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

doi:10.1016/j.neuroscience.2006.04.047

Neuroscience

Volume 141, Issue 1, 2006, Pages 19-25

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

Abstract

Adenosine is known to modulate the function of neostriatal neurons. Adenosine acting on A_2A receptors increases the phosphorylation of dopamine- and cAMP-regulated phosphoprotein of M_r 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 A_2A 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 A_2A receptor/G_olf/cAMP/PKA signaling. The A₁ receptor-induced late decrease in Thr34 phosphorylation was mediated by a postsynaptic G_i mechanism, resulting in inhibition of D₁ and A_2A receptor-coupled G_olf/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 A_2A receptor signaling. Activation of adenosine A₁ receptors first potentiated and then antagonized adenosine A_2A receptor/DARPP-32

Conclusion

Endogenous adenosine activates both A_2A 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 G_i proteins, inhibit dopamine D₁ receptor/G_olf/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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A1R is signaling through Giα/o and is expressed in many tissues, including the brain (Dunwiddie and Masino, 2001), with its stimulation leading to the inhibition of adenylyl cyclase (AC) and thereby reducing cyclic adenosine monophosphate (cAMP) production (Burnstock, 2008; Fredholm et al., 2005), an important secondary messenger involved in numerous biological functions. Reduced cAMP produced from A1R stimulation inhibits cAMP-dependent protein kinase A (PKA) in neurons thereby modulating neuropeptide and neurotransmitter release (Yabuuchi et al., 2006). In addition, the dissociation of the Gα-subunit from heterotrimeric G-protein in response to the stimulation of the A1R also engages the phospholipase C (PLC) pathway through the release of Gβγ dimers in specific cell types (Biber et al., 1997).
Physical and emotional pain deteriorates the quality of well-being. Also, numerous non-invasive and invasive treatments for diagnosed diseases such as cancer medications and surgical procedures cause various types of pain. Despite the multidisciplinary approaches available to manage pain, the unmet needs for medication with minimal side effects are substantial. Especially with the surge of opioid crisis during the last decades, non-opioid analgesics may reduce life-threatening overdosing and addictive liability. Although many clinical trials supported the potential potency of cannabis and cannabidiol (CBD) in pain management or treatment, the long-term benefits of cannabis or CBD are still not evident. At the same time, growing evidence shows the risk of overusing cannabis and CBD. Therefore, it is urgent to develop novel analgesic medications that minimize side effects. All four well-identified adenosine receptors, A₁, A_2A, A_2B, and A₃, are implicated in pain. Recently, a report demonstrated that an adenosine A₁R-specific positive allosteric modulator (PAM) is a potent analgesic without noticeable side effects. Also, several A₃R agonists are being considered as promising analgesic agent. However, the importance of adenosine in pain is relatively underestimated. To help readers understand, first, we will summarize the historical perspective of the adenosine system in preclinical and clinical studies. Then, we will discuss possible interactions of adenosine and opioids or the cannabis system focusing on pain. Overall, this review will provide the potential role of adenosine and adenosine receptors in pain treatment.
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We have recently demonstrated that N(6)-cyclopentyladenosine (CPA), an adenosine A1 receptor agonist, acts centrally to induce a visceral antinociception. Since serotonin (5-HT), cannabinoid (CB), dopamine or opioid signaling in the central nervous system is involved in the regulation of visceral sensation, we made a hypothesis that the signaling may play a role in the CPA-induced visceral antinociception. Visceral sensation was evaluated by colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Subcutaneously administered CPA significantly increased the threshold of colonic distension-induced AWR. Intracisternal injection of either 5-HT_1A or 5-HT_2A receptor antagonist blocked the CPA-induced visceral antinociception while 5-HT_1B antagonist did not block the CPA-induced visceral antinociception. Subcutaneous injection of dopamine D₁ receptor antagonist, CB₁ receptor antagonist or naloxone significantly blocked the CPA-induced visceral antinociception while neither subcutaneous injection of dopamine D₂ receptor antagonist nor CB₂ receptor antagonist blocked the CPA-induced anti-pain action. These results suggest that 5-HT_1A, 5-HT_2A, dopamine D₁, CB₁ receptors and the opioid system in the CNS may specifically mediate the CPA-induced visceral antinociception. These findings may help in understanding the physiological relevance of central adenosine with special reference to the pathophysiology of altered visceral sensation especially in irritable bowel syndrome.
Changes in ERK1/2 phosphorylation in the rat striatum and medial prefrontal cortex following administration of the adenosine A <inf>1</inf> receptor agonist and antagonist
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This antagonistic interaction functions to regulate a number of substrates downstream to PKA. For instance, the D1 agonist stimulated DARPP-32 phosphorylation at a PKA site (T34) in striatonigral neurons, while the A1 agonist CCPA via a postsynaptic A1-Gαi/o mechanism induced a late inhibition of T34 phosphorylation of DARPP-32 [20]. DPCPX and the adenosine receptor antagonist caffeine increased c-fos expression, while the D1 antagonist SCH23390 abolished the effect of caffeine in striatonigral neurons [21].
The extracellular signal-regulated kinase (ERK) is enriched in the central nervous system, including the dopamine responsive regions such as the striatum and medial prefrontal cortex (mPFC). The kinase is sensitive to changing cellular and synaptic input and is implicated in the regulation of synaptic transmission and plasticity. In this study, the role of a G_αi/o protein-coupled adenosine A₁ receptor in the regulation of ERK1/2 was investigated in the rat brain in vivo. We found that an A₁ agonist CPA after an intraperitoneal injection reduced ERK1/2 phosphorylation in the nucleus accumbens (NAc) and mPFC. In contrast, a single dose of an A₁ antagonist DPCPX induced a rapid and transient increase in ERK1/2 phosphorylation in the caudate putamen (CPu), NAc, and mPFC. Pretreatment with a dopamine D₁ receptor antagonist SCH23390 abolished the DPCPX-induced ERK1/2 phosphorylation in the striatum and mPFC. Coadministration of DPCPX and a D₁ agonist SKF81297 at a low dose induced a greater elevation of ERK1/2 phosphorylation. Activation or blockade of A₁ receptors had no effect on total ERK1/2 expression in the striatum and mPFC. These results reveal an existence of an inhibitory linkage from adenosine A₁ receptors to ERK1/2 in striatal and mPFC neurons. This inhibitory linkage seems to form a dynamic balance with positive dopamine D₁ receptor signaling to control the ERK1/2 pathway.
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Adenosine can activate PKA in D2R-MSNs under the conditions of dopamine depletion or with blockade of D2R. Our results developed the interaction between D1R and A1R in D1R-MSNs and the interaction between D2R and A2AR in D2R-MSNs proposed by the analyses of DARPP-32 phosphorylation in slices and in vivo (Nishi et al., 1997, 2011; Lindskog et al., 1999; Yabuuchi et al., 2006). Phosphorylation of Rap1gap at S505 and S563 has been shown to decrease its GAP activity on Rap1 (McAvoy et al., 2009).
Medium spiny neurons (MSNs) expressing dopamine D1 receptor (D1R) or D2 receptor (D2R) are major components of the striatum. Stimulation of D1R activates protein kinase A (PKA) through G_olf to increase neuronal activity, while D2R stimulation inhibits PKA through G_i. Adenosine A2A receptor (A2AR) coupled to G_olf is highly expressed in D2R-MSNs within the striatum. However, how dopamine and adenosine co-operatively regulate PKA activity remains largely unknown. Here, we measured Rap1gap serine 563 phosphorylation to monitor PKA activity and examined dopamine and adenosine signals in MSNs. We found that a D1R agonist increased Rap1gap phosphorylation in striatal slices and in D1R-MSNs in vivo. A2AR agonist CGS21680 increased Rap1gap phosphorylation, and pretreatment with the D2R agonist quinpirole blocked this effect in striatal slices. D2R antagonist eticlopride increased Rap1gap phosphorylation in D2R-MSNs in vivo, and the effect of eticlopride was blocked by the pretreatment with the A2AR antagonist SCH58261. These results suggest that adenosine positively regulates PKA in D2R-MSNs through A2AR, while this effect is blocked by basal dopamine in vivo. Incorporating computational model analysis, we propose that the shift from D1R-MSNs to D2R-MSNs or vice versa appears to depend predominantly on a change in dopamine concentration.
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Rapid reportRole of adenosine A1 receptors in the modulation of dopamine D1 and adenosine A2a receptor signaling in the neostriatum

Abstract

Section snippets

Preparation and incubation of neostriatal slices

Results

Discussion

Conclusion

Acknowledgments

Neurosci Lett

Parkinsonism Relat Disord

Trends Neurosci

Neuron

Neuroscience

Neurosci Lett

Prog Neurobiol

Neuroscience

Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers

J Neurosci

Postsynaptic antagonistic interaction between adenosine A1 and dopamine D1 receptors

Neuroreport

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

DARPP-32, regulator of the efficacy of dopaminergic neurotransmission

Science

Rapid report
Role of adenosine A₁ receptors in the modulation of dopamine D₁ and adenosine A_2a receptor signaling in the neostriatum

Presynaptic control of striatal glutamatergic neurotransmission by adenosine A₁-A_2A receptor heteromers

Postsynaptic antagonistic interaction between adenosine A₁ and dopamine D₁ receptors

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