Stress system changes in alcoholics with and without depressive symptomatology

描述（由申请人提供）：早期长期戒断酒精依赖的特征是下丘脑-肾上腺-肾上腺（HPA）轴适应性强。然而，虽然广泛的临床和临床前研究表明，强直性和阶段性HPA轴的变化与增加的渴望和复发强烈相关，但仍不清楚这些标志物是否反映了肾上腺水平的反馈失调，或更中枢介导的垂体上过程;或两者兼而有之。此外，在酒精依赖个体中报告的抑郁性神经病的高患病率不仅使这些慢性HPA轴改变复合，而且还增加了酒精的负面强化作用。因此，在有和没有高度抑郁性精神病的依赖个体中，描绘支撑渴望和复发升高的谨慎和收敛的压力系统机制将是阐明更好地定制治疗开发的有效标志物的关键。在目前的试点项目中，我们的目标是系统地探讨中央（下丘脑）和外周（垂体和肾上腺）HPA轴功能的完整性，使用组合和对比的挑战方法，酒精依赖的个人和不抑郁症（15 AD+Dep / 15 AD-Dep）相比，社会饮酒控制，有和没有抑郁症（15 SD+Dep / 15 SD-Dep）。所有酒精依赖受试者将早期戒酒并寻求治疗，并将与对照组一起沿着参加两次实验室会议。第一个将包括联合地塞米松抑制/CRH刺激试验（DEX-CRH），第二个将包括联合地塞米松抑制/应激图像呈现（DEX-Stress）。所有实验室检查的顺序将在受试者中随机分配和平衡。将在基线、激发后即刻和常规恢复时间点（直至激发后1小时）采集酒精渴求、消极情绪、心血管输出量、血浆皮质醇和ACTH指标。虽然最初的地塞米松抑制试验反映了垂体促肾上腺皮质激素细胞在肾上腺水平上对ACTH和皮质醇的释放施加负调节反馈的能力，但随后的CRH试验评估了垂体分泌ACTH的能力。暴露于个性化的压力图像也将探测不同于系统CRH评估的中枢功能，系统CRH可能“绕过”HPA轴的下丘脑成分。我们认为，基础HPA轴的神经，以及记录在酒精依赖人群和个人与DS，可能反映适应不同的压力系统机制。因此，阐明这些机制将对高度流行的酗酒者亚群的药理学靶点的发展产生重大影响。

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.