Magnetic resonance spectroscopy (MRS) and imaging (MRI) allow studies of brain amino acid neurotransmitters in vivo. Recent developments of MR permit not only measurements of neurotransmitter levels, but of synthesis and release, also. The technique is enhanced by the candidate's use of mathematics to interpret measurements quantitatively. The candidate applied an unusual background in MRS, MRI, math, and neurochemistry to alcoholism and (2) improve his education in pharmacology, diagnosis, and treatment of alcoholism. The program will combine MR with other measurements to study neurotransmission and energetics, improve mathematical models of neurotransmission and metabolism, and apply them to pharmacology of alcoholism. His other long term goal is dissemination of MR methods and mathematics for study design and interpretation. The leaders of Psychiatry at Yale have deliberately fostered integration of basic and clinical research, and they have invested heavily in MR research. For education and collaboration with the candidate, there are NIAAA and VA Alcohol Research Centers and laboratories and faculty who are well-established in the field of alcoholism. The grant will free the candidate from other commitments so that he can focus on learning about and researching alcoholism. The development plan has three parts: (1) Education in diagnosis, treatment, neurochemistry, and pathophysiology of alcoholism, (2) Research for more detailed knowledge of pathways of neurotransmitter metabolism, clinical correlates of the basic data, and validation of models of neurotransmission. Two projects are proposed. (1) Measure rates of brain glutamate neurotransmission and glucose utilization in alcohol-dependent patients during detoxification, testing for correlations of those parameters with each other and with measures of cognitive function and electrophysiology, which is funded through the NIAAA Center for Translational Neuroscience in Alcoholism (CTNA) at Yale. (2) Validate and further develop the mathematical models of glutamate and GABA neurotransmission, combining measurements of isotopic labeling in rats with microdialysis measurements of ECF levels of brain glutamate, glutamine, and GABA.
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