DOPAMINE INFLUENCE IN FOREBRAIN REWARD CIRCUITS IN ADULT VOLUNTEERS

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 物质使用障碍（SUD）在美国是一个全国性的健康问题，一些重要的政府举措已经针对SUD的公共健康影响（例如，2010年）。此外，国家吸毒问题研究所将预防和及早发现青少年吸毒成瘾问题作为高度优先领域。然而，药物使用的隐蔽性和早期发病以及某些方法的侵入性（例如，用于研究成人的PET成像限制了对SUD高风险儿童和青少年人群的研究。 大量的研究表明，神经核（NAcc）和眶额皮质、边缘前脑结构以及支配这两个区域的中脑边缘多巴胺能（DA）系统参与了对一系列刺激物（包括食物、性，特别是滥用药物）的享乐反应。这些区域的功能异常与SUD有关。然而，在接触任何成瘾物质之前，对这些神经回路的前驱特征知之甚少。一些证据表明，发病前中脑边缘DA音调的个体间差异有助于物质使用和SUD的责任差异。因此，重要的是要检查可能的神经生物学差异，在这个电路之间的青年在高风险和低风险的SUD，如果可能的话，这样做的背景下，一个动态的研究中，该系统面临着一种物质，有可能滥用。非侵入性功能磁共振成像（fMRI）的发展为研究药物暴露前神经回路的前驱特征提供了理想的机会。这些技术已经为健康青少年的奖赏回路和成瘾者的奖赏回路对滥用药物的反应提供了有用的数据。对SUD高风险与低风险青年的奖励回路的调查似乎是下一个合乎逻辑的步骤。 为了以创新的方式解决这个问题，我们的团队开发了一个原始的预期，冲突和奖励（ACR）功能磁共振成像任务，该任务将评估大脑奖励系统和冲动控制神经回路的激活。在我们将其应用于患者群体的研究之前，证明这项新任务在正常人的脑回路中产生激活是很重要的。因此，我们希望在将其应用于儿童之前，先在健康志愿者中进行试验。为了评估兴奋剂药物与此任务性能的关系，我们建议在安慰剂和兴奋剂药物给药期间测试该任务。 该项目的目标是双重的。首先，是确定修改和缩短的预期、冲突和奖励（ACR）任务是否在最近资助的K12补助金（1 K12：DA 000357 - 06 A1）中被设计用于专门测试ADHD儿童的SUD高风险与低风险 ; P.I.：Ivanov）和Jin Fan博士正在准备的R21提案产生了与原始ACR任务（GCO # 04-1034 PS*）相同的大脑激活模式。其次，是确定K12和R21提案中使用的口服哌甲酯激发的时间和剂量参数是否产生了关于成年志愿者腹侧纹状体（包括NAcc）和眶额皮质多巴胺张力个体间变化的有用数据。拟议研究的初步数据将用于开发K12和R21项目的ACR任务和哌甲酯挑战程序。 假设： 哌醋甲酯将放大安慰剂期间健康成年志愿者ACR任务的任务特异性激活。具体来说，哌甲酯将产生更大的： (1)与安慰剂相比，丘脑和顶叶下小叶和上级小叶的线索相关激活; (2)前扣带回和前额叶皮层的激活比 安慰剂; (3)与安慰剂相比，腹侧纹状体（包括NAcc）在奖励预期期间的激活; (4)与安慰剂相比，在奖励结果中眶额皮层的激活。

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.