Stress system changes in alcoholics with and without depressive symptomatology

描述(由申请人提供)：酒精依赖早期长期戒断的特征是下丘脑-垂体-肾上腺(HPA)轴的强烈适应。然而，尽管广泛的临床和临床前研究表明，紧张性和相性HPA轴的变化都与渴望和复发的增加密切相关，但目前尚不清楚这些标志物反映的是肾上腺水平的反馈失调，还是更中枢介导的垂体腺上过程；或者两者兼而有之。此外，据报道，在酒精依赖者中抑郁症状的高发不仅加剧了这些慢性HPA轴的改变，还增加了酒精的负面强化作用。因此，在既有或没有高度抑郁症状的依赖者中，描述支持提高渴望和复发的谨慎和集中的应激系统机制将是阐明更好地定制治疗开发的有效标记物的关键。在目前的试点项目中，我们的目标是系统地探索中枢(下丘脑)和外周(垂体和肾上腺)HPA轴功能的完整性，使用综合和对比的挑战方法，在有和没有抑郁症状的酒精依赖者中(15 AD Dep/15 AD-Dep)与有和不有抑郁症状的社会饮酒对照组(15 SD Dep/15 SD-Dep)进行比较。所有酒精依赖参与者都将早期戒酒并寻求治疗，并将与对照组一起参加两次实验室会议。第一项包括联合地塞米松抑制/CRH刺激试验(DEX-CRH)和第二项联合地塞米松抑制/压力表象试验(DEX-STREST)。所有实验课程的顺序将是随机的，并在不同的受试者之间保持平衡。酒精渴望、消极情绪、心血管输出量、血浆皮质醇和促肾上腺皮质激素的测量将在基线、挑战后立即和常规恢复时间点收集，直到刺激后1小时。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对ACTH和皮质醇的释放纯粹在肾上腺水平应用负调控反馈的能力，但随后的CRH试验评估了垂体分泌ACTH的能力。暴露在个性化的应激图像中也将探测到不同于全身CRH评估的中枢功能，这可能会“绕过”HPA轴的下丘脑部分。我们认为，基础HPA轴过度驱动，在酒精依赖人群和DS患者中都有很好的文献记载，可能反映了对不同应激系统机制的适应。因此，阐明这些机制将对酗酒者高流行亚群的药理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.