Tonic inhibition of accumbal spiny neurons by extrasynaptic ?4?? 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 ?4, ?, and ? subunits that mediate tonic inhibition, thereby influencing neuronal excitability. Both the selective ?-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 ?(-/-) or ?4(-/-) 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 ?4(-/-) mice did not differ in their expression of cocaine-conditioned place preference (CPP). Importantly, however, mice with the ?4 deletion specific to D1-expressing neurons (?4(D1-/-)) showed increased CPP. Furthermore, THIP administered systemically or directly into the NAc of WT, but not ?4(-/-) or ?4(D1-/-) mice, blocked cocaine enhancement of CPP. In comparison, ?4(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, ?4?? GABAARs may represent a viable target for the development of novel therapeutics to better understand and influence addictive behaviors.

SUBMITTER: Maguire EP 

PROVIDER: S-EPMC3891962 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature