Behavioral Neuroscience Laboratory, Department of Psychology, Boğaziçi University, 34342, Istanbul, Turkey.
Psychopharmacology (Berl). 2024 Jul;241(7):1399-1415. doi: 10.1007/s00213-024-06571-3. Epub 2024 Mar 9.
Ketamine produces dissociative, psychomimetic, anxiolytic, antidepressant, and anesthetic effects in a dose dependent manner. It has a complex mechanism of action that involve alterations in other glutamate receptors. The metabotropic glutamate receptor 5 (mGluR5) has been investigated in relation to the psychotic and anesthetic properties of ketamine, while its role in mediating the therapeutic effects of ketamine remains unknown.
We investigated the role of mGluR5 on the antidepressant, anxiolytic and fear memory-related effects of ketamine in adult male Wistar rats.
Two sets of experiments were conducted. We first utilized the positive allosteric modulator CDPPB to investigate how acute mGluR5 activation regulates the therapeutic effects of ketamine (10 mg/kg). We then tested the synergistic antidepressant effect of mGluR5 antagonism and ketamine by combining MTEP with a sub-effective dose of ketamine (1 mg/kg). Behavioral despair, locomotor activity, anxiety-like behavior, and fear memory were respectively assessed in the forced swim test (FST), open field test (OFT), elevated plus maze (EPM), and auditory fear conditioning.
Enhancing mGluR5 activity via CDPPB occluded the antidepressant effect of ketamine without changing locomotor activity. Furthermore, concomitant administration of MTEP and ketamine exhibited a robust synergistic antidepressant effect. The MTEP + ketamine treatment, however, blocked the anxiolytic effect observed by sole administration of MTEP or the low dose ketamine.
These findings suggest that suppressed mGluR5 activity is required for the antidepressant effects of ketamine. Consequently, the antagonism of mGluR5 enhances the antidepressant effectiveness of low dose ketamine, but eliminates its anxiolytic effects.
氯胺酮以剂量依赖的方式产生分离、拟精神病、抗焦虑、抗抑郁和麻醉作用。它的作用机制复杂，涉及其他谷氨酸受体的改变。代谢型谷氨酸受体 5（mGluR5）已被研究与氯胺酮的精神病和麻醉特性有关，而其在介导氯胺酮治疗效果中的作用尚不清楚。
我们在成年雄性 Wistar 大鼠中研究 mGluR5 在氯胺酮的抗抑郁、抗焦虑和恐惧记忆相关作用中的作用。
进行了两组实验。我们首先利用正变构调节剂 CDPPB 来研究急性 mGluR5 激活如何调节氯胺酮（10mg/kg）的治疗效果。然后，我们通过将 MTEP 与亚有效剂量的氯胺酮（1mg/kg）结合，测试 mGluR5 拮抗和氯胺酮的协同抗抑郁作用。在强迫游泳试验（FST）、旷场试验（OFT）、高架十字迷宫（EPM）和听觉恐惧条件反射中分别评估行为绝望、运动活动、焦虑样行为和恐惧记忆。
通过 CDPPB 增强 mGluR5 活性会阻止氯胺酮的抗抑郁作用，而不改变运动活动。此外，MTEP 和氯胺酮的联合给药表现出强大的协同抗抑郁作用。然而，MTEP+氯胺酮治疗阻断了单独给予 MTEP 或低剂量氯胺酮观察到的抗焦虑作用。
这些发现表明，抑制 mGluR5 活性是氯胺酮抗抑郁作用所必需的。因此，mGluR5 的拮抗作用增强了低剂量氯胺酮的抗抑郁效果，但消除了其抗焦虑作用。
