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.
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.
Shen
Hai-Ying
HY
Molecular Neuropharmacology Laboratory, Department of Neurology, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Coelho
Joana E
JE
Ohtsuka
Nobuhisa
N
Canas
Paula M
PM
Day
Yuan-Ji
YJ
Huang
Qing-Yuan
QY
Rebola
Nelson
N
Yu
Liqun
L
Boison
Detlev
D
Cunha
Rodrigo A
RA
Linden
Joel
J
Tsien
Joe Z
JZ
Chen
Jiang-Fan
JF
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*
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