fMRI Characterization of Acute Tolerance to Cocaine

可卡因急性耐受性的功能磁共振成像表征

• 批准号: 6799747
• 负责人: JOHN J. A. MAROTA
• 金额: $ 17.75万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-25 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6799747
• 关键词: autoradiography; biological models; brain electrical activity; chemical stimulation; cocaine; corpus striatum; dopamine; drug habituation; drug tolerance; functional magnetic resonance imaging; injection /infusion; laboratory rat; limbic system; neurochemistry; neurophysiology; neurotoxicology; neurotransmitter transport; prefrontal lobe /cortex; self medication; somesthetic sensory cortex

DESCRIPTION: (provided by the applicant) The action of cocaine on the central nervous system is complex. Development of acute tolerance to cocaine has been investigated extensively and has been described in both human and animal studies. Acute tolerance is characterized by rapid and sometimes complete loss of behavioral and cardiovascular efficacy of cocaine after prolonged or repeated acute exposure despite a stable, elevated plasma concentration. As indicated by both our preliminary data collected in rats using fMRI to elucidate regions of local neural stimulation and supported by behavioral data in humans, while bolus administration of cocaine stimulates neuronal activity in multiple brain structures, a prolonged infusion results in a progressive reversal of this stimulation process. Therefore, the central hypothesis to be tested by this application is that cocaine acts not only to stimulate neural activity in brain but also to terminate and/or reverse activation in stimulated structures and that this process of acute inactivation is suppressed in the chronically cocaine-exposed state. The purpose of these experiments are three fold. Firstly, they are designed to establish that the reversal of fMRI signal observed during a prolonged, constant infusion of cocaine reflects a cocaine-dependent process exerted upon structures activated by cocaine. Furthermore, we will demonstrate that rapid repeated administration of cocaine produces acute tolerance to the stimulating effects. Secondly, we will demonstrate that the reversal of fMRI activation signal accurately reflects a decrease in neuronal activity in cocaine activated brain structures. Because of the importance of dopamine and the D1 receptor both in brain reward circuitry and the mechanism of central stimulation induced by cocaine, we will investigate the relationship between dopamine release and cocaine-mediated reversal of cocaine induced brain activation. Specifically, we will correlate changes in synaptic dopamine with generation and termination of activation signal. Thirdly, using a rat model of chronic exposure to cocaine in which rats are trained to self-administer drug, we will demonstrate that mesolimbic structures are sensitive to repeated prior exposure to cocaine which results to a shift in the balance between activation and acute inactivation within these regions.

描述：（由申请人提供） 可卡因对中枢神经系统的作用很复杂。发展 对可卡因的急性耐受性已得到广泛研究并已得到证实 在人类和动物研究中都有描述。急性耐受的特点是 行为和心血管功效迅速且有时完全丧失 尽管可卡因稳定、升高，但长期或反复急性接触后 血浆浓度。 正如我们使用功能磁共振成像在大鼠中收集的初步数据所示 阐明局部神经刺激区域并得到行为数据的支持 在人类中，推注可卡因会刺激神经元活动 在多个大脑结构中，长时间的输注会导致进行性的 这种刺激过程的逆转。因此，中心假设为 通过该应用程序测试的是可卡因不仅可以刺激神经 大脑的活动，而且还可以终止和/或逆转受刺激的激活 结构，并且这种急性失活过程在 长期接触可卡因的状态。 这些实验的目的有三个。首先，它们的设计目的是 确定在长时间、 持续输注可卡因反映了可卡因依赖性过程 可卡因激活的结构。此外，我们将证明快速 重复服用可卡因会产生对刺激物的急性耐受性 影响。其次，我们将证明功能磁共振成像激活的逆转 信号准确地反映了可卡因激活后神经元活动的减少 大脑结构。由于多巴胺和 D1 受体的重要性 在大脑奖赏回路和中枢刺激诱导机制中 通过可卡因，我们将研究多巴胺释放与 可卡因介导的可卡因诱导的大脑激活的逆转。具体来说，我们 将突触多巴胺的变化与突触多巴胺的产生和终止相关联 激活信号。第三，使用长期接触可卡因的大鼠模型 哪些老鼠经过训练可以自我给药，我们将证明 中脑边缘结构对重复接触可卡因很敏感， 导致激活和急性失活之间平衡的转变 在这些区域内。