Rapid Antidepressant Action and Restoration of Excitatory Synaptic Strength After Chronic Stress by Negative Modulators of Alpha5-Containing GABAA Receptors
Open accessAbstract
Selective serotonin reuptake inhibitors (SSRIs) are the primary pharmacological treatment for depression, but SSRIs are effective in only half of the patients and typically take several weeks to relieve symptoms. The NMDA receptor antagonist ketamine exerts a rapid antidepressant action, but has troubling side effects. We hypothesized that negative allosteric modulators of GABAA receptors would exert similar effects on brain activity as ketamine, but would not exert as many side effects if targeted only to GABAA receptors containing α5 subunits, which are enriched in the hippocampus and prefrontal cortex. Here, we show that the α5-selective negative modulator L-655,708 reversed the alterations in hedonic behavior in the sucrose preference and social interaction tests produced by two different chronic stress paradigms in rats within 24 h of systemic administration. Similar effects were observed with another α5-selective negative modulator, MRK-016. L-655,708 had no effect on hedonic or open-field behavior in unstressed animals. Within 24 h, L-655,708 injection also restored the strength of pathologically weakened excitatory synaptic transmission at the stress-sensitive temporoammonic-CA1 synapse, measured electrophysiologically, and increased levels of the GluA1 subunit of the AMPA receptor, measured with western blotting. We suggest that the ability of L-655,708 to restore excitatory synaptic strength rapidly may underlie its ability to restore stress-induced behavioral alterations rapidly, supporting evidence that dysfunction of multiple excitatory synapses in cortico-mesolimbic reward pathways contributes, in part, to the genesis of depression. Negative allosteric modulators of α5 subunit-containing GABAA receptors represent a promising novel class of fast-acting and clinically viable antidepressant compounds.
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Subsequent preclinical experiments supported the hypothesis that negative allosteric modulators of GABA A receptors containing alpha5 subunits would produce a ketamine-like rapid antidepressant response.
“Subsequent preclinical experiments supported this hypothesis [152,273].”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [273]
α5GABAARs have been implicated in anxiety, fear and/or response to chronic stress.
“In addition, γ2GABAARs [11], α1GABAARs [10, 12], α3GABAARs [13] (but see [14-16] for contradictory findings), and more recently, α5GABAARs [16-18, 4] have been implicated in anxiety, fear and/or response to chronic stress.”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [17]
Both positive and negative allosteric modulation of α5GABAARs produces rapid antidepressant-like effects and/or reductions in stress-related behaviors in rodents exposed to chronic stress.
“Interestingly, both positive and negative allosteric modulation of α5GABAARs produces rapid antidepressant-like effects and/or reductions in stress-related behaviors in rodents exposed to chronic stress [17, 18, 140, 141].”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [17]
Administration of partial inverse agonists at the benzodiazepine binding site of alpha5-containing GABAA receptors promotes coherent network activity via disinhibition of excitatory neurotransmission and exerts rapid antidepressant actions in several animal tests.
“Further supporting this hypothesis, administration of partial inverse agonists at the benzodiazepine binding site of alpha5-containing GABAA receptors, which are selectively expressed in the forebrain, including prefrontal cortex and hippocampus, promote coherent network activity via disinhibition of excitatory neurotransmission 45 and exert rapid antidepressant actions in several animal tests 46–”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [46]
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- Authors
- Fischell, J., Van Dyke, A. M., Kvarta, M. D., LeGates, T. A., & Thompson, S. M.
- Affiliations
- University of Maryland, Baltimore (US)
- Corresponding author
- Thompson, Scott M
- Venue
- Neuropsychopharmacology
- Published
- 2015-04-22
- Volume
- 40
- Issue
- 11
- Pages
- 2499-2509
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC4569955
- OpenAlex
- W2056406527
- Cited by
- 122
- References
- 65
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 5 · 2023: 9 · 2022: 14 · 2021: 10 · 2020: 9 · 2019: 24 · 2018: 21 · 2017: 9 · 2016: 8 · 2015: 1
- FWCI
- 9.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (2t32ns063391-21)
- National Institute of Mental Health (R01MH086828)
- National Institute of General Medical Sciences (T32GM008181)
- National Institute of Neurological Disorders and Stroke (T32NS007375, T32-NS063391)
- 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
- alpha5 GABA-A receptor, negative allosteric modulators, chronic stress, depression, excitatory synaptic transmission, hedonic behavior, sucrose preference, social interaction, ketamine, hippocampus, prefrontal cortex
- MeSH terms
- Animals, Antidepressive Agents, Chronic Disease, Disease Models, Animal, Exploratory Behavior, Feeding Behavior, Imidazoles, Isoxazoles, Male, Synaptic Transmission, Random Allocation, Receptors, GABA-A, Restraint, Physical, Social Behavior, Stress, Psychological, Synapses, Triazines, Rats, Sprague-Dawley, Receptors, AMPA, GABA Modulators, Dietary Sucrose, Tissue Culture Techniques, CA1 Region, Hippocampal
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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