The major objective of this application is to seek an understanding of the-intracellular signalling mechanisms by which dopamine exerts its effects in striatal neurons in the basal ganglia. This includes an understanding not only of the intracellular messengers that mediate the dopaminergic signal but also an understanding of how this signal is integrated together with that of a variety of other neurotransmitters impinging on striatal neurons. A major goal of the proposed studies is to generate, by novel technologies, genetically altered animals that will serve as models in which to study dopamine signalling pathways. These studies will allow the characterization of the involvement of individual components of the dopaminergic signalling pathways without the use of non-specific inhibitors. In addition, it also allows the analysis of the effect of these mutations in whole animals in which the complexity of interacting neurotransmitter pathways is preserved in the basal ganglia as well as other brain regions. Additional goals of the proposed studies are to use recently introduced molecular biological techniques to identify novel components of the dopamine signalling pathways. Specifically the yeast two-hybrid technique will be used to isolate proteins that interact with the phosphoproteins or with the enzymes that regulate their phosphorylation and dephosphorylation. These studies will be of particular importance in understanding such diseases as Parkinson's disease and schizophrenia which result in part from defects in dopamine- signalling pathways. In addition, the availability of mouse models in which specific components of dopamine-signalling pathways are deficient may be useful in the development of new therapeutic strategies for the treatment of such diseases.
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