The corticotropin-releasing factor receptor-1 pathway mediates the negative affective states of opiate withdrawal
The corticotropin-releasing factor receptor-1 pathway mediates the negative affective states of opiate withdrawal
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DOI：
10.1073/pnas.0506999102
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发表时间：
2005-12-20
影响因子：
11.1
通讯作者：
Papaleo, F
中科院分区：
文献类型：
--
作者：
Contarino, A;Papaleo, F
阿片类药物戒断的负性情感症状强烈地激发了觅药行为，并可能引发海洛因滥用的复吸。迄今为止，没有药物存在，有效地缓解阿片类药物戒断的负面情感症状。促肾上腺皮质激素释放因子（CRF）系统已被假设为介导的药物依赖的动机作用。OF信号由两种不同的受体传递，称为CRF受体-1（CRF 1）和CRF 2。在这里，我们报告说，在小鼠中CRF 1受体通路的遗传破坏消除了阿片类药物戒断的负面情感状态。特别是，无论是CRF，受体杂合（CRF 1 +/-）或纯合（CRF 1-/-）无效突变小鼠避免环境线索反复配对的早期阿片类药物戒断。这些结果不是由于改变了联想学习过程，因为CRF 1 +/-和CRF 1-/-小鼠对与κ-阿片受体激动剂U-50，488 H配对的环境线索表现出可靠的条件性位置厌恶。我们还研究了CRF，受体缺乏对阿片类药物戒断诱导的强啡肽活性的影响，在脑桥核，大脑的分子机制被认为是药物戒断的负面情感状态的基础。与行为指标一致，我们发现，在阿片类药物戒断的早期阶段，CRF 1 +/-或CRF 1-/-都没有显示出强啡肽mRNA水平在延髓核中的增加。这项研究揭示了CRF/CRF 1受体通路在阿片类戒断的负性情感状态中的重要作用，并提出了治疗阿片类成瘾的治疗策略。
The negative affective symptoms of opiate withdrawal powerfully motivate drug-seeking behavior and may trigger relapse to heroin abuse. To date, no medications exist that effectively relieve the negative affective symptoms of opiate withdrawal. The corticotropin-releasing factor (CRF) system has been hypothesized to mediate the motivational effects of drug dependence. The OF signal is transmitted by two distinct receptors named CRF receptor-1 (CRF1) and CRF2. Here we report that genetic disruption of CRF1 receptor pathways in mice eliminates the negative affective states of opiate withdrawal. In particular, neither CRF, receptor heterozygous (CRF1+/-) nor homozygous (CRF1-/-) null mutant mice avoided environmental cues repeatedly paired with the early phase of opiate withdrawal. These results were not due to altered associative learning processes because CRF1+/- and CRF1-/- mice displayed reliable, conditioned place aversions to environmental cues paired with the kappa-opioid receptor agonist U-50,488H. We also examined the impact of CRF, receptor-deficiency upon opiate withdrawal-induced dynorphin activity in the nucleus accumbens, a brain molecular mechanism thought to underlie the negative affective states of drug withdrawal. Consistent with the behavioral indices, we found that, during the early phase of opiate withdrawal, neither CRF1+/- nor CRF1-/- showed increased dynorphin mRNA levels in the nucleus accumbens. This study reveals a cardinal role for CRF/CRF1 receptor pathways in the negative affective states of opiate withdrawal and suggests therapeutic strategies for the treatment of opiate addiction.