Role of adenosine A2A receptors in parkinsonian motor impairment and l-DOPA-induced motor complications. Prog Neurobiol

University of Cagliari, Department of Toxicology, Via Ospedale 72, 09124 Cagliari, Italy.
Progress in Neurobiology (Impact Factor: 9.99). 01/2008; 83(5):293-309. DOI: 10.1016/j.pneurobio.2007.07.001
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ABSTRACT Adenosine A2A receptors have a unique cellular and regional distribution in the basal ganglia, being particularly concentrated in areas richly innervated by dopamine such as the caudate-putamen and the globus pallidus. Adenosine A2A receptors are selectively located on striatopallidal neurons and are capable of forming functional heteromeric complexes with dopamine D2 and metabotropic glutamate mGlu5 receptors. Based on the unique cellular and regional distribution of this receptor and in line with data showing that A2A receptor antagonists improve motor symptoms in animal models of Parkinson's disease (PD) and in initial clinical trials, A2A receptor antagonists have emerged as an attractive non-dopaminergic target to improve the motor deficits that characterize PD. Experimental data have also shown that A2A receptor antagonists do not induce neuroplasticity phenomena that complicate long-term dopaminergic treatments. The present review provides an updated summary of results reported in the literature concerning the biochemical characteristics and basal ganglia distribution of A2A receptors. We subsequently aim to examine the effects of adenosine A2A antagonists in rodent and primate models of PD and of l-DOPA-induced dyskinesia. Finally, concluding remarks are made on post-mortem human brains and on the translation of adenosine A2A receptor antagonists in the treatment of PD.

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    • "It is interesting to note that the interaction of adenosine with dopamine in the basal ganglia is not only limited to A1 and D1 receptors, but a well described interaction exists between A2 receptors mainly located on striato-pallidal neurons and D2 receptors. It has been demonstrated that the formation of heterometric complexes between these receptors improves motor symptoms in animal models of Parkinson's disease (PD) and in initial clinical trials (for a review see Morelli et al., 2007). "
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    ABSTRACT: γ-Aminobutyric acid A receptor (GABAAR)-mediated postsynaptic currents were recorded in brain slices from substantia nigra pars reticulate neurons. The selective adenosine A1 receptor (A1R) antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), increased the frequency, but not the amplitude of spontaneous inhibitory post-synaptic currents (IPSCs) in the presence of the dopamine D1 receptor agonist SKF 38393 (SKF) and phosphodiesterase 10A inhibitors (papaverine or AE90074). Under these conditions, DPCPX also increased the amplitude of evoked IPSCs (eIPSCs). The effect of DPCPX was also examined in a mouse model of Parkinson's disease (PD), generated by unilateral denervation of the dopaminergic input to the striatum. In this model, SKF alone was sufficient to increase sIPSCs frequency and eIPSCs amplitude, and these effects were not potentiated by DPCPX. To confirm a depressive effect of A1Rs on the synaptic release of GABA we used the selective A1R agonist 5′-chloro-5′-deoxy-N6-(±)-(endo-norborn-2-yl)adenosine (5′Cl5′d-(±)-ENBA) which has limited peripheral actions. We found that 5′Cl5′d-(±)-ENBA decreased sIPSCs frequency, without affecting their amplitude, and decreased eIPSCs amplitude. Importantly, in the PD mouse model, 5′Cl5′d-(±)-ENBA prevented the increase in sIPSC frequency and eIPSC amplitude produced by SKF. Since exaggerated DA transmission along the striato-nigral pathway is involved in the motor complications (e.g. dyskinesia) caused by prolonged and intermittent administration of l-DOPA, we examined the effect of A1R activation in mice with unilateral DA denervation. We found that 5′Cl5′d-(±)-ENBA, administered in combination with l-DOPA, reduced the development of abnormal involuntary movements. These results indicate the potential benefit of A1R agonists for the treatment of l-DOPA-induced dyskinesia and hyperkinetic disorders providing a mechanistic framework for the study of the interaction between DA and adenosine in the striatonigral system.
    Experimental Neurology 08/2014; 261. DOI:10.1016/j.expneurol.2014.08.022 · 4.70 Impact Factor
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    • "Given the numerous motor complications that can occur in response to levadopa treatment, adenosine A 2A receptor antagonists may provide a reasonable alternative for co-administration with DBS. Adenosine A 2A receptors are highly expressed in the neostriatum, and adenosine A 2A antagonists exert motor effects in rodents and primates that are consistent with antiparkinsonian actions (Ferr e et al., 2001, 2004, 2008; Schwarzschild et al., 2006; Morelli et al., 2007; Salamone et al., 2008b; Collins et al., 2010b). In studies using the jaw movement model, adenosine A 2A antagonists have been shown to significantly reverse the TJMs induced by DA depletion, DA antagonism, and cholinomimetic administration (Correa et al., 2004; Simola et al., 2004; Salamone et al., 2008a; Collins et al., 2010a; Pinna et al., 2010). "
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    ABSTRACT: Deep brain stimulation (DBS) of the subthalamic nucleus is increasingly being employed as a treatment for parkinsonian symptoms, including tremor. The present studies used tremulous jaw movements, a pharmacological model of tremor in rodents, to investigate the tremorolytic effects of subthalamic DBS in rats. Subthalamic DBS reduced the tremulous jaw movements induced by the dopamine D2 family antagonist pimozide and the D1 family antagonist ecopipam, as well as the cholinomimetics pilocarpine and galantamine. The ability of DBS to suppress tremulous jaw movements was dependent on the neuroanatomical locus being stimulated (subthalamic nucleus vs. a striatal control site), as well as the frequency and intensity of stimulation used. Importantly, administration of the adenosine A2A receptor antagonist MSX-3 reduced the frequency and intensity parameters needed to attenuate tremulous jaw movements. These results have implications for the clinical use of DBS, and future studies should determine whether adenosine A2A antagonism could be used to enhance the tremorolytic efficacy of subthalamic DBS at low frequencies and intensities in human patients.
    European Journal of Neuroscience 04/2013; 38(1). DOI:10.1111/ejn.12212 · 3.18 Impact Factor
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    • "A 2A receptors are positively coupled to adenylate cyclase and, either at the level of second messengers or through the formation of receptor heterodimers, negatively influence dopamine D 2 receptor activity [3] [4] [5] [6]. On the basis of this anatomical and functional organization, A 2A receptors acting in concert with D 2 and D 1 receptors are capable of affecting planning and execution of movements [7] [8]. Moreover, the low levels of A 2A receptors expressed in brain areas other than the BG are at the basis of the low incidence of nonmotor side effects observed in clinical trials so far performed [9]. "
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    ABSTRACT: Dyskinesia, a major complication of treatment of Parkinson's disease (PD), involves two phases: induction, which is responsible for dyskinesia onset, and expression, which underlies its clinical manifestation. The unique cellular and regional distribution of adenosine A(2A) receptors in basal ganglia areas that are richly innervated by dopamine, and their antagonistic role towards dopamine receptor stimulation, have positioned A(2A) receptor antagonists as an attractive nondopaminergic target to improve the motor deficits that characterize PD. In this paper, we describe the biochemical characteristics of A(2A) receptors and the effects of adenosine A(2A) antagonists in rodent and primate models of PD on L-DOPA-induced dyskinesia, together with relevant biomarker studies. We also review clinical trials of A(2A) antagonists as adjuncts to L-DOPA in PD patients with motor fluctuations. These studies have generally demonstrated that the addition of an A(2A) antagonist to a stable L-DOPA regimen reduces OFF time and mildly increases dyskinesia. However, limited clinical data suggest that the addition of an A(2A) antagonist along with a reduction of L-DOPA might maintain anti-Parkinsonian benefit and reduce dyskinesia. Whether A(2A) antagonists might reduce the development of dyskinesia has not yet been tested clinically.
    06/2012; 2012(11):489853. DOI:10.1155/2012/489853
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