CHRONIC MORPHINE--REGULATION OF ION CONDUCTANCES

长期使用阿片类药物会导致对阿片类药物的耐受和依赖 毒品。一种被广泛接受的耐受细胞基础机制 是受体与效应器的解偶联，因此更大的受体 需要占用才能获得给定的响应。这一机制具有 已被提出用于抑制钙电流的阿片类药物，腺苷 环化酶和递质释放与钾的激活 洋流。依赖性是由一系列异常响应定义的 在戒毒之后。一些依赖的体征和症状可以 在药物去除后不久被测量，而其他的，如 重拾寻毒行为和渴求，持续数月或 好几年了。依附关系的表达被认为是由 发展适应变化，以应对持续的 存在激动剂。在细胞水平上，第一个适应性反应 要被识别的是腺酰环化酶的上调。这个 由此介导的细胞和突触生理学的适应 然而，上调在很大程度上还没有被探索过。有两个 这项提案的目标。第一个是定义导致 蓝斑内阿片类活动的激活和终止 (LC)。更好地了解受体和受体之间的事件 效应器(钾和钙通道)处理机负责 可以确定为急性脱敏。第二个目标是 腹段多巴胺细胞活动调节的研究 慢性吗啡治疗后面积(VTA)。这项研究将集中在 CAMP级联对脑片GABA突触电位的影响。 突触调节改变的开始和持续时间均由 CAMP的级联将在慢性吗啡后确定 治疗。这些原子核的选择是基于广泛的知识。 阿片类药物在细胞、生化和行为水平上的作用。 LC已被用作急性和慢性阿片类药物的模型系统 行为。VTA被认为在激励方面很重要 滥用药物。对细胞内调节变化的了解 在急性和长期戒断吗啡过程中的突触水平 将有助于开发更有效的协议 预防吸毒复发。

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.