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Tonic inhibition of accumbal spiny neurons by extrasynaptic 4 GABAA receptors modulates the actions of psychostimulants
journal contribution
posted on 2023-06-08, 16:51 authored by E P Maguire, T MacPherson, J D Swinny, Claire Dixon, M B Herd, D Belelli, D N Stephens, Sarah KingSarah King, J J LambertWithin 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 a4, ß, and d subunits that mediate tonic inhibition, thereby influencing neuronal excitability. Both the selective d-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 d-/- or a4-/- 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 a4-/- mice did not differ in their expression of cocaine-conditioned place preference (CPP). Importantly, however, mice with the a4 deletion specific to D1-expressing neurons (a4D1-/-) showed increased CPP. Furthermore, THIP administered systemically or directly into the NAc of WT, but not a4-/- or a4D1-/- mice, blocked cocaine enhancement of CPP. In comparison, a4D2-/- 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, a4ßd GABAARs may represent a viable target for the development of novel therapeutics to better understand and influence addictive behaviors.
Funding
G1000008
GABAA receptors in neurobiology of drug and alcohol addictions; G0211; MRC; G0802715
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Publication status
- Published
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- Published version
Journal
Journal of NeuroscienceISSN
0270-6474Publisher
Society for NeuroscienceExternal DOI
Issue
3Volume
34Page range
823-838Department affiliated with
- Clinical and Experimental Medicine Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2014-03-11First Open Access (FOA) Date
2014-07-15First Compliant Deposit (FCD) Date
2014-03-11Usage metrics
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