CELLULAR NEUROBIOLOGY OF ENDORPHINS: ROLE IN DRUG ABUSE

研究的总体目标是 确定内源性阿片肽的分级作用， 对特定的中枢神经系统神经生理 过程，并应用这些机制的知识，以更好地 了解潜在的神经化学底物， 加强滥用阿片类药物的性质。 这些研究将 专注于一个主要的阿片类药物含有独特的电路 边缘皮质网络包含几个位点的前强啡肽- 和脑啡肽原衍生肽。 细胞外和 细胞内记录技术将用于研究 选定的部分已建立的内嗅皮层- 在麻醉的，自由的- 移动和体外制剂。 以这种方式，更精确地 神经药理学知识将获得有关领域 在自我刺激和寻求毒品方面都很重要 行为 这些研究的目的是：1）尝试 以确定是否阿片肽包含在特定的 该系统的电路作为神经递质发挥作用; 2）是否 阿片类药物寻求行为有独特的细胞相关性; 以及3）阿片肽和相关的阿片受体是否 在这个端脑解剖系统中， 这种行为。 说服我的实验目标，在体内研究 将使用阿片类生物碱、阿片肽和 局部应用的特异性阿片受体激动剂（和拮抗剂） 离子电渗疗法和微气动方法，以及通过i. v.或 i. p.全身途径。 体外研究将采用药物灌注 以及局部应用技术。 内源性的作用 将在体内研究阿片类物质在正常突触过程中的作用 并且在体外通过电刺激含有阿片样物质的 途径。 将使用单电极电压钳方法 用于分析更隐蔽的电压依赖性阿片效应。 在对自由活动动物的研究中， 记录将从神经元在电路描述 在清醒的动物中， 参与了一项海洛因自我注射协议 使用此 范例阿片类药物奖励现象的细胞相关性将 在更相关的准备中进行研究。

The overall objectives of the research are directed toward establishing the hierarchical role endogenous opioid peptides may have on specific central nervous system neurophysiological processes, and to apply knowledge of these mechanisms to better understand the potential neurochemical substrates underlying reinforcing properties of opiate drugs of abuse. These studies will be focused on the unique opioid-containing circuits within a major limbic-cortical network containing several loci of prodynorphin- and proenkephalin-derived peptides. Both extracellular and intracellular recording techniques will be employed in investigate selected portions of an established entorhinal cortical- hippocampal-accumbens network in both anesthetized, freely- moving, and in vitro preparations. In this fashion, more precise neuropharmacological knowledge will be gained regarding areas established as important in both self-stimulation and drug-seeking behavior. The objectives of these studies will be to: 1) attempt to determine whether opioid peptides contained within specific circuits of this system function as neurotransmitters; 2) whether there are unique cellular correlates of opiate seeking behavior; and 3) whether the opioid peptides and relevant opiate receptors in this telencenphalic anatomical system are critically involved in this behavior. Persuant to my experimental goals, in vivo studies will employ the use of opiate alkaloids, opioid peptides and specific opiate receptor agonists (and antagonists) applied by local iontophoresis and micropneumatic methods, as well as by i.v. or i.p. systemic routes. In vitro studies will employ drug superfusion as well as local application techniques. The role of endogenous opioids in normal synaptic processes will be investigated in vivo and in vitro by electrical stimulation of opioid-containing pathways. Single-electrode voltage clamp methods will be used for analysis of the more covert voltage-dependent opioid effects. In a major committment to studies in freely moving animals, recordings will be made from neurons in the circuits described above (i.e. hippocampus and nucleus accumbens) in awake animals involved in a heroin self-administration protocol. Using this paradigm the cellular correlates of opiate reward phenomena will be investigated in a more relevant preparation.