Tonic inhibition of accumbal spiny neurons by extrasynaptic 4 GABAA receptors modulates the actions of psychostimulants

Maguire, E P, MacPherson, T, Swinny, J D, Dixon, C I, Herd, M B, Belelli, D, Stephens, D N, King, S L and Lambert, J J (2014) Tonic inhibition of accumbal spiny neurons by extrasynaptic 4 GABAA receptors modulates the actions of psychostimulants. Journal of Neuroscience, 34 (3). pp. 823-838. ISSN 0270-6474

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Abstract

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 (α4D1−/−) showed increased CPP. Furthermore, THIP administered systemically or directly into the NAc of WT, but not α4−/− or α4D1−/− mice, blocked cocaine enhancement of CPP. In comparison, α4D2−/− 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.

Item Type: Article
Schools and Departments: Brighton and Sussex Medical School > Clinical and Experimental Medicine
Subjects: B Philosophy. Psychology. Religion > BF Psychology
Depositing User: Catrina Hey
Date Deposited: 11 Mar 2014 16:46
Last Modified: 05 Oct 2017 18:26
URI: http://sro.sussex.ac.uk/id/eprint/47816

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GABAA receptors in neurobiology of drug and alcohol addictionsG0211MRCG0802715
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