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。发展中的 对可卡因的急性耐受性进行了广泛的调查，并已被 在人类和动物研究中都有描述。急性耐受性的特点是 行为和心血管功效迅速丧失，有时甚至完全丧失。 长期或反复急性暴露后的可卡因，尽管 血浆浓度。 正如我们使用功能磁共振成像在大鼠身上收集的初步数据所表明的那样 阐明局部神经刺激的区域，并由行为数据支持 在人类中，虽然团注可卡因刺激神经元活动 在多个大脑结构中，长时间的灌流会导致进行性的 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的作用不仅仅是刺激神经 大脑中的活动还能终止和/或逆转受刺激的激活 结构，并且这一急性失活过程在 长期接触可卡因的状态。 这些实验的目的有三个方面。首先，它们的设计目的是 证实了在长时间的， 持续输注可卡因反映了对可卡因依赖的过程 被可卡因激活的结构。此外，我们将展示快速 反复服用可卡因会对刺激产生强烈的耐受性 效果。其次，我们将证明fMRI激活的逆转 SIGNAL准确反映了可卡因激活后神经元活性的下降 大脑结构。因为多巴胺和d1受体的重要性 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逆转可卡因诱导的脑激活。具体来说，我们 将突触多巴胺的变化与脑电活动的产生和终止联系起来 激活信号。第三，使用慢性暴露于可卡因的大鼠模型 哪些大鼠被训练成自我给药，我们将证明 中脑边缘结构对反复接触可卡因敏感， 结果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.