MRL Department of Neuroscience, Merck & Co., Inc., West Point, PA, USA.
Pharmacol Biochem Behav. 2012 Mar;101(1):35-40. doi: 10.1016/j.pbb.2011.11.006. Epub 2011 Nov 25.
Currently prescribed antidepressants affect the reuptake and/or metabolism of biogenic amines. Unfortunately for patients, these treatments require several weeks to produce significant symptom remission. However, recently it has been found that ketamine, a dissociative anesthetic agent that noncompetitively antagonizes NMDA (N-Methyl-d-aspartic acid) receptors, has rapid antidepressant effects at sub-anesthetic doses in clinically depressed patients. These findings indicate that modulation of the glutamatergic system could be an efficient way to achieve antidepressant activity. For this reason, other mechanisms influencing glutamatergic functioning have gained interest. For example, the metabotropic glutamate receptor 7 (mGluR7) allosteric agonist AMN082 (N,N'-dibenzyhydryl-ethane-1,2-diamine dihydrochloride) has been shown to be effective in the forced swim and tail-suspension test, behavioral assays sensitive to antidepressants. Here we extend the characterization of AMN082 by demonstrating its effects on differential reinforcement of low rates of responding (DRL)-30, another assay sensitive to antidepressants. Furthermore, we show the engagement of glutamatergic signaling by demonstrating the ability of the selective AMPA (2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid) receptor antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione) to reverse the effects of AMN082 in the tail suspension test. In contrast, NBQX failed to reverse the effects of imipramine in the same behavioral test. Finally, we report that behaviorally efficacious doses of AMN082 modulate phosphorylation of AMPA and NMDA receptor subunits in the hippocampus. These results suggest that the antidepressant-like effects of AMN082 are, at least in part, due to modulation of AMPA and NMDA receptor activity. Therefore, our findings confirm the hypothesis that mGluR7 could represent a novel target for treating depression.
目前处方的抗抑郁药会影响生物胺的再摄取和/或代谢。不幸的是，这些治疗方法需要数周时间才能产生显著的症状缓解。然而，最近发现氯胺酮（一种非竞争性拮抗 NMDA（N-甲基-D-天冬氨酸）受体的分离麻醉剂）在亚麻醉剂量下对临床抑郁患者具有快速的抗抑郁作用。这些发现表明，调节谷氨酸能系统可能是一种有效的实现抗抑郁活性的方法。出于这个原因，其他影响谷氨酸能功能的机制引起了人们的兴趣。例如，代谢型谷氨酸受体 7（mGluR7）别构激动剂 AMN082（N，N'-二苄基乙二胺二盐酸盐）已被证明在强迫游泳和悬尾试验中有效，这些行为试验对抗抑郁药敏感。在这里，我们通过证明其在差异强化低反应率（DRL）-30 中的作用来扩展 AMN082 的特征，这是另一种对抗抑郁药敏感的试验。此外，我们通过证明选择性 AMPA（2-氨基-3-（5-甲基-3-氧代-1,2-恶唑-4-基）丙氨酸）受体拮抗剂 NBQX（2,3-二羟基-6-硝基-7-磺胺基苯并[f]喹喔啉-2,3-二酮）的能力来证明谷氨酸能信号的参与，以逆转 AMN082 在悬尾试验中的作用。相比之下，NBQX 未能在相同的行为试验中逆转丙咪嗪的作用。最后，我们报告行为有效剂量的 AMN082 调节海马体中 AMPA 和 NMDA 受体亚基的磷酸化。这些结果表明，AMN082 的抗抑郁样作用至少部分是由于调节 AMPA 和 NMDA 受体活性。因此，我们的发现证实了 mGluR7 可能代表治疗抑郁症的新靶点这一假说。
