This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The Neuro-chemical mechanisms by which ethanol induces self-administration and dependence are poorly understood. Using PET we have documented decreased brain GABA activity in alcoholics. While decreased GABA function could explain the use of alcohol as a way of increasing inhibitory neurotransmission it does not explain the addictive behavior per se. We hypothesize that the loss of control and the compulsive administration of alcohol in the alcoholic is secondary to decreased GABA modulation of the dopamine system, which results in abnormal function of brain regions modulated by DA and in accentuated responses to stimuli that increase DA. This makes alcohol more reinforcing but it also enhances the aversive quality of stressful stimuli. We also hypothesize that abnormal DA activity leads to dysfunction of orbit frontal regions, which we postulate is one of the mechanisms leading to the loss of control and the drive to compulsively administer alcohol. In alcoholic subjects we have documented reductions in DA D2 receptors, which are mostly located in the GABA cells, however no studies have been done to measure the function of the DA cells in alcoholics. DA release in brain, which we measure with PET and [11C] raclopride, provides an indirect measure of the function of the DA cells.
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