Molecular Neurobiology

, Volume 33, Issue 3, pp 199–213

Changes in the expression of G protein-coupled receptor kinases and β-arrestins in mouse brain during cannabinoid tolerance

A role for ras-ERK cascade
  • Tiziana Rubino
  • Daniela Viganò
  • Fabrizio Premoli
  • Chiara Castiglioni
  • Silvia Bianchessi
  • Renata Zippel
  • Daniela Parolaro
Article

DOI: 10.1385/MN:33:3:199

Cite this article as:
Rubino, T., Viganò, D., Premoli, F. et al. Mol Neurobiol (2006) 33: 199. doi:10.1385/MN:33:3:199

Abstract

The focus of our study was to determine the role of G protein-coupled receptor kinases (GRKs) and β-arrestins in agonist-induced CB1 receptor modulation during cannabinoid tolerance and their dependence from the extracellular signal-regulated kinase (ERK) cascade. In wild-type mice, chronic Δ9-tetrahydrocannabinol (THC) exposure significantly activated specific GRK and β-arrestin subunits in all the considered brain areas (striatum, cerebellum, hippocampus, and prefrontal cortex), suggesting their involvement in the adaptive processes underlying CB1 receptor downregulation and desensitization. These events were ERK-dependent in the striatum and cerebellum, because they were prevented in the genetic (Ras-GRF1 knockout mice) and pharmacological (SL327-pretreated mice) models of ERK activation inhibition, whereas in the hippocampus and prefrontal cortex, they appeared to be mostly ERK-independent. In the latter areas, ERK activation after chronic THC increased the transcription factors cyclic adenosine monophosphate response element-binding protein and Fos B as well as a downstream protein known as brain-derived neurotrophic factor. As a whole, our data suggest that in the striatum and cerebellum, THC-induced ERK activation could represent a key signaling event to initiate homologous desensitization of CB1 receptor, accounting for the development of tolerance to THC-induced hypolocomotion. In the prefrontal cortex and hippocampus, THC-induced alteration in GRKs and β-arrestins primarily depends on other kinases, whereas ERK activation could be part of the molecular adaptations that underlie the complex behavioral phenotype that defines the addicted state.

Index Entries

Cannabinoid toleranceGRKsβ-arrestinsERK pathwayCB1 receptor regulationRas-GRF1 knockout miceSL327

Copyright information

© Humana Press Inc. 2006

Authors and Affiliations

  • Tiziana Rubino
    • 1
  • Daniela Viganò
    • 1
  • Fabrizio Premoli
    • 1
  • Chiara Castiglioni
    • 1
  • Silvia Bianchessi
    • 1
  • Renata Zippel
    • 2
  • Daniela Parolaro
    • 1
  1. 1.DBSF, Pharmacology Section, and Neuroscience CenterUniversity of InsubriaBusto Arsizio (VA)Italy
  2. 2.Department of Biomolecular Sciences and BiotechnologyUniversity of MilanMilanItaly