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The Journal of Neuroscience, March 19, 2008, 28(12):2970-2975; doi:10.1523/JNEUROSCI.5255-07.2008

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Brief Communications
A Critical Role of the Adenosine A_2A Receptor in Extrastriatal Neurons in Modulating Psychomotor Activity as Revealed by Opposite Phenotypes of Striatum and Forebrain A_2A Receptor Knock-Outs

Hai-Ying Shen,¹ Joana E. Coelho,¹ Nobuhisa Ohtsuka,² Paula M. Canas,⁴ Yuan-Ji Day,³ Qing-Yuan Huang,¹ Nelson Rebola,⁴ Liqun Yu,¹ Detlev Boison,⁵ Rodrigo A. Cunha,⁴ Joel Linden,³ Joe Z. Tsien,² and Jiang-Fan Chen¹

¹Molecular Neuropharmacology Laboratory, Department of Neurology and ²Department of Pharmacology, Boston University School of Medicine, Boston, Massachusetts 02118, ³Department of Medicine, University of Virginia, Charlottesville, Virginia 22908, ⁴Center for Neuroscience of Coimbra, Institute of Biochemistry, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal, and ⁵Robert S. Dow Neurobiology Laboratories, Legacy Research, Portland, Oregon 97232

Correspondence should be addressed to Dr. Jiang-Fan Chen at Department of Neurology, Boston University School of Medicine, 715 Albany Street, E301, Boston, MA 02118. Email: chenjf{at}bu.edu

The function of striatal adenosine A_2A receptors (A_2ARs) is well recognized because of their high expression levels and the documented antagonistic interaction between A_2ARs and dopamine D₂ receptors in the striatum. However, the role of extrastriatal A_2ARs in modulating psychomotor activity is largely unexplored because of the low level of expression and lack of tools to distinguish A_2ARs in intrinsic striatal versus nonstriatal neurons. Here, we provided direct evidence for the critical role of A_2ARs in extrastriatal neurons in modulating psychomotor behavior using newly developed striatum-specific A_2AR knock-out (st-A_2AR KO) mice in comparison with forebrain-specific A_2AR KO (fb-A_2AR KO) mice. In contrast to fb-A_2AR KO (deleting A_2ARs in the neurons of striatum as well as cerebral cortex and hippocampus), st-A_2AR KO mice exhibited Cre-mediated selective deletion of the A_2AR gene, mRNA, and proteins in the neurons (but not astrocytes and microglial cells) of the striatum only. Strikingly, cocaine- and phencyclidine-induced psychomotor activities were enhanced in st-A_2AR KO but attenuated in fb-A_2AR KO mice. Furthermore, selective inactivation of the A_2ARs in extrastriatal cells by administering the A_2AR antagonist KW6002 into st-A_2AR KO mice attenuated cocaine effects, whereas KW6002 administration into wild-type mice enhanced cocaine effects. These results identify a critical role of A_2ARs in extrastriatal neurons in providing a prominent excitatory effect on psychomotor activity. These results indicate that A_2ARs in striatal and extrastriatal neurons exert an opposing modulation of psychostimulant effects and provide the first direct demonstration of a predominant facilitatory role of extrastriatal A_2ARs.

Key words: adenosine A_2A receptor; cocaine; PCP; psychomotor activity; striatum A_2AR knock-out; forebrain A_2AR knock-out

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Received Nov. 27, 2007; revised Dec. 26, 2007; accepted Jan. 16, 2008.

Correspondence should be addressed to Dr. Jiang-Fan Chen at Department of Neurology, Boston University School of Medicine, 715 Albany Street, E301, Boston, MA 02118. Email: chenjf{at}bu.edu

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