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: 7605351
• 负责人: ILYAN IVANOV
• 金额: $ 1.46万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7605351
• 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.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 物质使用障碍(SUD)在美国是一个如此严重的全国性健康问题，以至于政府的几个重要举措都瞄准了SUD对公共健康的影响(例如，2010年健康人)。此外，NIDA已将预防和及早识别青少年成瘾定为高度优先领域。然而，药物使用的隐蔽性和早发性，以及用于研究成人的一些方法(例如，PET成像)的侵袭性，限制了对儿童和青少年人群的调查，这些人群是SUD的高危人群。 大量研究表明，伏隔核(NAcc)和眼眶额叶皮质、边缘前脑结构以及支配这两个区域的中脑边缘多巴胺(DA)系统参与了对一系列强化剂的享乐反应，包括食物、性，特别是滥用药物。这些区域的功能异常被认为与SUD有关。然而，在接触任何令人上瘾的物质之前，人们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基调的个体间差异导致了对药物使用和SUD的易感性的差异。因此，重要的是要检查患有SUD的高风险和低风险青年之间在这一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，在该研究中，系统面临一种可能被滥用的物质。无创功能磁共振成像(FMRI)的发展为在药物暴露前检测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关于健康青少年奖赏回路的有用数据，以及成瘾个人奖赏回路对药物滥用的反应。对高风险与低风险的青少年进行奖励回路的调查似乎是下一个合乎逻辑的步骤。 为了以一种创新的方式处理这个问题，我们的团队开发了一个原始的预期、冲突和奖励(ACR)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电路。在我们将这项新任务应用于患者组的研究之前，重要的是要证明这项新任务在正常人中产生了拟议的大脑回路的激活。因此，我们希望先在健康志愿者中试验这项任务，然后再将其应用于儿童。为了评估刺激性药物与这项任务的表现的关系，我们建议在服用安慰剂和刺激性药物的过程中对这项任务进行测试。 这个项目的目标有两个。首先，确定最近资助的K12拨款(1 K12：DA000357-06A1；P.I.：Ivanov)和金凡博士正在准备的R21建议中，专门针对高风险和低风险多动症儿童设计的修改和缩短的预期、冲突和奖励(ACR)任务是否产生与原始ACR任务(GCO#04-1034PS*)相同的脑激活模式。第二，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能产生关于成年志愿者腹侧纹状体(包括NAcc)和眶前皮质多巴胺张力的个体间差异的有用数据。拟议研究的试点数据将用于为K12和R21项目制定ACR任务和哌醋甲酯挑战程序。 假设： 哌醋甲酯将放大在安慰剂期间在健康成年志愿者的ACR任务中看到的任务特异性激活。具体地说，哌醋甲酯将产生更多： (1)与线索相关的丘脑、顶下小叶和顶上小叶的激活作用强于安慰剂； (2)与冲突相关的前扣带回和前额叶皮质的激活程度高于安慰剂组； (3)与安慰剂相比，奖赏预期对腹侧纹状体(包括NAcc)的激活作用更强； (4)在奖赏结果中，眶前叶皮质的激活程度高于安慰剂。