CANNABINOID MODULATION OF SYNAPTIC TRANSMISSION

大麻素对突触传递的调节

• 批准号: 6338715
• 负责人: Stanley A Thayer
• 金额: $ 40.85万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-22 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6338715
• 关键词: cannabinoid receptor; cannabinoids; corpus striatum; electrophysiology; gamma aminobutyrate; inhibitor /antagonist; laboratory rat; neural transmission; neurons; neuropharmacology; neurophysiology; receptor expression; substantia nigra; tissue /cell culture; voltage /patch clamp

The psychoactive ingredient in marijuana, delta9-tetrahydrocannabinol (THC), produces euphoria in humans. THC activates cannabinoid receptors that modulate ion channels and second messenger systems. In order to link molecular studies to behavioral experiments, it is essential to know the effects of these drugs on synaptic networks. Cannabimimetics inhibited glutamatergic synaptic transmission but failed to affect inhibitor neurotransmission between cultured rat hippocampal neurons. Anatomical evidence suggests that cannabinoid receptors are located on gamma- aminobutyric acid (GABA) containing striatal projections to the substantia nigra. Experiments are proposed to determine the effects of the cannabimimetic drugs on synaptic transmission between cells cultured from the rat striatum and substantia nigra. The first objective is to determine whether activation of cannabinoid receptors inhibit GABAergic neurotransmission. Neurons from striatum and substantia nigra will be grown together in primary tissue culture and synaptic activity recorded. The whole-cell configuration of the patch clamp technique will be used to record inhibitory and excitatory postsynaptic currents (IPSCs & EPSCs) evoked by stimulation of the presynaptic neuron with an extracellular electrode. The mechanism of cannabinoid-mediated effects in striatonigral co-vultures will be determined. Anatomical data, previous work with hippocampal synapses, and cannabinoid-mediated effects on ion channels, all suggest that cannabinoid receptors participate in presynaptic inhibition. A presynaptic site of action predicts that cannabinoid receptor agonists will increase the coefficient of variation of evoked postsynaptic currents, increase the number of synaptic failures, and not affect responses elicited by direct application of agonist. The pharmacology of cannabinoid-mediated effects in striatonigral co-cultures will be characterized. Pharmacologic properties to be evaluated include the potency of agonists, the intrinsic activity of partial agonists and the rate of desensitization to agonists. These studies will enhance our understanding of now cannabinoids affect synaptic transmission. Effects on inhibitory systems have not previously been examined. If the pharmacological effects of the cannabinoids are specific to particular brain regions it might be possible to separate their abuse potential from their clinically useful attributes.

大麻中的精神活性成分，δ 9-四氢大麻酚 (THC)在人体内产生欣快感。THC激活大麻素受体 调节离子通道和第二信使系统。为联动 从分子研究到行为实验，了解 这些药物对突触网络的影响。抑制类大麻素 突触传递，但未能影响抑制剂 培养的大鼠海马神经元之间的神经传递。解剖 有证据表明大麻素受体位于γ- 含氨基丁酸（GABA）的纹状体投射到 黑鬼实验提出，以确定的影响， 大麻类药物对培养细胞间突触传递的影响 大鼠纹状体和黑质。第一个目标是确定 大麻素受体的激活是否抑制GABA能 神经传递纹状体和黑质的神经元将被 在原代组织培养中一起生长并记录突触活性。 膜片钳技术的全细胞配置将用于 记录抑制性和兴奋性突触后电流（IPSC和EPSC） 由突触前神经元的细胞外 电极上大麻素介导纹状体黑质效应的机制 将确定共同秃鹰。解剖数据，以前的工作与 海马突触，以及大麻素介导的对离子通道的影响， 都表明大麻素受体参与了突触前神经元的 抑制作用突触前作用部位预示着大麻素 受体激动剂将增加诱发的变异系数， 突触后电流，增加突触失败的数量，而不是 影响直接应用激动剂引起的反应。的 纹状体黑质共培养物中大麻素介导作用的药理学 将被定性。待评价的药理学特性包括 激动剂的效力，部分激动剂的内在活性， 对激动剂的脱敏率。这些研究将加强我们的 大麻素对突触传递的影响。影响 抑制系统以前没有被研究过。如果 大麻素的药理学作用是特定的， 大脑区域，也许可以将他们的滥用潜力与 它们的临床有用属性。