A number of important neurologic, mental health and drug abuse problems involve dysfunctioning or losses of the monoarninergic systems of the human brain, and in particular the dopaminergic neurons. In vivo imaging of these systems using radiopharmaceuticals and Positron Emission Tomography (PET provides a unique and valuable approach to the study of these diseases in the living human brain. Choices of appropriate radiotracers, alone and in combinations, will be crucial for the success of such in vivo imaging. This Project will examine animal models of such diseases, using a novel approach of dual in vivo radiotracer studies of the vesicular monoamine transporter (VMAT2 and the dopamine neuronal membrane transporter (DAT). The potential in vivo regulation of these binding sites by disease processes and chronic drug treatments will be evaluated. The short term regulation of such transporters b kinase-mediated phosphorylation reactions will be studied. The relationship between the two transporters, proposed here as markers of nerve terminal integrity (VMAT2) and nerve terminal function (DAT), will be examined over tim in models of degeneration and recovery in animal models of Parkinson's disease and drug abuse. Studies will subsequently be done to determine whether measure of numbers of terminals (VMAT2), functional status (DAT), or function on a per terminal basis (DAT/VMAT'2) provides the best sensitivity for measuring in viv the effects of current and new therapeutic approaches to changing the course o these diseases. This Project will provide crucial information on the proper approach to be taken for in vivo tomographic radionuclide of monoaminergic terminal-related disease inception, progression or treatment in a general patient population. Finally, synthetic radiochemistry efforts will be undertaken to extend this approach to measuring the VMAT2 outside the heavily-dopaminergic innervated striaturn, opening up new avenues of research into the role of monoaminergic (particularly, serotonergic and adrenergic) terminals in a wider variety of neurologic, mental health and drug abuse diseases.
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