Stress, HPA Axis Dysfunction, and Relapse in Alcoholism

描述（由申请人提供）：下丘脑-垂体-肾上腺（HPA）系统被认为是应激诱导复发的关键生物学环节。下丘脑轴在大脑和身体对压力、恢复和适应的行为和生理反应之间提供了一个调节反馈网络。创伤和慢性酒精使用都会对HPA对压力的反应产生持续的干扰。长期饮酒也可能损害应激诱导的神经类固醇（直接调节gaba能活性的化合物）的释放。因此，戒断期间糖皮质激素和神经类固醇反应的改变可能会损害中枢神经系统对环境压力源作出适当反应的能力，从而增加复发的可能性。然而，应激、复发和下丘脑轴紊乱之间的关系尚不明确。在拟议的研究中，研究者将扩大他们在压力、下丘脑轴障碍和物质使用障碍方面的广泛工作，以直接评估创伤、压力和酒精使用对酒精依赖中垂体-肾上腺皮质功能的贡献。然后将确定肾上腺皮质破坏和间歇性应激对预期饮酒行为的相对贡献。假设：我们假设：(1)终生的创伤、近期的压力和长期饮酒会增加HPA轴的破坏；(2)糖皮质激素和神经类固醇释放的改变以及间歇性压力会预测饮酒的回归。方法：对100名寻求治疗、戒酒1个月的酒精依赖者进行研究。标准化评估将用于评估儿童和成人创伤以及最近（六个月）的压力。将测量垂体-肾上腺（包括ACTH、皮质醇和神经类固醇）对神经内分泌[羊促肾上腺皮质激素释放激素（oCRH）、促肾上腺皮质激素和地塞米松]和经验（公开、演讲）挑战的反应。在神经内分泌评估后的6个月内，对饮酒行为和间歇性应激进行前瞻性评估。

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.