Marked global reduction in mGluR5 receptor binding in smokers and ex-smokers determined by [11C]ABP688 positron emission tomography
Marked global reduction in mGluR5 receptor binding in smokers and ex-smokers determined by [11C]ABP688 positron emission tomography
复制标题
DOI：
10.1073/pnas.1210984110
复制
发表时间：
2013-01-08
影响因子：
11.1
通讯作者：
Hasler, Gregor
中科院分区：
文献类型：
--
作者：
Akkus, Funda;Ametamey, Simon M.;Hasler, Gregor
尼古丁成瘾是一个主要的公共卫生问题，导致原发性阿片能功能障碍。我们测量了人脑中谷氨酸受体的结合，为吸烟者谷氨酸系统的异常提供了直接证据。由于代谢型谷氨酸受体5（mGluR 5）的拮抗作用减少了大鼠和小鼠的尼古丁自我给药，因此mGluR 5被认为与尼古丁成瘾有关。通过使用[C-11] ABP 688的正电子发射断层扫描，观察到mGluR 5受体特异性结合至变构位点。我们发现14名吸烟者的灰质中mGluR 5分布体积比（DVR）显著降低（20.6%; P < 0.0001）。双侧内侧眶额皮质的减少最为显著。与14名非吸烟者相比，14名戒烟者的平均灰质mGluR 5 DVR整体降低（11.5%; P < 0.005），吸烟者与戒烟者之间的平均灰质mGluR 5 DVR差异有统计学意义（9.2%; P < 0.01）。反映当前尼古丁消耗、依赖和戒断的临床变量与mGluR 5 DVR不相关。这种mGluR 5受体结合的减少可能是对长期尼古丁给药诱导的谷氨酸慢性增加的适应，在戒烟者中观察到的下调减少可能是由于受体的不完全恢复，特别是因为戒烟者平均戒烟仅25周。这些结果鼓励开发和测试直接靶向多巴胺能系统的抗成瘾药物。
Nicotine addiction is a major public health problem, resulting in primary glutamatergic dysfunction. We measured the glutamate receptor binding in the human brain and provided direct evidence for the abnormal glutamate system in smokers. Because antagonism of the metabotropic glutamate receptor 5 (mGluR5) reduced nicotine self-administration in rats and mice, mGluR5 is suggested to be involved in nicotine addiction. mGluR5 receptor binding specifically to an allosteric site was observed by using positron emission tomography with [C-11]ABP688. We found a marked global reduction (20.6%; P < 0.0001) in the mGluR5 distribution volume ratio (DVR) in the gray matter of 14 smokers. The most prominent reductions were found in the bilateral medial orbito-frontal cortex. Compared with 14 nonsmokers, 14 ex-smokers had global reductions in the average gray matter mGluR5 DVR (11.5%; P < 0.005), and there was a significant difference in average gray matter mGluR5 DVR between smokers and ex-smokers (9.2%; P < 0.01). Clinical variables reflecting current nicotine consumption, dependence and abstinence were not correlated with mGluR5 DVR. This decrease in mGluR5 receptor binding may be an adaptation to chronic increases in glutamate induced by chronic nicotine administration, and the decreased down-regulation seen in the ex-smokers could be due to incomplete recovery of the receptors, especially because the ex-smokers were abstinent for only 25 wk on average. These results encourage the development and testing of drugs against addiction that directly target the glutamatergic system.