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.

Public Health Relevance

Alcoholism is among the top three causes of preventable death and disease in the US (Room, 2005) and is characterized by robust stress system adaptations as well as a high prevalence of depressive symptoms (Sinha et al., 2011, Anthenelli, 2009). We propose to systematically examine the relative contribution of chronic drinking and depressive symptoms on stress system function in alcohol dependent individuals and socially drinking controls with and without high levels of depressive symptoms. Findings will help elucidate relapse-related stress system mechanisms in a highly prevalent and often overlooked sub-population of alcoholics, which in turn, will encourage the development of better tailored therapies for alcohol addiction.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Small Research Grants (R03)
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Biobehavioral Mechanisms of Emotion, Stress and Health Study Section (MESH)
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Grandison, Lindsey
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Yale University
Schools of Medicine
New Haven
United States
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Milivojevic, Verica; Ansell, Emily; Simpson, Christine et al. (2017) Peripheral Immune System Adaptations and Motivation for Alcohol in Non-Dependent Problem Drinkers. Alcohol Clin Exp Res 41:585-595
Fox, Helen C; Milivojevic, Verica; Angarita, Gustavo A et al. (2017) Peripheral immune system suppression in early abstinent alcohol-dependent individuals: Links to stress and cue-related craving. J Psychopharmacol 31:883-892