DOPAMINE INFLUENCE IN FOREBRAIN REWARD CIRCUITS IN ADULT VOLUNTEERS

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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. Substance use disorders (SUD) present such a national health problem in the U.S that several important government initiatives have targeted the public health impact of SUD (e.g., Healthy People 2010). Further, the NIDA has established prevention and early identification of addiction among adolescents as high priority areas. However, the insidious and early onset of substance use and the invasive nature of some of the methodologies (e.g., PET imaging) used to study adults have limited the investigation of child and adolescent populations at high risk for SUD. A large body of research has implicated the nucleus accumbens (NAcc) and orbital frontal cortex, limbic forebrain structures, and the mesolimbic dopaminergic (DA) system that innervates both regions, in the hedonic response to a range of reinforcers, including food, sex, and particularly drugs of abuse. Abnormal function in these regions has been implicated in SUD. Yet, little is known about the prodromal characteristics of these neural circuits prior to exposure to any addictive substance. Some evidence suggest that inter-individual variation in premorbid mesolimbic DA tone contributes to differences in liability to substance use and SUD. Thus, it is important to examine possible neurobiological differences in this circuitry between youth at high and low risk for SUD, and if possible, to do so in the context of a dynamic study in which the system is confronted with a substance that has potential for abuse. The development of the non-invasive functional magnetic resonance imaging (fMRI) has provided an ideal opportunity to examine the prodromal characteristics of neural circuits prior to drug exposure. These techniques have already provided useful data on reward circuits in healthy adolescents and the response of reward circuits to drugs of abuse in addicted individuals. The investigation of reward circuits in youth at high- versus low-risk for SUD would seem to be the next logical step. In order to approach this problem in an innovative way our team has developed an original Anticipation, Conflict, and Reward (ACR) fMRI task that will assess both the activation of the brain reward system and the neurocircuitry of impulse control. It is important to demonstrate that this new task produces activation in the proposed brain circuitry in normals before we apply it to the study of patient groups. Therefore, we wish to pilot the task in healthy volunteers before applying it to children. In order to assess the relationship of stimulant medication to performance on this task, we propose that the task be tested both during administration of placebo and stimulant medication. The objective of this project is two-fold. First, is to determine whether the modified and shortened Anticipation, Conflict, and Reward (ACR) task that was designed to specifically test children with ADHD at high- versus low-risk for SUD in a recently funded K12 grant (1 K12 : DA000357-06A1 ; P.I.: Ivanov) and a R21 proposal that is being prepared by Dr. Jin Fan yields the same pattern of brain activation as the original ACR task (GCO # 04-1034 PS*). Second, is to determine whether the timing and dosing parameters for the oral methylphenidate challenge to be used in the K12 and R21 proposals yields useful data on the inter-individual variation in dopamine tone in the ventral striatum (including the NAcc) and orbitofrontal cortex of adult volunteers. The pilot data from the proposed study will be used to develop the ACR task and the methylphenidate challenge procedures for the K12 and R21 projects. HYPOTHESES: Methylphenidate will amplify task-specific activation on the ACR task seen during placebo in healthy adult volunteers. Specifically, methylphenidate will produce greater: (1) Cue-related activation of thalamus and inferior and superior parietal lobules than placebo; (2) Conflict-related activation of the anterior cingulate gyrus and the anterior prefrontal cortex than placebo; (3) Activation of ventral striatum (including NAcc) during reward anticipation than placebo; (4) Activation of orbitofrontal cortex during reward outcome than placebo.