Frenois François, Cador Martine, Caillé Stéphanie, Stinus Luis, Le Moine Catherine
Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5541 Interactions Neuronales et Comportements, BP28, Université Victor Segalen, Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux cedex, France.
Eur J Neurosci. 2002 Oct;16(7):1377-89. doi: 10.1046/j.1460-9568.2002.02187.x.
In morphine-dependent rats, low naloxone doses have been shown to induce conditioned place aversion, which reflects the negative motivational component of opiate withdrawal. In contrast, higher naloxone doses are able to induce a 'full' withdrawal syndrome, including overt somatic signs. The c-fos gene is commonly used as a marker of neuronal reactivity to map the neural substrates that are recruited by various stimuli. Using in situ hybridization, we have analysed in the brain of morphine-dependent rats the effects of acute withdrawal syndrome precipitated by increasing naloxone doses on c-fos mRNA expression. Morphine dependence was induced by subcutaneous implantation of slow-release morphine pellets for 6 days and withdrawal was precipitated by increasing naloxone doses inducing the motivational (7.5 and 15 micro g/kg) and somatic (30 and 120 micro g/kg) components of withdrawal. Our mapping study revealed a dissociation between a set of brain structures (extended amygdala, lateral septal nucleus, basolateral amygdala and field CA1 of the hippocampus) which exhibited c-fos mRNA dose-dependent variations from the lowest naloxone doses, and many other structures (dopaminergic and noradrenergic nuclei, motor striatal areas, hypothalamic nuclei and periaqueductal grey) which were less sensitive and recruited only by the higher doses. In addition, we found opposite dose-dependent variations of c-fos gene expression within the central (increase) and the basolateral (decrease) amygdala after acute morphine withdrawal. Altogether, these results emphasize that limbic structures of the extended amygdala along with the lateral septal nucleus, the basolateral amygdala and CA1 could specifically mediate the negative motivational component of opiate withdrawal.
在吗啡依赖大鼠中，低剂量纳洛酮已被证明可诱发条件性位置厌恶，这反映了阿片类药物戒断的负性动机成分。相比之下，较高剂量的纳洛酮能够诱发“完全”戒断综合征，包括明显的躯体症状。c-fos基因通常用作神经元反应性的标志物，以绘制由各种刺激募集的神经底物。通过原位杂交，我们在吗啡依赖大鼠的脑中分析了增加纳洛酮剂量引发的急性戒断综合征对c-fos mRNA表达的影响。通过皮下植入缓释吗啡丸6天诱导吗啡依赖，通过增加纳洛酮剂量引发戒断，这些剂量可诱发戒断的动机性（7.5和15微克/千克）和躯体性（30和120微克/千克）成分。我们的图谱研究揭示了一组脑结构（扩展杏仁核、外侧隔核、基底外侧杏仁核和海马的CA1区）之间的分离，这些结构从最低纳洛酮剂量开始就表现出c-fos mRNA的剂量依赖性变化，而许多其他结构（多巴胺能和去甲肾上腺素能核、运动纹状体区域、下丘脑核和导水管周围灰质）敏感性较低，仅在较高剂量时才被募集。此外，我们发现急性吗啡戒断后，中央杏仁核（增加）和基底外侧杏仁核（减少）内c-fos基因表达存在相反的剂量依赖性变化。总之，这些结果强调，扩展杏仁核的边缘结构以及外侧隔核、基底外侧杏仁核和CA1区可能特异性介导阿片类药物戒断的负性动机成分。
