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Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes
Open accessAbstract
GABAA (γ-aminobutyric acid, type A) receptors are a family of ligand-gated ion channels that are essential for the regulation of central nervous system function. Benzodiazepines — which non-selectively target GABAA receptors containing the α1, α2, α3 or α5 subunits — have been in clinical use for decades and are still among the most widely prescribed drugs for the treatment of insomnia and anxiety disorders. However, their use is limited by side effects and the risk of drug dependence. In the past decade, the identification of separable key functions of GABAA receptor subtypes suggests that receptor subtype-selective compounds could overcome the limitations of classical benzodiazepines; furthermore, they might be valuable for novel indications such as chronic pain, depression, schizophrenia, cognitive enhancement and stroke.
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“Since benzodiazepines enhance the effect of GABA on GABAA receptors 72 ,”
From Developmental timing and critical windows for the treatment of psychiatric disorders (2016) · cites this paper as [72]
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“However, BZDs have addictive properties and are associated with abuse liability, physical dependence, and tolerance, limiting their long-term use [18].”
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“, 2008; Rudolph and Knoflach, 2011), studies using intra-cerebral microinfusions of broadly acting GABA agonists and antagonists may be complemented by studies using more selective ligands, to target specific GABA receptors subtypes (Rudolph and Knoflach, 2011), and opto- and pharmacogenetic methods, to modulate GABA…”
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“These receptors modulate processes as diverse as sleep, anxiety, learning and memory, seizures, depressive symptomatology, and reward (Rudolph and Knoflach, 2011).”
Self-citationGABAA receptor subtype involvement in addictive behaviour
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“…by 𝛼1-containing and 𝛼2- (and perhaps 𝛼3-) subunit containing receptors respectively, while an action at 𝛼5-containing receptors makes a significant contribution to the well-characterized amnestic effects of benzodiazepines (Collinson et al. 2006; Mohler et al. 2002; Rudolph & Knoflach 2011).”
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“5 2 GABAA receptors, particularly abundant in the hippocampus, display valuable cognition enhancing properties (in chronological order) [544–555].”
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“For each case, we noted the clinical phenotype according to the classification previously described: (1) epilepsy associated with fever sensibility, (2) early developmental epileptic encephalopathy, and (3) genetic generalized epilepsy.”
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“…and through the use of BZD inhibition in the altered mice and in wild-type mice, were able to determine the activities controlled by each a subtype (Crestani et al., 2001, 2002; Löw et al., 2000; McKernan et al., 2000; van Rijnsoever et al., 2004; Rudolph et al., 1999; Rudolph and Knoflach, 2011).”
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“…options for insomnia include benzodiazepine and non-benzodiazepine hypnotics that target γ-aminobutyric acid (GABA)A receptors and other hypnotics including melatonin receptor agonists (Ebert et al., 2006; Rudolph and Knoflach, 2011), the latter of which are sometimes referred to as chronobiotics.”
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“sedative action of diazepam was abolished, but the anxiolytic action was maintained.(26) In contrast, for the equivalent a2H101R mouse, the anxiolytic effect of diazepam was abolished, but the sedative effect remained intact.”
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“, 2012) and pharmacologically (Rudolph and Knoflach, 2011) diverse receptor subtypes within distinct regions (Wisden et al.”
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GABA Pharmacology: The Search for Analgesics
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“Preclinical studies with transgenic mice and/or selective ligands suggested that diverse receptor isoforms have a different role in mediating the action of drugs in specific disorders: α1 is implicated in epilepsy and in sedative/hypnotic effects, α2/α3 mediate anxiolytic and analgesic actions, α5 is involved in learn…”
Background
Metadata
- Authors
- Rudolph, U., & Knoflach, F.
- Affiliations
- Harvard University (US)
- F. Hoffmann-La Roche AG (CH)
- Corresponding author
- Rudolph, Uwe
- Venue
- Nature Reviews Drug Discovery
- Published
- 2011-07-29
- Volume
- 10
- Issue
- 9
- Pages
- 685-697
- ISSN
- 1474-1776 (ISSN-L)
- 1474-1784
- PMC
- PMC3375401
- OpenAlex
- W2013775967
- Semantic Scholar
- bfb4fcd647899053b94eaf5edf1fe9e748076c6b
- Cited by
- 733
- References
- 111
- Citations by year
- 2026: 41 · 2025: 42 · 2024: 35 · 2023: 46 · 2022: 43 · 2021: 55 · 2020: 49 · 2019: 56 · 2018: 51 · 2017: 58 · 2016: 52 · 2015: 45 · 2014: 62 · 2013: 58 · 2012: 38
- FWCI
- 4.90
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Reviews Drug Discovery (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R21MH087829, R01MH080006, R03MH085149, MH087829, MH085149, MH080006)
- National Institute on Drug Abuse (DA027051, DA026578, R03DA026578, R03DA027051)
- National Institute of General Medical Sciences (R01GM086448, GM086448)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Health Sciences › Medicine › Clinical Neurology › Epilepsy research and treatment
- Keywords
- GABAA receptor, benzodiazepines, GABAA receptor subtypes, ligand-gated ion channels, chronic pain, depression, schizophrenia, cognitive enhancement, stroke, drug addiction
- MeSH terms
- Analgesics, Animals, Anxiety Disorders, Benzodiazepines, Depressive Disorder, Humans, Hypnotics and Sedatives, Sleep Initiation and Maintenance Disorders, Mutation, Receptors, GABA-A, Schizophrenia, Nootropic Agents, GABA Modulators, Substance-Related Disorders, Stroke
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