ADRENORECEPTOR FUNCTION AFTER CHRONIC OPIATE TREATMENT

长期阿片类药物治疗后的肾上腺素受体功能

• 批准号: 3207846
• 负责人: HYLAN C MOISES
• 金额: $ 16.06万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-06-01 至 1993-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3207846
• 关键词: alpha adrenergic receptor; beta adrenergic receptor; brain mapping; cerebral cortex; drug addiction; drug interactions; drug withdrawal; electrophysiology; hippocampus; laboratory rat; morphine; neuropharmacology; norepinephrine; opiate alkaloid; radiotracer; receptor sensitivity

The primary goal of this research is to characterize the effects of long-term opiate administration on central adrenoceptor function, with an overall effort aimed at clarifying the role of noradrenergic mechanisms in the mediation of the physiological and behavioral changes associated with chronic opiate abuse. This work is predicated on previous demonstrations of alterations in presynaptic alpha2 and postsynaptic beta-adrenoceptor function in hippocampus in chronic morphine-treated animals. The specific aims are to delineate events at the cellular and molecular level which underlie these receptor adaptations and to determine whether similar alterations in adrenoceptor function can be generalized to the amygdala. Much of the work will involve intracellular recording from hippocampal pyramidal cells (HPCs) and amygdala neurons in brain slice preparations during bath superfusion of test substances in known concentration. Changes in postsynaptic beta-adrenoceptor function will be assessed by comparing the concentration-effect relationship of agonists for inhibiting calcium-activated potassium responses in HPCs in slices from control and chronic morphine-treated rats. Similar measurements will be taken during administration of agents which act beyond the beta-adrenoceptor to effect closure of the underlying conductance to reveal alterations in post-receptor events. Assessments will be made of changes in postsynaptic alpha2-adrenoceptor function by comparing the hyperpolarizing effect of alpha2-adrenergic agonists in neurons recorded in amygdala slices form control and experimental animals. In a second aspect of the work, chronic opiate effects on presynaptic alpha2-adrenoceptor function will be examine by comparing the inhibitory effects of agonists on electrically-evoked release of 3H-NE in hippocampal and amygdala slices in vitro and on synaptic release of NE in the dentate gyrus in situ. These measurements of alpha2 and beta-adrenoceptor-mediated physiological action will be conducted at multiple time points after chronic treatment with morphine or the kappa-agonist U50,488H to examine the relationship between alterations in presynaptic and postsynaptic adrenoceptor function and the emergence or expression of opiate dependence. The proposed research, in contributing to our understanding of the adaptations in central noradrenergic function that accompany prolonged opiate exposure, might help to promote effective new strategies in the treatment of narcotic dependency in man.

这项研究的主要目标是表征效果 中央肾上腺素受体的长期鸦片给药 功能，旨在阐明的总体努力 生理介导的去肾上腺素能机制 和与慢性鸦片滥用相关的行为变化。 这项工作基于先前的改动演示 在突触前的α2和突触后β-肾上腺素受体功能中 在慢性吗啡治疗的动物中的海马中。 具体 目的是在细胞和分子水平上描述事件 这些受体适应的基础并确定 是否可以使用类似的adrenoceptor函数更改 概括为杏仁核。 大部分工作将涉及 海马锥体细胞（HPC）的细胞内记录 浴期间的脑切片制剂中的杏仁核神经元 已知浓度中测试物质的超级灌注。 更改 在突触后β-肾上腺肾上腺肾上腺素函数中，将通过 比较激动剂的浓度效应关系 在HPC中抑制钙激活的钾反应 从对照和慢性吗啡处理的大鼠中切片。 相似的 在管理代理期间将进行测量 超越β-肾上腺素受体来实现关闭 揭示受伤后变化的基本电导 事件。 评估突触后的变化 通过比较超极化，α2-肾上腺素受体功能 记录在记录的神经元中α2-肾上腺素能激动剂的作用 杏仁核切片形成控制和实验动物。 在 工作的第二个方面，慢性鸦片对突触前的影响 通过比较 激动剂对电诱发的释放的抑制作用 在体外和突触中的海马和杏仁核切片中的3H-NE 在原位释放NE。 这些测量值 alpha2和β-肾上腺素摄像器介导的生理动作 将在慢性治疗后在多个时间点进行 使用吗啡或Kappa-Amanist U50,488H检查 突触前和突触后的改变之间的关系 肾上腺素的功能以及阿片类药物的出现或表达 依赖。 拟议的研究，为我们的 了解中央甲肾上腺素能的适应 长时间鸦片暴露伴随的功能可能有助于 促进有效的新策略用于治疗麻醉品 对人的依赖。