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

J Recept Signal Transduct Res. 2015 Feb;35(1):98-106. doi: 10.3109/10799893.2014.1003659. Epub 2015 Mar 17.

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, 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.

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 ([(3)H]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 [(35)S]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.

Keywords: CP55940; G-protein; antinociception; delta-9-tetrahydrocannabinol; knock-out.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arrestins / genetics*
  • Brain / drug effects
  • Brain / metabolism*
  • Cannabinoid Receptor Agonists / administration & dosage
  • Cannabinoid Receptor Agonists / metabolism
  • Cannabinoids / genetics
  • Cannabinoids / metabolism*
  • Cyclohexanols / administration & dosage
  • Dronabinol / administration & dosage
  • Mice
  • Mice, Knockout
  • Piperidines / administration & dosage
  • Pyrazoles / administration & dosage
  • Receptor, Cannabinoid, CB1 / genetics*
  • Receptor, Cannabinoid, CB1 / metabolism
  • Rimonabant
  • Sequence Deletion
  • beta-Arrestins

Substances

  • Arrestins
  • Cannabinoid Receptor Agonists
  • Cannabinoids
  • Cyclohexanols
  • Piperidines
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • beta-Arrestins
  • Dronabinol
  • 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol
  • Rimonabant