The economic and social burdens on society that are a direct result of substance dependence are enormous. As such, determining the neural mechanisms of phenotypes that confer risk for the development of this disorder is crucial for advancing scientifically-based prevention and treatment strategies. Associations between variation in cognitive processes and substance dependence liability have been demonstrated, and the corticostriatal dopamine system has been implicated in these relationships. Further, recent evidence has demonstrated an important role of the dopamine D2 receptor in controlling aspects of impulsivity, cognitive control and drug abuse. Therefore, the D2 receptor may represent a mechanistic link between cognitive control processes and risk for the development of substance dependence. Because the D2 receptor can exist in two conformational states - a state in which dopamine displays high affinity for the receptor and has greater functional activity, and a state in which dopamine displays less affinity for the receptor and is less functionally active - determining whether variation in receptor availability detected with standard neuroimaging techniques (i.e. PET) reflect variation in receptor state (high versus low) is critical to understanding the relationship between cognitive processes and risk for substance dependence. Because we have found an association between a naturally occurring variation of trait impulsivity and D2 radioligand binding in vivo, this proposal will attempt to examine this question using behavioral pharmacological techniques to probe D2-like receptor states (Aim 1) and using this information to examine a possible neural mechanism by which variation in receptor state may influence global brain function (Aim 2). These results will provide evidence for a mechanism by which variation within a biological system can influence higher- order processes that have direct relevance to substance dependence. The advancements in the characterization of the link between the D2 receptor system and impulsivity offered in this proposal will provide an important step in understanding how manipulations of the dopamine system may be utilized to enhance cognitive control and therefore mitigate risk for the development of substance dependence.
