Abstract：
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.
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.
摘要：
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。
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。
