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发复发的关键生物学环节。HPA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调节反馈网络。创伤和长期饮酒都会使HPA对压力的反应产生持续的干扰。长期使用酒精也可能损害应激诱导的神经类固醇的释放，神经类固醇是直接调节GABA能活性的化合物。因此，糖皮质激素和神经类固醇反应性的改变，在禁欲可能会损害中枢神经系统的能力，安装一个适当的反应，环境的压力，提高复发的可能性。然而，压力，复发和HPA轴紊乱之间的关系仍然是暂时的。在拟议的研究中，研究人员将扩大他们对压力，HPA轴紊乱和物质使用障碍的广泛研究，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情景应激对预期饮酒行为的相对贡献。假设：我们假设：（1）终生创伤、近期压力和长期饮酒将增加HPA轴的破坏，（2）糖皮质激素和神经类固醇释放的改变以及偶发性压力将预测饮酒的恢复。方法：将对100名寻求治疗、戒酒一个月的酒精依赖受试者进行研究。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[绵羊促肾上腺皮质激素释放激素（oCRH）、促皮质激素和地塞米松]和经验（公开、演讲）激发的反应。神经内分泌评估后，将对饮酒行为和情景压力进行六个月的前瞻性评估。 重要性：如果我们的假设得到支持，以前的创伤，生物应激反应机制，并在未来的饮酒行为持续的压力之间的明确联系将得到证明。确定一个特定的生物学机制，这种关联的基础将提供一个肥沃的框架，有针对性的药理学干预措施，以减少复发，在这个脆弱的人群的发展。此外，阐明压力反应生物系统和外部压力源的共同贡献将为治疗师和患者提供一系列特定的风险因素，以进行重点治疗。

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.