
刺激支配内耳的胆碱能传出神经元，在激活传入细胞和外周内脏毛细胞上的不同的ACh受体(AChRs)后，对前庭和听觉生理有深刻的、明确的影响。传出兴奋前庭传入的快慢兴奋分别由含α4β2*的烟碱型AChRs(NAChRs)和M胆碱型AChRs(MAChRs)介导。在听觉方面，α9α10nAChRs介导传出抑制失真产物耳声发射(DPOAEs)。以前对这些突触机制的描述使用了胆碱能药物，当系统地给药时，这些药物也到达中枢神经系统，这可能限制它们在探测传出功能方面的效用，而不考虑中枢效应。使用外周作用的胆碱能药物与局部应用策略可能是有用的，但这种方法仍然相对未被探索。我们采用多种给药途径，在小鼠和龟的传出刺激过程中结合前庭传入和DPOAE记录，以确定带电的mAChR或α9α10nAChR拮抗剂是否仍能与内耳的传出突触靶点相结合。荷电的mAChR拮抗剂格列吡酯和甲基托拉明可阻断腹膜内、中耳或直接外淋巴给药后传出介导的小鼠前庭传入的缓慢兴奋。两种mAChR拮抗剂在给药到中耳时都是有效的，在传入记录的对侧，这表明它们在首次进入外淋巴室后获得了血管通路。相反，荷电的α9α10nAChR拮抗剂仅在外淋巴管直接给药时才能阻断传出对DPOAEs的抑制，但全身给药时不能到达传出突触。这些数据表明，传出机制是进一步表征内耳药物通路的可行靶点。
Stimulation of cholinergic efferent neurons innervating the inner ear has profound, well-characterized effects on vestibular and auditory physiology, after activating distinct ACh receptors (AChRs) on afferents and hair cells in peripheral endorgans. Efferent-mediated fast and slow excitation of vestibular afferents are mediated by α4β2*-containing nicotinic AChRs (nAChRs) and muscarinic AChRs (mAChRs), respectively. On the auditory side, efferent-mediated suppression of distortion product otoacoustic emissions (DPOAEs) is mediated by α9α10nAChRs. Previous characterization of these synaptic mechanisms utilized cholinergic drugs, that when systemically administered, also reach the CNS, which may limit their utility in probing efferent function without also considering central effects. Use of peripherally-acting cholinergic drugs with local application strategies may be useful, but this approach has remained relatively unexplored. Using multiple administration routes, we performed a combination of vestibular afferent and DPOAE recordings during efferent stimulation in mouse and turtle to determine whether charged mAChR or α9α10nAChR antagonists, with little CNS entry, can still engage efferent synaptic targets in the inner ear. The charged mAChR antagonists glycopyrrolate and methscopolamine blocked efferent-mediated slow excitation of mouse vestibular afferents following intraperitoneal, middle ear, or direct perilymphatic administration. Both mAChR antagonists were effective when delivered to the middle ear, contralateral to the side of afferent recordings, suggesting they gain vascular access after first entering the perilymphatic compartment. In contrast, charged α9α10nAChR antagonists blocked efferent-mediated suppression of DPOAEs only upon direct perilymphatic application, but failed to reach efferent synapses when systemically administered. These data show that efferent mechanisms are viable targets for further characterizing drug access in the inner ear.
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