fMRI Characterization of Acute Tolerance to Cocaine

描述：（申请人提供） 可卡因对中枢神经系统的作用是复杂的。发展 对可卡因的急性耐受性已经进行了广泛的研究， 在人类和动物研究中都有描述。急性耐受性的特点是 快速，有时完全丧失行为和心血管功效， 长期或反复急性接触可卡因后， 血浆浓度 正如我们使用fMRI在大鼠中收集的初步数据所示， 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，虽然可卡因的推注给药刺激神经元活动， 在多个大脑结构中，长时间的输注会导致渐进性 这一刺激过程的逆转。因此，中心假设是 这个应用程序测试的是，可卡因不仅可以刺激神经系统， 活动，但也终止和/或逆转激活刺激 这种急性失活的过程被抑制， 长期接触可卡因 这些实验有三个目的。首先，它们旨在 建立了在长时间的， 可卡因的持续注入反映了可卡因依赖的过程， 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的急性耐受性， 方面的影响.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的神经元活动的减少 大脑结构由于多巴胺和D1受体的重要性， 无论是在大脑奖赏回路和中枢刺激诱导的机制 通过可卡因，我们将研究多巴胺释放和 可卡因介导的可卡因诱导的脑激活的逆转。我们特别 将突触多巴胺的变化与神经递质的产生和终止联系起来。 激活信号第三，利用大鼠慢性可卡因暴露模型， 哪些老鼠被训练来自我给药，我们将证明， 中脑边缘结构对先前重复暴露于可卡因敏感， 导致激活和急性失活之间的平衡发生变化 在这些区域内。

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.