title: The effects of beta-arrestin1 deletion on acute cannabinoid activity, brain cannabinoid receptors and tolerance to cannabinoids in mice.
abstract: BACKGROUND
  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.
  
  
  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.
  
  
  CONCLUSIONS
  Beta-arrestin1 appeared to mediate the actions of CP55940, but did not affect the activity of THC.
  
  
  CONCLUSIONS
  Beta-arrestin1 regulates cannabinoid CB1 receptor sensitivity in an agonist-selective manner, but may not be the primary mediator of tolerance to cannabinoid agonists.
authors.affiliation: Department of Pharmaceutical Sciences, Campbell University College of Pharmacy & Health Sciences , Buies Creek, NC , USA.
authors.forename: Chris S
authors.initials: CS
authors.lastname: Breivogel
authors.forename: Manan S
authors.initials: MS
authors.lastname: Vaghela
mesh_terms: D000818:Animals; D019390:Arrestins / Q000235:genetics*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D063386:Cannabinoid Receptor Agonists / Q000008:administration & dosage / Q000378:metabolism; D002186:Cannabinoids / Q000235:genetics / Q000378:metabolism*; D003511:Cyclohexanols / Q000008:administration & dosage; D013759:Dronabinol / Q000008:administration & dosage; D051379:Mice; D018345:Mice, Knockout; D010880:Piperidines / Q000008:administration & dosage; D011720:Pyrazoles / Q000008:administration & dosage; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics* / Q000378:metabolism; D000077285:Rimonabant; D017384:Sequence Deletion; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids; D003511:Cyclohexanols; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000071557:beta-Arrestins; D013759:Dronabinol; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D000077285:Rimonabant
keywords: CP55940; G-protein; antinociception; delta-9-tetrahydrocannabinol; knock-out