EFFECTS OF DRUGS ON EXTRACELLULAR ARGININE LEVEL IN THE CEREBELLUM OF RAT

The ubiquitous nature of NO and its roles as a vasodilator and as an effector molecule in immunological reactions have implicated its function in many physiological and pathophysiological systems. In the neurochemical system, NO is believed to be involved in the transduction mechanism between fast-acting transmitter molecules and soluble guanylate cyclase. However, it does not seem to follow the strict mechanisms of traditional neurotransmitters in that its action does not require storage vesicles and specific receptors. As such, it is imperative to determine the conditions required for its production so as to define its regulation. The study of NO however, has been hindered in no small part by the fact that NO is extremely labile and reacts readily with other molecules, making its quantification and even detection a serious challenge. Much of the knowledge so far has been inferred from the metabolisms of closely related substances in in vitro tissue preparations. The approach taken in this thesis is to measure cerebellar arginine, the substrate of nitric oxide synthase (NOS), by the technique of microdialysis using conscious, freely-moving animals. Through the characteristic response to specific NOS inhibitors (L-NMMA, DNMMA and L-NAME) and an NO producer, SNP, the profile of extracellular arginine was assessed to be representative of NO metabolism. The availabilty of arginine in the extracellular spaces was found to be nerve-impulse dependent and originating from either presynaptic terminals or glial cells. Subsequently, the effects of excitatory (NMDA) and inhibitory (GABA) amino acids and their respective antagonists on the levels of arginine were investigated. While no clearcut relationship was established between NMDA or GABA and the NO system, it was evident that arginine concentration was influenced by these amino acids and that the maintenance of a basal level was important to proper functioning of the central nervous system.

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• SIM EE MIN