Division of Molecular Psychiatry, Translational Research Center, University Hospital of Psychiatry, University of Bern, 3000, Bern 60, Switzerland.
PET Center, Division of Nuclear Medicine, University Hospital, 8091, Zurich, Switzerland.
Transl Psychiatry. 2018 Jan 10;8(1):17. doi: 10.1038/s41398-017-0066-6.
Glutamate signaling plays a major role in addiction. Preclinical research strongly suggests an implication of G-protein-coupled metabotropic glutamate receptor subtype 5 (mGluR5) in nicotine addiction and alcohol use disorder. In humans, smoking is related to a global reduction in mGluR5 availability. In the present study, we investigated mGluR5 in vivo in patients with alcohol use disorder without the confounding effects of smoking. A total of 14 male subjects with alcohol use disorder and at least a 25-day abstinence and 14 matched male non-smoking healthy controls were included in the study. We employed positron emission tomography (PET) with the mGluR5-specific radiotracer [11C]ABP688, using a bolus/infusion protocol. We found increased mGluR5 DVR in several regions within the temporal lobe in patients, as compared to controls. The largest between-group difference was in the amygdala. There was a marked positive relation between mGluR5 DVR in the anterior cingulate and mGluR5 DVR in the orbitofrontal cortex in patients, but not in controls. In patients, lower temptation to drink was related to higher amygdala mGluR5 DVR. We did not find altered mGluR5 DVR in the basal ganglia of subjects recovering from alcohol use disorder. In conclusion, our study provides clinical evidence for altered mGluR5 signaling in the amygdala in alcohol use disorder. This alteration was associated with the temptation to drink. In addition, this study suggests abnormal mGluR5 signaling in a network underlying reward-related behavioral flexibility. These findings strengthen the case for pharmacological agents acting on mGluR5 as promising candidates for the treatment of alcohol use disorder.
谷氨酸信号在成瘾中起着重要作用。临床前研究强烈表明，G 蛋白偶联代谢型谷氨酸受体 5（mGluR5）亚型参与了尼古丁成瘾和酒精使用障碍。在人类中，吸烟与 mGluR5 可用性的整体降低有关。在本研究中，我们在没有吸烟混杂影响的情况下，研究了患有酒精使用障碍的患者体内的 mGluR5。共纳入 14 名男性酒精使用障碍患者（至少 25 天戒断）和 14 名匹配的不吸烟健康男性对照者。我们采用正电子发射断层扫描（PET），使用 mGluR5 特异性放射性示踪剂[11C]ABP688，采用 bolus/infusion 方案。我们发现与对照组相比，患者颞叶内多个区域的 mGluR5 DVR 增加。两组间最大的差异在杏仁核。患者前扣带回皮质 mGluR5 DVR 与眶额皮质 mGluR5 DVR 之间存在显著正相关，但在对照组中没有。在患者中，饮酒诱惑与杏仁核 mGluR5 DVR 较高有关。我们没有发现从酒精使用障碍中恢复的患者基底节中 mGluR5 DVR 的改变。总之，我们的研究为酒精使用障碍患者杏仁核中 mGluR5 信号改变提供了临床证据。这种改变与饮酒的诱惑有关。此外，这项研究表明，与奖励相关的行为灵活性的基础网络中存在异常的 mGluR5 信号。这些发现为作用于 mGluR5 的药物作为治疗酒精使用障碍的有前途的候选药物提供了更有力的证据。
