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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

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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

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.

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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Data availability

The data used in the present study are available from the corresponding author upon reasonable request.

Abbreviations

AD:

antidepressant drug

BDNF:

brain derived neurotrophic factor

eEF2:

eukaryotic elongation factor 2

FST:

forced swim test

ip:

intraperitoneal

M:

5MPEP–2–(2–(3–methoxyphenyl)ethynyl)–5–methylpyridine

mGlu5 receptor:

metabotropic glutamate 5 receptor

mTOR:

mammalian target of rapamycin

NAM:

negative allosteric modulator

NSF:

novelty–suppressed feeding

PFC:

prefrontal cortex

RAAD:

rapid–acting antidepressant drug

SERT:

serotonin transporter

SPT:

sucrose preference test

SSRI:

selective serotonin reuptake inhibitor

TrkB:

tropomyosin receptor kinase B

TST:

tail suspension test

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Acknowledgments

This research was funded by the National Science Centre, Poland, grant number 2017/27/B/NZ7/01873 to A.P-P. and by Funds for the Statutory Activity of the Maj Institute of Pharmacology, Polish Academy of Sciences. The authors thank Aneta Kozioł for technical support during chemical synthesis.

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Authors and Affiliations

  1. Department of Neurobiology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, Kraków, 31-343, Poland

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

  2. Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, Kraków, 31-343, Poland

    Katarzyna Kaczorowska

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  1. Agnieszka Pałucha-Poniewiera
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  2. Anna Rafało-Ulińska
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Contributions

AP-P – designed and supervised the project, planned all experiments, performed behavioral experiments, interpreted experimental data, and wrote the manuscript.; AR-U – performed all Western blots and ELISA experiments and analyzed the data; MS, YB – performed behavioral experiments; KK – designed and performed M-5MPEP synthesis.

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Correspondence to Agnieszka Pałucha-Poniewiera.

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Pałucha-Poniewiera, A., Rafało-Ulińska, A., Santocki, M. et al. 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. Pharmacol. Rep (2024). https://doi.org/10.1007/s43440-024-00588-3

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