Parkinson's disease afflicts 1 in every 1000 adults, rising exponentially in incidence after the age of fifty. The symptoms of this debilitating psycho-motor illness are thought to result from a functional imbalance between cholinergic and dopaminergic systems of the neostriatum. The treatment of this disease has been hampered by the absence of a clear picture of the neuromodulatory actions of these systems in the neostriatum. Electrophysiological studies in other excitable cells have demonstrated that acetylcholine (ACh) and dopamine (DA) exert their effects on electrical excitability primarily by altering the properties of voltage-dependent ionic conductances. These alterations are reflected in the integration of synaptic input, action potential shape and spike patterning. Previous studies of neostriatal neurons have not been able to provide a similar level of understanding because of their reliance upon techniques that cannot definitively characterize ionic conductances or the molecular mechanisms mediating their modulation. In this project, recently developed whole-cell and patch voltage-clamp techniques that overcome these shortcomings will be used to characterize the effects of ACh and DA on the ionic conductances of identified neostriatal neurons dissociated from adult and juvenile rats. It is the central thesis of this proposal that ACh and DA exert their principal effects on neostriatal function by modulating ionic conductances and that the interaction between these transmitters occurs at the level of the molecular events mediating this modulation in individual neostriatal neurons. The proposed experiments test this hypothesis in mature neostriatal neurons with techniques capable of measuring single or multi-channel ionic currents while controlling the biologically relevant variables: transmembrane voltage and the biochemical composition of the intra- and extra-cellular environment. Specifically, the proposal has three aims pertinent to a test of this hypothesis: (1) to characterize the effects of ACh and DA on the biophysical properties of potassium and calcium conductances in morphologically and immunocytochemically identified postnatal rat neostriatal neurons. Phenotypic identification of studied neurons will focus upon axonal projections using retrograde tracing and transmitter immunocytochemistry; (2) to characterize the role of different receptor subtypes, GTP-binding proteins and second messenger systems in mediating the modulatory effects of ACh and DA; and (3) to characterize the nature of the interaction between cholinergic and dopaminergic signalling pathways in the modulation of ionic conductances. An understanding of the actions of ACh and DA on the electrical excitability of neostriatal neurons should be of significance to the development of effective therapies for Parkinson's disease. The actions of these modulators are also of relevance to the clinical management of Huntington's disease and the psycho-motor side-effects of neuroleptic treatment of schizophrenia.
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