ALTERATIONS OF NEUROENDOCRINE STRESS RESPONSIVITY IN SPECIFIC ADDICTIVE DISEAS...

海洛因、可卡因和酒精成瘾，单独和各种相互依赖的组合，通常与 合并症和其他重大医疗并发症，特别是丙型肝炎和艾滋病，仍然是主要的个人问题 以及我们国家和世界面临的公共卫生问题。双向翻译研究，这是 将通过这里的项目1、2和3之间的交互来完成，该项目将允许 拓展对特定成瘾剂动态分子神经生物学的基本认识 一种药物或行为类型的治疗前和治疗期间的疾病。这个项目将 探讨未经治疗的下丘脑-垂体-肾上腺(HPA)轴的非典型应激反应 成瘾性疾病，包括阿片系统对该轴的调节作用以及 与多巴胺和谷氨酸能系统的相互作用。将检验几个假设：1.1) 丁丙诺啡是一种部分MU激动剂，具有一定的kappa阿片受体活性，将允许 HPA轴；1.2)精氨酸加压素对垂体前叶的调节，可能是新的靶点 治疗干预，在成瘾周期中改变，并在有效期间正常化 治疗；1.3)可卡因成瘾者恢复正常HPA轴功能的过程将是缓慢的 通过行为治疗有效管理；2)未经治疗的可卡因依赖，同时 酒精或阿片类药物滥用或依赖，将导致正常压力的显著变化。 在有效治疗抑郁症的过程中，压力反应性的变化将恢复正常；以及4) 对挑战或挑衅性测试的反应可能不同，甚至基础激素水平也可能不同 不同的是，在具有特定功能或可能功能基因变异、或变异或单倍型的人中，a) 与成瘾或b)基因有关，该基因的表达会因长期接触可卡因或 海洛因可能与基础或测试反应激素水平有关。内源性阿片系统的作用， 以及HPA轴的其他特定组件将以标准和新的挑战进行研究 化合物及其组合，包括CRF、精氨酸加压素、合成ACTH、美曲酮、 阿片类拮抗剂强啡肽A(1-13)在特定成瘾性疾病患者和正常人中的应用 志愿者。

Heroin, cocaine, and alcohol addictions, alone and in various combinations of codependency, often with comorbidity and other major medical complications, especially hepatitis C and AIDS, remain major personal and public health problems confronting our nation and the world. Bidirectional translational research, which will be accomplished by interactions among Projects 1, 2, and 3 herein and this project, will allow the expansion of a fundamental understanding of the dynamic molecular neurobiology of specific addictive diseases in stages prior to andduring treatment of a pharmacological or behavioral type. This project will explore the atypical stress responsivity of the hypothalamic-pituitary-adrenal (HPA) axis seen in untreated addictive diseases, including the contributions of the opioid system in the modulation of that axis and interactions with the dopaminergic and glutamatergic systems. Several hypotheses will be tested: 1.1) that buprenorphine, a partial mu agonist with some kappa opioid receptor activity, will permit normalization of the HPA axis; 1.2) that the regulation of anterior pituitary by arginine vasopressin, a possible target for novel therapeutic intervention, becomes altered during cycles of addiction and normalizes during effective treatment; and 1.3) that restoration of normal HPA axis function will occur slowly in cocaine addicts effectively managed with behavioral treatment; 2) that untreated cocaine dependency, with concurrent alcohol or opioid abuse or dependency, will result in significant alterations in normal stress.responsivity; 3) that alterations of stress responsivity will normalize during effective treatment for depression; and 4) that responses to challenge or provocative tests may be different, and even basal levels of hormone may be different, in persons with a specific functional or possibly functional gene variant, or a variant or haplotype, a) associated with an addiction or b) of a gene whose expression is altered by chronic exposure to cocaine or heroin may be related to basal or test response hormone levels. The role of the endogenous opioid system, and other specific components of the HPA axis will be studied with standard and novel challenge compounds, and combinations thereof, including CRF, arginine vasopressin, synthetic ACTH, metyrapone, opioid antagonists dynorphin A(1-13) in patients with specific addictive diseases and normal volunteers.