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Effects of pharmacological agents on mammalian vestibular function
Three studies were largely conducted to evaluate physiological status of animals anesthetized with different anesthetic protocols and pharmacological effects on vestibular function using vestibular sensory evoked potentials (VsEP) in the intact mice. In the first study, the physiological status of mice anesthetized with ketamine/xylazine (K/X) was compared to those with urethane/xylazine (U/X) anesthesia during VsEP testing conditions. The U/X anesthesia provided a longer lasting anesthesia, prolonged survival times and less compromised physiological conditions compared to K/X anesthesia in mice. Simple non-invasive O2 supplementation and brain temperature control improved the physiological conditions and minimized changes in VsEP responses. In the second study, clinical agents (e.g., meclizine and diazepam) and a potential clinical agent (e.g., JNJ7777120) were tested to identify a useful dose range and characterize time course and extent of drug actions on vestibular function. Effects on peripheral and central components of the VsEP were modest in all three drugs and were relatively slow to develop in meclizine and JNJ7777120. Meclizine and diazepam act centrally to exert their suppression effects, whereas JNJ7777120 acts in the periphery by enhancing macular responses to transient high frequency stimuli. In the third study, a non-clinical agent (e.g., XE-991, KCNQ channel blocker) was tested to better understand the normal function of KCNQ channels and their importance to vestibular function in the intact animals. XE-991 modestly produced a dose-dependent enhancement of VsEP at doses of 0.5 mg/kg and higher and also showed a dose-dependent suppression at doses of 2.5 mg/kg and higher. The findings suggest that KCNQ channels play a critical role in vestibular function and their regulation by efferent action via muscarinic acetylcholine receptors (mAChRs) may function to adjust the dynamic response characteristics of vestibular afferents. Collectively, these studies showed that using pharmacological agents and VsEP is beneficial to resolve the questions related to vestibular afferent and efferent synaptic mechanisms. These in vivo studies determined sites of and time course of drug action in the intact vestibular system. Clinically, the findings of this work may aid the development of more accurate and effective intervention strategies for the treatment of dizziness and vertigo.
Lee, Choongheon, "Effects of pharmacological agents on mammalian vestibular function" (2016). ETD collection for University of Nebraska - Lincoln. AAI10247068.