OPIOID ACTION IN HIPPOCAMPUS

阿片类药物已被证明对许多神经元有作用。 中枢神经系统。然而，他们的职能作用(S) 哺乳动物大脑中的神经递质或神经调质 人们对此知之甚少。以下实验将评估这些操作 阿片类药物，作用于药理学定义的受体亚型，如 大鼠脑内CA1区突触传递的神经调节剂 海马体；大脑的一个区域，含有低浓度的 内源性脑啡肽，但中至高浓度MU和 三角洲阿片受体。这些实验将利用细胞外和 细胞内电生理技术描述的影响 阿片类药物对突触传递和脑片单个神经元的影响 准备工作。第一组实验将集中于确定 Mu和Delta阿片类药物底物的来源和位置 受体激动剂增强CA1区突触兴奋性 海马体的。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阿片类药物增加的机制 CA1锥体记录的群体峰和细胞内EPSP 神经元。第二组实验将确定受体 阿片类药物作用对CA1区锥体细胞的选择性 Mu和Delta阿片受体在海马片中的位置，以及 Mu和Delta类阿片对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可能的细胞机制的策略 Delta阿片类药物作用于海马区中间神经元，以及这种作用是否 作用于神经元间神经末梢或胞体。我们会做的 首先，通过尝试用钾来阻断脑啡肽效应 通道拮抗剂，同时记录来自锥体神经元或 中间神经元。接下来，我们将考察选择性MU和 Delta阿片类药物对海马神经元间电压敏感钙的影响 回应。为了更直接地评估阿片类药物的作用部位，我们将 选择性灌流时测量海马片GABA的释放 在河豚毒素存在和不存在的情况下，Mu或Delta脑啡肽，以及 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。在这项拨款提案中描述的调查应该 提高我们对阿片类药物特定受体亚型的理解 作用于这些反应的细胞机制，作用 阿片类药物可能在海马体中发挥神经调节剂的作用，并且其多样性 阿片类药物控制海马区输出的机制。在……里面 此外，由于海马体等边缘结构已被证明 参与正常和不正常的行为状态，如学习， 癫痫和情绪行为，这些研究可能会产生新的见解，如 阿片类药物与这些现象之间的相互作用。

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.