Antagonistic cannabinoid CB 1/dopamine D 2 receptor interactions in striatal CB 1/D 2 heteromers. A combined neurochemical and behavioral analysis

Abstract

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.