| First Author | Nguyen PT | Year | 2012 |
| Journal | Biol Psychiatry | Volume | 71 |
| Issue | 8 | Pages | 714-24 |
| PubMed ID | 22264443 | Mgi Jnum | J:283279 |
| Mgi Id | MGI:6386061 | Doi | 10.1016/j.biopsych.2011.11.027 |
| Citation | Nguyen PT, et al. (2012) beta-arrestin2 regulates cannabinoid CB1 receptor signaling and adaptation in a central nervous system region-dependent manner. Biol Psychiatry 71(8):714-24 |
| abstractText | BACKGROUND: Cannabinoid CB(1) receptors (CB(1)Rs) mediate the effects of triangle up(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. beta-arrestin2 mediates receptor desensitization, internalization, and signaling, but its role in these CB(1)R effects and receptor regulation is unclear. METHODS: CB(1)R signaling and behaviors (antinociception, hypothermia, catalepsy) were assessed in beta-arrestin2-knockout (betaarr2-KO) and wild-type mice after THC administration. Cannabinoid-stimulated [(35)S]GTPgammaS and [(3)H]ligand autoradiography were assessed by statistical parametric mapping and region-of-interest analysis. RESULTS: beta-arrestin2 deletion increased CB(1)R-mediated G-protein activity in subregions of the cortex but did not affect CB(1)R binding, in vehicle-treated mice. betaarr2-KO mice exhibited enhanced acute THC-mediated antinociception and hypothermia, with no difference in catalepsy. After repeated THC administration, betaarr2-KO mice showed reduced CB(1)R 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 betaarr2-KO compared with wild-type mice. Enhanced tolerance to THC-induced catalepsy was observed in betaarr2-KO mice. CONCLUSIONS: beta-arrestin2 regulation of CB(1)R signaling following acute and repeated THC administration was region-specific, and results suggest that multiple, overlapping mechanisms regulate CB(1)Rs. The observations that betaarr2-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 CB(1)R interactions with beta-arrestin2 might produce improved cannabinoid analgesics with reduced motor suppression. |
