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The Journal of Neuroscience, February 1, 2002, 22(3):1054-1062

Persistent Behavioral Sensitization to Chronic L-DOPA Requires A_2A Adenosine Receptors

Silva Fredduzzi^{1, 2}, Rosario Moratalla³, Angela Monopoli², Beatriz Cuellar³, Kui Xu¹, Ennio Ongini², Francesco Impagnatiello^{1, 2}, Michael A. Schwarzschild¹, and Jiang-Fan Chen¹

¹ Molecular Neurobiology Laboratory, Massachusetts General Hospital, Boston, Massachusetts 02129, ² Schering-Plough Research Institute, San Raffaele Science Park, 20132 Milan, Italy, and ³ Cajal Institute, Madrid 20082, Spain

To investigate the role of A_2A adenosine receptors in adaptive responses to chronic intermittent dopamine receptor stimulation, we compared the behavioral sensitization elicited by repeated L-DOPA treatment in hemiparkinsonian wild-type (WT) and A_2A adenosine receptor knock-out (A_2A KO) mice. Although the unilateral nigrostriatal lesion produced by intrastriatal injection of 6-hydroxydopamine was indistinguishable between WT and A_2A KO mice, they developed strikingly different patterns of behavioral sensitization after daily treatment with low doses of L-DOPA for 3 weeks. WT mice initially displayed modest contralateral rotational responses and then developed progressively greater responses that reached a maximum within 1 week and persisted for the duration of the treatment. In contrast, any rotational behavioral sensitization in A_2A KO mice was transient and completely reversed within 2 weeks. Similarly, the time to reach the peak rotation was progressively shortened in WT mice but remained unchanged in A_2A KO mice. Furthermore, daily L-DOPA treatment produced gradually sensitized grooming in WT mice but failed to induce any sensitized grooming in A_2A KO mice. Finally, repeated L-DOPA treatment reversed the 6-OHDA-induced reduction of striatal dynorphin mRNA in WT but not A_2A KO mice, raising the possibility that the A_2A receptor may contribute to L-DOPA-induced behavioral sensitization by facilitating adaptations within the dynorphin-expressing striatonigral pathway. Together these results demonstrate that the A_2A receptor plays a critical role in the development and particularly the persistence of behavioral sensitization to repeated L-DOPA treatment. Furthermore, they raise the possibility that the maladaptive dyskinetic responses to chronic L-DOPA treatment in Parkinson's disease may be attenuated by A_2A receptor inactivation.

Key words: A_2A adenosine receptor; L-DOPA; behavioral sensitization; Parkinson's disease; dyskinesia; dynorphin

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Copyright © 2002 Society for Neuroscience  0270-6474/02/2231054-09$05.00/0

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