Stress response and HPA regulation in cocaine addiction

描述（由申请人提供）：该提案调查了可卡因成瘾者对压力源的行为和神经生物学反应如何改变。据推测，可卡因成瘾与增加的行为反应性的应激源，这是一个结果的适应不良的改变，下丘脑-垂体-肾上腺（HPA）轴的反应性，由于破坏肾上腺皮质类固醇受体介导的反馈抑制。考虑到压力作为药物渴望和复吸的决定因素的既定作用，对压力源的持续行为高反应性可能导致戒断成瘾者复吸的高发生率，这是有效管理可卡因成瘾的主要障碍。本发明的核心特征是使用可卡因成瘾的大鼠自我给药（SA）模型，其中应激反应中的成瘾相关变化将由在长时间使用（LgA）条件下自我给药可卡因的大鼠之间的差异暗示，所述LgA条件引起SA的升级模式和对可卡因诱导的复发的易感性增加（即，10小时接触2.0 mg/kg/inf），在短期接触（ShA大鼠）条件下测试的大鼠不会产生这些效应（即，3-h获得较低的可卡因剂量）和非自我给药的偶联盐水对照。这些群体的应激反应将使用一系列综合的行为，药理学和分子研究进行调查。对压力源的行为反应的差异将通过检查由压力源、电击脚、在高架十字迷宫和防御性埋葬范例中测量的“焦虑”样行为以及对新奇事物的运动反应所引起的熄灭的可卡因寻求行为的恢复来评估。平行研究将检查HPA轴的激活，通过相同的应激源测量激素分泌，mRNA表达和糖皮质激素（GR）和/或盐皮质激素（MR）受体激活的增加。为了检验HPA轴的反应性改变是MR和/或GR介导的负反馈紊乱的结果这一假设，将使用原位杂交组织化学和Western印迹分析来测量垂体和各种脑反馈位点中的MR和GR mRNA和蛋白质表达。在研究地塞米松诱导的HPA轴抑制和甲吡酮诱导的HPA轴去抑制的实验中，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.