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

Hai Ying Shen, Joana E. Coelho, Nobuhisa Ohtsuka, Paula M. Canas, Yuan Ji Day, Qing Yuan Huang, Nelson Rebola, Liqun Yu, Detlev Boison, Rodrigo A. Cunha, Joel Linden, Joe Z. Tsien, Jiang Fan Chen

Research output: Contribution to journalArticle

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Abstract

The function of striatal adenosine A2A receptors (A 2ARs) is well recognized because of their high expression levels and the documented antagonistic interaction between A2ARs and dopamine D2 receptors in the striatum. However, the role of extrastriatal A2ARs 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 A2ARs in extrastriatal neurons in modulating psychomotor behavior using newly developed striatum-specific A2AR knock-out (st-A2AR KO) mice in comparison with forebrain-specific A2AR KO (fb-A2AR KO) mice. In contrast to fb-A2AR KO (deleting A2ARs in the neurons of striatum as well as cerebral cortex and hippocampus), st-A 2ARKO 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-A2AR KO but attenuated in fb-A2AR KO mice. Furthermore, selective inactivation of the A2ARs in extrastriatal cells by administering the A2AR antagonist KW6002 into st-A2AR KO mice attenuated cocaine effects, whereas KW6002 administration into wild-type mice enhanced cocaine effects. These results identify a critical role of A2ARs in extrastriatal neurons in providing a prominent excitatory effect on psychomotor activity. These results indicate that A2ARs 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 A2ARs.

Original languageEnglish (US)
Pages (from-to)2970-2975
Number of pages6
JournalJournal of Neuroscience
Volume28
Issue number12
DOIs
StatePublished - Mar 19 2008

Fingerprint

Adenosine A2A Receptors
Prosencephalon
Phenotype
Neurons
Corpus Striatum
Cocaine
Knockout Mice
Phencyclidine
Dopamine D2 Receptors
Astrocytes
Cerebral Cortex
Hippocampus
Messenger RNA

Keywords

  • Adenosine A receptor
  • Cocaine
  • Forebrain AR knock-out
  • PCP
  • Psychomotor activity
  • Striatum AR knock-out

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

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. / Shen, Hai Ying; Coelho, Joana E.; Ohtsuka, Nobuhisa; Canas, Paula M.; Day, Yuan Ji; Huang, Qing Yuan; Rebola, Nelson; Yu, Liqun; Boison, Detlev; Cunha, Rodrigo A.; Linden, Joel; Tsien, Joe Z.; Chen, Jiang Fan.

In: Journal of Neuroscience, Vol. 28, No. 12, 19.03.2008, p. 2970-2975.

Research output: Contribution to journalArticle

Shen, Hai Ying ; Coelho, Joana E. ; Ohtsuka, Nobuhisa ; Canas, Paula M. ; Day, Yuan Ji ; Huang, Qing Yuan ; Rebola, Nelson ; Yu, Liqun ; Boison, Detlev ; Cunha, Rodrigo A. ; Linden, Joel ; Tsien, Joe Z. ; Chen, Jiang Fan. / 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. In: Journal of Neuroscience. 2008 ; Vol. 28, No. 12. pp. 2970-2975.
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abstract = "The function of striatal adenosine A2A receptors (A 2ARs) is well recognized because of their high expression levels and the documented antagonistic interaction between A2ARs and dopamine D2 receptors in the striatum. However, the role of extrastriatal A2ARs 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 A2ARs in extrastriatal neurons in modulating psychomotor behavior using newly developed striatum-specific A2AR knock-out (st-A2AR KO) mice in comparison with forebrain-specific A2AR KO (fb-A2AR KO) mice. In contrast to fb-A2AR KO (deleting A2ARs in the neurons of striatum as well as cerebral cortex and hippocampus), st-A 2ARKO 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-A2AR KO but attenuated in fb-A2AR KO mice. Furthermore, selective inactivation of the A2ARs in extrastriatal cells by administering the A2AR antagonist KW6002 into st-A2AR KO mice attenuated cocaine effects, whereas KW6002 administration into wild-type mice enhanced cocaine effects. These results identify a critical role of A2ARs in extrastriatal neurons in providing a prominent excitatory effect on psychomotor activity. These results indicate that A2ARs 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 A2ARs.",
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AU - Ohtsuka, Nobuhisa

AU - Canas, Paula M.

AU - Day, Yuan Ji

AU - Huang, Qing Yuan

AU - Rebola, Nelson

AU - Yu, Liqun

AU - Boison, Detlev

AU - Cunha, Rodrigo A.

AU - Linden, Joel

AU - Tsien, Joe Z.

AU - Chen, Jiang Fan

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N2 - The function of striatal adenosine A2A receptors (A 2ARs) is well recognized because of their high expression levels and the documented antagonistic interaction between A2ARs and dopamine D2 receptors in the striatum. However, the role of extrastriatal A2ARs 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 A2ARs in extrastriatal neurons in modulating psychomotor behavior using newly developed striatum-specific A2AR knock-out (st-A2AR KO) mice in comparison with forebrain-specific A2AR KO (fb-A2AR KO) mice. In contrast to fb-A2AR KO (deleting A2ARs in the neurons of striatum as well as cerebral cortex and hippocampus), st-A 2ARKO 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-A2AR KO but attenuated in fb-A2AR KO mice. Furthermore, selective inactivation of the A2ARs in extrastriatal cells by administering the A2AR antagonist KW6002 into st-A2AR KO mice attenuated cocaine effects, whereas KW6002 administration into wild-type mice enhanced cocaine effects. These results identify a critical role of A2ARs in extrastriatal neurons in providing a prominent excitatory effect on psychomotor activity. These results indicate that A2ARs 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 A2ARs.

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