CHRONIC MORPHINE--REGULATION OF ION CONDUCTANCES

长期使用阿片类药物导致对阿片类药物的耐受性和依赖性。 药一种被广泛接受的耐受性细胞基础机制 是受体与效应物的解偶联， 需要占用以获得给定响应。这一机制 已被提议用于阿片类药物对钙电流的抑制，腺苷酸 环化酶和递质的释放以及钾的激活 水流依赖性是由一系列异常反应定义的 除去药物后。依赖的一些迹象和症状可以 在药物去除后不久进行测量，而其他人，如 恢复药物寻求行为和渴望，持续数月或 年依赖性的表达被认为是由 发展适应性变化，以应对持续的 激动剂的存在。在细胞水平上，第一个适应性反应 是腺苷酸环化酶的上调。的 细胞和突触生理学中的适应由这种 然而，上调在很大程度上尚未被探索。有两 这一提案的目标。第一个是定义导致 蓝斑阿片样物质激活与终止 （LC）.随着对受体和受体之间的事件的更好理解， 效应器（钾和钙通道）负责的处理器 急性脱敏的症状。第二个目标是 研究腹段多巴胺细胞活性的调节 慢性吗啡治疗后的VTA。本研究将侧重于 cAMP级联反应对脑片GABA突触电位的影响。 突触调节改变的发生和持续时间都是由 cAMP级联将在慢性吗啡后测定， 治疗这些核的选择是基于广泛的知识 阿片类药物在细胞、生物化学和行为水平上的作用。 LC已被用作急性和慢性阿片样物质的模型系统 行动VTA被认为是重要的动机方面 滥用药物细胞调节改变的知识 急性和长期吗啡戒断期间的突触水平 将有助于开发更有效的协议， 预防吸毒复吸。

Chronic use of opioids results in tolerance to and dependance on the drug. One widely accepted mechanism for the cellular basis of tolerance is an uncoupling of receptor from effector so that greater receptor occupancy is required to obtain a given response. This mechanism has been proposed for opioid inhibition for calcium currents, adenylyl cyclase and transmitter release and the activation of potassium currents. Dependance is defined by a series of abnormal responses following removal of drug. Some signs and symptoms of dependance can be measured soon after removal of the drug, whereas others, such as the return to drug seeking behaviors and craving, persist for months or years. The expression of dependance is thought to result from the development of adaptive changes that occur in response to the continued presence of agonist. At the cellular level, the first adaptive response to be recognized was an upregulation of adenylyl cyclase. The adaptations in cellular and synaptic physiology mediated by this upregulation have, however, been largely unexplored. There are two goals of this proposal. The first is to define the events that lead to the activation and termination of opioid actions in locus coeruleus (LC). With a better understanding of the events between receptor and effector (potassium and calcium channels) the processors responsible for acute desensitization can be identified. The second goal is to study the regulation of dopamine cell activity in the ventral-segmental area (VTA) after chronic morphine treatment. This study will focus on the effects of the cAMP cascade on GABA synaptic potentials in slices. Both the onset and duration of altered synaptic regulation mediated by the cAMP cascade will be determined following chronic morphine treatment. The choice of these nuclei is based on extensive knowledge of opioid action at the cellular, biochemical and behavioral levels. The LC has been used as a model system for acute and chronic opioid actions. The VTA is thought to be important in the motivational aspects of drug abuse. Knowledge of alterations in regulation at the cellular and synaptic levels during acute and prolonged withdrawal from morphine will help in the development of more efficient protocols for the prevention of relapse to drug use.