Neural Basis of Benzodiazepine Reward: Requirement for α2 Containing GABAA Receptors in the Nucleus Accumbens
Open accessAbstract
Despite long-standing concerns regarding the abuse liability of benzodiazepines, the mechanisms underlying properties of benzodiazepines that may be relevant to abuse are still poorly understood. Earlier studies showed that compounds selective for α1-containing GABAA receptors (α1GABAARs) are abused by humans and self-administered by animals, and that these receptors may underlie a preference for benzodiazepines as well as neuroplastic changes observed in the ventral tegmental area following benzodiazepine administration. There is some evidence, however, that even L-838, 417, a compound with antagonistic properties at α1GABAARs and agonistic properties at the other three benzodiazepine-sensitive GABAA receptor subtypes, is self-administered, and that the α2GABAARs may have a role in benzodiazepine-induced reward enhancement. Using a two-bottle choice drinking paradigm to evaluate midazolam preference and an intracranial self-stimulation (ICSS) paradigm to evaluate the impact of midazolam on reward enhancement, we demonstrated that mice carrying a histidine-to-arginine point mutation in the α2 subunit which renders it insensitive to benzodiazepines (α2(H101R) mice) did not prefer midazolam and did not show midazolam-induced reward enhancement in ICSS, in contrast to wild-type controls, suggesting that α2GABAARs are necessary for the reward enhancing effects and preference for oral benzodiazepines. Through a viral-mediated knockdown of α2GABAARs in the nucleus accumbens (NAc), we demonstrated that α2 in the NAc is necessary for the preference for midazolam. Findings imply that α2GABAARs in the NAc are involved in at least some reward-related properties of benzodiazepines, which might partially underlie repeated drug-taking behavior.
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α2GABAARs in the NAc are necessary to maintain midazolam preference in a two-bottle choice drinking test.
“Moreover, positive modulation of α2GABAARs is required for the reward-enhancing effects of benzodiazepines [106], and α2GABAARs in the NAc are necessary to maintain midazolam preference in a two-bottle choice drinking test [107].”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [107]
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An emerging circuit pharmacology of GABAA receptors
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Behlke, L. M., Foster, R. A., Liu, J., Benke, D., Benham, R. S., Nathanson, A. J., Yee, B. K., Zeilhofer, H. U., Engin, E., & Rudolph, U. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2016.49 · Cited by 57 · see citing works
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- Authors
- Engin, E., Bakhurin, K. I., Smith, K. S., Hines, R. M., Reynolds, L. M., Tang, W., Sprengel, R., Moss, S. J., & Rudolph, U.
- Affiliations
- Harvard University (US)
- Tufts University (US)
- Max Planck Institute for Medical Research (DE)
- Corresponding author
- Engin, Elif
- ORCID
- Venue
- Neuropsychopharmacology
- Published
- 2014-02-19
- Volume
- 39
- Issue
- 8
- Pages
- 1805-1815
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC4059902
- OpenAlex
- W1993753770
- Cited by
- 40
- References
- 64
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 1 · 2020: 2 · 2019: 3 · 2018: 2 · 2017: 3 · 2016: 8 · 2015: 6 · 2014: 5
- FWCI
- 3.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Digital Library (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Canadian Institutes of Health Research
- National Institute of Mental Health (R01MH080006, MH097446, R01MH097446)
- National Institute on Drug Abuse (R03DA027051)
- National Institute of Neurological Disorders and Stroke (R01NS051195, NS 056359, NS 051195, R01NS056359, NS081735)
- 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 reward, nucleus accumbens, midazolam, drug preference, intracranial self-stimulation, abuse liability, GABAA receptor subtypes
- MeSH terms
- Animals, Choice Behavior, Male, Mice, Transgenic, Midazolam, Nucleus Accumbens, Receptors, GABA-A, Reward, GABA Modulators, Mice
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