Cited by 67Neuroscience and Neuropharmacology ResearchEpilepsy research and treatmentNicotinic Acetylcholine Receptors Study

Valium without dependence? Individual GABAA receptor subtype contribution toward benzodiazepine addiction, tolerance, and therapeutic effects

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Cheng, Tianze, Wallace, Dominique Marie, Ponteri, Benjamin Bixby, Tuli, Mahir·2018·Neuropsychiatric Disease and Treatment

Abstract

Abstract: Benzodiazepines are one of the most prescribed medications as first-line treatment of anxiety, insomnia, and epilepsy around the world. Over the past two decades, advances in the neuropharmacological understanding of gamma aminobutyric acid (GABA) A receptors revealed distinct contributions from each subtype and produced effects. Recent findings have highlighted the importance of α1 containing GABA A receptors in the mechanisms of addiction and tolerance in benzodiazepine treatments. This has shown promise in the development of tranquilizers with minimal side effects such as cognitive impairment, dependence, and tolerance. A valium-like drug without its side effects, as repeatedly demonstrated in animals, is achievable. Keywords: benzodiazepines, subtype, tolerance, dependence, anxiolytic, GABA A receptor

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Crossref · 10.2147/ndt.s164307

Cites

132 of 132 references verified0 citation errors · 0 not checkable

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  • Benzodiazepines and z-drugs are positive allosteric modulators of the GABA-A receptor and produce their clinical effects by enhancing the effect of GABA at the GABA-A receptor.

    “Benzodiazepines and z-drugs are positive allosteric modulators of the GABA-A receptor, producing their clinical effects by enhancing the effect of the neurotransmitter GABA at the GABA-A receptor (Cheng, Wallace, Ponteri, & Tuli, 2018; Gunja, 2013).”

    From Pharmacological principles for safe benzodiazepine and Z-drug dose reduction (2026) · cites this paper as Cheng, Wallace, Ponteri, & Tuli, 2018

    The “Pharmacological targets of benzodiazepine” section describes benzodiazepines as GABA-A receptor positive allosteric modulators and says they increase inhibitory signaling through chloride-channel activity. The paper discusses zolpidem’s GABA-A receptor effects, but the passages do not establish the same mechanism for z-drugs as a class. Its statement that benzodiazepines do not enhance GABA’s binding does not contradict the claim that they enhance GABA’s effect. (LLM, conf=0.85)

    Experimental — accuracy not yet measured
  • Preclinical models suggest uncoupling-loss of allosteric modulation at the benzodiazepine site-as a likely mechanism of benzodiazepine tolerance.

    “Preclinical models suggest uncoupling – loss of allosteric modulation at the benzodiazepine site – as a likely mechanism (Cheng et al., 2018).”

    From Pharmacological principles for safe benzodiazepine and Z-drug dose reduction (2026) · cites this paper as Cheng et al., 2018

  • The potency of BDZ may play a role in tolerance development, as full agonists produce more tolerance than partial agonists.

    “It has been shown that the potency of BDZ may play a role in tolerance development, as full agonists produce more tolerance than partial agonists (Cheng et al., 2018).”
  • The physiological mechanisms of benzodiazepine tolerance and adaptation remain uncertain, with mixed findings on reduced number or sensitivity of GABA-A receptors.

    “The physiological mechanisms of benzodiazepine tolerance and adaptation remain uncertain, with mixed findings on reduced number or sensitivity of GABA-A receptors (Cheng et al., 2018).”

    From Pharmacological principles for safe benzodiazepine and Z-drug dose reduction (2026) · cites this paper as Cheng et al., 2018

  • Chronic benzodiazepine use down-regulates adenosine receptors and up-regulates glutamatergic NMDA and AMPA receptors, likely compensating for enhanced GABA activity.

    “Chronic benzodiazepine use also down-regulates adenosine receptors and up-regulates glutamatergic NMDA and AMPA receptors, likely compensating for enhanced GABA activity (Cheng et al., 2018).”

    From Pharmacological principles for safe benzodiazepine and Z-drug dose reduction (2026) · cites this paper as Cheng et al., 2018

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1 of the 133 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. [45]Rudolph U Crestani F Benke D Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes Nature 1999 401 6755 796 800 10548105

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Authors
Cheng, T., Wallace, D. M., Ponteri, B. B., & Tuli, M.
Affiliations
  • Pitzer College (US)
  • Portland State University (US)
  • University of British Columbia (CA)
Corresponding author
Cheng, Tianze
Venue
Neuropsychiatric Disease and Treatment
Published
2018-05
Volume
Volume 14
Pages
1351-1361
ISSN
  • 1176-6328 (ISSN-L)
  • 1178-2021
OpenAlex
W2804391210
Cited by
66
References
133
Citations by year
2026: 3 · 2025: 8 · 2024: 10 · 2023: 23 · 2022: 5 · 2021: 7 · 2020: 5 · 2019: 5
FWCI
0.58
Type
journal article
Language
en
Open access
Locations
  • Neuropsychiatric Disease and Treatment (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Dove Medical Press (Taylor and Francis Group) (submittedVersion, cc-by-nc)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
Keywords
benzodiazepines, GABAA receptor subtypes, alpha1 subunit, benzodiazepine dependence, tolerance (pharmacology and immunology), anxiolytic effects, tranquilizers, cognitive impairment

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