TY - JOUR
T1 - Tonic inhibition of accumbal spiny neurons by extrasynaptic α4βδ GABAA receptors modulates the actions of psychostimulants
AU - Maguire, Edward P.
AU - Macpherson, Tom
AU - Swinny, Jerome
AU - Dixon, Claire I.
AU - Herd, Murray B.
AU - Belelli, Delia
AU - Stephens, David N.
AU - King, Sarah L.
AU - Lambert, Jeremy J.
PY - 2014/1/15
Y1 - 2014/1/15
N2 - 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.
AB - 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.
U2 - 10.1523/JNEUROSCI.3232-13.2014
DO - 10.1523/JNEUROSCI.3232-13.2014
M3 - Article
C2 - 24431441
SN - 1529-2401
VL - 34
SP - 823
EP - 838
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 3
ER -