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The Journal of Neuroscience, March 1, 2006, 26(9):2513-2521; doi:10.1523/JNEUROSCI.4712-05.2006

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Cellular/Molecular
Dopamine D₃ Receptors Regulate GABA_A Receptor Function through a Phospho-Dependent Endocytosis Mechanism in Nucleus Accumbens

Guojun Chen,¹ Josef T. Kittler,² Stephen J. Moss,³ and Zhen Yan¹

¹Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, New York 14214, ²Department of Physiology, University College London, London WC1E 6BT, United Kingdom, and ³Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Correspondence should be addressed to Dr. Zhen Yan, Department of Physiology and Biophysics, State University of New York at Buffalo, 124 Sherman Hall, Buffalo, NY, 14214. Email: zhenyan{at}buffalo.edu

The dopamine D₃ receptor, which is highly enriched in nucleus accumbens (NAc), has been suggested to play an important role in reinforcement and reward. To understand the potential cellular mechanism underlying D₃ receptor functions, we examined the effect of D₃ receptor activation on GABA_A receptor (GABA_AR)-mediated current and inhibitory synaptic transmission in medium spiny neurons of NAc. Application of PD128907 [(4aR,10bR)-3,4a,4,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol hydrochloride], a specific D₃ receptor agonist, caused a significant reduction of GABA_AR current in acutely dissociated NAc neurons and miniature IPSC amplitude in NAc slices. This effect was blocked by dialysis with a dynamin inhibitory peptide, which prevents the clathrin/activator protein 2 (AP2)-mediated GABA_A receptor endocytosis. In addition, the D₃ effect on GABA_AR current was prevented by agents that manipulate protein kinase A (PKA) activity. Infusion of a peptide derived from GABA_AR subunits, which contains an atypical binding motif for the clathrin AP2 adaptor complex and the major PKA phosphorylation sites and binds with high affinity to AP2 only when dephosphorylated, diminished the D₃ regulation of IPSC amplitude. The phosphorylated equivalent of the peptide was without effect. Moreover, PD128907 increased GABA_AR internalization and reduced the surface expression of GABA_A receptor subunits in NAc slices, which was prevented by dynamin inhibitory peptide or cAMP treatment. Together, our results suggest that D₃ receptor activation suppresses the efficacy of inhibitory synaptic transmission in NAc by increasing the phospho-dependent endocytosis of GABA_A receptors.

Key words: nucleus accumbens; dopamine D₃ receptor; GABA_A receptor; trafficking; dynamin; protein kinase A

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Received Nov. 3, 2005; revised Jan. 24, 2006; accepted Jan. 24, 2006.

Correspondence should be addressed to Dr. Zhen Yan, Department of Physiology and Biophysics, State University of New York at Buffalo, 124 Sherman Hall, Buffalo, NY, 14214. Email: zhenyan{at}buffalo.edu

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