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.