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可能 对特定的中枢神经系统有神经生理学作用 进程，并将这些机制的知识应用于更好地 了解潜在的神经化学底物 增强滥用鸦片类药物的特性。这些研究将 将重点放在主要药物中独特的阿片类药物环路 包含几个前强啡肽基因的边缘-皮质网络- 和脑啡肽原衍生的多肽。胞外和 细胞内记录技术将被用于研究 已建立的内嗅皮层的精选部分- 海马-伏隔神经网络在麻醉下，自由- 可移动的和体外的制剂。以这种方式，更精确地 将获得有关领域的神经药理学知识 在自我刺激和寻求毒品方面都很重要 行为。这些研究的目标是：1)尝试 以确定在特定情况下是否包含阿片肽 这个系统的回路起神经递质的作用；2)是否 阿片类药物寻找行为有独特的细胞关联； 3)阿片肽及相关阿片受体 在这一端脑解剖系统中， 这种行为。对我的实验目标有说服力，体内研究 将使用阿片类生物碱、阿片肽和 局部应用特异性阿片受体激动剂(和拮抗剂) 离子导入和微气动法，以及静脉注射。或 IP地址。系统性路线。体外研究将采用药物灌流 以及本地应用技术。内源性的作用 正常突触过程中的阿片类药物将在体内进行研究 并在体外通过电刺激含阿片类药物 小路。将使用单电极电压钳位法 用于分析更隐蔽的电压依赖阿片类药物效应。 在一个主要致力于自由活动动物研究的项目中， 录音将从所描述的电路中的神经元进行 清醒动物的上述脑区(即海马体和伏隔核) 参与了海洛因自我给药方案。使用这个 阿片类奖赏现象的细胞关联将 将在更相关的准备工作中进行调查。

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.