Investigation of NMDA receptor antagonist as antidepressant in animals

我们最近的双盲临床试验表明，氯胺酮（一种NMDA拮抗剂）产生快速起效，强大的，和持久的抗抑郁作用的患者谁是典型的抗抑郁治疗耐药。我们假设靶向AMPA/NMDA受体是快速缓解抑郁症症状的有效策略。为了进一步验证AMPA/NMDA通量假说，并开发基于这种氯胺酮现象的新药，我们进行了一系列动物实验。我们发现，亚麻醉剂量的氯胺酮治疗产生快速起效的抗抑郁药样作用在两个行为范例，学习无助测试和强迫游泳测试。单次给药后，效果至少持续一周以上。MK-801（地佐环平）和Ro 25 -6981（一种NR 2B选择性拮抗剂）也具有抗抑郁样作用;然而，这些作用的持续时间不如氯胺酮。在与习得性无助测试类似的方案中，用氯胺酮处理的动物在被动回避测试中表现良好，因此氯胺酮在动物中的抗抑郁样作用不太可能是由于与氯胺酮使用相关的学习和记忆退化。用NBQX（AMPA受体拮抗剂）预处理可阻断氯胺酮、MK-801和Ro 25 -6981在强迫游泳试验中诱导的不动性降低，表明这些药物的抗抑郁样作用需要AMPA通量。氯胺酮改变了氯胺酮处理动物海马组织中GluR 1的磷酸化，NBQX预处理也阻断了这种作用。综上所述，我们的动物研究结果强烈支持AMPA受体参与氯胺酮的抗抑郁样作用和AMPA/NMDA通量策略，以开发新的抗抑郁药。未来的研究需要进一步阐明这种氯胺酮抗抑郁剂样作用所涉及的受体亚型和脑区。

Our recent double blind clinical trials demonstrated that ketamine (an NMDA antagonist) produced rapid onset, robust, and long-pasting antidepressive actions in the patients who are resistant to typical antidepressant treatment. We have hypothesized that targeting AMPA/NMDA receptor throughput is an effective strategy for rapid relief of depression symptoms. To further test the AMPA/NMDA throughput hypothesis and to develop new medication based on this ketamine phenomenon, we conducted a series of animal experiments. We found that subanesthetic doses of ketamine treatment produced rapid onset antidepressant-like effects in two behavioral paradigms, the learned helpless test and the forced swim test. The effects lasted at least more than a week after a single drug administration. MK-801 (dizocilpine) and Ro25-6981, a NR2B selective antagonist, also exerted antidepressant-like effects; these effects, however, were not sustained as long as those of ketamine. Animals treated with ketamine in a similar regiment to the learned helpless test performed well on passive avoidance tests, thus the antidepressant-like effects of ketamine in animal is unlikely due to learning and memory deterioration associated with ketamine use. Pre-treatment with NBQX, an AMPA receptor antagonist, blocked ketamine-, MK-801- and Ro25-6981-induced immobility reductions in the forced swim test, indicating the antidepressant-like effects of these agents require AMPA throughput. Ketamine altered GluR1 phosphorylation in hippocampal tissues from ketamine treated animals, the effects was also blocked by NBQX pretreatment. Taken together, our animal findings strongly support the involvement of AMPA receptors in ketamine_s antidepressant-like action and the AMPA/NMDA throughput strategy to develop novel antidepressive agents. Future studies are required to further elucidate the receptor subtype(s) and the brain region(s) involved in this ketamine antidepressant-like action.