title: 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.
abstract: The function of striatal adenosine A(2A) receptors (A(2A)Rs) is well recognized because of their high expression levels and the documented antagonistic interaction between A(2A)Rs and dopamine D(2) receptors in the striatum. However, the role of extrastriatal A(2A)Rs in modulating psychomotor activity is largely unexplored because of the low level of expression and lack of tools to distinguish A(2A)Rs in intrinsic striatal versus nonstriatal neurons. Here, we provided direct evidence for the critical role of A(2A)Rs in extrastriatal neurons in modulating psychomotor behavior using newly developed striatum-specific A(2A)R knock-out (st-A(2A)R KO) mice in comparison with forebrain-specific A(2A)R KO (fb-A(2A)R KO) mice. In contrast to fb-A(2A)R KO (deleting A(2A)Rs in the neurons of striatum as well as cerebral cortex and hippocampus), st-A(2A)R KO mice exhibited Cre-mediated selective deletion of the A(2A)R 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(2A)R KO but attenuated in fb-A(2A)R KO mice. Furthermore, selective inactivation of the A(2A)Rs in extrastriatal cells by administering the A(2A)R antagonist KW6002 into st-A(2A)R KO mice attenuated cocaine effects, whereas KW6002 administration into wild-type mice enhanced cocaine effects. These results identify a critical role of A(2A)Rs in extrastriatal neurons in providing a prominent excitatory effect on psychomotor activity. These results indicate that A(2A)Rs 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(2A)Rs.
authors: Molecular Neuropharmacology Laboratory, Department of Neurology, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors: Hai-Ying
authors: HY
authors: Shen
authors: Joana E
authors: JE
authors: Coelho
authors: Nobuhisa
authors: N
authors: Ohtsuka
authors: Paula M
authors: PM
authors: Canas
authors: Yuan-Ji
authors: YJ
authors: Day
authors: Qing-Yuan
authors: QY
authors: Huang
authors: Nelson
authors: N
authors: Rebola
authors: Liqun
authors: L
authors: Yu
authors: Detlev
authors: D
authors: Boison
authors: Rodrigo A
authors: RA
authors: Cunha
authors: Joel
authors: J
authors: Linden
authors: Joe Z
authors: JZ
authors: Tsien
authors: Jiang-Fan
authors: JF
authors: Chen
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D003042:Cocaine / Q000494:pharmacology; D003342:Corpus Striatum; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons; D010622:Phencyclidine / Q000494:pharmacology; D016548:Prosencephalon; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology*; D011687:Purines / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000172:deficiency* / Q000502:physiology*
chemical_list: C501120:Dlx5 protein, mouse; D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D018398:Homeodomain Proteins; D011687:Purines; D043705:Receptor, Adenosine A2A; C111599:istradefylline; D003042:Cocaine; D010622:Phencyclidine