The effects of beta-arrestin1 deletion on acute cannabinoid activity, brain cannabinoid receptors and tolerance to cannabinoids in mice

Abstract

Context: 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. Objective: To determine the role of beta-arrestin1 in cannabinoid activity. Materials and methods: Beta-arrestin1 −/− mice and their wild-type (+/+) counterparts were assayed for antinociceptive and temperature-decreasing effects of two ligands, Δ⁹-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. Results: 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 ([³H]SR141716A) 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 [³⁵S]GTPγS 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. Discussion: Beta-arrestin1 appeared to mediate the actions of CP55940, but did not affect the activity of THC. Conclusion: Beta-arrestin1 regulates cannabinoid CB₁ receptor sensitivity in an agonist-selective manner, but may not be the primary mediator of tolerance to cannabinoid agonists.

• antinociception
• CP55940
• delta-9-tetrahydrocannabinol
• G-protein
• knock-out

Acknowledgements

C57BL/6 beta-arrestin1 −/− and beta-arrestin1 +/+ mice were generously supplied by Dr. Robert Lefkowitz of Duke University (Durham, NC).

Declaration of interest

The authors declare no conflicts of interest relevant to the contents of this article.

This work was supported by the Campbell University College of Pharmacy & Health Sciences.