PRECIPITATED CANNABINOID WITHDRAWAL

描述：（申请人摘要） 大麻是美国最广泛滥用的药物之一，其使用是 在年轻人中的增长。 在科学家和一般 在人口中，大麻通常被视为相对无害的药物 低成瘾倾向。 这种观点的一个原因是缺乏 突然停止长期大量使用后出现的戒断症状。 这种轻微影响的一个原因可能是长（36小时）的半衰期。 δ 9-四氢大麻酚（δ 9-THC），主要的精神活性物质 大麻的成分 大脑可能会在长时间的 药物的代谢和排泄。 在最近完成的一项研究中，我们 发现注射新开发的大麻素拮抗剂SR 14716 A 在长期接受δ 9-THC治疗的大鼠中， 以极度活跃为特征的突然戒断综合征， 行为紊乱，以及某些非常不寻常的症状，如快速 前爪的类似震颤的内侧-外侧运动。 我们建议检查行为，药理学和生化 大麻素戒断症状 在第一个系列的 实验中我们提出了关于效应的剂量要求的问题， 必要的暴露时间，以及可能出现的最大症状 在高剂量和长时间暴露于δ 9-THC后诱发。 在第二 一组实验，我们检查了介导沉淀的解剖部位， 使用三种方法的大麻素戒断： 即刻早期基因c-for诱导的突然戒断， 不连续微量注射拮抗剂以产生效果， 神经递质的细胞外水平的变化（通过体内测定） 微透析），发生在沉淀撤退。 在第三个系列中 在实验中，我们将研究沉淀提取对 使用电生理学技术研究大脑中的神经元活动。 这些 实验可能提供关于大麻素性质的新信息 戒断，并建议可能的治疗戒断症状， 在人类停止长期大量使用药物后发生。

DESCRIPTION: (Applicant's Abstract) Marijuana is among the most widely abused drugs in the U.S. and its use is on the increase among the young. Among scientists and in the general population, marijuana is frequently viewed as a relatively innocuous drug with low addiction liability. One reason for this view is the paucity of withdrawal symptoms that occur upon abrupt cessation of chronic heavy use. One reason for such mild effects may be the long (36 hour) half life of delta 9-tetrahydrocannabinol (delta 9-THC), the main psychoactive constituent of marijuana. The brain may adapt during the long period of metabolism and excretion of the drug. In a recently completed study, we found that injections of the newly-developed cannabinoid antagonist SR14716A in rats chronically treated with delta 9-THC elicited a dramatic precipitated withdrawal syndrome characterized by extreme hyperactivity, disorganization of behavior, and certain very unusual symptoms such as rapid tremor-like medial-lateral movements of the forepaws. We propose to examine the behavioral, pharmacological and biochemical features of precipitated cannabinoid withdrawal. In the first series of experiments we address questions about the dose-requirements for the effect, the necessary durations of exposure, and the maximal syndrome that can be evoked following high doses and long exposures to delta 9-THC. In a second set of experiments we examine the anatomical sites that mediate precipitated cannabinoid withdrawal using three approaches: the distribution of the immediate-early gene c-for induced by precipitated withdrawal, the ability of discrete microinjections of the antagonist to produce the effect, and changes in extracellular levels of neurotransmitters (measured by in vivo microdialysis) that occur during precipitated withdrawal. In a third series of experiments we will investigate the effect of precipitated withdrawal on neuronal activity in the brain using electrophysiological techniques. These experiments may provide new information about the nature of cannabinoid withdrawal, and suggest possible treatments of the withdrawal symptoms that occur in humans following cessation of chronic heavy use of the drug.