OPIOID ACTION IN HIPPOCAMPUS

海马体中的阿片类药物作用

基本信息

批准号：
2120215
负责人：
Carl R. Lupica
金额：
$ 8.81万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-07-01 至 1995-06-30
项目状态：
已结题

项目摘要

Opioids have been demonstrated to have actions on many neurons of the central nervous system. However, their functional role(s) as neurotransmitters or neuromodulators in the mammalian brain remains poorly understood. The following experiments will evaluate the actions of opioids, acting at pharmacologically defined receptor subtypes, as neuromodulators of synaptic transmission in the CA1 region of the hippocampus; an area of the brain possessing low concentrations of endogenous enkephalin peptides but moderate to high concentrations mu and delta opioid receptors. These experiments will utilize extracellular and intracellular electrophysiological techniques to describe the effects of opioids on synaptic transmission and on individual neurons in brain slice preparations. The first set of experiments will focus on determining the source and locations of the substrates upon which mu and delta opioid receptor agonists act to increase synaptic excitability in the CA1 region of the hippocampus. In particular, these experiments will utilize extracellular, whole-cell, and conventional intracellular recordings to determine the mechanisms by which mu and delta opioids act to increase population spikes and intracellular EPSPs recorded from CA1 pyramidal neurons. The second set of experiments will determine the receptor selectivity of opioid actions on CAI pyramidal cells, the relative locations of mu and delta opioid receptors in the hippocampal slice, and the actions of mu and delta opioids on subpopulations of CAl interneurons. The third set of experiments will utilize various strategies to determine the possible cellular mechanisms by which mu and delta opioids act upon hippocampal interneurons, and whether this action is exercised upon interneuron nerve terminals or somata. We will do this, first, by attempting to block enkephalin effects with potassium channel antagonists while recording from pyramidal neurons or interneurons. Next, we will examine the effects of selective mu and delta opioids on hippocampal interneuron voltage-sensitive calcium responses. To more directly assess the site of opioid action, we will measure GABA release from hippocampal slices while superfusing selective mu or delta enkephalins in the presence and absence of tetrodotoxin, and we will characterize these selective enkephalin effects on interneurons and pyramidal neurons, simultaneously, using paired intracellular recordings. The investigations described in this grant proposal should improve our understanding of the specific receptor subtypes that opioids act upon, the cellular mechanisms mediating these responses, the roles opioids may play as neuromodulators in the hippocampus, and the diversity of cellular, mechanisms by which opioids control hippocampal output. In addition, since limbic structures like the hippocampus have been shown to participate in normal and abnormal behavioral states such as learning, epilepsy, and emotional behavior, these studies may yield new insights as to the interaction between opioids and these phenomena.

已证明阿片类药物对许多神经元采取了行动中枢神经系统。但是，它们的功能作用是哺乳动物大脑中的神经递质或神经调节剂理解不佳。以下实验将评估动作阿片类药物，作用于药理学定义的受体亚型在CA1区域的突触传播的神经调节剂海马；大脑的区域，具有低浓度的内源性脑脑肽，但中度至高浓度MU和三角洲阿片类药物受体。这些实验将利用细胞外和细胞内电生理技术来描述关于突触传播和大脑切片中各个神经元的阿片类药物准备。第一组实验将集中于确定 MU和Delta阿片类药物的底物的来源和位置受体激动剂作用于增加CA1区域的突触兴奋性海马。特别是，这些实验将使用细胞外，全细胞和常规细胞内记录确定MU和Delta阿片类药物提高的机制从CA1锥体记录的人口峰值和细胞内EPSP 神经元。第二组实验将确定受体阿片类药物对CAI锥体细胞的选择性，相对 Mu和Delta阿片受体的位置在海马切片中，以及 MU和Delta阿片类药物对CAL亚群的作用中间神经元。第三组实验将利用各种确定MU和MU和三角洲阿片类药物对海马中间神经元作用，以及该动作是否在间神经神经终端或索马塔上行使。我们会做的首先，这是通过尝试用钾阻塞ankephalin效应的从锥体神经元或中间神经元。接下来，我们将研究选择性MU和海马间神经元间电压敏感钙的三角洲阿片类药物回答。要更直接评估阿片类药物措施的地点，我们将测量从海马切片中释放的GABA，而超级选择性选择性在存在和不存在四毒素的情况下，mu或delta enkephalins和我们将表征这些选择性ankephalin对中间神经元的影响和锥体神经元同时使用成对的细胞内录音。本赠款提案中描述的调查应提高我们对阿片类药物的特定受体亚型的理解采取行动，介导这些反应的细胞机制，即作用阿片类药物可能会在海马中作为神经调节剂和多样性发挥作用阿片类药物控制海马输出的细胞，机制。在此外，由于已经显示出像海马这样的边缘结构参与正常和异常行为状态，例如学习，癫痫和情感行为，这些研究可能会产生新的见解阿片类药物与这些现象之间的相互作用。