Biological Psychiatry：麻醉剂克他命具有快速抗抑郁效果
目前，抑郁症治疗药物大多都有药效迟缓的缺陷，从服药到见效往往需要几周的时间。抑郁症往往对患者带来严重的精神折磨，而且影响患者工作生活能力，因此，临床治疗迫切需要药效迅速的药物。最近，科学家研究发现，常用麻醉剂克他命能在数小时内改善抑郁症病情。相关论文发表在2008年2月的爱思唯尔期刊《生物精神病学》（Biological Psychiatry）上。
克他命是一种n甲基d天冬氨酸 (NMDA)受体阻断剂。Maeng和同事在研究中发现，克他命抗抑郁症机理在于它对α-氨基-3-羟基-5-甲基-4-丙酸(AMPA)受体的激励作用。这表明，激励AMPA受体能够快速改善抑郁症病情。
文章通信作者Husseini Manji博士说：“通过瞄准新的药物标靶，例如NMDA或AMPA，我们也许能够实现迂回前进的效果。回避导致目前的抗抑郁药物疗效迟缓的若干药物作用阶段，从而达到快速起效的目的。目前的抗抑郁药物最终作用目标是一致的，但有些药物起作用要经过若干生物化学步骤，这浪费了很多时间。现在，我们发现了关键标靶，直接瞄准标靶，所以见效快。”
克他命虽具有抗抑郁效果，但还有一些明显的缺陷。《生物精神病学》杂志的编辑，同时还受聘于耶鲁大学医学院和美国退役军人协会康涅狄格医疗服务系统的医学博士John H. Krystal说：“克他命作为迄今为止发现的唯一有效的NMDA受体阻断剂会引起感知激变，损伤认知力。”同时，它和苯环己哌啶属同一类药物，有致幻等副作用。Krystal同时指出：“能够直接促进谷氨酸受体活动的药物谷氨酸受体调控剂（AMPAkines）可能会产生与克他命相似的抗抑郁效果，而且不具有副作用。”对谷氨酸受体调控剂（AMPAkines）的抗抑郁效果研究将成为下一步研究的重点。（科学网 荔涛/编译）
生物谷推荐原始出处：
（Biological Psychiatry），doi:10.1016/j.biopsych.2007.05.028 ，Sungho Maeng, Husseini K. Manji
Cellular Mechanisms Underlying the Antidepressant Effects of Ketamine: Role of α-Amino-3-Hydroxy-5-Methylisoxazole-4-Propionic Acid Receptors
Sungho Maenga, Carlos A. Zarate Jra, Jing Dua, Robert J. Schloessera, Joseph McCammona, Guang Chena and Husseini K. Manji
, a, 
aLaboratory of Molecular Pathophysiology and Experimental Therapeutics, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, and Department of Health & Human Services, Bethesda, Maryland.
Received 7 August 2006; revised 14 May 2007; accepted 23 May 2007. Available online 23 July 2007.
Background
Ketamine exerts a robust, rapid, and relatively sustained antidepressant effect in patients with major depression. Understanding the mechanisms underlying the intriguing effects of N-methyl d-aspartate (NMDA) antagonists could lead to novel treatments with a rapid onset of action.
Methods
The learned helplessness, forced swim, and passive avoidance tests were used to investigate ketamine’s behavioral effects in mice. Additional biochemical and behavioral experiments were undertaken to determine whether the antidepressant-like properties of ketamine and other NMDA antagonists involve α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor throughput.
Results
Subanesthetic doses of ketamine treatment caused acute and sustained antidepressant-like effects. At these doses, ketamine did not impair fear memory retention. MK-801 (dizocilpine) and Ro25-6981, an NR2B selective antagonist, also exerted antidepressant-like effects; these effects, however, were not sustained as long as those of ketamine. Pre-treatment with NBQX, an AMPA receptor antagonist, attenuated both ketamine-induced antidepressant-like behavior and regulation of hippocampal phosphorylated GluR1 AMPA receptors.
Conclusions
NMDA antagonists might exert rapid antidepressant-like effects by enhancing AMPA relative to NMDA throughput in critical neuronal circuits.
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