| First Author | Maguire EP | Year | 2014 |
| Journal | J Neurosci | Volume | 34 |
| Issue | 3 | Pages | 823-38 |
| PubMed ID | 24431441 | Mgi Jnum | J:205569 |
| Mgi Id | MGI:5545832 | Doi | 10.1523/JNEUROSCI.3232-13.2014 |
| Citation | Maguire EP, et al. (2014) Tonic Inhibition of Accumbal Spiny Neurons by Extrasynaptic alpha4betadelta GABAA Receptors Modulates the Actions of Psychostimulants. J Neurosci 34(3):823-38 |
| abstractText | 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 alpha4, beta, and delta subunits that mediate tonic inhibition, thereby influencing neuronal excitability. Both the selective delta-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 delta(-/-) or alpha4(-/-) 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 alpha4(-/-) mice did not differ in their expression of cocaine-conditioned place preference (CPP). Importantly, however, mice with the alpha4 deletion specific to D1-expressing neurons (alpha4(D1-/-)) showed increased CPP. Furthermore, THIP administered systemically or directly into the NAc of WT, but not alpha4(-/-) or alpha4(D1-/-) mice, blocked cocaine enhancement of CPP. In comparison, alpha4(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, alpha4betadelta GABAARs may represent a viable target for the development of novel therapeutics to better understand and influence addictive behaviors. |
