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The Journal of Neuroscience, December 27, 2006, 26(52):13548-13555; doi:10.1523/JNEUROSCI.3554-06.2006

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Neurobiology of Disease
Forebrain Adenosine A_2A Receptors Contribute to L-3,4-Dihydroxyphenylalanine-Induced Dyskinesia in Hemiparkinsonian Mice

Danqing Xiao,¹ Elena Bastia,¹ Yue-Hang Xu,¹ Caroline L. Benn,¹ Jang-Ho J. Cha,¹ Tracy S. Peterson,³ Jiang-Fan Chen,² and Michael A. Schwarzschild¹

¹Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, ²Department of Neurology, Boston University School of Medicine, Boston, Massachusetts 02118, and ³Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, California 95616

Correspondence should be addressed to Michael A. Schwarzschild, Department of Neurology, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129. Email: MichaelS{at}helix.mgh.harvard.edu

Adenosine A_2A receptor antagonists provide a promising nondopaminergic approach to the treatment of Parkinson's disease (PD). Initial clinical trials of A_2A antagonists targeted PD patients who had already developed treatment complications known as L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) in an effort to improve symptoms while reducing existing LID. The goal of this study is to explore the effect of A_2A antagonists and targeted A_2A receptor depletion on the actual development of sensitized responses to L-DOPA in mouse models of LID in PD. Hemiparkinsonian mice (unilaterally lesioned with 6-OHDA) were treated daily for 3 weeks with a low dose of L-DOPA (2 mg/kg) preceded by a low dose of selective A_2A antagonist (KW-6002 [(E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione] at 0.03 or 0.3 mg/kg, or SCH58261 [5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine] at 0.03 mg/kg) or vehicle intraperitoneally. In control mice, contralateral rotational responses to daily L-DOPA gradually increased over the initial week before reaching a persistent maximum. Both A_2A antagonists inhibited the development of sensitized contralateral turning, with KW-6002 pretreatment reducing the sensitized rotational responses by up to threefold. The development of abnormal involuntary movements (a measure of LID) as well as rotational responses was attenuated by the postnatal depletion of forebrain A_2A receptors in conditional (Cre/loxP system) knock-out mice. These pharmacological and genetic data provide evidence that striatal A_2A receptors play an important role in the neuroplasticity underlying behavioral sensitization to L-DOPA, supporting consideration of early adjunctive therapy with an A_2A antagonist to reduce the risk of LID in PD.

Key words: 6-hydroxydopamine; Parkinson's disease; basal ganglia; conditional A_2A knock-out; KW-6002; A_2A receptor antagonist

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Received Aug. 16, 2006; revised Nov. 7, 2006; accepted Nov. 23, 2006.

Correspondence should be addressed to Michael A. Schwarzschild, Department of Neurology, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129. Email: MichaelS{at}helix.mgh.harvard.edu

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				H.-Y. Shen, J. E. Coelho, N. Ohtsuka, P. M. Canas, Y.-J. Day, Q.-Y. Huang, N. Rebola, L. Yu, D. Boison, R. A. Cunha, et al. A Critical Role of the Adenosine A2A Receptor in Extrastriatal Neurons in Modulating Psychomotor Activity as Revealed by Opposite Phenotypes of Striatum and Forebrain A2A Receptor Knock-Outs J. Neurosci., March 19, 2008; 28(12): 2970 - 2975. [Abstract] [Full Text] [PDF]

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