DOPAMINE INFLUENCE IN FOREBRAIN REWARD CIRCUITS IN ADULT VOLUNTEERS

多巴胺对成年志愿者前脑奖励回路的影响

• 批准号: 7718166
• 负责人: ILYAN IVANOV
• 金额: $ 0.91万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7718166
• 关键词: Adolescent; Adult; Alcohol or Other Drugs use; Anterior; Area; Attention deficit hyperactivity disorder; Brain; Characteristics; Child; Computer Retrieval of Information on Scientific Projects Database; Conflict (Psychology); Cues; Data; Development; Dopamine; Dose; Drug Exposure; Early identification; Exposure to; Food; Functional Magnetic Resonance Imaging; Funding; Government; Grant; Health; Healthy People 2010; Individual; Inferior; Institution; Invasive; Investigation; Lobule; Methodology; Methylphenidate; National Institute of Drug Abuse; Nature; Neurobiology; Nucleus Accumbens; Oral; Outcome; Parietal; Patients; Pattern; Performance; Pharmaceutical Preparations; Placebos; Population; Positron-Emission Tomography; Prefrontal Cortex; Prevention; Procedures; Prosencephalon; Public Health; Range; Research; Research Personnel; Resources; Rewards; Risk; SECTM1 gene; Source; Structure; Substance Use Disorder; System; Techniques; Testing; Thalamic structure; Time; United States National Institutes of Health; Variant; Ventral Striatum; Youth; addiction; cingulate gyrus; design; drug of abuse; early onset substance use; frontal lobe; healthy volunteer; hedonic; innovation; neural circuit; reinforcer; response; sex; volunteer

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 药物滥用障碍 (SUD) 在美国是一个全国性的健康问题，以至于政府的几项重要举措都针对了 SUD 的公共卫生影响（例如，Healthy People 2010）。此外，国家药物滥用管理局已将青少年成瘾的预防和早期识别确定为高度优先领域。然而，物质使用的隐匿性和早期发病性以及用于研究成人的一些方法（例如 PET 成像）的侵入性限制了对 SUD 高风险儿童和青少年人群的调查。 大量研究表明，伏隔核（NAcc）和眶额皮质、边缘前脑结构以及支配这两个区域的中边缘多巴胺能（DA）系统与一系列强化物（包括食物、性，特别是滥用药物）的享乐反应有关。这些区域的功能异常与 SUD 有关。然而，人们对这些神经回路在接触任何成瘾物质之前的前驱特征知之甚少。一些证据表明，病前中脑边缘 DA 音调的个体间差异导致了物质使用和 SUD 倾向的差异。因此，重要的是要检查 SUD 高风险和低风险青少年之间该回路中可能存在的神经生物学差异，如果可能的话，在动态研究的背景下这样做，其中系统面临可能被滥用的物质。非侵入性功能磁共振成像（fMRI）的发展为检查药物暴露前神经回路的前驱特征提供了理想的机会。这些技术已经提供了有关健康青少年的奖赏回路以及成瘾者的奖赏回路对滥用药物的反应的有用数据。对 SUD 高风险和低风险青少年的奖励回路进行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种原创的预期、冲突和奖励 (ACR) fMRI 任务，该任务将评估大脑奖励系统的激活和冲动控制的神经回路。在我们将其应用于患者群体的研究之前，重要的是要证明这项新任务会在正常人的大脑回路中产生激活。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点。为了评估兴奋剂药物与该任务表现的关系，我们建议在服用安慰剂和兴奋剂药物期间对该任务进行测试。 该项目的目标有两个。首先，是确定在最近资助的 K12 拨款（1 K12：DA000357-06A1；PI：Ivanov）和 Jin Fan 博士正在准备的 R21 提案中，修改和缩短的预期、冲突和奖励 (ACR) 任务是否会产生与原始 ACR 任务相同的大脑激活模式，该任务旨在专门测试高风险与低风险 ADHD 儿童的 SUD 情况（GCO# 04-1034 PS*)。其次，是确定 K12 和 R21 提案中使用的口服哌醋甲酯挑战的时间和剂量参数是否可以产生关于成年志愿者腹侧纹状体（包括 NAcc）和眶额皮质中多巴胺张力的个体间变化的有用数据。拟议研究的试点数据将用于开发 K12 和 R21 项目的 ACR 任务和哌醋甲酯挑战程序。 假设： 哌醋甲酯会放大健康成年志愿者在安慰剂期间观察到的 ACR 任务的特定任务激活。具体来说，哌醋甲酯会产生更多： (1) 与安慰剂相比，丘脑以及顶下小叶和顶上小叶的提示相关激活； (2) 与安慰剂相比，前扣带回和前额叶皮质的冲突相关激活； (3) 奖励预期期间腹侧纹状体（包括 NAcc）的激活程度高于安慰剂； (4) 与安慰剂相比，奖励结果期间眶额皮质的激活。