ACUTE DESENSITIZATION AND TOLERANCE TO OPIATES IN THE LOCUS COERULEUS

蓝斑的急性脱敏和阿片类药物耐受

• 批准号: 6237954
• 负责人: GEORGE AGHAJANIAN
• 金额: $ 11.08万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 1998-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6237954
• 关键词: NMDA receptors; animal poison; calcium channel blockers; clonidine; cyclic AMP; drug addiction; drug tolerance; drug withdrawal; electrophysiology; glutamates; laboratory rat; locus coeruleus; microdialysis; morphine; neuropharmacology; neurotoxins; opiate alkaloid; phosphorylation; tissue /cell culture

The general purpose of this project is to study the molecular and cellular mechanisms underlying the phenomena of opiate tolerance, dependence and withdrawal using the LC as a cellular model for chronic opiate studies. Specific aims are: I. To study mechanisms underlying acute desensitization and tolerance to opiates in the locus coeruleus of naive and morphine-dependent rats. These studies will be done using electrophysiological (conventional intracellular and whole-cell recordings in brain slices) and biochemical techniques. II. To study the effects of chronic administration of naltrexone (an opiate antagonist) and buprenorphine (a mixed agonist-antagonist) on the locus coeruleus. Both biochemical and electrophysiological techniques will be employed. III. To investigate further the glutamatergic mechanisms underlying opiate dependence and withdrawal. Electrophysiological and microdialysis techniques will be employed. The phenomenon of long-term desensitization to glutamate in locus coeruleus neurons will be studied in both naive and morphine-dependent animals. We also propose to extend studies on the role of glutamate in the development of opiate dependence. IV. To study the role of glutamatergic mechanisms in the action of various systemically-administered agents used in the suppression of opiate withdrawal. Microdialysis techniques will be employed to study the effect of systemically and/or locally applied agents on glutamate levels in the LC. The proposed research on the mechanisms underlying opiate tolerance, dependence and withdrawal should lead to the development of newer and better methods for the treatment of withdrawal symptoms in opiate-addicted humans.

该项目的一般目的是研究分子和细胞 鸦片耐受性，依赖性和 使用LC作为慢性鸦片研究的细胞模型的戒断。 具体目的是： I.研究急性脱敏的基础机制和对 鸦片中的鸦片基因和吗啡依赖性大鼠的基因座。这些 研究将使用电生理学（常规 大脑切片中的细胞内和全细胞记录）和生化 技术。 ii。研究长期给药纳曲酮的影响（ 阿片类拮抗剂）和丁丙诺啡（混合激动剂 - 抗抗激体） 基因座。生化和电生理技术都将 被雇用。 iii。进一步研究阿片类药物的基础机制 依赖和退出。电生理和微透析 技术将被采用。长期脱敏的现象 在幼稚和 吗啡依赖性动物。我们还建议扩展有关该角色的研究 谷氨酸在鸦片依赖性的发展中。 iv。研究谷氨酸能机制在各种作用中的作用 用于抑制阿片类药物的全身管理剂 提取。将采用微透析技术来研究效果 在全身和/或本地施用的药物上的谷氨酸水平 LC。 提出的关于鸦片耐受性基础机制的研究， 依赖和提取应导致更新的发展和 更好地治疗阿片类药物中戒断症状的方法 人类。