Antagonism at the NR2B subunit of NMDA receptors induces increased connectivity of the prefrontal and subcortical regions regulating reward behavior
Antagonism at the NR2B subunit of NMDA receptors induces increased connectivity of the prefrontal and subcortical regions regulating reward behavior
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DOI：
10.1007/s00213-017-4823-2
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发表时间：
2018-04-01
影响因子：
3.4
通讯作者：
Sartorius, Alexander
中科院分区：
文献类型：
--
作者：
Gass, Natalia;Becker, Robert;Sartorius, Alexander
有证据表明，氯胺酮的快速抗抑郁功效可能是由于其对含有 NR2B 亚基的 NMDA 受体 (NMDAR) 的拮抗作用。由于氯胺酮同样阻断含有 NR2A 和 NR2B 的 NMDAR，并且与其他受体具有亲和力，因此 NR2B 选择性药物可能会改善治疗效率和副作用。我们的目的是比较 (S)-氯胺酮和两种不同类型的 NR2B 选择性拮抗剂对大鼠功能性脑网络的影响，以找到它们作用交叉的共同回路，并可能解释它们的抗抑郁作用。实验设计包括四组平行的大鼠(N = 37)，每个人接受 (S)-氯胺酮、CP-101,606、Ro 25-6981 或盐水。化合物注射后，我们获得了静息态功能磁共振成像时间序列。我们使用图论方法来计算大脑网络特性。氯胺酮和 CP-101,606 降低了全局聚类系数和小世界指数。在节点水平上，所有化合物都会诱导介导情绪处理的奖励和认知方面的区域的连通性增加，例如腹内侧前额叶皮层、隔膜核和伏隔核。背侧海马和涉及感觉处理和厌恶的区域，例如上丘和下丘，表现出相反的作用。氯胺酮和 NR2B 选择性化合物的共同作用与抑郁症中报道的作用相同，但方向相反。奖赏回路的上调可能部分是拮抗剂抗抑郁和抗快感缺失作用的基础，并且可能作为测试假定抗抑郁药的转化成像表型，特别是针对 NR2B 受体亚型的抗抑郁药。
Evidence indicates that ketamine's rapid antidepressant efficacy likely results from its antagonism of NR2B-subunit-containing NMDA receptors (NMDAR). Since ketamine equally blocks NR2A- and NR2B-containing NMDAR, and has affinity to other receptors, NR2B-selective drugs might have improved therapeutic efficiency and side effect profile.We aimed to compare the effects of (S)-ketamine and two different types of NR2B-selective antagonists on functional brain networks in rats, in order to find common circuits, where their effects intersect, and that might explain their antidepressant action.The experimental design comprised four parallel groups of rats (N = 37), each receiving (S)-Ketamine, CP-101,606, Ro 25-6981 or saline. After compound injection, we acquired resting-state functional magnetic resonance imaging time series. We used graph theoretical approach to calculate brain network properties.Ketamine and CP-101,606 diminished the global clustering coefficient and small-worldness index. At the nodal level, all compounds induced increased connectivity of the regions mediating reward and cognitive aspects of emotional processing, such as ventromedial prefrontal cortex, septal nuclei, and nucleus accumbens. The dorsal hippocampus and regions involved in sensory processing and aversion, such as superior and inferior colliculi, exhibited an opposite effect.The effects common to ketamine and NR2B-selective compounds were localized to the same brain regions as those reported in depression, but in the opposite direction. The upregulation of the reward circuitry might partially underlie the antidepressant and anti-anhedonic effects of the antagonists and could potentially serve as a translational imaging phenotype for testing putative antidepressants, especially those targeting the NR2B receptor subtype.