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Role of adenosine A1 receptors in the modulation of dopamine D1 and adenosine A2a receptor signaling in the neostriatum

https://doi.org/10.1016/j.neuroscience.2006.04.047Get rights and content

Abstract

Adenosine is known to modulate the function of neostriatal neurons. Adenosine acting on A2A receptors increases the phosphorylation of dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa (DARPP-32) at Thr34 (the cAMP-dependent protein kinase [PKA] site) in striatopallidal neurons, and opposes dopamine D2 receptor signaling. In contrast, the role of adenosine A1 receptors in the regulation of dopamine/DARPP-32 signaling is not clearly understood. Here, we investigated the effect of adenosine A1 receptors on D1, D2 and A2A receptor signaling using mouse neostriatal slices. An A1 receptor agonist, 2-chloro-N6-cyclopentyladenosine (100 nM), caused a transient increase, followed by a transient decrease, in DARPP-32 Thr34 phosphorylation. Our data support the following model for the actions of the A1 receptor agonist. The A1 receptor-induced early increase in Thr34 phosphorylation was mediated by presynaptic inhibition of dopamine release, and the subsequent removal of tonic inhibition by D2 receptors of A2A receptor/Golf/cAMP/PKA signaling. The A1 receptor-induced late decrease in Thr34 phosphorylation was mediated by a postsynaptic Gi mechanism, resulting in inhibition of D1 and A2A receptor-coupled Golf/cAMP/PKA signaling in direct and indirect pathway neurons, respectively. In conclusion, A1 receptors play a major modulatory role in dopamine and adenosine receptor signaling.

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

References (24)

  • S. Ferre et al.

    Stimulation of high-affinity adenosine A2 receptors decreases the affinity of dopamine D2 receptors in rat striatal membranes

    Proc Natl Acad Sci U S A

    (1991)
  • A.A. Fienberg et al.

    DARPP-32, regulator of the efficacy of dopaminergic neurotransmission

    Science

    (1998)
  • Cited by (0)

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