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
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Article info
Publication history
Published online: January 24, 2012
Accepted:
November 30,
2011
Received in revised form:
October 25,
2011
Received:
August 4,
2011
Identification
Copyright
© 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
