Craving can be reliably elicited in the laboratory with humans, is associated with alcohol dependence, and is a primary target of biological and behavioral interventions. Activation of mesolimbic and mesocortical structures has been implicated in the development and expression of craving for alcohol and other drugs. Dopamine (D4) receptors are localized to these same structures and our preliminary work has suggested that a D4 antagonist moderates the experience of craving after exposure to alcohol. Our preliminary research has also suggested that the DRD4 VNTR polymorphism is a genetic factor that influences alcohol-elicited craving.
The aims of this competitive continuation are to expand and improve this line of research by incorporating imaging technology (BOLD fMRI). Specifically, the aims are to determine whether exposure to alcohol increases activation of mesolimbic and prefrontal brain structures using BOLD fMRI, to determine whether this activation is correlated with the subjective experience of craving, to determine whether the DRD4 VNTR polymorphism influences this activation, and to determine whether a medication targeting dopamine receptors attenuates this activation. Two separate studies are proposed to meet the specific aims of the proposed research. In the first study, the hemodynamic activation of specific brain structures will be compared after exposure to an alcoholic stimulus versus exposure to an isocaloric control stimulus. To test the influence of the DRD4 VNTR, individuals with the risk allele will be compared to individuals without the risk allele in terms of their hemodynamic activation and subjective craving. It is expected that exposure to the alcoholic stimulus will increase subjective craving as well as increase activation of the brain structures of interest, and it is expected that the individuals with the 7 repeat allele will demonstrate the greatest craving and activation. In the second study, subjects will be randomly assigned to pretreatinent with olanzapine (5 mg) or an active control prior to exposure to the alcoholic and control stimuli. It is expected that olanzapine will attenuate subjective craving and hemodynamic activation associated with the alcoholic stimuli and that this effect will be significantly more pronounced among individuals with the risk allele. The proposed work should establish the influence of alcohol cues on mesocortical and mesolimbic structures and elucidate important biological mechanisms that moderate the expression of craving and loss of control over drinking. The successful completion of the proposed research is also expected to advance our understanding of the role of genetic factors in the development of craving and loss of control drinking. ? ?
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