Receptorpharmacological models for the therapy of labyrinthine vertigo

In the mammalian labyrinth, GABAA receptor subtypes are involved in the excitatory neurotransmission between the vestibular type II hair cells and the afferent neurons. Additional afferent ionophoric receptor channels, sensitive to further transmitter candidates, are discussed for both types I and II hair cells. GABA accelerates excitotoxic cell death in cortical neurons. This GABA-ergic neurotoxic action forms an appropriate pathophysiological model explaining peripheral labyrinthine disorders characterized by the spontaneous labyrinthine nystagmus and vertigo in man. A calculated GABAA receptor antagonism was envisaged in order to attenuate the pathological vestibular imbalance following one-sided GABA-accelerated vestibular neurotoxicity. Moderate allosteric blockers of the GABAA receptor channel and weak inverse agonists of the benzodiazepine binding site meet some requirements for potentially successful clinical application. The suppressing action of the suitable drugs picrotoxin and flumazenil on labyrinthine nystagmus and vertigo, tested in clinical trials, supports the hypothesis that GABAA receptors are involved in vestibular neurotransmission, even in humans. The test results promise the development of a successful vestibular receptorpharmacology in the near future.