ADRENORECEPTOR FUNCTION AFTER CHRONIC OPIATE TREATMENT

本研究的主要目的是描述 中枢肾上腺素受体的长期阿片类药物给药 的作用，并作出总体努力， 去甲肾上腺素能机制介导的生理 以及与长期阿片类药物滥用相关的行为变化。 这项工作是基于以前的示范改建 突触前α 2和突触后β肾上腺素受体功能 在慢性吗啡处理的动物的海马中。 具体 目的是在细胞和分子水平上描述事件 它们是这些受体适应的基础 肾上腺素受体功能的类似改变是否 广泛分布于杏仁核。 大部分工作将涉及 海马锥体细胞的细胞内记录 和杏仁核神经元在脑片制备过程中浴 已知浓度的供试品灌流。 变化 突触后β-肾上腺素受体功能将通过以下方法进行评估： 比较激动剂的浓度-效应关系， 抑制HPCs的钙激活钾反应， 来自对照组和慢性吗啡治疗组大鼠的切片。 类似 将在施用药剂期间进行测量， 作用于β-肾上腺素能受体以外， 潜在的电导，以揭示后受体的变化 事件 将对突触后神经元的变化进行评估。 α 2肾上腺素能受体功能，通过比较超极化 α 2-肾上腺素能激动剂在神经元中的作用 杏仁核切片来自对照和实验动物。 中 第二方面的工作，慢性阿片类药物对突触前神经元的影响， α 2-肾上腺素受体功能将通过比较 激动剂对电诱发释放的抑制作用 ~3H-NE在离体海马和杏仁核脑片及突触内的表达 齿状回原位NE释放。 这些测量 α 2和β-肾上腺素受体介导的生理作用 将在长期治疗后的多个时间点进行 用吗啡或κ-激动剂U50，488H检查 突触前和突触后的变化之间的关系 肾上腺素受体功能与阿片样物质的产生或表达 依赖 这项研究旨在为我们的 了解中枢去甲肾上腺素能神经系统的适应性 长期暴露于阿片类药物可能有助于 促进有效的治疗麻醉药品的新战略 人的依赖性。

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.