背景:代谢型谷氨酸5(mGlu5)受体的部分负变构调节剂(NAM)是完全拮抗剂和NAM的极好替代品,因为它们保留了治疗效果并具有更宽的治疗窗口。这里,我们调查了部分mGlu5NAM,2-(2-(3-甲氧基苯基)乙炔基)-5-甲基吡啶(M-5MPEP),诱导快速和持续的抗抑郁作用,速效抗抑郁药(RAADs)如氯胺酮的特征,在老鼠身上。
方法:采用悬尾试验(TST)研究急性抗抑郁样作用。使用飞溅试验研究了四次腹膜内(ip)给药后24小时的持续作用,旨在测量冷漠状态,蔗糖偏好试验(SPT),反映了快感缺失,还有TST.Westernblot和ELISA技术用于测量脑源性神经营养因子(BDNF)和选定的蛋白质水平。
方法:采用悬尾试验(TST)研究急性抗抑郁样作用。使用飞溅试验研究了四次腹膜内(ip)给药后24小时的持续作用,旨在测量冷漠状态,蔗糖偏好试验(SPT),反映了快感缺失,还有TST.Westernblot和ELISA技术用于测量脑源性神经营养因子(BDNF)和选定的蛋白质水平。
结论:部分mGlu5受体NAM,M-5MPEP,在BDNF依赖性机制中诱导快速和持续的抗抑郁样作用,并增强小鼠的(R)-氯胺酮作用,表明这两种物质的作用机制和它们作为RAAD治疗抑郁症的实际用途的可能性。
BACKGROUND: Partial negative allosteric modulators (NAM) of the metabotropic glutamate 5 (mGlu5) receptor are an excellent alternative to full antagonists and NAMs because they retain therapeutic effects and have a much broader therapeutic window. Here, we investigated whether partial mGlu5 NAM, 2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine (M-5MPEP), induced a fast and sustained antidepressant-like effect, characteristic of rapid-acting antidepressant drugs (RAADs) like ketamine, in mice.
METHODS: A tail suspension test (TST) was used to investigate acute antidepressant-like effects. Sustained effects were studied 24 h after the four intraperitoneal (ip) administrations using the splash test, designed to measure apathy-like state, the sucrose preference test (SPT), reflecting anhedonia, and the TST. Western blot and ELISA techniques were used to measure brain-derived neurotrophic factor (BDNF) and selected protein levels.
METHODS: A tail suspension test (TST) was used to investigate acute antidepressant-like effects. Sustained effects were studied 24 h after the four intraperitoneal (ip) administrations using the splash test, designed to measure apathy-like state, the sucrose preference test (SPT), reflecting anhedonia, and the TST. Western blot and ELISA techniques were used to measure brain-derived neurotrophic factor (BDNF) and selected protein levels.
CONCLUSIONS: Partial mGlu5 receptor NAM, M-5MPEP, induced rapid and sustained antidepressant-like effects in the BDNF-dependent mechanism and enhanced (R)-ketamine action in mice, indicating both substances\' convergent mechanisms of action and the possibility of their practical use in treating depression as RAAD.