CANNABINOID EFFECTS ON MEMBRANES AND THEIR CONSTITUENTS

大麻素对膜及其成分的影响

• 批准号: 3208335
• 负责人: ALAN S BLOOM
• 金额: $ 12.82万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-07-01 至 1991-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3208335
• 关键词: adenylate cyclase; amphetamines; cannabinoids; cell membrane; chemical structure function; drug adverse effect; drug metabolism; hydropathy; laboratory rabbit; laboratory rat; marijuana abuse; membrane lipids; membrane permeability; membrane potentials; membrane proteins; membrane structure; neurochemistry; neurons; neuropharmacology; phenytoin; pyrenes; synaptosomes

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.

delta-9-四氢大麻酚（THC）在行为上是主要行为 大麻中的活性化合物，该物质被数百万 年轻的美国人。 它和其他大麻素很高 可影响流动性或脂质排序的亲脂化合物 生物膜。 这使我们提出了这样的假设 膜是大麻素的识别地点， 对THC的耐受性会导致物理特性的变化或 这些膜的脂质组成。 此外，我们还有 提出THC改变了神经元膜的功能 包括它们充当离子半渗透障碍的能力 并保持跨膜电位差。 这 将进行以下实验以测试这些 假设。 使用荧光研究膜流动性 极化技术将继续。 大麻素的影响 来自六个大脑区域的Synapitc质膜（SPM）将是 使用两个探针进行比较； DPH主要监视 内部酰基链尾区和TMA-DPH，可监视 在膜表面附近运动。 效果 用THC慢性治疗SPM的六个 大脑区域也将被检查 SPM脂质以确定是否发生公差 膜水平。 大麻素对横向运动的影响 膜内也将通过测量pyrene来确定 准分子形成。 横向运动的变化 膜可能参与大麻素对 酶系统，例如受体刺激的腺苷酸环化酶。 THC降低了突触体的积累 四苯基膦（TPP），表明突触体是 通过THC去极化。 我们对这一现象的研究将是 扩展以包括检查其他大麻素的影响 以及是否发生公差。 基础的机制 THC诱导了使用使用的膜电位变化 将使用药物研究TPP积累以修改 离子跨膜的运输。 另外， 将测量突触体离子通量上的大麻素 直接地。 拟议研究的完成应使我们 更充分地了解膜扰动在 大麻素和发育中的神经化学作用 容忍。