Stress response and HPA regulation in cocaine addiction

描述（由申请人提供）：本提案研究可卡因成瘾个体对压力源的行为和神经生物学反应是如何改变的。据推测，可卡因成瘾与对压力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被破坏导致下丘脑-垂体-肾上腺（HPA）轴的反应性发生不适应改变的结果。考虑到压力作为药物渴望和复发的决定因素的既定作用，对压力源的持续行为过度反应可能导致戒断成瘾者复发率高，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大鼠自我给药（SA）可卡因成瘾模型，在该模型中，在长时间获取（LgA）条件下，自我给药的大鼠之间的差异会导致SA模式升级，并增加对可卡因诱导复发的易感性（即10小时获取2.0 mg/kg/inf），从而暗示了成瘾相关的应激反应变化。在短时间接触（即3小时接触较低可卡因剂量）条件下测试的大鼠（ShA大鼠）和非自我给药的盐水对照。这些群体的应激反应将通过一系列综合行为学、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压力源对已消失的可卡因寻求行为的恢复，电脚电击，“焦虑”-类似行为在高+迷宫和防御性埋葬范式中测量，以及对新事物的运动反应来评估。平行研究将通过激素分泌、mRNA表达和糖皮质激素（GR）和/或矿皮质激素（MR）受体激活的增加来测量相同的应激源对HPA轴的激活。为了验证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，我们将使用原位杂交组织化学和Western blot分析来测量垂体和脑各反馈部位的MR和GR mRNA和蛋白表达。负反馈将在地塞米松诱导的HPA轴抑制和metyrapone诱导的HPA轴去抑制的实验中进一步在功能水平上进行分析。

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.