Stress, HPA Axis Dysfunction, and Relapse in Alcoholism

压力、HPA 轴功能障碍和酗酒复发

• 批准号: 7425979
• 负责人: BRYON H. ADINOFF
• 金额: $ 33.62万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-20 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7425979
• 关键词: Abstinence; Address; Adrenal Cortex; Adrenal Glands; Adult; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholic Intoxication; Alcoholism; Alcohols; Behavioral; Biological; Boutos; Brain; Childhood; Chronic stress; Clinical; Cognition; Corticotropin; Corticotropin-Releasing Hormone; Cosyntropin; Development; Dexamethasone; Disruption; Emotions; Equilibrium; Feedback; Functional disorder; Glucocorticoids; Health Personnel; Heart; Human; Hydrocortisone; Hypothalamic structure; Individual; Intervention; Laboratories; Link; Measures; Mediating; Methods; Neuraxis; Neurosecretory Systems; Organism; Patients; Physiological; Pituitary Gland; Pituitary-Adrenal System; Play; Population; Probability; Process; Public Speaking; Recovery; Regulation; Relapse; Relative (related person); Research Personnel; Rewards; Risk; Risk Factors; Role; Steroids; Stress; Substance Use Disorder; System; Trauma; Trier Social Stress Test; Vulnerable Populations; Work; alcohol relapse; biological adaptation to stress; chronic alcohol ingestion; drinking; drinking behavior; environmental stressor; hypothalamic-pituitary-adrenal axis; immune function; prevent; programs; prospective; psychologic; response; stressor

DESCRIPTION (provided by applicant): The hypothalamic-pituitary-adrenal (HPA) system is posited as a key biologic link in stress-induced relapse. The HPA axis provides a regulatory feedback network between the brain and the body's behavioral and physiologic responses to stress, recovery, and adaptation. Both trauma and chronic alcohol use produce persistent disturbances in the HPA response to stress. The chronic use of alcohol may also impair the stress-induced release of neurosteroids, compounds that directly modulate GABAergic activity. Thus, altered glucocorticoid and neurosteroid responsiveness during abstinence may impair the central nervous system's ability to mount an appropriate response to environmental stressors, heightening the probability of relapse. However, the relationship between stress, relapse, and HPA axis disturbances remains tentative. In the proposed study, the investigators will expand their extensive work on stress, HPA axis disturbances, and substance use disorders to directly assess the contribution of trauma, stress, and alcohol use upon pituitary-adrenocortical functioning in alcohol dependence. The relative contribution of adrenocortical disruption and episodic stress to prospective drinking behaviors will then be determined. Hypothesis: We hypothesize (1) that lifetime trauma, recent stress, and chronic alcohol use will additively contribute to HPA axis disruption, (2) alterations in glucocorticoid and neurosteroid release as well as episodic stress will predict a return to drinking. Methods: One hundred treatment-seeking, one-month abstinent, alcohol-dependent subjects will be studied. Standardized assessments will be used to assess childhood and adult trauma as well as recent (six months) stress. Pituitary-adrenal (including ACTH, cortisol, and neurosteroids) responses to both neuroendocrine [ovine corticotropin releasing hormone (oCRH), cosyntropin, and dexamethasone] and experiential (public, speaking) challenges will be measured. Drinking behavior and episodic stress will be prospectively assessed for six months following neuroendocrine assessment. SIGNIFICANCE: If our hypotheses are supported, a definitive connection between previous trauma, biological stress response mechanisms, and ongoing stress upon prospective drinking behavior will be demonstrated. The identification of a specific biologic mechanism that underlies this association will provide a fertile framework for the development of targeted pharmacological interventions to decrease relapse in this vulnerable population. In addition, elucidating the concurrent contributions of stress-response biologic systems and externals stressors will provide the therapist and patient with a constellation of specific risk factors for focused treatment.

描述（由申请人提供）：将下丘脑 - 垂体 - 肾上腺（HPA）系统作为压力诱导的复发中的关键生物学联系。 HPA轴提供了大脑与身体对压力，恢复和适应的生理反应之间的调节反馈网络。创伤和慢性饮酒都会在HPA对压力的反应中持续扰动。长期使用酒精也可能会损害压力诱导的神经类固醇的释放，这些化合物直接调节GABA能活性。因此，戒酒期间糖皮质激素和神经固醇反应的改变可能会损害中枢神经系统对环境压力源的适当反应的能力，从而提高复发的可能性。但是，压力，复发和HPA轴障碍之间的关系仍然是暂时的。在拟议的研究中，研究人员将扩大其在压力，HPA轴障碍以及药物使用障碍上的广泛工作，以直接评估创伤，压力和酒精使用对垂体 - 肾上腺皮质功能在酒精依赖性方面的贡献。然后将确定肾上腺皮质破坏和情景压力对前瞻性饮酒行为的相对贡献。假设：我们假设（1）（1）寿命创伤，最近的压力和慢性酒精使用将有助于HPA轴的破坏，（2）糖皮质激素和神经类固醇释放以及情景压力的改变将预测饮酒的回报。方法：将研究一百个寻求治疗，一个月戒酒，依赖酒精的受试者。标准化评估将用于评估童年和成人创伤以及最近（六个月）的压力。垂体 - 肾上腺（包括ACTH，皮质醇和神经类固醇）对神经内分泌[椭圆性皮质激素释放激素（OCRH），cosyntropin和dexamethashasone]和体验（公共，说话）挑战的反应。神经内分泌评估后，将对饮酒行为和情节压力进行前瞻性评估。 意义：如果我们的假设得到支持，将证明先前创伤，生物压力反应机制和对前瞻性饮酒行为的持续压力之间的明确联系。基于该关联的特定生物学机制的鉴定将为开发有针对性的药理学干预措施提供一个肥沃的框架，以减少这种脆弱人群的复发。此外，阐明应力反应生物系统和外部压力源的并发贡献将为治疗师和患者提供集中治疗的特定风险因素的星座。