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：（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被广泛研究，并且已经 在人类和动物研究中描述。急性公差的特征是 行为和心血管功效的快速，有时完全失去 可卡因长时间或重复急性暴露后，尽管稳定，升高 血浆浓度。 正如我们使用fMRI在大鼠中收集的两个初步数据所示 阐明局部神经刺激的区域，并得到行为数据的支持 在人类中，可卡因的推注刺激神经元活性 在多个大脑结构中，长时间的输注导致进行性 逆转这种刺激过程。因此，中心假设为 通过此应用测试的是可卡因不仅起作用刺激神经 大脑的活性，但也终止和/或刺激的激活 结构和这种急性失活的过程在 长期暴露于可卡因状态。 这些实验的目的是三倍。首先，它们被设计为 确定在延长，延长的，fMRI信号的逆转 可卡因的恒定输注反映了可卡因依赖性过程 可卡因激活的结构。此外，我们将证明这一点 重复给药可卡因会产生刺激性的急性耐受性 效果。其次，我们将证明fMRI激活的逆转 信号准确地反映了可卡因激活的神经元活性的降低 大脑结构。由于多巴胺和D1受体的重要性 在大脑奖励电路和中央刺激的机制中 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脑激活。具体来说，我们 将将突触多巴胺的变化与产生和终止 激活信号。第三，使用长期暴露于可卡因的大鼠模型 哪些大鼠接受了自我管理药物的训练，我们将证明 中唇结构对重复暴露于可卡因的重复敏感，而可卡因 结果转移了激活和急性失活之间的平衡 在这些地区。