title: Adenosine A2A receptors in neuroadaptation to repeated dopaminergic stimulation: implications for the treatment of dyskinesias in Parkinson's disease.
abstract: The A2A 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 A2A antagonists in animal models of PD. The unique neuronal localization of the adenosine A2A receptor in the basal ganglia and its extensive interactions with dopaminergic and glutamatergic systems led the authors to investigate a potential role of the A2A 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 A2A receptor function may enhance understanding and management of dyskinesia in PD. Recent studies from several laboratories suggest that the A2A 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 A2A 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 A2A 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 A2A receptor blockade. Potential presynaptic, postsynaptic (cellular), and trans-synaptic (network) mechanisms are discussed.
authors.affiliation: Molecular Neurobiology Laboratory, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02118, USA. chenjf@bu.edu
authors.forename: Jiang-Fan
authors.initials: JF
authors.lastname: Chen
authors.forename: Silva
authors.initials: S
authors.lastname: Fredduzzi
authors.forename: Elena
authors.initials: E
authors.lastname: Bastia
authors.forename: Liqun
authors.initials: L
authors.lastname: Yu
authors.forename: Rosario
authors.initials: R
authors.lastname: Moratalla
authors.forename: Ennio
authors.initials: E
authors.lastname: Ongini
authors.forename: Michael A
authors.initials: MA
authors.lastname: Schwarzschild
mesh_terms: D058917:Adenosine A2 Receptor Antagonists; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D004361:Drug Tolerance / Q000235:genetics; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy*; D006801:Humans; D007980:Levodopa / Q000009:adverse effects; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000503:physiopathology*; D011687:Purines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology
chemical_list: C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D018491:Dopamine Agonists; D018696:Neuroprotective Agents; D011687:Purines; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D014230:Triazoles; C111599:istradefylline; D007980:Levodopa; D016627:Oxidopamine; D000661:Amphetamine; D004298:Dopamine