ADRENORECEPTOR FUNCTION AFTER CHRONIC OPIATE TREATMENT

这项研究的主要目标是描述这些影响的特征 长期服用阿片类药物对中枢肾上腺素能受体的影响 职能，总体努力旨在澄清 去甲肾上腺素在生理应激反应中的作用机制 以及与慢性阿片类药物滥用相关的行为变化。 这项工作是建立在以前的改装演示基础上的 突触前α2和突触后β-肾上腺素能受体功能 在慢性吗啡处理的动物的海马区。具体的 目的是在细胞和分子水平上描绘事件 它们是这些受体适应的基础，并确定 肾上腺素能受体功能是否会发生类似的改变 泛指杏仁核。大部分工作将涉及 海马锥体细胞(HPC)的细胞内记录 和杏仁核神经元在洗澡期间的脑片制备中的变化 在已知浓度下对测试物质进行灌流。变化 在突触后，β-肾上腺素受体功能将通过 两种激动剂的量效关系比较 抑制血管内皮细胞钙激活钾反应 对照组和慢性吗啡处理组大鼠的切片。类似 将在以下代理的管理过程中进行测量 超越β-肾上腺素能受体的作用以关闭 潜在电导揭示受体后的变化 事件。将对突触后的变化进行评估 α2-肾上腺素能受体功能的超极化比较 α2-肾上腺素能激动剂对脑神经元电活动的影响 扁桃体切片形成对照和实验动物。在一个 工作的第二个方面，慢性阿片类药物对突触前的影响 α2-肾上腺素能受体功能将通过比较 激动剂对电刺激释放的抑制作用 ~3H-NE在体外培养的海马和杏仁核脑片及突触上的分布 齿状回内去甲肾上腺素的原位释放。这些测量结果 α2和β肾上腺素能受体介导的生理作用 将在慢性治疗后的多个时间点进行 用吗啡或kappa激动剂U50,488H检查 突触前和突触后改变的关系 肾上腺素能受体功能与阿片类药物的产生或表达 依赖。拟议的研究，在为我们的 对中枢去甲肾上腺素能神经元适应的认识 长期接触阿片类药物的功能，可能有助于 推动有效的麻醉药品治疗新战略 对人的依赖。

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.