Differential roles of GABAA receptor subtypes in benzodiazepine-induced enhancement of brain-stimulation reward
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Benzodiazepines such as diazepam are widely prescribed as anxiolytics and sleep aids. Continued use of benzodiazepines, however, can lead to addiction in vulnerable individuals. Here, we investigate the neural mechanisms of the behavioral effects of benzodiazepines using the intracranial self-stimulation (ICSS) test, a procedure with which the reward-enhancing effects of these drugs can be measured. Benzodiazepines bind nonselectively to several different GABA(A) receptor subtypes. To elucidate the α subunit(s) responsible for the reward-enhancing effects of benzodiazepines, we examined mice carrying a histidine-to-arginine point mutation in the α1, α2, or α3 subunit, which renders the targeted subunit nonresponsive to diazepam, other benzodiazepines and zolpidem. In wild-type and α1-point-mutated mice, diazepam caused a dose-dependent reduction in ICSS thresholds (reflecting a reward-enhancing effect) that is comparable to the reduction observed following cocaine administration. This effect was abolished in α2- and α3-point-mutant mice, suggesting that these subunits are necessary for the reward-enhancing action of diazepam. α2 Subunits appear to be particularly important, since diazepam increased ICSS thresholds (reflecting an aversive-like effect) in α2-point-mutant animals. Zolpidem, an α1-preferring benzodiazepine-site agonist, had no reward-enhancing effects in any genotype. Our findings implicate α2 and α3 subunit containing GABA(A) receptors as key mediators of the reward-related effects of benzodiazepines. This finding has important implications for the development of new medications that retain the therapeutic effects of benzodiazepines but lack abuse liability.
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Positive modulation of α2GABAARs is required for the reward-enhancing effects of benzodiazepines.
“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 [106]
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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
- Reynolds, L. M., Engin, E., Tantillo, G., Lau, H. M., Muschamp, J. W., Carlezon, W. A., & Rudolph, U.
- Affiliations
- McLean Hospital (US)
- Harvard University (US)
- Corresponding author
- Engin, Elif
- Venue
- Neuropsychopharmacology
- Published
- 2012-07-04
- Volume
- 37
- Issue
- 11
- Pages
- 2531-2540
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC3442348
- OpenAlex
- W2028283774
- Cited by
- 49
- References
- 58
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 3 · 2022: 1 · 2021: 2 · 2020: 2 · 2019: 3 · 2018: 5 · 2017: 3 · 2016: 5 · 2015: 6 · 2014: 10 · 2013: 3 · 2012: 2
- FWCI
- 2.77
- 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)
- Funders
- National Institutes of Health
- National Institute on Drug Abuse (R03DA026578)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Keywords
- benzodiazepines, diazepam, GABAA receptor subtypes, intracranial self-stimulation, aversive effects, zolpidem, abuse liability
- MeSH terms
- Analysis of Variance, Animals, Behavior, Animal, Benzodiazepines, Brain, Cocaine, Dose-Response Relationship, Drug, Electric Stimulation, Male, Mice, Inbred C57BL, Mice, Transgenic, Receptors, GABA-A, Reinforcement Schedule, Reward, Self Stimulation, Point Mutation, GABA Agents, Dopamine Uptake Inhibitors, Protein Subunits, Mice
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