β-Arrestin2 Regulates Cannabinoid CB1 Receptor Signaling and Adaptation in a Central Nervous System Region–Dependent Manner

Nguyen, Peter T.; Schmid, Cullen L.; Raehal, Kirsten M.; Selley, Dana E.; Bohn, Laura M.; Sim-Selley, Laura J.

doi:10.1016/j.biopsych.2011.11.027

« Previous Next »Biological Psychiatry
Volume 71, Issue 8 , Pages 714-724, 15 April 2012

β-Arrestin2 Regulates Cannabinoid CB₁ Receptor Signaling and Adaptation in a Central Nervous System Region–Dependent Manner

Peter T. Nguyen
- Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, Virginia
Cullen L. Schmid
- Departments of Molecular Therapeutics and Neuroscience, The Scripps Research Institute, Jupiter, Florida
Kirsten M. Raehal
- Departments of Molecular Therapeutics and Neuroscience, The Scripps Research Institute, Jupiter, Florida
Dana E. Selley
- Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, Virginia
Laura M. Bohn
- Departments of Molecular Therapeutics and Neuroscience, The Scripps Research Institute, Jupiter, Florida
Laura J. Sim-Selley
- Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, Virginia
- Address correspondence to Laura J. Sim-Selley, Ph.D., Box 980524, 1112 E. Clay Street, Richmond, VA 23298

Received 4 August 2011; received in revised form 25 October 2011; accepted 30 November 2011. published online 24 January 2012.

Background

Cannabinoid CB₁ receptors (CB₁Rs) mediate the effects of ▵⁹-tetrahydrocannabinol (THC), the psychoactive component in marijuana. Repeated THC administration produces tolerance and dependence, which limit therapeutic development. Moreover, THC produces motor and psychoactive side effects. β-arrestin2 mediates receptor desensitization, internalization, and signaling, but its role in these CB₁R effects and receptor regulation is unclear.

Methods

CB₁R signaling and behaviors (antinociception, hypothermia, catalepsy) were assessed in β-arrestin2-knockout (βarr2-KO) and wild-type mice after THC administration. Cannabinoid-stimulated [³⁵S]GTPγS and [³H]ligand autoradiography were assessed by statistical parametric mapping and region-of-interest analysis.

Results

β-arrestin2 deletion increased CB₁R-mediated G-protein activity in subregions of the cortex but did not affect CB₁R binding, in vehicle-treated mice. βarr2-KO mice exhibited enhanced acute THC-mediated antinociception and hypothermia, with no difference in catalepsy. After repeated THC administration, βarr2-KO mice showed reduced CB₁R desensitization and/or downregulation in cerebellum, caudal periaqueductal gray, and spinal cord and attenuated tolerance to THC-mediated antinociception. In contrast, greater desensitization was found in hypothalamus, cortex, globus pallidus, and substantia nigra of βarr2-KO compared with wild-type mice. Enhanced tolerance to THC-induced catalepsy was observed in βarr2-KO mice.

Conclusions

β-arrestin2 regulation of CB₁R signaling following acute and repeated THC administration was region-specific, and results suggest that multiple, overlapping mechanisms regulate CB₁Rs. The observations that βarr2-KO mice display enhanced antinociceptive responses to acute THC and decreased tolerance to the antinociceptive effects of the drug, yet enhanced tolerance to catalepsy, suggest that development of cannabinoid drugs that minimize CB₁R interactions with β-arrestin2 might produce improved cannabinoid analgesics with reduced motor suppression.

Key Words: Beta-arrestin , cannabinoid receptors , GPCR , statistical parametric mapping , tolerance