Antagonistic cannabinoid CB1/dopamine D2 receptor interactions in striatal CB1/D2 heteromers. A combined neurochemical and behavioral analysis.
In vitro results show the ability of the CB(1) receptor agonist CP 55,940 to reduce the affinity of D(2) receptor agonist binding sites in both the dorsal and ventral striatum including the nucleus accumbens shell. This antagonistic modulation of D(2) receptor agonist affinity was found to remain and even be enhanced after G-protein activation by Gpp(NH)p. Using the FRET technique in living HEK-293T cells, the formation of CB(1)-D(2) receptor heteromers, independent of receptor occupancy, was demonstrated. These data thereby indicate that the antagonistic intramembrane CB(1)/D(2) receptor-receptor interactions may occur in CB(1)/D(2) formed heteromers. Antagonistic CB(1)/D(2) interactions were also discovered at the behavioral level through an analysis of quinpirole-induced locomotor hyperactivity in rats. The CB(1) receptor agonist CP 55,940 at a dose that did not change basal locomotion was able to block quinpirole-induced increases in locomotor activity. In addition, not only the CB(1) receptor antagonist rimonobant but also the specific A(2A) receptor antagonist MSX-3 blocked the inhibitory effect of CB(1) receptor agonist on D(2)-like receptor agonist-induced hyperlocomotion. Taken together, these results give evidence for the existence of antagonistic CB(1)/D(2) receptor-receptor interactions within CB(1)/D(2) heteromers in which A(2A) receptors may also participate.
Marcellino
Daniel
D
Department of Neuroscience, Karolinska Institutet, Retzius väg 8, 17177 Stockholm, Sweden.
Carriba
Paulina
P
Filip
Malgorzata
M
Borgkvist
Anders
A
Frankowska
Malgorzata
M
Bellido
Inmaculada
I
Tanganelli
Sergio
S
Müller
Christa E
CE
Fisone
Gilberto
G
Lluis
Carme
C
Agnati
Luigi F
LF
Franco
Rafael
R
Fuxe
Kjell
K
D000818:Animals; D001522:Behavior, Animal; D002461:Cell Line, Transformed; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D003511:Cyclohexanols / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology; D018491:Dopamine Agonists; D065127:Dopamine D2 Receptor Antagonists; D004347:Drug Interactions; D031541:Fluorescence Resonance Energy Transfer / Q000379:methods; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D006801:Humans; D008164:Luminescent Proteins / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000502:physiology*; D011485:Protein Binding / Q000187:drug effects; D019257:Quinpirole / Q000494:pharmacology; D011859:Radiography; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D043882:Receptors, Cannabinoid / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D014162:Transfection / Q000379:methods
D003511:Cyclohexanols; D018491:Dopamine Agonists; D065127:Dopamine D2 Receptor Antagonists; D008164:Luminescent Proteins; D043884:Receptor, Cannabinoid, CB1; D043882:Receptors, Cannabinoid; D017448:Receptors, Dopamine D2; D019257:Quinpirole; D006165:Guanylyl Imidodiphosphate; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D004298:Dopamine