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Cited by 71Treatment of Major DepressionNeuroscience and Neuropharmacology ResearchNeurotransmitter Receptor Influence on Behavior

Targeting metabotropic glutamate receptors for the treatment of depression and other stress-related disorders

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Dogra, Shalini, Conn, P. Jeffrey·2021·Neuropharmacology
DOI 10.1016/j.neuropharm.2021.108687PMC PMC8435015
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Abstract

The discovery of robust antidepressant effects of ketamine in refractory patients has led to increasing focus on agents targeting glutamatergic signaling as potential novel antidepressant strategy. Among the agents targeting the glutamatergic system, compounds acting at metabotropic glutamate (mGlu) receptors are among the most promising agents under studies for depressive disorders. Further, the receptor diversity, distinct distribution in the CNS, and ability to modulate the glutamatergic neurotransmission in the brain areas implicated in mood disorders make them an exciting target for stress-related disorders. In preclinical models, antidepressant and anxiolytic effects of mGlu 5 negative allosteric modulators (NAMs) have been reported. Interestingly, mGlu 2/3 receptor antagonists show fast and sustained antidepressant-like effects similar to that of ketamine in rodents. Excitingly, they can also induce antidepressant effects in the animal models of treatment-resistant depression and are devoid of the side-effects associated with ketamine. Unfortunately, clinical trials of both mGlu 5 and mGlu 2/3 receptor NAMs have been inconclusive, and additional trials using other compounds with suitable preclinical and clinical properties are needed. Although group III mGlu receptors have gained less attention, mGlu 7 receptor ligands have been shown to induce antidepressant-like effects in rodents. Collectively, compounds targeting mGlu receptors provide an alternative approach to fill the outstanding clinical need for safer and more efficacious antidepressants. This article is part of the special Issue on "Glutamate Receptors - mGluRs".

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  • miR-335, miR-1202, miR-29b-3p, and miR-134-5p may regulate depression through inhibiting GRM4 expression, affecting Ca2+ influx into prefrontal cortex neurons and extracellular glutamate concentration.

    “MiR-335, miR-1202, miR-29b-3p, and miR-134-5p may regulate depression through inhibiting the expression of GRM4 gene (Fig. 5), that in turn affect the influx of Ca2+ into the prefrontal cortex neurons and the extracellular concentration of glutamate.277–283”

    From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [277]

    The section “Blockade of mGlu4 receptor signaling may induce antidepressant effects” (page unavailable) reports that miR-29b-3p acts on Grm4 and that its overexpression lowered Grm4 expression and improved depressive symptoms in stress-exposed rats. Our copy does not link miR-335, miR-1202, or miR-134-5p to GRM4 inhibition, or describe the claimed downstream effects on Ca2+ influx in prefrontal cortex neurons and extracellular glutamate concentration. (LLM, conf=0.87)

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Cited by

Sorted by citations

Authors
Dogra, S., & Conn, P. J.
Affiliations
Vanderbilt University (US)
Corresponding author
Conn, P. Jeffrey
ORCID
Venue
Neuropharmacology
Publisher
Elsevier BV
Published
2021-09
Volume
196
Pages
108687
ISSN
0028-3908 (ISSN-L)
DOI
10.1016/j.neuropharm.2021.108687
PMC
PMC8435015
OpenAlex
W3173876705
Cited by
71
References
12
Citations by year
2026: 10 · 2025: 19 · 2024: 12 · 2023: 16 · 2022: 14
FWCI
1.33
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuropharmacology (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institutes of Health (R01MH062646, R37NS031373)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
metabotropic glutamate receptors, depression, treatment-resistant depression, stress-related disorders, ketamine, antidepressants, glutamatergic neurotransmission, anxiolytic effects
MeSH terms
Allosteric Regulation, Animals, Anxiety Disorders, Brain, Depressive Disorder, Major, Major Depressive Disorder, Humans, Ketamine, Stress, Psychological, Receptors, Metabotropic Glutamate, Excitatory Amino Acid Antagonists, Molecular Targeted Therapy, Depressive Disorder, Treatment-Resistant, Receptor, Metabotropic Glutamate 5

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