title: Changes in the expression of G protein-coupled receptor kinases and beta-arrestins in mouse brain during cannabinoid tolerance: a role for RAS-ERK cascade.
abstract: The focus of our study was to determine the role of G protein-coupled receptor kinases (GRKs) and beta-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 Delta9-tetrahydrocannabinol (THC) exposure significantly activated specific GRK and beta- 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 brainderived 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 beta-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.
authors.affiliation: DBSF, Pharmacology Section, and Neuroscience Center, University of Insubria, Busto Arsizio (VA), Italy. tiziana.rubino@uninsubria.it
authors.forename: Tiziana
authors.initials: T
authors.lastname: Rubino
authors.forename: Daniela
authors.initials: D
authors.lastname: Viganò
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Premoli
authors.forename: Chiara
authors.initials: C
authors.lastname: Castiglioni
authors.forename: Silvia
authors.initials: S
authors.lastname: Bianchessi
authors.forename: Renata
authors.initials: R
authors.lastname: Zippel
authors.forename: Daniela
authors.initials: D
authors.lastname: Parolaro
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D013759:Dronabinol / Q000378:metabolism* / Q000494:pharmacology; D004361:Drug Tolerance; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D051606:G-Protein-Coupled Receptor Kinase 1 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D000071557:beta-Arrestins; D018631:ras Proteins / Q000378:metabolism*; D020666:ras-GRF1 / Q000235:genetics / Q000378:metabolism
chemical_list: D019390:Arrestins; D019208:Brain-Derived Neurotrophic Factor; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D016760:Proto-Oncogene Proteins c-fos; D043884:Receptor, Cannabinoid, CB1; D014157:Transcription Factors; D000071557:beta-Arrestins; D020666:ras-GRF1; D013759:Dronabinol; D017346:Protein Serine-Threonine Kinases; D051606:G-Protein-Coupled Receptor Kinase 1; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins