Partial mGlu5 receptor NAM, M-5MPEP, induces rapid and sustained antidepressant-like effects in the BDNF-dependent mechanism and enhances (R)-ketamine action in mice

IF 3.6 3区医学 Q2 PHARMACOLOGY & PHARMACY Pharmacological Reports Pub Date : 2024-04-18 DOI:10.1007/s43440-024-00588-3

Agnieszka Pałucha-Poniewiera, Anna Rafało-Ulińska, Michal Santocki, Yana Babii, Katarzyna Kaczorowska

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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

Conclusion

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.

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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（R）-氯胺酮在小鼠体内的作用

背景mGlu5（metabotropic glutamate 5，mGlu5）受体的部分负性异位调节剂（NAM）是完全拮抗剂和 NAMs 的绝佳替代品，因为它们保留了治疗效果，而且治疗窗口更广。在此，我们研究了部分 mGlu5 NAM--2-（2-（3-甲氧基苯基）乙炔基）-5-甲基吡啶（M-5MPEP）--是否能在小鼠体内诱导快速和持续的抗抑郁样作用，这是氯胺酮等速效抗抑郁药（RAAD）的特征。在四次腹腔注射（ip）24小时后，使用旨在测量类似冷漠状态的泼溅试验、反映失神的蔗糖偏好试验（SPT）和TST对持续效应进行了研究。采用 Western 印迹和 ELISA 技术测量脑源性神经营养因子 (BDNF) 和特定蛋白质的水平。在四次腹腔注射（ip）24小时后，使用旨在测量类似冷漠状态的泼溅试验、反映失神的蔗糖偏好试验（SPT）和TST对持续效应进行研究。结论部分 mGlu5 受体 NAM（M-5MPEP）在 BDNF 依赖性机制中诱导了快速和持续的抗抑郁样作用，并增强了（R）-氯胺酮在小鼠体内的作用，表明这两种物质的作用机制趋同，并有可能作为 RAAD 实际用于治疗抑郁症。

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来源期刊

Pharmacological Reports 医学-药学

CiteScore

8.40

自引率

0.00%

发文量

审稿时长

6 months

期刊介绍： Pharmacological Reports publishes articles concerning all aspects of pharmacology, dealing with the action of drugs at a cellular and molecular level, and papers on the relationship between molecular structure and biological activity as well as reports on compounds with well-defined chemical structures. Pharmacological Reports is an open forum to disseminate recent developments in: pharmacology, behavioural brain research, evidence-based complementary biochemical pharmacology, medicinal chemistry and biochemistry, drug discovery, neuro-psychopharmacology and biological psychiatry, neuroscience and neuropharmacology, cellular and molecular neuroscience, molecular biology, cell biology, toxicology. Studies of plant extracts are not suitable for Pharmacological Reports.