Neural bases for addictive properties of benzodiazepines
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Benzodiazepines are widely used in clinics and for recreational purposes, but will lead to addiction in vulnerable individuals. Addictive drugs increase the levels of dopamine and also trigger long-lasting synaptic adaptations in the mesolimbic reward system that ultimately may induce the pathological behaviour. The neural basis for the addictive nature of benzodiazepines, however, remains elusive. Here we show that benzodiazepines increase firing of dopamine neurons of the ventral tegmental area through the positive modulation of GABA(A) (gamma-aminobutyric acid type A) receptors in nearby interneurons. Such disinhibition, which relies on alpha1-containing GABA(A) receptors expressed in these cells, triggers drug-evoked synaptic plasticity in excitatory afferents onto dopamine neurons and underlies drug reinforcement. Taken together, our data provide evidence that benzodiazepines share defining pharmacological features of addictive drugs through cell-type-specific expression of alpha1-containing GABA(A) receptors in the ventral tegmental area. The data also indicate that subunit-selective benzodiazepines sparing alpha1 may be devoid of addiction liability.
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An underlying mechanism for the addictive properties of benzodiazepines and α1-preferring GABAergic compounds is VTA dopaminergic disinhibition.
“An underlying mechanism for the addictive properties of benzodiazepines and α1-preferring GABAergic compounds has been identified to be VTA dopaminergic disinhibition [104].”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [104]
Benzodiazepines and z-drugs have reinforcing properties and can be misused.
“In addition to their therapeutic potential, these medications also have reinforcing properties (1–3) and thus can be misused”
From Prevalence and correlates of the misuse of z-drugs and benzodiazepines in the National Survey on Drug Use and Health (2023) · cites this paper as [3]
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- Authors
- Tan, K. R., Brown, M., Labouèbe, G., Yvon, C., Creton, C., Fritschy, J.-M., Rudolph, U., & Lüscher, C.
- Affiliations
- University of Geneva (CH)
- University of Zurich (CH)
- Harvard University (US)
- Corresponding author
- Lüscher, Christian
- Venue
- Nature
- Published
- 2010-02
- Volume
- 463
- Issue
- 7282
- Pages
- 769-774
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2871668
- OpenAlex
- W1973651679
- Cited by
- 397
- References
- 49
- Citations by year
- 2026: 14 · 2025: 19 · 2024: 15 · 2023: 23 · 2022: 17 · 2021: 29 · 2020: 22 · 2019: 24 · 2018: 21 · 2017: 21 · 2016: 39 · 2015: 22 · 2014: 28 · 2013: 28 · 2012: 32
- FWCI
- 13.30
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Archive ouverte UNIGE (University of Geneva) (acceptedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- National Institute on Drug Abuse (R01DA019022, DA019022)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Keywords
- benzodiazepines, drug addiction, ventral tegmental area, dopaminergic neurons, GABAA receptor, alpha1 subunit, interneurons, disinhibition, synaptic plasticity, drug reinforcement, mesolimbic reward system
- MeSH terms
- Action Potentials, Administration, Oral, Animals, Benzodiazepines, Dopamine, Electric Conductivity, gamma-Aminobutyric Acid, Interneurons, Mice, Inbred C57BL, Midazolam, Models, Biological, Morphine, Neuronal Plasticity, Neurons, Organ Specificity, Receptors, GABA-A, Substrate Specificity, Behavior, Addictive, Ventral Tegmental Area, Receptors, AMPA, Glutamic Acid, Mice, Inhibitory Postsynaptic Potentials, In Vitro Techniques
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