Effects of Cocaine Self-administration: fMRI of Awake Non-human Primates

可卡因自我给药的影响：清醒非人类灵长类动物的功能磁共振成像

• 批准号: 7296158
• 负责人: JOHN J. A. MAROTA
• 金额: $ 24.65万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7296158
• 关键词: Abstinence; Acute; Animal Model; Animals; Behavior; Blood Vessels; Brain; Brain Mapping; Cerebrovascular Circulation; Cerebrum; Chronic; Cocaine; Confined Spaces; Contrast Media; Core-Binding Factor; Coupling; Cues; Data; Development; Drug Exposure; Environment; Eye; Functional Magnetic Resonance Imaging; Goals; Hand; Human; Image; Imaging Techniques; Infusion procedures; Intravenous; Invasive; Investigation; Juice; Long-Term Effects; Longitudinal Studies; Macaca; Macaca mulatta; Magnetic Resonance Imaging; Maps; Metabolism; Modeling; Monkeys; Motion; Nucleus Accumbens; Ocular Fixation; Operant Conditioning; Pattern; Perfusion; Pharmaceutical Preparations; Photic Stimulation; Physiology; Purpose; Resolution; Saccades; Self Administration; Self-Administered; Signal Transduction; Techniques; Technology; Testing; Training; Visual; Visual Cortex; Week; Weight; Withdrawal; awake; cingulate cortex; drug abstinence; experience; human subject; model development; neuroadaptation; nonhuman primate; response; sample fixation

DESCRIPTION (provided by applicant): Functional magnetic resonance imaging (fMRI) is an ideal technique for longitudinal studies to investigate long-term effects of chronic cocaine use because non-invasive imaging permits direct comparison of the acute response to drug in the same subject when drug naive, after chronic cocaine exposure, and in withdrawal. While ethical concerns preclude these studies in humans, they can be performed in animal models. Therefore, the purpose of this proposal is to use a non-human primate model to map the response to acute administration of cocaine with the high spatial and temporal resolution permitted by contrast agent- enhanced fMRI to elucidate the longitudinal adaptations of drug exposure and withdrawal. The rhesus monkey (Macaca mulatta) is an ideal candidate for these imaging studies because these animals can be trained to self-administer cocaine and neural adaptations have been identified after long-term cocaine exposure. More importantly, however, we have imaged a robust region-specific pattern of brain activation in the awake, behaving monkey produced by cocaine. Therefore, the goal of this proposal is to develop an awake, behaving non-human primate model of cocaine self-administration that is applicable for use in an MRI scanner. Accordingly, drug self-administration must be accomplished by awake macaques in a confined space, and with a minimum of motion. We propose to apply our extensive experience at training this species for awake, behaving imaging to the development of cocaine self-administration using eye-fixation as an operant conditioning technique. We will train macaques to make visual saccade and eye fixation on visual cues to signal self-administration and compare results of training with traditional lever pressing strategy modified for use in the MRI environment. We will employ these drug exposed monkeys to investigate longitudinal effects of long-term cocaine exposure and withdrawal on regional cerebral blood flow and cerebral vascular physiology critical to the formation of fMRI signal. We anticipate that these studies will elucidate how cocaine exposure and withdrawal influence acute response to drug anlteration in baseline perfusion. These studies will also inform us concerning adaptations of cerebral vasculature and aid in interpretation of fMRI data acquired in human subjects.

描述（由申请人提供）：功能磁共振成像（fMRI）是纵向研究的理想技术，用于研究长期使用可卡因的长期影响，因为非侵入性成像允许直接比较同一受试者在未曾用药、长期接触可卡因后和戒断时对药物的急性反应。虽然伦理问题阻碍了这些在人类身上的研究，但它们可以在动物模型中进行。因此，本提案的目的是使用非人类灵长类动物模型来绘制对可卡因急性给药的反应，并具有造影剂增强功能磁共振成像允许的高空间和时间分辨率，以阐明药物暴露和戒断的纵向适应。恒河猴（Macaca mulatta）是这些成像研究的理想候选者，因为这些动物可以被训练来自我施用可卡因，并且在长期接触可卡因后已经确定了神经适应。然而，更重要的是，我们在可卡因产生的清醒、有行为能力的猴子中观察到了一种强大的区域特异性大脑激活模式。因此，该提案的目标是开发一种清醒的、有行为能力的非人类灵长类动物可卡因自我给药模型，适用于 MRI 扫描仪。因此，自我给药必须由清醒的猕猴在有限的空间内完成，并且运动最少。我们建议将我们在训练该物种进行清醒、行为成像方面的丰富经验应用于使用眼睛固定作为操作条件反射技术来开发可卡因自我管理。我们将训练猕猴进行视觉扫视和眼睛注视视觉线索，以发出自我管理信号，并将训练结果与改良后用于 MRI 环境的传统杠杆按压策略进行比较。我们将利用这些暴露于药物的猴子来研究长期可卡因暴露和戒断对区域脑血流和脑血管生理学的纵向影响，这对功能磁共振成像信号的形成至关重要。我们预计这些研究将阐明可卡因暴露和戒断如何影响基线灌注中药物改变的急性反应。这些研究还将告诉我们有关脑血管系统适应性的信息，并帮助解释在人类受试者中获得的功能磁共振成像数据。