CANNABINOID MODULATION OF SYNAPTIC TRANSMISSION

大麻中的精神活性成分Delta9-四氢大麻酚 (THC)，会在人类中产生快感。THC激活大麻素受体 调节离子通道和第二信使系统。为了链接到 从分子研究到行为实验，有必要了解 这些药物对突触网络的影响。大麻仿制药被禁止 谷氨酸能突触传递但不影响抑制物 培养的大鼠海马神经元之间的神经传递。解剖学 有证据表明，大麻素受体位于伽玛- 含有纹状体向实质投射的氨基丁酸(GABA) 黑。建议进行实验，以确定 拟大麻药物对体外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 大麻素受体激活是否抑制GABA能 神经传递。纹状体和黑质的神经元 在原代组织培养中共同生长，并记录突触活动。 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 由细胞外刺激突触前神经元引起的 电极。大麻素在纹状体黑质的作用机制 共同秃鹫将被确定。解剖数据，以前的工作 海马区突触和大麻素对离子通道的中介作用， 所有这些都表明大麻素受体参与突触前反应 抑制力。突触前作用部位预测大麻素 受体激动剂会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 直接应用激动剂引起的情感反应。这个 大麻素介导的纹状体黑质共培养效应的药理学研究 将被描述为。待评估的药理特性包括 激动剂的效力，部分激动剂的内在活性和 对激动剂的脱敏率。这些研究将加强我们的 现在对大麻类物质影响突触传递的了解。对……的影响 抑制系统以前没有被检查过。如果 大麻素的药理作用是特定的 大脑区域也许可以将它们的滥用潜力与 它们在临床上有用的属性。

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.