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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02AA013430-04
Application #
6889259
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Witt, Ellen
Project Start
2002-05-01
Project End
2007-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
4
Fiscal Year
2005
Total Cost
$99,392
Indirect Cost
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Jiang, Lihong; Mason, Graeme F; Rothman, Douglas L et al. (2011) Cortical substrate oxidation during hyperketonemia in the fasted anesthetized rat in vivo. J Cereb Blood Flow Metab 31:2313-23
Valentine, Gerald W; Mason, Graeme F; Gomez, Rosane et al. (2011) The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [(1)H]-MRS. Psychiatry Res 191:122-7
Patel, Anant B; de Graaf, Robin A; Rothman, Douglas L et al. (2010) Evaluation of cerebral acetate transport and metabolic rates in the rat brain in vivo using 1H-[13C]-NMR. J Cereb Blood Flow Metab 30:1200-13
Boumezbeur, Fawzi; Mason, Graeme F; de Graaf, Robin A et al. (2010) Altered brain mitochondrial metabolism in healthy aging as assessed by in vivo magnetic resonance spectroscopy. J Cereb Blood Flow Metab 30:211-21
van Eijsden, Pieter; Behar, Kevin L; Mason, Graeme F et al. (2010) In vivo neurochemical profiling of rat brain by 1H-[13C] NMR spectroscopy: cerebral energetics and glutamatergic/GABAergic neurotransmission. J Neurochem 112:24-33
Boumezbeur, Fawzi; Petersen, Kitt F; Cline, Gary W et al. (2010) The contribution of blood lactate to brain energy metabolism in humans measured by dynamic 13C nuclear magnetic resonance spectroscopy. J Neurosci 30:13983-91
Jiang, Lihong; Herzog, Raimund I; Mason, Graeme F et al. (2009) Recurrent antecedent hypoglycemia alters neuronal oxidative metabolism in vivo. Diabetes 58:1266-74
Befroy, Douglas E; Petersen, Kitt Falk; Dufour, Sylvie et al. (2008) Increased substrate oxidation and mitochondrial uncoupling in skeletal muscle of endurance-trained individuals. Proc Natl Acad Sci U S A 105:16701-6
Mason, Graeme F; Petersen, Kitt Falk; de Graaf, Robin A et al. (2007) Measurements of the anaplerotic rate in the human cerebral cortex using 13C magnetic resonance spectroscopy and [1-13C] and [2-13C] glucose. J Neurochem 100:73-86
Mason, Graeme F; Petrakis, Ismene L; de Graaf, Robin A et al. (2006) Cortical gamma-aminobutyric acid levels and the recovery from ethanol dependence: preliminary evidence of modification by cigarette smoking. Biol Psychiatry 59:85-93

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