Striatal adenosine A2A and cannabinoid CB1 receptors form functional heteromeric complexes that mediate the motor effects of cannabinoids.
The mechanism of action responsible for the motor depressant effects of cannabinoids, which operate through centrally expressed cannabinoid CB1 receptors, is still a matter of debate. In the present study, we report that CB1 and adenosine A2A receptors form heteromeric complexes in co-transfected HEK-293T cells and rat striatum, where they colocalize in fibrilar structures. In a human neuroblastoma cell line, CB1 receptor signaling was found to be completely dependent on A2A receptor activation. Accordingly, blockade of A2A receptors counteracted the motor depressant effects produced by the intrastriatal administration of a cannabinoid CB1 receptor agonist. These biochemical and behavioral findings demonstrate that the profound motor effects of cannabinoids depend on physical and functional interactions between striatal A2A and CB1 receptors.
Carriba
Paulina
P
Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain.
Ortiz
Oskar
O
Patkar
Kshitij
K
Justinova
Zuzana
Z
Stroik
Jessica
J
Themann
Andrea
A
Müller
Christa
C
Woods
Anima S
AS
Hope
Bruce T
BT
Ciruela
Francisco
F
Casadó
Vicent
V
Canela
Enric I
EI
Lluis
Carme
C
Goldberg
Steven R
SR
Moratalla
Rosario
R
Franco
Rafael
R
Ferré
Sergi
S
D058908:Adenosine A2 Receptor Agonists; D000704:Analysis of Variance; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D001522:Behavior, Animal; D002186:Cannabinoids / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002461:Cell Line, Transformed; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004347:Drug Interactions; D006801:Humans; D008164:Luminescent Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D043705:Receptor, Adenosine A2A / Q000172:deficiency / Q000502:physiology*; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000172:deficiency / Q000502:physiology*; D014162:Transfection
D058908:Adenosine A2 Receptor Agonists; D001095:Arachidonic Acids; D002186:Cannabinoids; D008164:Luminescent Proteins; D043705:Receptor, Adenosine A2A; D043884:Receptor, Cannabinoid, CB1; C119325:arachidonyl-2-chloroethylamide; D000242:Cyclic AMP