PRECIPITATED CANNABINOID WITHDRAWAL

描述：(申请人摘要) 大麻是美国滥用最广泛的毒品之一，它的用途是 在年轻人中的增长。在科学家中和在一般情况下 在人口中，大麻经常被视为一种相对无害的毒品 成瘾倾向低。这种观点的一个原因是缺乏 突然停止长期大量使用时出现的戒断症状。 如此温和的影响的一个原因可能是较长的(36小时)半衰期 三角洲9-四氢大麻酚(Delta 9-THC)，主要精神活性物质 大麻的成分。大脑可能会在长时间的 药物的新陈代谢和排泄。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SR14716A 在长期服用Delta 9-THC的大鼠中，引起了戏剧性的 以极度多动为特征的急性期戒断综合征， 行为紊乱，以及某些非常不寻常的症状，如快速 前爪震颤样的内侧-外侧运动。 我们建议检查行为，药理和生化 大麻素催促戒断的特点。在第一个系列中 我们的实验解决了关于剂量-效果要求的问题， 必要的暴露时间，以及可能出现的最大症状 在高剂量和长期接触Delta9-THC后诱发。一秒钟内 一组实验，我们检查了调解沉淀的解剖部位 使用三种方法戒除大麻素：大麻的分布 即刻-早期基因c-for诱导的催促戒断，能力 对拮抗剂进行离散的微量注射以产生这种效果，以及 细胞外神经递质水平的变化(通过活体测量 微透析)，在催促戒断过程中发生。在第三季中 在实验中，我们将研究催促戒断对 使用电生理学技术在大脑中的神经元活动。这些 实验可能提供有关大麻素性质的新信息 戒断，并对戒断症状提出可能的治疗建议 在停止长期大量使用该药物后，在人类身上发生。

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.