背景:氯胺酮产生解离,心理模拟,抗焦虑药,抗抑郁药,和剂量依赖的麻醉效果。它具有复杂的作用机制,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。
目的:我们研究了mGluR5对抗抑郁药的作用,氯胺酮对成年雄性Wistar大鼠的抗焦虑和恐惧记忆相关作用。
方法:进行两组实验。我们首先利用正变构调节剂CDPPB来研究急性mGluR5活化如何调节氯胺酮(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(lmg/kg)组合来测试mGluR5拮抗作用和氯胺酮的协同抗抑郁作用。行为绝望,运动活动,类似焦虑的行为,和恐惧记忆分别在强迫游泳测试(FST)中进行评估,露天试验(OFT),高架加迷宫(EPM),和听觉恐惧调节。
结果:通过CDPPB增强mGluR5活性可阻断氯胺酮的抗抑郁作用而不改变运动活性。此外,同时给予MTEP和氯胺酮显示出强大的协同抗抑郁作用.MTEP+氯胺酮治疗,然而,阻断通过单独施用MTEP或低剂量氯胺酮观察到的抗焦虑作用。
结论:这些研究结果表明,抑制mGluR5活性是氯胺酮的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功效,但消除了它的抗焦虑作用。
BACKGROUND: 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.
OBJECTIVE: We investigated the role of mGluR5 on the antidepressant, anxiolytic and fear memory-related effects of ketamine in adult male Wistar rats.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.