Neuropharmacological targets for drug action in vestibular sensory pathways

The use of pharmacological agents is often the preferred approach to the management of vestibular dysfunction. In the vestibular sensory pathways, the sensory neuroepithelia are thought to be influenced by a diverse number of neuroactive substances that may act to enhance or inhibit the effect of the primary neurotransmitters [i.e., glutamate (Glu) and acetylcholine (ACh)] or alter their patterns of release. This review summarizes various efforts to identify drug targets including neurotransmitter and neuromodulator receptors in the vestibular sensory pathways. Identifying these receptor targets provides a strategic basis to use specific pharmacological tools to modify receptor function in the treatment and management of debilitating balance disorders. A review of the literature reveals that most investigations of the neuropharmacology of peripheral vestibular function have been performed using in vitro or ex vivo animal preparations rather than studying drug action on the normal intact vestibular system in situ. Such noninvasive approaches could aid the development of more accurate and effective intervention strategies for the treatment of dizziness and vertigo. The current review explores the major neuropharmacological targets for drug action in the vestibular system

Reducing auditory nerve excitability by acute antagonism of Ca2+-permeable AMPA receptors

Hearing depends on glutamatergic synaptic transmission mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). AMPARs are tetramers, where inclusion of the GluA2 subunit reduces overall channel conductance and C

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