Tonic inhibition of accumbal spiny neurons by extrasynaptic α4βδ GABAA receptors modulates the actions of psychostimulants

Edward P. Maguire, Tom Macpherson, Jerome D. Swinny, Claire I. Dixon, Murray B. Herd, Delia Belelli, David N. Stephens, Sarah L. King (Lead / Corresponding author), Jeremy J. Lambert (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    51 Citations (Scopus)


    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 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 (a4(D1-/-)) showed increased CPP. Furthermore, THIP administered systemically or directly into the NAc of WT, but not a4(-/-) or a4(D1-/-) mice, blocked cocaine enhancement of CPP. In comparison, a4(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, a4ßd GABAARs may represent a viable target for the development of novel therapeutics to better understand and influence addictive behaviors.
    Original languageEnglish
    Pages (from-to)823-838
    Number of pages16
    JournalJournal of Neuroscience
    Issue number3
    Publication statusPublished - 15 Jan 2014


    Dive into the research topics of 'Tonic inhibition of accumbal spiny neurons by extrasynaptic α4βδ GABAA receptors modulates the actions of psychostimulants'. Together they form a unique fingerprint.

    Cite this