Basic knowledge about central nervous system processes which regulate adaptive vestibuloocular reflex (VOR) changes can serve as the foundation for understanding and treating dysfunction of the vestibular system. Presently, knowledge of the neuropharmacological mechanisms of VOR adaptation is limited. The object of the proposed research is to study the role of excitatory glutamatergic and inhibitor GABAergic activity on this adaptation. This work will be conducted in those brain regions associated with VOR adaptation, namely, the vestibulo-cerebellum, the vestibular nucleus and Area II. Area II is a region in the goldfish hindbrain which is thought to be homologous to the propositus nucleus. NMDA and non-NMDA glutamatergic receptors which are present in these brain structures have been implicated in other adaptive and neuroblastic changes in the nervous systems. Nitric oxide (NO) whose levels are increased after glutamatergic stimulation have been put forth as a mediator of these neuroblastic changes. Firstly, experiments will investigate athe action of NMDA and non-NMDA antagonists within the vestibular and Area II nuclei on a adaptive VOR processes. Previous work from our laboratory has shown that antagonism NMDA receptors by MK-801 at non-cerebellar sites inhibit adaptive VOR chagnes. Secondly, experiments will study the role of NO on VOR adaptation in these brainstem nuclei. NO inhibition in the cerebellum has already been demonstrated in our own work to prevent VOR adaptation. Finally, the cerebellum has been hypothesized to induce adaptive changes in the vestibular nucleus presumably via the inhibitory influence of Purkinje cells. Therefore, a third set of experiments will be used to block the action of cerebellar Purkinje cells on the vestibular neurons using GABA antagonists. Cerebellar studies will also be conducted to confirm that a temperature induced inactivation of VOR adaptation correlates with increases in extracellular cerebellar GABA level and that application of GABA antagonists into the vestibulo-cerebellum impedes VOR. The effects of these agents on VOR adaptation will be assayed using broad band sinusoidal and velocity step vestibulo-visual stimulation. Velocity steps will measure the early dynamic and the later sustained components of VOR adaptation. The adaptive neuronal mechanisms during these 2 components are presumed to depend on activities in different central nervous system sites. Therefore, glutamatergic and GABAergic neuropharmacological experiments are expected to distinguish this difference.
