Adenosine caffeine structure12/8/2023 ![]() 1).įunctional interactions between dopamine D 2, adenosine A 2A, cannabinoid CB 1 and glutamate mGlu5 receptors in striatopallidal neurons. Of great importance, A 2A receptors exert a strong influence on DARPP-32, a dopamine and cAMP-regulated phosphoprotein, which is expressed at high levels in the GABAergic efferent neurons and is deeply involved in dopamine-mediated signalling ( Lindskog et al., 2002) ( Fig. In agreement with these studies, stimulation of adenosine A 2A receptors counteracts the D 2 receptor-mediated inhibition of cAMP formation and D 2 receptor-induced intracellular Ca 2+ responses ( Kull et al., 1999 Olah et al., 2000 Salim et al., 2000). The basis of this antagonistic action of adenosine A 2A receptors is their ability to decrease the binding affinity of D 2 receptors for dopamine as demonstrated in rat striatal membrane, in human striatal tissue and in different cell lines ( Ferré et al., 1991 Diaz-Cabiale et al., 2001 Hillion et al., 2002 Canals et al., 2003). Therefore, both structures may contribute to the therapeutic action of A 2A receptor antagonists.Īdenosine A 2A receptors exert an excitatory influence on striatopallidal neurons, in part through their antagonistic effect on dopamine D 2 receptor activation ( Fig. This suggests that blockade of pallidal A 2A receptors, by reducing extracellular GABA, may stabilize GP activity and in turn subthalamic nucleus (STN) activity ( Simola et al., 2006). In 6-hydroxydopamine (6-OHDA)-lesioned rats, intrapallidal infusion of A 2A receptor antagonists, while not eliciting any motor response per-se, does potentiate motor activity induced by l-DOPA or dopaminergic agonists. In addition, A 2A receptors are highly expressed in the globus pallidus (GP), mainly in the neuropil, where their stimulation enhances striatopallidal GABA outflow, and their blockade reduces it ( Rosin et al., 1998 Ochi et al., 2000 Shindou et al., 2003). This anatomical framework provides an important structural basis to our understanding of previously discovered A 2A/D 2 functional interactions. These receptors colocalize in the striatum with the dopamine D 2 receptor in the dendritic spines of enkephalin-rich striatopallidal GABA neurons and on glutamatergic terminals ( Schiffmann et al., 1991 Rosin et al., 1998). High densities of adenosine A 2A receptors are present in both the ventral and dorsal striatum of rodents and primates, including humans. The review will pay particular attention to recent results regarding specific A 2A receptor-receptor interactions and recent findings identifying urate, the end product of purine metabolism, as a novel prognostic biomarker and candidate neuroprotectant in PD.ġ) Localization of adenosine receptors and functional interactions with dopamine receptorsĮxtensive interactions between adenosine A 1 and A 2A receptors and the various dopamine receptors are present in brain at several levels, whereas the interactions between adenosine A 2A and dopamine D 2 receptors are restricted within the basal ganglia where they are of particular relevance to the characteristic motor dysfunction of PD. In this review we describe the interactions between dopamine and adenosine receptors that underpin the preclinical and clinical rationale for pursuing adenosine A 2A receptor antagonists as symptomatic and potentially neuroprotective treatment of PD. ![]() Based on the involvement of these nondopaminergic neurotransmitters in PD and the sometimes severe adverse effects that limit the mainstay use of dopamine-based antiparkinsonian treatments, recent assessments have called for a broadening of therapeutic options beyond the traditional dopaminergic drug arsenal. ![]() Moreover, adenosine because of the extensive interaction of its receptors with the dopaminergic system has been implicated in the in the pathophysiology of the disease. However, several other brain areas and neurotransmitters other than dopamine such as noradrenaline, 5-hydroxytryptamine and acetylcholine are affected in the disease. The motor symptoms of Parkinson's disease (PD) are due primarily to the degeneration of the dopaminergic neurons in the nigrostriatal pathway. ![]()
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