title: Tonic inhibition of accumbal spiny neurons by extrasynaptic α4βδ GABAA receptors modulates the actions of psychostimulants.
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 (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.
authors.affiliation: Division of Neuroscience, Medical Research Institute, Ninewells Hospital and Medical School, Ninewells Hospital, Dundee University, Dundee, DD19SY, United Kingdom, School of Psychology, University of Sussex, Falmer, Brighton, BN1 9QG, United Kingdom, and Institute for Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth PO1 2DT, United Kingdom.
authors.forename: Edward P
authors.initials: EP
authors.lastname: Maguire
authors.forename: Tom
authors.initials: T
authors.lastname: Macpherson
authors.forename: Jerome D
authors.initials: JD
authors.lastname: Swinny
authors.forename: Claire I
authors.initials: CI
authors.lastname: Dixon
authors.forename: Murray B
authors.initials: MB
authors.lastname: Herd
authors.forename: Delia
authors.initials: D
authors.lastname: Belelli
authors.forename: David N
authors.initials: DN
authors.lastname: Stephens
authors.forename: Sarah L
authors.initials: SL
authors.lastname: King
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Lambert
mesh_terms: D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology*; D011963:Receptors, GABA-A / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*
chemical_list: D000697:Central Nervous System Stimulants; C546261:Gabra4 protein, mouse; D011963:Receptors, GABA-A
keywords: GABAA receptors; THIP; addiction; gaboxadol; nucleus accumbens