The effects of beta-arrestin1 deletion on acute cannabinoid activity, brain cannabinoid receptors and tolerance to cannabinoids in mice.
Previous studies have indicated a role for beta-arrestin2 in the regulation of brain cannabinoid effects and cannabinoid CB1 receptors, but whether beta-arrestin1 has a role has not been investigated. To determine the role of beta-arrestin1 in cannabinoid activity. Beta-arrestin1 -- mice and their wild-type () counterparts were assayed for antinociceptive and temperature-decreasing effects of two ligands, Δ(9)-tetrahydrocannabinol (THC) and CP55940, after both single and repeated administration. In vitro assays examined the effects of deletion on CB1 receptor density, agonist-binding and G-protein activation. Deletion of beta-arrestin1 diminished the effects of CP55940 in both antinociception (latency to tail withdrawal) and temperature-depression assays in mice. However, deleting beta-arrestin1 had no effect on the actions of THC in either assay. Antagonist radioligand ((3)HSR141716A) saturation binding indicated no difference between beta-arrestin1 and -- mice in the density or affinity for cannabinoid CB1 receptors in brain membranes. CP55940 agonist binding in brain membranes from beta-arrestin1 mice exhibited high- and intermediate-affinity sites, but beta-arrestin1 -- membranes exhibited an additional site with low affinity. CP55940 produced greater stimulation of (35)SGTPγS binding to membranes from whole brain of beta-arrestin1 -- than mice. The rates of the development of tolerance to chronic THC or CP55940 administration did not appear to be affected by genotype. Beta-arrestin1 appeared to mediate the actions of CP55940, but did not affect the activity of THC. Beta-arrestin1 regulates cannabinoid CB1 receptor sensitivity in an agonist-selective manner, but may not be the primary mediator of tolerance to cannabinoid agonists.