University of Sussex
Browse
823.full.pdf (7.55 MB)

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

Download (7.55 MB)
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 Lambert
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 (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

History

Publication status

  • Published

File Version

  • Published version

Journal

Journal of Neuroscience

ISSN

0270-6474

Publisher

Society for Neuroscience

Issue

3

Volume

34

Page range

823-838

Department affiliated with

  • Clinical and Experimental Medicine Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2014-03-11

First Open Access (FOA) Date

2014-07-15

First Compliant Deposit (FCD) Date

2014-03-11

Usage metrics

    University of Sussex (Publications)

    Categories

    No categories selected

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC