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 CB1 receptor agonist CP 55,940 to reduce the affinity of D2 receptor agonist binding sites in both the dorsal and ventral striatum including the nucleus accumbens shell. This antagonistic modulation of D2 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 CB1–D2 receptor heteromers, independent of receptor occupancy, was demonstrated. These data thereby indicate that the antagonistic intramembrane CB1/D2 receptor–receptor interactions may occur in CB1/D2 formed heteromers. Antagonistic CB1/D2 interactions were also discovered at the behavioral level through an analysis of quinpirole-induced locomotor hyperactivity in rats. The CB1 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 CB1 receptor antagonist rimonobant but also the specific A2A receptor antagonist MSX-3 blocked the inhibitory effect of CB1 receptor agonist on D2-like receptor agonist-induced hyperlocomotion. Taken together, these results give evidence for the existence of antagonistic CB1/D2 receptor–receptor interactions within CB1/D2 heteromers in which A2A receptors may also participate.