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Adenosine A_2A receptors in neuroadaptation to repeated dopaminergic stimulation

Implications for the treatment of dyskinesias in Parkinson’s disease

From the Molecular Neurobiology Laboratory, Department of Neurology (Drs. Chen, Fredduzzi, Bastia, Yu, and Schwarzschild), Massachusetts General Hospital and Harvard Medical School, Boston, MA; Molecular Neuropharmacology Laboratory, Department of Neurology (Drs. Chen and Yu), Boston University School of Medicine, Boston, MA; Schering-Plough Research Institute (Drs. Fredduzzi, Bastia, and Ongini), San Raffaele Science Park, Milan, Italy; and Cajal Institute (Dr. Moratalla), Madrid, Spain.

Address correspondence and reprint requests to Dr. Jiang-Fan Chen, Department of Neurology, Boston University School of Medicine, 715 Albany Street, E301, Boston, MA 02118; e-mail: chenjf{at}bu.edu

The A_2A receptor has recently attracted considerable interest as a potential target for Parkinson’s disease (PD) therapy based on the motor-enhancing and neuroprotective effects of A_2A antagonists in animal models of PD. The unique neuronal localization of the adenosine A_2A receptor in the basal ganglia and its extensive interactions with dopaminergic and glutamatergic systems led the authors to investigate a potential role of the A_2A receptor in the development of behavioral sensitization in response to repeated dopaminergic stimulation. Because dopamine-induced behavioral sensitization shares several neurochemical and behavioral features with dyskinesia, characterizing this novel aspect of A_2A receptor function may enhance understanding and management of dyskinesia in PD. Recent studies from several laboratories suggest that the A_2A receptor may be an important mediator of maladaptive changes in response to long-term dopamine stimulation. The authors summarize their investigation of the role of A_2A receptors in two paradigms of behavioral sensitization elicited by daily treatment with either L-dopa in hemiparkinsonian mice or amphetamine in naive mice. The results demonstrate that the A_2A receptor is required for the development of behavioral sensitization in response to repeated L-dopa treatment in hemiparkinsonian mice and repeated amphetamine administration in normal mice. Together with pharmacologic studies, these results raise the possibility that the maladaptive dyskinetic responses to long-term L-dopa management of PD may be attenuated by A_2A receptor blockade. Potential presynaptic, postsynaptic (cellular), and trans-synaptic (network) mechanisms are discussed.

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				D. Xiao, E. Bastia, Y.-H. Xu, C. L. Benn, J.-H. J. Cha, T. S. Peterson, J.-F. Chen, and M. A. Schwarzschild Forebrain Adenosine A2A Receptors Contribute to L-3,4-Dihydroxyphenylalanine-Induced Dyskinesia in Hemiparkinsonian Mice J. Neurosci., December 27, 2006; 26(52): 13548 - 13555. [Abstract] [Full Text] [PDF]