Morisot Nadège, Rouibi Khalil, Contarino Angelo
1] Université Bordeaux, INCIA, UMR 5287, Bordeaux, France [2] CNRS, INCIA, UMR 5287, Bordeaux, France.
Neuropsychopharmacology. 2015 Jul;40(8):1990-2000. doi: 10.1038/npp.2015.49. Epub 2015 Feb 12.
Vulnerability to stressful life events is a hallmark of drug dependence that may persist long after cessation of drug intake and dramatically fuel key clinical features, such as deregulated up-shifted motivational states and craving. However, to date, no effective therapy is available for reducing vulnerability to stressful events in former drug users and drug-dependent patients, mostly because of poor knowledge of the mechanisms underlying it. In this study, we report that genetic inactivation of the stress-responsive corticotropin-releasing factor receptor-2 (CRF2-/-) completely eliminates the reemergence of increased nonrewarded nose-pokes, reflecting up-shifted motivational states, triggered by ethological environmental stressors long after cessation of morphine administration in mice. Accordingly, CRF2 receptor deficiency completely abolishes the increase in biomarkers of synthesis of major brain motivational substrates, such as ventral tegmental area (VTA) dopamine (DA) and amygdala γ-aminobutyric acid (GABA) systems, associated with the stress-induced reemergence of up-shifted motivational states long after opiate withdrawal. Nevertheless, neither CRF2 receptor deficiency nor long-term opiate withdrawal affects amygdala CRF or hypothalamus CRF expression, indicating preserved brain stress-coping systems. Moreover, CRF2 receptor deficiency does not influence the locomotor or the anxiety-like effect of long-term opiate withdrawal. Thus, the present results reveal an essential and specific role for the CRF2 receptor in the stress-induced reemergence of up-shifted motivational states and related alterations in brain motivational systems long after opiate withdrawal. These findings suggest new strategies for the treatment of the severe and long-lasting vulnerability that inexorably follows drug withdrawal and hinder drug abstinence.
易受应激性生活事件影响是药物依赖的一个标志，这种易感性可能在停止药物摄入后长期存在，并极大地助长关键的临床特征，如失调的、上移的动机状态和渴望。然而，迄今为止，尚无有效的疗法可降低既往吸毒者和药物依赖患者对应激事件的易感性，主要原因是对其潜在机制了解不足。在本研究中，我们报告应激反应性促肾上腺皮质激素释放因子受体2基因失活（CRF2-/-）可完全消除在小鼠停止吗啡给药很久之后，由行为学环境应激源引发的、反映上移动机状态的无奖励鼻触增加的再次出现。相应地，CRF2受体缺陷完全消除了与阿片类药物戒断很久之后应激诱导的上移动机状态再次出现相关的主要脑动机底物合成生物标志物的增加，如腹侧被盖区（VTA）多巴胺（DA）和杏仁核γ-氨基丁酸（GABA）系统。然而，CRF2受体缺陷和长期阿片类药物戒断均不影响杏仁核CRF或下丘脑CRF的表达,表明脑应激应对系统保持完整。此外，CRF2受体缺陷不影响长期阿片类药物戒断的运动或焦虑样效应。因此，本研究结果揭示了CRF2受体在阿片类药物戒断很久之后应激诱导的上移动机状态再次出现以及脑动机系统相关改变中起着重要且特定的作用。这些发现为治疗药物戒断后不可避免地出现的、阻碍药物戒断的严重且持久的易感性提供了新策略。
