We hypothesize that decreased GABAergic modulation of dopamine (DA) activity in alcoholics results in abnormal function of brain regions receiving DAergic efferents and in accentuated responses to stimuli that increase DA which enhance the reinforcing properties of ethanol and favor the emergence of compulsive alcohol administration. In this proposal we will use PET to evaluate the DA system in alcoholics in two separate studies; one to evaluate the DA system at rest and the other during pharmacological activation. We hypothesize that at rest DA abnormalities in alcoholics will not be observed in the DA cells per se but on postsynaptic elements and on projection areas and that during DA stimulation responses will be accentuated. To evaluate the DA system at rest we will use a multiple tracer approach to assess in the same subject different elements involved in the propagation of the DA signal; DA terminals (using [11C]raclopride, a DA D2 receptor ligand) and the activity of regions connected with the DA system (using 2-deoxy 2-[18F]fluoro-D-glucose ([18F]FDG)) during early and late alcohol withdrawal. To evaluate the DA system during pharmacological activation we will measure the response to methylphenidate (MP), a drug that increases synaptic DA by inhibiting DA transporters. The responsivity of the DA system will be measured indirectly using PET to measure the effects of MP on [11C]raclopride binding and on brain glucose metabolism. Because DA competes with [11C]raclopride for the D2 receptors, this strategy enables us to assess relative changes in DA induced by MP, while the metabolic measure will allow us to assess the response of the brain to changes in DA concentration. Our working hypotheses are that detoxified alcoholics: (1) At rest have decreases in D2 receptor availability but not in DA transporters which persist after protracted alcohol withdrawal. Changes in D2 receptors will be associated with decreased activity in frontal metabolism. (2) Have accentuated responses to stimuli that increase DA concentration (which will show as increased metabolic and DA changes with MP). The proposed study will enable to determine if the DA system is abnormal in alcoholics; the functional consequences of these abnormalities and the effects of detoxification. This knowledge will provide an essential context for understanding the neurochemical mechanisms underlying alcoholism.
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