OPIOID ACTION IN HIPPOCAMPUS

海马体中的阿片类药物作用

• 批准号: 3214367
• 负责人: Carl R. Lupica
• 金额: $ 8.55万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/3214367
• 关键词: biological signal transduction; calcium channel; dendrites; electrophysiology; endogenous opioid; enkephalins; experimental brain lesion; gamma aminobutyrate; hippocampus; inhibitor /antagonist; interneurons; laboratory rat; membrane channels; neural transmission; neuropharmacology; neurotransmitters; opioid receptor; pyramidal cells; stimulant /agonist; synapses; voltage /patch clamp

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.

阿片类药物已被证明对大脑皮层的许多神经元有作用。 中枢神经系统 然而，他们的职能作用， 哺乳动物大脑中的神经递质或神经调质 不太了解。 以下实验将评估这些操作 阿片类药物，作用于特定的受体亚型，如 突触传递的神经调质在CA 1区的 海马体;大脑的一个区域，具有低浓度的 内源性脑啡肽，但中到高浓度μ和 δ阿片受体 这些实验将利用细胞外和 细胞内电生理技术来描述的影响， 阿片类药物对突触传递和脑切片中单个神经元的作用 准备工作 第一组实验将侧重于确定 μ和δ阿片样物质的来源和位置 受体激动剂的作用是增加CA 1区的突触兴奋性 海马体的一部分。 特别是，这些实验将利用 细胞外、全细胞和常规细胞内记录， 确定mu和delta阿片类药物作用于增加 从CA 1锥体细胞记录的群体尖峰和细胞内EPSP 神经元 第二组实验将确定受体 阿片类药物对CAI锥体细胞作用的选择性， 海马切片中μ和δ阿片受体的位置，以及 μ和δ阿片类药物对CA 1亚群的作用 中间神经元 第三组实验将利用各种 策略，以确定可能的细胞机制， δ阿片类药物作用于海马中间神经元，这种作用是否 在中间神经元神经末梢或胞体上行使。 我们将尽 首先，通过尝试用钾来阻断脑啡肽的作用， 通道拮抗剂，同时记录锥体神经元或 中间神经元 接下来，我们将研究选择性mu和 δ阿片类药物对海马中间神经元电压敏感性钙离子的影响 应答 为了更直接地评估阿片类药物的作用部位，我们将 测量海马脑片在选择性灌流时GABA的释放 在存在和不存在河豚毒素的情况下，μ或δ脑啡肽，和 我们将描述这些选择性脑啡肽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. 本资助提案中描述的调查应 提高我们对阿片类药物 调节这些反应的细胞机制， 阿片类药物可能在海马体中起神经调质的作用， 阿片类药物控制海马输出的细胞机制。 在 此外，由于海马体等边缘结构已被证明 参与正常和异常的行为状态，如学习， 癫痫和情绪行为，这些研究可能会产生新的见解， 阿片类药物和这些现象之间的相互作用。