CORTICOSTEROIDS, STRESS, AND NICOTINE DEPENDENCE

皮质类固醇、压力和尼古丁依赖性

• 批准号: 3213164
• 负责人: OVIDE POMERLAU
• 金额: $ 25.25万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-05-01 至 1993-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3213164
• 关键词: blood chemistry; corticosteroids; dexamethasone; drug addiction; drug addiction antagonist; drug receptors; drug tolerance; high performance liquid chromatography; hormone receptor; nicotine; radioimmunoassay; stress; tobacco abuse

Recent animal research suggests that corticosteroid down-regulation of the nicotine receptor, resulting in decreased sensitivity to nicotine's effects, may help to explain the phenomena of acute and chronic tolerance to nicotine. An implication of this observation for understanding nicotine self-administration via smoking in humans is that increased nicotine intake in the context of psychological stress or other conditions where corticosteroid levels are enhanced may represent behavioral compensation for situation-specific decreases in nicotine sensitivity. The long-term objective of the proposed project is to explore the role of corticosteroid mechanisms in modulating nicotine sensitivity and modifying nicotine self- administration in smokers. Over a 5-year period, three Phases of research will be conducted using repeated-measures designs with male subjects 21 to 45 years of age. The specific aims of Phase I are to determine the effects of corticosteroid activity upon nicotine self-administration via smoking by administering different doses of a synthetic corticosteroid, dexamethasone (IA); to test the possibility that increased nicotine intake following dexamethasone is the result of non-specific enhancement of smoking behavior by comparing the smoking of nicotine and non-nicotine cigarettes (IB); and to characterize the effects of different corticosteroid receptor agonists (fludrocortisone, hydrocortisone, and dexamethasone) upon sensitivity to nicotine, as defined by heart rate and cortisol increases and core temperature decreases in response to intravenous administration of a fixed dose of nicotine (IC). The objectives of Phase II are to examine the effects of different levels of a psychological stressor known to increase corticosteroid activity (mental arithmetic) on nicotine intake via smoking (IIA) and on sensitivity to nicotine following intravenous administration of a fixed nicotine dose(IIC); and to test the possibility that increased nicotine intake occurs as a side effect of stress-induced enhancement of smoking behavior by comparing the smoking of nicotine and non-nicotine cigarettes (IIB). The goal of Phase III is to study the interactions between nicotine dependence--reflecting differences in chronic tolerance-- and the variables studied in Phases I & II by varying the dosage od dexamethasone in both highly-dependent and less-dependent smokers (IIIA); to characterize the response to stress in such smokers by presenting different levels of a psychological stressor (IIIB); and to determine whether sensitivity to nicotine is associated irreversibly with history of nicotine use by examining the effects of nicotine infusion in highly- dependent smokers, less-dependent smokers, ex-smokers, and never-smokers following dexamethasone or placebo administration (IIIC). Overall, the project seeks to identify mechanisms whose elucidation may increase the understanding of smoking and nicotine dependence and lead to the development of new tools for treating smoking.

最近的动物研究表明，皮质类固醇的下调， 尼古丁受体，导致对尼古丁的敏感性降低 影响，可能有助于解释急性和慢性耐受现象 尼古丁。 这一观察对理解尼古丁的意义 人类通过吸烟自我给药的原因是， 在心理压力或其他情况下， 皮质类固醇水平的提高可能代表行为补偿 尼古丁敏感性的特定情况下降。 长期 该项目的目的是探索皮质类固醇在 调节尼古丁敏感性和改变尼古丁自身 吸烟者的管理 在五年的时间里，研究的三个阶段 将采用重复测量设计，对21至 45岁 第一阶段的具体目标是确定 通过吸烟进行尼古丁自我给药后皮质类固醇活性 使用不同剂量的合成皮质类固醇地塞米松 (IA);测试尼古丁摄入量增加的可能性， 地塞米松是非特异性增强吸烟行为的结果 通过比较尼古丁和非尼古丁香烟的吸烟情况（IB）;以及 为了表征不同皮质类固醇受体激动剂的作用， （氟氢可的松、氢化可的松和地塞米松）对 尼古丁，如心率和皮质醇增加和核心定义 静脉注射固定剂量的 尼古丁（IC） 第二阶段的目标是审查 不同程度的心理压力会增加 通过吸烟摄入尼古丁时皮质类固醇活性（心算） (IIA)以及静脉给药后对尼古丁的敏感性 固定尼古丁剂量（IIC）;并测试增加 尼古丁的摄入是压力诱导的增强的副作用， 吸烟行为，通过比较尼古丁和非尼古丁的吸烟 香烟（IIB）。 第三阶段的目标是研究 尼古丁依赖--反映了慢性耐受性的差异-- 以及在第一阶段和第二阶段通过改变剂量 在高度依赖和低依赖吸烟者中使用地塞米松（IIIA）; 为了描述这些吸烟者对压力的反应， 不同程度的心理压力（IIIB）;并确定 对尼古丁的敏感性是否与吸烟史不可逆相关 尼古丁的使用，通过检查尼古丁输注的影响，在高度- 依赖性吸烟者、依赖性较低的吸烟者、戒烟者和从不吸烟者 地塞米松或安慰剂给药后（IIIC）。 总体看 该项目旨在确定一些机制，阐明这些机制可能会增加 了解吸烟和尼古丁依赖，并导致 开发治疗吸烟的新工具。