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 合并症和其他主要的医疗并发症，特别是丙型肝炎和艾滋病，仍然是主要的个人 以及我们国家和世界面临的公共卫生问题。双向翻译研究， 将通过项目1、2和3之间的互动来完成，本项目将允许 扩展了对特定成瘾的动态分子神经生物学的基本理解 药物或行为类型治疗前和治疗期间的疾病。该项目将 探索未治疗的下丘脑-垂体-肾上腺（HPA）轴的非典型应激反应性。 成瘾性疾病，包括阿片系统在调节该轴中的作用， 与多巴胺能和多巴胺能系统的相互作用。将测试几个假设：1.1）， 丁丙诺啡是一种具有某些κ阿片受体活性的部分μ激动剂， 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，在有效治疗期间正常化。 可卡因成瘾者HPA轴功能恢复缓慢 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着改变。 在有效治疗抑郁症的过程中，压力反应的改变将正常化;以及4） 对激发或刺激性试验的反应可能不同，甚至激素的基础水平也可能不同。 不同的，在具有特定功能或可能功能的基因变体或变体或单倍型的人中，a） 或B）其表达因长期暴露于可卡因而改变的基因，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， 和HPA轴的其他特定组件将以标准和新颖的挑战进行研究 化合物及其组合，包括CRF，精氨酸加压素，合成ACTH，甲吡酮， 阿片受体拮抗剂强啡肽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.