Laboratório de Neurociências, Instituto Nacional de Ciência e Tecnologia Translacional em Medicina, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, 88806-000 Criciúma, SC, Brazil.
Behav Brain Res. 2011 Aug 1;221(1):166-71. doi: 10.1016/j.bbr.2011.02.024. Epub 2011 Mar 21.
A growing body of evidence has pointed to the N-methyl-d-aspartate (NMDA) receptor antagonists as a potential therapeutic target for the treatment of major depression. The present study investigated the possibility of synergistic interactions between antidepressant imipramine with the uncompetitive NMDA receptor antagonist ketamine. Wistar rats were acutely treated with ketamine (5 and 10mg/kg) and imipramine (10 and 20mg/kg) and then subjected to forced swimming tests. The cAMP response element bindig (CREB) and brain-derived neurotrophic factor (BDNF) protein levels and protein kinase C (PKC) and protein kinase A (PKA) phosphorylation were assessed in the prefrontal cortex, hippocampus and amygdala by imunoblot. Imipramine at the dose of 10mg/kg and ketamine at the dose of 5mg/kg did not have effect on the immobility time; however, the effect of imipramine (10 and 20mg/kg) was enhanced by both doses of ketamine. Ketamine and imipramine alone or in combination at all doses tested did not modify locomotor activity. Combined treatment with ketamine and imipramine produced stronger increases of CREB and BDNF protein levels in the prefrontal cortex, hippocampus and amygdala, and PKA phosphorylation in the hippocampus and amygdala and PKC phosphorylation in prefrontal cortex. The results described indicate that co-administration of antidepressant imipramine with ketamine may induce a more pronounced antidepressant activity than treatment with each antidepressant alone. This finding may be of particular importance in the case of drug-resistant patients and could suggest a method of obtaining significant antidepressant actions whilst limiting side effects.
越来越多的证据表明，N-甲基-D-天冬氨酸（NMDA）受体拮抗剂可能成为治疗重度抑郁症的潜在治疗靶点。本研究探讨了抗抑郁药丙咪嗪与非竞争性 NMDA 受体拮抗剂氯胺酮协同作用的可能性。Wistar 大鼠急性给予氯胺酮（5 和 10mg/kg）和丙咪嗪（10 和 20mg/kg），然后进行强迫游泳试验。通过免疫印迹法评估前额叶皮质、海马和杏仁核中的 cAMP 反应元件结合蛋白（CREB）和脑源性神经营养因子（BDNF）蛋白水平以及蛋白激酶 C（PKC）和蛋白激酶 A（PKA）磷酸化。丙咪嗪 10mg/kg 剂量和氯胺酮 5mg/kg 剂量对不动时间没有影响；然而，丙咪嗪（10 和 20mg/kg）的作用被两种剂量的氯胺酮增强。氯胺酮和丙咪嗪单独或联合使用在所有测试剂量下均未改变运动活性。氯胺酮和丙咪嗪联合治疗在额叶皮质、海马和杏仁核中产生更强的 CREB 和 BDNF 蛋白水平增加，以及海马和杏仁核中的 PKA 磷酸化和前额叶皮质中的 PKC 磷酸化。描述的结果表明，与单独使用每种抗抑郁药相比，联合使用抗抑郁药丙咪嗪和氯胺酮可能会产生更明显的抗抑郁作用。这一发现对于耐药患者可能尤为重要，并可能提示一种获得显著抗抑郁作用而限制副作用的方法。
