Tonic Inhibition of Accumbal Spiny Neurons by Extrasynaptic α4βδ GABA A Receptors Modulates the Actions of Psychostimulants
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Within the nucleus accumbens (NAc), synaptic GABAA receptors (GABAARs) mediate phasic inhibition of medium spiny neurons (MSNs) and influence behavioral responses to cocaine. We demonstrate that both dopamine D1- and D2-receptor-expressing MSNs (D-MSNs) additionally harbor extrasynaptic GABAARs incorporating α4, β, and δ subunits that mediate tonic inhibition, thereby influencing neuronal excitability. Both the selective δ-GABAAR agonist THIP and DS2, a selective positive allosteric modulator, greatly increased the tonic current of all MSNs from wild-type (WT), but not from δ(-/-) or α4(-/-) mice. Coupling dopamine and tonic inhibition, the acute activation of D1 receptors (by a selective agonist or indirectly by amphetamine) greatly enhanced tonic inhibition in D1-MSNs but not D2-MSNs. In contrast, prolonged D2 receptor activation modestly reduced the tonic conductance of D2-MSNs. Behaviorally, WT and constitutive α4(-/-) mice did not differ in their expression of cocaine-conditioned place preference (CPP). Importantly, however, mice with the α4 deletion specific to D1-expressing neurons (α4(D1-/-)) showed increased CPP. Furthermore, THIP administered systemically or directly into the NAc of WT, but not α4(-/-) or α4(D1-/-) mice, blocked cocaine enhancement of CPP. In comparison, α4(D2-/-) mice exhibited normal CPP, but no cocaine enhancement. In conclusion, dopamine modulation of GABAergic tonic inhibition of D1- and D2-MSNs provides an intrinsic mechanism to differentially affect their excitability in response to psychostimulants and thereby influence their ability to potentiate conditioned reward. Therefore, α4βδ GABAARs may represent a viable target for the development of novel therapeutics to better understand and influence addictive behaviors.
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α4GABAARs play opposing roles in the reinforcing properties of other drugs of abuse.
“While α4GABAARs are expressed in both D1+ and D2+ neurons, and have been shown to play opposing roles in the reinforcing properties of other drugs of abuse [115], the relative abundance of the receptor in the two neuronal populations is not clear.”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [115]
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- Authors
- Maguire, E. P., Macpherson, T., Swinny, J. D., Dixon, C. I., Herd, M. B., Belelli, D., Stephens, D. N., King, S. L., & Lambert, J. J.
- Affiliations
- University of Sussex (GB)
- University of Portsmouth (GB)
- University of Dundee (GB)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2014-01-15
- Volume
- 34
- Issue
- 3
- Pages
- 823-838
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3891962
- OpenAlex
- W1984941790
- Cited by
- 69
- References
- 58
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 6 · 2023: 6 · 2022: 4 · 2021: 7 · 2019: 4 · 2018: 8 · 2017: 2 · 2016: 7 · 2015: 7 · 2014: 12
- FWCI
- 4.27
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Sussex Research Online (University of Sussex) (submittedVersion, cc-by)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Tenovus
- 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
- extrasynaptic GABAA receptors, tonic inhibition, nucleus accumbens, medium spiny neurons, dopamine D1 receptor, dopamine D2 receptor, cocaine, conditioned place preference, psychostimulants, THIP, positive allosteric modulators, neuronal excitability, addiction
- MeSH terms
- Central Nervous System Stimulants, Animals, Conditioning, Psychological, Male, Mice, Inbred C57BL, Mice, Transgenic, Neural Inhibition, Nucleus Accumbens, Receptors, GABA-A, Synapses, Mice, Knockout, Mice
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