Rapid reportRole of adenosine A1 receptors in the modulation of dopamine D1 and adenosine A2a receptor signaling in the neostriatum
Section snippets
Preparation and incubation of neostriatal slices
Male C57BL/6 mice (6–8 weeks old) were killed by decapitation. All mice used in this study were handled in accordance with the Declaration of Helsinki and the Guide for the Care and Use of Laboratory Animals as adopted and promulgated by the U.S. National Institutes of Health, and the specific protocols were approved by the Institutional Animal Care and Use Committee of Kurume University School of Medicine. The number of mice used and their suffering were minimized. The brains were rapidly
Results
The role of adenosine A1 receptors in the regulation of DARPP-32 Thr34 phosphorylation was investigated in neostriatal neurons. The adenosine A1 receptor agonist, CCPA (100 nM), induced time-dependent, biphasic changes in DARPP-32 Thr34 phosphorylation (Fig. 1A). Treatment of neostriatal slices with CCPA transiently increased the level of phospho-Thr34 DARPP-32 by 2.2-fold at 1 min of incubation, and subsequently decreased it by 40% at 5 min. The effects of CCPA on DARPP-32 Thr34
Discussion
In this study, we have demonstrated that adenosine A1 receptors modulate signaling in both direct and indirect pathway neurons in the neostriatum (Fig. 4). In direct pathway neurons, adenosine A1 receptors antagonized dopamine D1 receptor/DARPP-32 signaling. In contrast, in indirect pathway neurons, adenosine A1 receptors induced biphasic effects on adenosine A2A receptor signaling. Activation of adenosine A1 receptors first potentiated and then antagonized adenosine A2A receptor/DARPP-32
Conclusion
Endogenous adenosine activates both A2A and A1 receptors, both of which can exert antagonistic effects on dopaminergic signaling. A1 receptors, expressed at presynaptic dopaminergic terminals, decrease dopamine release, thereby decreasing activation of D1 receptors in direct pathway neurons and D2 receptors in indirect pathway neurons. In addition, in direct pathway neurons, A1 receptors, via activation of Gi proteins, inhibit dopamine D1 receptor/Golf/PKA/DARPP-32 signaling. Similarly, in
Acknowledgments
This research was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (to A.N.) and grants from the U.S.P.H.S. (MH40899 and DA10044 to P.G.), the USA Medical Research and Materiel Command NETRP program to Intra-Cellular Therapies, Inc. (award W81XWH-04-2-0009), the Picower Foundation and the Michael Stern Parkinson’s Research Foundation (to P.G.). The authors thank Yukako Terasaki, Keiko Fujisaki and Michiko Koga for excellent technical
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