Evidence for a Significant Role of α3-Containing GABAAReceptors in Mediating the Anxiolytic Effects of Benzodiazepines
Open accessAbstract
The GABA(A) receptor subtypes responsible for the anxiolytic effects of nonselective benzodiazepines (BZs) such as chlordiazepoxide (CDP) and diazepam remain controversial. Hence, molecular genetic data suggest that alpha2-rather than alpha3-containing GABA(A) receptors are responsible for the anxiolytic effects of diazepam, whereas the anxiogenic effects of an alpha3-selective inverse agonist suggest that an agonist selective for this subtype should be anxiolytic. We have extended this latter pharmacological approach to identify a compound, 4,2'-difluoro-5'-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-á]pyridin-3-yl]biphenyl-2-carbonitrile (TP003), that is an alpha3 subtype selective agonist that produced a robust anxiolytic-like effect in both rodent and non-human primate behavioral models of anxiety. Moreover, in mice containing a point mutation that renders alpha2-containing receptors BZ insensitive (alpha2H101R mice), TP003 as well as the nonselective agonist CDP retained efficacy in a stress-induced hyperthermia model. Together, these data show that potentiation of alpha3-containing GABA(A) receptors is sufficient to produce the anxiolytic effects of BZs and that alpha2 potentiation may not be necessary.
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α3GABAARs have been implicated in anxiety, fear and/or response to chronic stress, with contradictory findings.
“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 [13]
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- Authors
- Dias, R., Sheppard, W. F. A., Fradley, R. L., Garrett, E. M., Stanley, J. L., Tye, S. J., Goodacre, S., Lincoln, R. J., Cook, S. M., Conley, R., Hallett, D., Humphries, A. C., Thompson, S. A., Wafford, K. A., Street, L. J., Castro, J. L., Whiting, P. J., Rosahl, T. W., Atack, J. R., McKernan, R. M., Dawson, G. R., & Reynolds, D. S.
- Affiliations
- MSD (UK) Limited (United Kingdom) (GB)
- Corresponding author
- Dias, Rebecca
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2005-11-16
- Volume
- 25
- Issue
- 46
- Pages
- 10682-10688
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6725841
- OpenAlex
- W2151414518
- Cited by
- 247
- References
- 32
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 5 · 2023: 5 · 2022: 6 · 2021: 6 · 2020: 6 · 2019: 5 · 2018: 11 · 2017: 6 · 2016: 10 · 2015: 5 · 2014: 14 · 2013: 12 · 2012: 17
- FWCI
- 8.95
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Keywords
- GABAA receptor, alpha3 subunit, benzodiazepines, anxiolytic effects, alpha2 subunit, chlordiazepoxide, diazepam, stress-induced hyperthermia, anxiety, non-human primates
- MeSH terms
- Animals, Anxiety, Benzodiazepines, Dose-Response Relationship, Drug, Humans, Male, Mice, Transgenic, Protein Binding, Receptors, GABA-A, Saimiri, Anti-Anxiety Agents, Rats, Sprague-Dawley, Protein Subunits, Mice, Rats, GABA-A Receptor Agonists
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