During CTNA-1 we used high resolution Positron Emission Tomography (PET) and the D2 receptor radiotracer [11 C]raclopride to study two parameters of DA transmission: D2 receptor density and amphetamine-induced intrasynaptic DA release in the ventral striatum in currently abstinent alcoholic subjects and healthy controls and found: 1) decreased D2 receptors in all striatal subregions in recently detoxified alcohol dependent patients compared to controls, 2) a relationship between the decrease in D2 receptors and the severity of daily drinking in all striatal subregions, and 3) a regionally selective decrease in amphetamine induced DA release in the ventral striatum in alcohol dependent subjects compared to controls. Low DA transmission in the ventral striatum and low striatal D2 receptors availability may both be predisposing factors to developing alcohol dependence or could alternatively reflect the effects of long term use on the reward circuitry in the brain. We now propose now to examine dopamine transmission with PET and [11 C]raclopride and the amphetamine challenge in +FH versus -FH matched healthy volunteers. The striatal [11 CJraclopride binding potential (BP) and the specific to nonspecific equilibrium partition coefficient (V3"""""""") will be measured and compared between the two groups (SA1). Amphetamine-induced reduction in [11 C]raclopride V3"""""""" will be compared between the two groups (SA2). In the high risk group we predict that decreased D2 will be related to severity of drinking measured by the amount of daily consumption. This will not be the case for -FH subjects indicating that low D2 is a marker for vulnerability rather than toxicity (SAS).This study builds on our current findings and extends the study of dopaminergic transmission to a high risk population. Confirming these alterations in at risk subjects prior to the onset of alcoholism will be a first step in understanding the biological basis of vulnerability. This could lead to developing a biomarker for identifying at risk subjects and possibly designing specific therapeutic strategies for prevention.
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