Functional antagonists at the NMDA receptor complex exhibit antidepressant actions

Trullas, Ramon; Skolnick, Phil

doi:10.1016/0014-2999(90)90204-j

Cited by 785Treatment of Major DepressionNeuroscience and Neuropharmacology ResearchNeurotransmitter Receptor Influence on Behavior

Functional antagonists at the NMDA receptor complex exhibit antidepressant actions

Trullas, Ramon, Skolnick, Phil·1990·European Journal of Pharmacology

DOI 10.1016/0014-2999(90)90204-j

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Abstract

Inescapable, but not escapable, stress inhibits the induction of Long Term Potentiation (LTP) in the CA1 region of hippocampus, a process that is dependent upon activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. Since inescapable stress also produces a syndrome of behavioral depression sensitive to clinically effective antidepressants, we examined the actions of functional antagonists at the NMDA receptor complex in animal models commonly used to evaluate potential antidepressants. A competitive NMDA antagonist (2-amino-7-phosphonoheptanoic acid [AP-7]), a non-competitive NMDA antagonist (Dizolcipine [MK-801]), and a partial agonist at strychnine-insensitive glycine receptors (1-aminocylopropanecarboxylic acid [ACPC]) mimicked the effects of clinically effective antidepressants in these models. These findings indicate that the NMDA receptor complex may be involved in the behavioral deficits induced by inescapable stress, and that substances capable of reducing neurotransmission at the NMDA receptor complex may represent a new class of antidepressants. Based on these findings, the hypothesis that pathways subserved by the NMDA subtype of glutamate receptors are involved in the pathophysiology of affective disorders may have heuristic value.

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AP-7 and MK-801, other NMDAR antagonists, produced antidepressant-like effects in mice before ketamine was clinically used for depression.
“The clinical use of NMDAR antagonists, such as ketamine, for the treatment of depression was preceded by the finding that other NMDAR antagonists, including AP-7 and MK-801, produced antidepressant-like effects in mice”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Trullas & Skolnick, 1990
MK-801 and AP-7 decrease immobility time in the forced-swim test in mice, a measure of antidepressant efficacy.
“Trullas and Skolnick, 1990, were the first to show that the NMDAR non-competitive channel blocker MK-801 and the competitive NMDAR inhibitor AP-7 decrease immobility time in the forced-swim test in mice, a measure of antidepressant efficacy 30.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [30]

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Authors: Trullas, R., & Skolnick, P.
Affiliations: National Institutes of Health (US)
ORCID: Skolnick, Phil
Venue: European Journal of Pharmacology
Publisher: Elsevier BV
Published: 1990-08
Volume: 185
Issue: 1
Pages: 1-10
ISSN: 0014-2999 (ISSN-L)
DOI: 10.1016/0014-2999(90)90204-j
OpenAlex: W2086305648
Cited by: 785
References: 48
Citations by year: 2026: 5 · 2025: 23 · 2024: 26 · 2023: 32 · 2022: 33 · 2021: 52 · 2020: 52 · 2019: 28 · 2018: 32 · 2017: 24 · 2016: 29 · 2015: 37 · 2014: 40 · 2013: 34 · 2012: 29
FWCI: 12.56
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: European Journal of Pharmacology (publishedVersion)
PubMed (publishedVersion)
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: NMDA receptor, antidepressant mechanism, inescapable stress, depression, long-term potentiation, hippocampal CA1, AP7, MK-801, ACPC, strychnine-insensitive glycine receptor, partial agonists, glutamate receptors, mood disorders
MeSH terms: Amino Acids, Amino Acids, Cyclic, Animals, Antidepressive Agents, Behavior, Animal, Brain Chemistry, Dose-Response Relationship, Drug, Imipramine, Immobilization, Male, Mice, Inbred C57BL, Motor Activity, Synaptic Transmission, Stress, Psychological, Strychnine, Swimming, 2-Amino-5-phosphonovalerate, Receptors, N-Methyl-D-Aspartate, Dizocilpine Maleate, Receptors, Neurotransmitter, Receptors, Glycine, Mice

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Functional antagonists at the NMDA receptor complex exhibit antidepressant actions

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