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CANNABINOID EFFECTS ON MEMBRANES AND THEIR CONSTITUENTS

大麻素对膜及其成分的影响

基本信息

批准号：
3208336
负责人：
ALAN S BLOOM
金额：
$ 14.09万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
1985
资助国家：
美国
起止时间：
1985-07-01 至 1992-06-30
项目状态：
已结题

项目摘要

Delta-9-Tetrahydrocannabinol (THC) is the principal behaviorally active compound in marijuana, a substance that is used by millions of young Americans. It and other cannabinoids are highly lipophilic compounds that can affect the fluidity or lipid ordering of biological membranes. This has led us to the hypothesis that membranes are recognition sites for the cannabinoids and that tolerance to THC results in changes in the physical properties or lipid composition of these membranes. In addition, we have proposed that THC alters the functioning of neuronal membranes including their ability to act as a semi-permeable barrier to ions and maintain a transmembrane potential difference. The following experiments will be carried out to test these hypotheses. Studies of membrane fluidity using fluorescence polarization techniques will be continued. Cannabinoid effects on synapitc plasma membranes (SPM) from six brain areas will be compared using two probes; DPH which primarily monitors the interior acyl chain tail region and TMA-DPH which monitors movement near the surface of the membrane. The effects of chronic treatment with THC on the fluidity of SPM from the six brain areas will also be examined as will the composition of the SPM lipids in order to determine if tolerance occurs at the membrane level. The effects of cannabinoids on lateral motion within membranes will also be determined by measuring pyrene excimer formation. Changes in lateral motion within the membrane may be involved in the effects of the cannabinoids on enzyme systems such as receptor-stimulated adenylate cyclase. THC decreases the synaptosomal accumulation of tetraphenylphosphonium (TPP) indicating that synaptosomes are depolarized by THC. Our studies of this phenomenon will be expanded to include examining the effects of other cannabinoids and whether or not tolerance occurs. Mechanisms underlying the THC induced change in membrane potential as measured using TPP accumulation will be studied using drugs to modify the transport of ions across membranes. In addition, the effects of the cannabinoids on synaptosomal ion flux will be measured directly. The completion of the proposed studies should enable us to more fully understand the role of membrane perturbation in the neurochemical effects of the cannabinoids and in the development of tolerance.

三角洲-9-四氢大麻酚(THC)是主要的行为大麻中的活性化合物，一种被数百万人使用的物质年轻的美国人。它和其他大麻素的含量很高会影响流动性或脂类有序性的亲脂化合物生物膜。这使我们得出这样的假设：膜是大麻素的识别部位，对THC的耐受性会导致物理性质或这些膜的脂类成分。此外，我们还有提出THC改变神经细胞膜的功能包括它们作为离子的半透屏障的能力并保持跨膜电位差。这个将进行以下实验来验证这些假设。用荧光法研究膜的流动性将继续使用偏振技术。大麻素对人体的影响来自六个脑区的突触质膜(SPM)将使用两个探针进行比较；DPH主要监控内酰链尾区和TMA-DPH的监控靠近膜表面的运动。的影响 THC慢性疗法对六味子SPM流动性的影响还将检查大脑区域以及大脑以确定耐受性是否发生在膜水平。大麻素对侧向运动的影响膜内的含量也将通过测量芘来确定准分子队形。内侧向运动的变化膜可能参与了大麻素对酶系统，如受体刺激的腺苷环化酶。 THC减少突触小体蓄积四苯基膦(TPP)表明突触体是被THC去极化。我们对这一现象的研究将是扩大到包括检查其他大麻素的影响以及是否出现了容忍。潜在的机制 THC诱导的膜电位变化将研究TPP的积累情况，使用药物修改离子的跨膜运输。此外，将测量大麻素对突触体离子通量的影响直接去吧。建议的研究完成后，我们应可为了更全面地了解膜摄动在细胞周期中的作用大麻素类化合物的神经化学效应及其发育过程宽容的一面。