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

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• 作者：Peter T. Nguyen^a ; Cullen L. Schmid^b ; Kirsten M. Raehal^b ; Dana E. Selley^a ; Laura M. Bohn^b ; Laura J. Sim-Selley^a ; ^{ljsimsel@vcu.edu}
• 关键词：Beta-arrestin ; cannabinoid receptors ; GPCR ; statistical parametric mapping ; tolerance
• 刊名：Biological Psychiatry
• 出版年：2012
• 出版时间：15 April, 2012
• 年：2012
• 卷：71
• 期：8
• 页码：714-724
• 全文大小：2106 K

文摘

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Background

Cannabinoid CB₁ receptors (CB₁Rs) mediate the effects of ?sup>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. ¦Â-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 ¦Â-arrestin2-knockout (¦Âarr2-KO) and wild-type mice after THC administration. Cannabinoid-stimulated [³⁵S]GTP¦ÃS and [³H]ligand autoradiography were assessed by statistical parametric mapping and region-of-interest analysis.

Results

¦Â-arrestin2 deletion increased CB₁R-mediated G-protein activity in subregions of the cortex but did not affect CB₁R binding, in vehicle-treated mice. ¦Âarr2-KO mice exhibited enhanced acute THC-mediated antinociception and hypothermia, with no difference in catalepsy. After repeated THC administration, ¦Âarr2-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 ¦Âarr2-KO compared with wild-type mice. Enhanced tolerance to THC-induced catalepsy was observed in ¦Âarr2-KO mice.

Conclusions

¦Â-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 ¦Âarr2-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 ¦Â-arrestin2 might produce improved cannabinoid analgesics with reduced motor suppression.