Stress system changes in alcoholics with and without depressive symptomatology

有或没有抑郁症状的酗酒者的压力系统变化

• 批准号: 8569149
• 负责人: Helen Cecilia Fox
• 金额: $ 7.1万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8569149
• 关键词: Adrenal Glands; Affective; Aftercare; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholism; Alcohols; American; Animals; Attenuated; Bypass; Cardiovascular system; Cessation of life; Chronic; Chronic stress; Clinical Research; Comorbidity; Corticotropin; Corticotropin-Releasing Hormone; Development; Dexamethasone; Disease; Endogenous depression; Exposure to; Family; Feedback; Foxes; Gender; High Prevalence; Hour; Human; Hydrocortisone; Hypothalamic structure; Imagery; Immune system; Individual; Interview; Laboratories; Measures; Mediating; Methodology; Moods; Neurosecretory Systems; Outcome; Output; Participant; Patients; Peripheral; Pilot Projects; Pituitary Gland; Plasma; Population; Process; Randomized; Recording of previous events; Recovery; Relapse; Relative (related person); Reporting; Risk; Role; Stress; Substance Withdrawal Syndrome; Surgeon; System; Testing; Time; alcohol craving; alcohol effect; alcohol misuse; alcoholism therapy; cost; craving; depressive symptoms; dexamethasone suppression test; drinking; follow-up; hypothalamic-pituitary-adrenal axis; negative mood; pre-clinical research; problem drinker; public health relevance; response; social; therapy development

DESCRIPTION (provided by applicant): Early protracted withdrawal from alcohol dependence is characterized by robust Hypothalamic-Pituitary- Adrenal (HPA) axis adaptations. However, while extensive clinical and preclinical research has shown that both tonic and phasic HPA axis changes are robustly associated with increased craving and relapse, it remains unclear whether these markers reflect feedback dysregulation at the level of the adrenals, or a more centrally mediated supra-pituitary process; or both. In addition, the high prevalence of depressive symptomatology reported in alcohol dependent individuals not only compounds these chronic HPA axis alterations but also increases the negative reinforcing effects of alcohol. As such, delineating the discreet and converging stress system mechanisms underpinning elevated craving and relapse in dependent individuals both with and without high depressive symptomatology will be key in elucidating efficacious markers for better tailored treatment development. In the current pilot project we aim to systematically probe the integrity of both central (hypothalamic) and peripheral (pituitary and adrenal) HPA axis function using combined and contrasting challenge methodologies in alcohol dependent individuals with and without depressive symptomatology (15 AD+Dep / 15 AD-Dep) compared with socially drinking controls, with and without depressive symptomatology (15 SD+Dep / 15 SD-Dep). All alcohol dependent participants will be early abstinent and treatment seeking, and will participate in two laboratory sessions along with controls. The first will comprise a combined Dexamethasone Suppression / CRH-stimulation test (DEX-CRH) and the second a combined Dexamethasone Suppression /Stress imagery presentation (DEX-Stress). The order of all laboratory sessions will be randomized and counterbalanced across subjects. Measures of alcohol craving, negative mood, cardiovascular output, plasma cortisol and ACTH will be collected at baseline, immediately following challenge and at regular recovery time-points until 1 hour after provocation. While the initial Dexamethasone Suppression Test reflects the capability of the pituitary corticotrophs in applying a negative regulatory feedback on the release of ACTH and cortisol purely at the level of the adrenals, the subsequent CRH test assesses the ability of the pituitary to secrete ACTH. Exposure to personalized stressful imagery will also probe central function distinct from that assessed by systemic CRH which may "bypass" the hypothalamic component of the HPA axis. We suggest that basal HPA axis overdrive, well-documented in both alcohol dependent populations and individuals with DS, is likely to reflect adaptations to divergent stress system mechanisms. As such, elucidating these mechanisms will have a major impact on the development of pharmacological targets in highly prevalent sub-populations of alcoholics.

描述（由申请人提供）：早期从酒精依赖的早期退出的特征是强大的下丘脑 - 垂体 - 肾上腺（HPA）轴适应。然而，尽管广泛的临床和临床前研究表明，滋补性和音阶HPA轴的变化都与渴望和复发的增加有着牢固的相关性，但尚不清楚这些标记是否反映了肾上腺水平的反馈失调，还是更中央介导的上sopra pitpra-tituitary过程；或两者兼而有之。此外，在酒精依赖的个体中报道的抑郁症状的高患病率不仅使这些慢性HPA轴改变化合物，而且还增加了酒精的负增强作用。因此，描述谨慎和融合应力系统机制是基于有或没有高抑郁症​​状学的依赖人的渴望提高和复发的基础的，这对于阐明有效标记的关键是为了更好地量身定制治疗的开发。在当前的试点项目中，我们旨在系统地探究中心（下丘脑）和外周（垂体和肾上腺和肾上腺）HPA轴功能的完整性，并使用与抑郁症状的症状相关的人（15 AD+DEP / 15 AD-DEP）在酒精依赖的人中的组合和对比挑战方法（与社会饮酒对照15 AD+DEP / 15 AD-DEP）相比，不具有压抑的症状（15 s 15 s）。所有依赖酒精的参与者将是早期的戒酒和寻求治疗，并将与对照一起参加两次实验室会议。第一个将包含聚集的地塞米松抑制 / CRH刺激测试（DEX-CRH），第二个将构成聚集的地塞米松抑制 /应力成像表现（DEX压力）。所有实验室会议的顺序将在受试者之间随机和平衡。渴望酒精的措施，负面情绪，心血管输出，血浆皮质醇和ACTH的措施将在基线时，挑战和常规恢复时间紧随其后，直到挑衅后1小时。虽然最初的地塞米松抑制测试反映了垂体皮质营养物在应用ACTH和皮质醇释放的负调节反馈方面纯粹在肾上腺的水平上，但随后的CRH测试评估垂体测试的能力。暴露于个性化的压力图像还将探测与全身性CRH评估的中心功能，该功能可能“绕过” HPA轴的下丘脑成分。我们建议，基础HPA轴超速驱动，在依赖酒精的人群和DS的个体中有充分的文献记录，可能反映了对发散应力系统机制的适应。因此，阐明这些机制将对高度普遍的酗酒者亚种群的药理目标发展产生重大影响。