Department of Biomedical Sciences, Marquette University, Milwaukee, Wisconsin 53201-1881, USA.
J Neurosci. 2013 Jul 17;33(29):11800-10. doi: 10.1523/JNEUROSCI.1969-13.2013.
Stressful life events are important contributors to relapse in recovering cocaine addicts, but the mechanisms by which they influence motivational systems are poorly understood. Studies suggest that stress may "set the stage" for relapse by increasing the sensitivity of brain reward circuits to drug-associated stimuli. We examined the effects of stress and corticosterone on behavioral and neurochemical responses of rats to a cocaine prime after cocaine self-administration and extinction. Exposure of rats to acute electric footshock stress did not by itself reinstate drug-seeking behavior but potentiated reinstatement in response to a subthreshold dose of cocaine. This effect of stress was not observed in adrenalectomized animals, and was reproduced in nonstressed animals by administration of corticosterone at a dose that reproduced stress-induced plasma levels. Pretreatment with the glucocorticoid receptor antagonist RU38486 did not block the corticosterone effect. Corticosterone potentiated cocaine-induced increases in extracellular dopamine in the nucleus accumbens (NAc), and pharmacological blockade of NAc dopamine receptors blocked corticosterone-induced potentiation of reinstatement. Intra-accumbens administration of corticosterone reproduced the behavioral effects of stress and systemic corticosterone. Corticosterone treatment acutely decreased NAc dopamine clearance measured by fast-scan cyclic voltammetry, suggesting that inhibition of uptake₂-mediated dopamine clearance may underlie corticosterone effects. Consistent with this hypothesis, intra-accumbens administration of the uptake₂ inhibitor normetanephrine potentiated cocaine-induced reinstatement. Expression of organic cation transporter 3, a corticosterone-sensitive uptake₂ transporter, was detected on NAc neurons. These findings reveal a novel mechanism by which stress hormones can rapidly regulate dopamine signaling and contribute to the impact of stress on drug intake.
应激性生活事件是导致可卡因康复者复吸的重要因素，但它们影响动机系统的机制仍不清楚。研究表明，应激可能通过增加大脑奖励回路对与药物相关刺激的敏感性，为复吸“奠定基础”。我们研究了应激和皮质酮对可卡因自我给药和消退后大鼠对可卡因引发的行为和神经化学反应的影响。急性电击足底应激暴露本身并不会恢复觅药行为，但会增强对亚阈值剂量可卡因的复吸。这种应激效应在肾上腺切除术动物中观察不到，在非应激动物中，给予皮质酮可复制应激诱导的血浆水平，从而产生这种效应。预先给予糖皮质激素受体拮抗剂 RU38486 并不能阻断皮质酮的作用。皮质酮增强可卡因诱导的伏隔核（NAc）细胞外多巴胺的增加，并且 NAc 多巴胺受体的药理学阻断阻止了皮质酮诱导的复吸增强。NAc 内给予皮质酮可复制应激和全身皮质酮的行为效应。皮质酮处理可急性降低快速扫描循环伏安法测量的 NAc 多巴胺清除率，这表明抑制摄取₂介导的多巴胺清除可能是皮质酮作用的基础。与该假说一致，NAc 内给予摄取₂抑制剂去甲麻黄碱可增强可卡因诱导的复吸。在 NAc 神经元上检测到有机阳离子转运蛋白 3 的表达，这是一种对皮质酮敏感的摄取₂转运体。这些发现揭示了应激激素可快速调节多巴胺信号的新机制，并有助于应激对药物摄入的影响。
