GABA/A receptors are a major target for ethanol in the brain. Chronic ethanol administration alters many aspects of GABA function in animals. Similarly, post-mortem human studies documented reductions in the density of binding to the benzodiazepine (BZ) site of the GABA/A receptor. Until recently, clinical studies were limited to GABA measurements in blood and cerebrospinal fluid (CSF). These studies suggest that GABA levels are normal in alcohol dependent patients, decline among the first month of sobriety, and recover within 6 months of their last drink. Recent neuroimaging advances now make it possible to measure aspects of GABA function in the human brain in vivo. Our group has advanced the quantification of regional GABA levels in the human cerebral cortex using 1H-magnetic resonance spectroscopy (1H-NMR). Using this technique, our pilot data indicate that GABA levels in the occipital cortex are reduced in male early onset alcoholic patients sober for 1 month relative to a matched group of healthy subjects. We have also contributed to the development of a single photon emission computerized tomography computerized tomography (SPECT) technique, employing [123I]-iomazenil, for assessing a measure, Vt, a measure related to the density of binding to BZ receptors. Employing this technique, we found reductions in frontal and occipital cortex BZ receptor binding from a similar group of recently detoxified alcoholic patients. The principal objective of this proposal is to provide the first longitudinal description of the recovery of brain GABA systems with sobriety in alcohol dependent alcoholic patients. Patients (n=50) would be assessed using both 1H-NMR and SPECT at 3 timepoints in relation to their last drink (,7 days, 1 month, 6 months). The first two assessments (,7 days, 1 month) would be completed as inpatients to insure sobriety. Results from patients would be compared to a matched healthy control group (n=25) studied at similar intervals. Both 1H-NMR and SPECT data would be segmented into components arising from gray matter, white matter, and CSF, providing a correction for gray matter atrophy. Further, metabolites measured simultaneously with GABA during 1H- NMR imaging, such as N-acetylaspartate and creatine, will provide additional information about cortical neuronal viability. Thus, this proposal would provide a multi-dimensional evaluation of GABA disturbances that may help to clarify both the pharmacologic and neurotoxic consequences of alcoholism.
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