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）是一种理想的纵向研究技术，用于调查慢性可卡因使用的长期影响，因为非侵入性成像可以直接比较同一受试者在初次吸毒、慢性可卡因暴露后和戒断时对药物的急性反应。虽然出于伦理考虑，这些研究不能在人类身上进行，但它们可以在动物模型上进行。因此，本研究的目的是利用非人类灵长类动物模型，利用对比剂增强功能磁共振成像（fMRI）所允许的高空间和时间分辨率，绘制急性给药可卡因的反应图，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，因为这些动物可以训练自己服用可卡因，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，我们已经在可卡因的作用下，在清醒的猴子大脑中形成了一个强大的特定区域的激活模式。因此，这项提议的目标是开发一种清醒的，行为的非人类灵长类动物的可卡因自我给药模型，适用于核磁共振扫描仪。因此，药物的自我给药必须由清醒的猕猴在一个有限的空间内完成，并以最小的运动。我们建议将我们在训练这一物种的清醒行为成像方面的丰富经验应用于可卡因自我给药的发展，将眼睛固定作为一种操作性条件反射技术。我们将训练猕猴对视觉线索进行视觉扫视和眼睛注视，以表明自我给药，并将训练结果与传统的杠杆按压策略进行比较。我们将利用这些药物暴露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，这些脑血流和脑血管生理学对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注时药物干预的急性反应。这些研究也将告诉我们有关脑血管系统的适应性，并有助于解释人类受试者获得的功能磁共振成像数据。

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.