Stress response and HPA regulation in cocaine addiction

描述(由申请人提供)：这项提案调查了对可卡因上瘾的个体的行为和神经生物学反应是如何改变的。假设可卡因成瘾与对应激源的行为反应性增加有关，这是由于肾上腺皮质类固醇受体介导的反馈抑制中断导致下丘脑-垂体-肾上腺轴(HPA)反应性的不良适应改变的结果。考虑到压力作为药物渴求和复吸的决定因素的既定作用，对应激源的持续行为高反应可能导致戒断性成瘾者的高复发率，这是有效管理可卡因成瘾的主要障碍。本提案的核心特征是使用一种可卡因成瘾的大鼠自我给药(SA)模型，其中与成瘾相关的应激反应的变化将隐含于在长时间接触(LGA)条件下自我给予可卡因(LGA)条件下的大鼠与在可卡因诱导的复发(即，10小时内获得2.0 mg/kg/inf)的易感性增加的大鼠之间的差异，在短期接触(SAA)条件下测试的大鼠(即，3小时获得较低剂量的可卡因)和非自我给予条件下的大鼠之间的差异，生理盐水对照组。将使用一系列综合的行为学、药理学和分子研究来研究这些群体的应激反应。对应激源的行为反应的差异将通过检查应激源、电击、类似于在高架加迷宫和防御性掩埋范例中测量的类似行为的“焦虑”行为以及对新奇事物的运动反应来评估消除的寻找可卡因的行为的恢复。平行研究将通过相同的应激源检测HPA轴的激活，如激素分泌、mRNA表达以及糖皮质激素(GR)和/或盐皮质激素(MR)受体激活的增加。为了验证HPA轴的反应性改变是MR和/或GR介导的负反馈干扰的结果这一假说，我们将采用原位杂交组织化学和Western印迹分析方法，检测脑垂体和脑内不同反馈部位MR和GR的mRNA和蛋白表达。在研究地塞米松诱导的抑制和美曲拉酮诱导的去抑制HPA轴的实验中，将在功能水平上进一步分析负反馈。

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.