一种选择性 mGlu7 受体拮抗剂 MMPIP 逆转了 AMN082 在大鼠中的抗抑郁样作用。
A selective mGlu7 receptor antagonist MMPIP reversed antidepressant-like effects of AMN082 in rats.
机构信息
Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Kraków, Poland.
出版信息
Behav Brain Res. 2013 Feb 1;238:109-12. doi: 10.1016/j.bbr.2012.10.004. Epub 2012 Oct 17.
Previous behavioural studies strongly indicated on potential antidepressant-like activity of mGlu7 positive allosteric modulator, AMN082 (N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride). However, the mechanism of action of this drug was not clear. Some recent data, showing possible off-target activities of AMN082 and its metabolites casted doubt on the role of mGlu7 receptor activation in the antidepressant-like activity of this compound. In the present study we used a selective mGlu7 receptor antagonist, MMPIP (6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazolo[4,5-c]pyridin-4(5H)-one), to investigate the role of mGlu7 receptor blockade in the antidepressant action of AMN082 in the forced swim test (FST) in rats. We showed that MMPIP (10 mg/kg, i.p.) completely reversed AMN082 (8 mg/kg, i.p.)-induced behavioural effects, including decreased immobility time and increased swimming time, suggesting the crucial role of mGlu7 receptor activation in the antidepressant-like effects of AMN082 in the FST. On the other hand, our studies showed, that AMN082 (8 mg/kg, i.p.)-induced decrease in locomotor activity was not affected by MMPIP (10 mg/kg, i.p.), indicating on other, non-mGlu7 receptor-dependent mechanisms involved in changes in locomotor activity of rats after AMN082 administration.
先前的行为研究强烈表明,mGlu7 正变构调节剂 AMN082(N,N'-二苄基乙二胺二盐酸盐)具有潜在的抗抑郁样活性。然而,这种药物的作用机制尚不清楚。最近的一些数据显示,AMN082 及其代谢物可能存在脱靶活性,这使得人们对 mGlu7 受体激活在该化合物抗抑郁样活性中的作用产生了怀疑。在本研究中,我们使用选择性 mGlu7 受体拮抗剂 MMPIP(6-(4-甲氧基苯基)-5-甲基-3-吡啶-4-基异噁唑并[4,5-c]吡啶-4(5H)-酮),来研究 mGlu7 受体阻断在 AMN082 在大鼠强迫游泳试验(FST)中的抗抑郁作用中的作用。我们发现,MMPIP(10mg/kg,ip)完全逆转了 AMN082(8mg/kg,ip)引起的行为效应,包括减少不动时间和增加游泳时间,这表明 mGlu7 受体激活在 AMN082 在 FST 中的抗抑郁样作用中起着关键作用。另一方面,我们的研究表明,MMPIP(10mg/kg,ip)不会影响 AMN082(8mg/kg,ip)引起的运动活性降低,这表明 AMN082 给药后大鼠运动活性的变化涉及其他非 mGlu7 受体依赖的机制。