CANNABINOID EFFECTS ON MEMBRANES AND THEIR CONSTITUENTS

Delta-9-Tetrahydrocannabinol（THC）是主要的行为学上 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。 它和其他大麻素是高度 可影响流动性或脂质排序的亲脂性化合物 生物膜。 这使我们产生了一个假设， 膜是大麻素的识别位点， 对THC的耐受性导致物理性质的变化，或 这些膜的脂质组成。 另外我们有 提出四氢大麻酚改变了神经细胞膜的功能 包括它们作为离子的半渗透屏障的能力 并保持跨膜电位差。 的 将进行以下实验来测试这些 假设 膜流动性的荧光研究 极化技术将继续进行。 大麻素对 突触质膜（SPM）从六个脑区将是 使用两个探头进行比较; DPH主要监测 内部酰基链尾区和TMA-DPH， 膜表面附近的运动。 的影响 THC慢性治疗对SPM流动性的影响 大脑区域也将被检查， SPM脂质，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 也将通过测量芘 激基缔合物形成 内的横向运动的变化 膜可能参与大麻素对 酶系统如受体刺激的腺苷酸环化酶。 四氢大麻酚减少突触体积累 四苯基磷（TPP），表明突触体是 被THC去极化 我们对这一现象的研究 扩大到包括检查其他大麻素的影响， 以及是否出现耐受性。 机制研究 THC诱导的膜电位变化，如使用 TPP的积累将使用药物来研究，以修改 离子穿过膜的运输。 此外， 将测量大麻素对突触体离子通量的影响 直接. 建议的研究完成后， 为了更全面地了解膜扰动在 大麻素的神经化学作用和在发育过程中 宽容。

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.