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: 7134143
• 负责人: JOHN J. A. MAROTA
• 金额: $ 21.46万
• 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 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7134143
• 关键词: Primates; cocaine; human; wakefulness

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(申请人提供)：功能磁共振成像(FMRI)是研究慢性可卡因使用的长期影响的纵向研究的理想技术，因为非侵入性成像允许直接比较同一受试者在药物未用时、慢性可卡因暴露后和戒断时对药物的急性反应。虽然出于伦理方面的考虑，这些研究无法在人类身上进行，但它们可以在动物模型中进行。因此，本研究的目的是使用非人类灵长类动物模型，以造影剂增强功能磁共振成像所允许的高空间和时间分辨率来绘制急性注射可卡因的反应图，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，因为这些动物可以接受自我注射可卡因的训练，而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，我们已经在由可卡因产生的清醒的、行为正常的猴子中拍摄到了一种强大的特定区域大脑激活模式。因此，这项提议的目标是开发一种清醒的、行为正常的可卡因自我给药的非人类灵长类动物模型，该模型适用于MRI扫描仪。因此，药物的自我给药必须通过在有限的空间中清醒的猕猴来完成，并且必须以最小的运动完成。我们建议将我们在训练这一物种清醒、行为成像方面的丰富经验应用于发展可卡因自我给药，使用眼睛固定作为一种操作性条件反射技术。我们将训练猕猴在视觉线索上进行视觉扫视和眼睛注视，以发出自我管理的信号，并将训练结果与传统的杠杆按压策略进行比较，以便在磁共振环境中使用。我们将利用这些暴露于药物的猴子来研究长期暴露和戒断可卡因对局部脑血流和脑血管生理的纵向影响，这些脑血管生理对fMRI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流中药物改变的急性反应。这些研究还将向我们提供有关脑血管适应的信息，并有助于解释在人类受试者中获得的功能磁共振数据。