Department of Pharmacology, School of Medicine, Medical Sciences, University of Tehran, Tehran, Iran.
J Psychopharmacol. 2010 Apr;24(4):585-94. doi: 10.1177/0269881109104845. Epub 2009 Apr 7.
Although there is evidence of the involvement of N-methyl-D-aspartate receptors (NMDAR) in the action of lithium, its role in the antidepressant effects of lithium in a behavioural model remains unclear. In this study, we evaluated the effects of NMDAR antagonists on the antidepressant-like effects of lithium in the mouse forced swimming test. Lithium (30 and 100 mg/kg, i.p.) significantly (P < 0.01) reduced the immobility times of mice, whereas at lower doses (5 and 10 mg/kg) had no effect. NMDA antagonists ketamine (2 and 5 mg/kg, i.p.), MK-801 (0.1 and 0.25 mg/kg, i.p.) and ifenprodil (1 and 3 mg/kg, i.p.) significantly (P < 0.05) decreased the immobility time. Lower doses of ketamine (0.5 and 1 mg/kg), MK-801 (0.01 and 0.05 mg/kg) and ifenprodil (0.1 and 0.5 mg/kg) had no effect. Combined treatment of subeffective doses of lithium (10 mg/kg) and ketamine (1 mg/kg), MK-801 (0.05 mg/kg) or ifenprodil (0.5 mg/kg) robustly (P < 0.001) exerted an antidepressant-like effect. The noneffective dose of a NMDA agonist (NMDA, 75 mg/kg, i.p.) prevented the antidepressant-like effect of lithium (30 mg/kg). None of the drugs at subactive doses or in combination with lithium had significant effect on the locomotor activity in the open field test. We for the first time suggested a role for NMDAR signalling in the antidepressant-like effects of lithium, providing a new approach for treatment of depression.
虽然有证据表明 N-甲基-D-天冬氨酸受体 (NMDAR) 参与了锂的作用，但它在锂的行为模型中的抗抑郁作用中的作用仍不清楚。在这项研究中，我们评估了 NMDAR 拮抗剂对锂在小鼠强迫游泳试验中抗抑郁样作用的影响。锂（30 和 100mg/kg，ip）显著（P < 0.01）减少了小鼠的不动时间，而较低剂量（5 和 10mg/kg）则没有影响。NMDA 拮抗剂氯胺酮（2 和 5mg/kg，ip）、MK-801（0.1 和 0.25mg/kg，ip）和ifenprodil（1 和 3mg/kg，ip）显著（P < 0.05）降低了不动时间。较低剂量的氯胺酮（0.5 和 1mg/kg）、MK-801（0.01 和 0.05mg/kg）和 ifenprodil（0.1 和 0.5mg/kg）则没有效果。锂（10mg/kg）和氯胺酮（1mg/kg）、MK-801（0.05mg/kg）或 ifenprodil（0.5mg/kg）的亚效剂量联合治疗，强烈（P < 0.001）发挥了抗抑郁样作用。NMDA 激动剂（NMDA，75mg/kg，ip）的无效剂量可阻止锂（30mg/kg）的抗抑郁样作用。亚有效剂量的药物或与锂联合使用，对旷场试验中的运动活动均无显著影响。我们首次提出了 NMDAR 信号在锂的抗抑郁样作用中的作用，为治疗抑郁症提供了一种新方法。
