Sex-dependent anti-stress effect of an α5 subunit containing GABAA receptor positive allosteric modulator
Open accessAbstract
Rationale: Current first-line treatments for stress-related disorders such as Major Depressive Disorder (MDD) act on monoaminergic systems and take weeks to achieve a therapeutic effect with poor response and low remission rates. Recent research has implicated the GABAergic system in the pathophysiology of depression, including deficits in interneurons targeting the dendritic compartment of cortical pyramidal cells. Objectives: The present study evaluates whether SH-053-2'F-R-CH3 (denoted "α5-PAM"), a positive allosteric modulator selective for α5-subunit containing GABAA receptors found predominantly on cortical pyramidal cell dendrites has anti-stress effects. Methods: Female and male C57BL6/J mice were exposed to unpredictable chronic mild stress (UCMS) and treated with α5-PAM acutely (30 minutes prior to assessing behavior) or chronically before being assessed behaviorally. Results: Acute and chronic α5-PAM treatments produce a pattern of decreased stress-induced behaviors (denoted as “behavioral emotionality”) across various tests in female, but not in male mice. Behavioral Z-scores calculated across a panel of tests designed to best model the range and heterogeneity of human symptomatology confirmed that acute and chronic α5-PAM treatments consistently produce significant decreases in behavioral emotionality in several independent cohorts of females. The behavioral responses to α5-PAM could not be completely accounted for by differences in drug brain disposition between female and male mice. In mice exposed to UCMS, expression of the Gabra5 gene was increased in the frontal cortex after acute treatment and in hippocampus after chronic treatment with α5-PAM in females only, and these expression changes correlated with behavioral emotionality. Conclusions: We showed that acute and chronic positive modulation of α5 subunit-containing GABAA receptors elicit anti-stress effects in a sex-dependent manner, suggesting novel therapeutic modalities.
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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 [18]
The α5 positive allosteric modulator SH-053-2′F-R-CH3 increased α5 transcript expression in the prelimbic cortex and hippocampus of female mice exposed to chronic stress.
“The α5 positive allosteric modulator SH-053-2′F-R-CH3 increased α5 transcript expression in the prelimbic cortex and hippocampus of female mice exposed to chronic stress [18].”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [18]
Effects observed with positive allosteric modulators are likely due to an increase in the activity of α5GABAARs.
“Experiments with positive allosteric modulators, on the other hand, were conducted shortly after drug administration [18], and the effects observed are likely to be the result of an increase in the activity of α5GABAARs.”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [18]
Experiments with positive allosteric modulators were conducted shortly after drug administration.
“Experiments with positive allosteric modulators, on the other hand, were conducted shortly after drug administration [18], and the effects observed are likely to be the result of an increase in the activity of α5GABAARs.”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [18]
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References 77 · Cited by 67
- Authors
- Piantadosi, S. C., French, B. J., Poe, M. M., Timić, T., Marković, B. D., Pabba, M., Seney, M. L., Oh, H., Orser, B. A., Savić, M. M., Cook, J. M., & Sibille, E.
- Affiliations
- University of Pittsburgh (US)
- University of Wisconsin–Milwaukee (US)
- University of Belgrade (RS)
- Centre for Addiction and Mental Health (CA)
- University of Toronto (CA)
- Corresponding author
- Sibille, Etienne
- ORCID
- Venue
- Frontiers in Pharmacology
- Publisher
- Frontiers Media SA
- Published
- 2016-11-22
- Volume
- 7
- Pages
- 446-446
- ISSN
- 1663-9812 (ISSN-L)
- PMC
- PMC5118774
- OpenAlex
- W2553022533
- Cited by
- 67
- References
- 77
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 10 · 2023: 5 · 2022: 8 · 2021: 9 · 2020: 3 · 2019: 10 · 2018: 10 · 2017: 5
- FWCI
- 4.67
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Pharmacology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- FarFar (University of Belgrade, Faculty of Chemistry (Belgrade, Serbia)) (submittedVersion, cc-by)
- Funders
- National Institutes of Health (MH093723, MH096463, HL118561)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- alpha5 GABA-A receptor, positive allosteric modulators, sex differences, anti-stress effects, chronic unpredictable mild stress, major depressive disorder, GABAergic system, cortical pyramidal neurons, hippocampus, frontal cortex
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