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

描述（由申请人提供）：功能性磁共振成像（fMRI）是研究长期使用可卡因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初治、慢性可卡因暴露后和戒断时对药物的急性反应。虽然伦理问题排除了在人类中进行这些研究，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灵长类动物模型，以造影剂增强的fMRI所允许的高空间和时间分辨率来绘制对可卡因急性给药的反应，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，我们已经在清醒的猴子中描绘了一个强大的特定区域的大脑激活模式，可卡因产生了行为。因此，本提案的目标是开发一种清醒的、行为正常的非人灵长类动物可卡因自我给药模型，该模型适用于MRI扫描仪。因此，药物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。我们建议运用我们丰富的经验，在训练这个物种清醒，行为成像可卡因自我管理的发展，使用眼睛固定作为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，以发出自我管理信号，并将训练结果与修改后用于MRI环境的传统杠杆按压策略进行比较。我们将使用这些药物暴露的猴子调查长期可卡因暴露和戒断对局部脑血流量和脑血管生理功能磁共振成像信号的形成至关重要的纵向影响。我们预期这些研究将阐明可卡因暴露和戒断如何影响基线灌注中对药物替代的急性反应。这些研究也将告知我们有关脑血管系统的适应性，并有助于解释在人类受试者中获得的fMRI数据。

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.