Stress response and HPA regulation in cocaine addiction

可卡因成瘾中的应激反应和 HPA 调节

• 批准号: 7275351
• 负责人: John R. Mantsch
• 金额: $ 1.38万
• 依托单位: MARQUETTE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7275351
• 关键词: anxiety; behavioral /social science research tag; cocaine; drug addiction; glucocorticoids; hormone regulation /control mechanism; hypothalamic pituitary adrenal axis; in situ hybridization; laboratory rat; mineralocorticoids; physiologic stressor; psychopharmacology; self medication; stress; substance abuse related behavior; western blottings

DESCRIPTION (provided by applicant): This proposal investigates how behavioral and neurobiological responses to stressors are altered in individuals addicted to cocaine. It is hypothesized that cocaine addiction is associated with an increased behavioral reactivity to stressors that is a consequence of maladaptive alterations in the responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis due to disrupted adrenocorticosteroid receptor-mediated feedback inhibition. Considering the established role of stress as a determinant of drug craving and relapse, persistent behavioral hyper-reactivity to stressors could contribute to the high incidence of relapse in abstinent addicts, a major obstacle for the effective management of cocaine addiction. The core feature of the present proposal is the use of a rat self-administration (SA) model of cocaine addiction in which addiction-related changes in stress responses will be implied from differences between rats self-administering cocaine under long-access (LgA) conditions that give rise to escalating patterns of SA and increased susceptibility to cocaine-induced relapse (i.e., 10-h access to 2.0 mg/kg/inf), rats tested under short-access (ShA rats) conditions that do not produce these effects (i.e., 3-h access to a lower cocaine dose) and non-self-administering, yoked-saline controls. Stress responses in these groups will be investigated using a series of integrated behavioral, pharmacological, and molecular studies. Differences in the behavioral reponses to stressors will be assessed by examining the reinstatement of extinguished cocaine-seeking behavior by a stressor, electric footshock, "anxiety"-Iike behaviors measured in the elevated plus-maze and defensive burying paradigms, and locomotor responses to novelty. Parallel studies will examine the activation of the HPA axis by the same stressors measured as increases in hormonal secretion, mRNA expression and glucocorticoid (GR) and/or mineralocortioid (MR) receptor activation. In order to test the hypothesis that altered responsiveness of the HPA axis is the consequence of disturbances in MR and/or GR-mediated negative feedback, MR and GR mRNA and protein expression in the pituitary gland and various brain feedback sites will be measured using in situ hybridization histochemistry and Western blot analysis. Negative feedback will be further analyzed at a functional level in experiments investigating dexamethasone-induced suppression and metyrapone-induced disinhibition of the HPA axis.

描述（由申请人提供）：该提案调查了沉迷于可卡因的个体对压力源的行为和神经生物学反应如何改变。假设可卡因成瘾与对压力源的行为反应性增加有关，这是下丘脑 - 垂体 - 肾上腺肾上腺（HPA）轴的反应性疾病的结果，这是由于下降丘脑 - 肾上腺皮质激素受体受体介导的反馈抑制而导致的下丘脑 - 垂体 - 肾上腺（HPA）轴的反应性。考虑到压力的确定作用是药物渴望和复发的决定因素，对压力源的持续行为性过度反应可能会导致戒烟成瘾者的复发高发生率，这是有效管理可卡因成瘾的主要障碍。 The core feature of the present proposal is the use of a rat self-administration (SA) model of cocaine addiction in which addiction-related changes in stress responses will be implied from differences between rats self-administering cocaine under long-access (LgA) conditions that give rise to escalating patterns of SA and increased susceptibility to cocaine-induced relapse (i.e., 10-h access to 2.0 mg/kg/inf），在短期（SHA大鼠）条件下测试的大鼠不产生这些作用（即3-H访问可卡因剂量较低的可卡因剂量）和非自助式盐分控制。这些组的应力反应将使用一系列综合行为，药理和分子研究研究。将通过检查压力源灭绝可卡因的行为，电动脚印，“焦虑”行为来评估压力源的行为再生对压力源的差异，这是在升高的加人迷宫和防御性掩埋范式中测得的行为，以及对新颖性的大型运动的反应。平行研究将通过与激素分泌，mRNA表达和糖皮质激素（GR）和/或矿体皮质类药物（MR）受体激活相同的应力来检查HPA轴的激活。为了测试假说，HPA轴改变的反应性是MR和/或GR介导的负反馈的干扰的结果，将使用原位杂交组织化学组织和Western Blot分析来测量垂体中MR和GR mRNA和蛋白质表达。负反馈将在调查地塞米松诱导的抑制作用和甲酰胺诱导的HPA轴的抑制作用的实验中进一步分析。