title: Haloperidol and clozapine differentially affect the expression of arrestins, receptor kinases, and extracellular signal-regulated kinase activation.
abstract: Dopamine and other G protein-coupled receptors (GPCRs) represent the major target of antipsychotic drugs. GPCRs undergo desensitization via activation-dependent phosphorylation by G protein-coupled receptor kinases (GRKs) followed by arrestin binding. Arrestins and GRKs are major regulators of GPCR signaling. We elucidated changes in expression of two arrestins and four GRKs following chronic (21 days) treatment with haloperidol (1 mg/kg i.p.) or clozapine (20 mg/kg i.p.) 2 or 24 h after the last injection in 11 brain regions. Haloperidol decreased GRK3 in ventrolateral caudate-putamen and transiently down-regulated GRK5 in globus pallidus and caudal caudate-putamen. Clozapine also caused a short-term suppression of the GRK5 expression in the caudal caudate-putamen and globus pallidus, but, unlike haloperidol, elevated GRK5 in the caudal caudate-putamen after 24 h. Unlike haloperidol, clozapine decreased arrestin2 and GRK3 in hippocampus and GRK3 in globus pallidus but increased arrestin2 in the core of nucleus accumbens and ventrolateral caudate-putamen and GRK2 in prefrontal cortex. Clozapine, but not haloperidol, induced long-term activation of extracellular signal-regulated kinase (ERK) 2 in ventrolateral caudate-putamen and transient in prefrontal cortex. The data demonstrate that haloperidol and clozapine differentially affect the expression of arrestins and GRKs and ERK activity, which may play a role in determining their clinical profile.
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Preston Research Building, Room 422, Nashville, TN 37232, USA.
authors.forename: Mohamed Rafiuddin
authors.initials: MR
authors.lastname: Ahmed
authors.forename: Vsevolod V
authors.initials: VV
authors.lastname: Gurevich
authors.forename: Kevin N
authors.initials: KN
authors.lastname: Dalby
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Benovic
authors.forename: Eugenia V
authors.initials: EV
authors.lastname: Gurevich
mesh_terms: D000818:Animals; D019390:Arrestins / Q000235:genetics*; D001921:Brain; D001923:Brain Chemistry / Q000187:drug effects; D003024:Clozapine / Q000494:pharmacology*; D016616:Cryoultramicrotomy; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000235:genetics; D054770:G-Protein-Coupled Receptor Kinase 3 / Q000235:genetics; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000235:genetics; D054768:G-Protein-Coupled Receptor Kinases / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects*; D006220:Haloperidol / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D019390:Arrestins; D054770:G-Protein-Coupled Receptor Kinase 3; C496569:Grk2 protein, rat; C517851:Grk3 protein, rat; D054769:G-Protein-Coupled Receptor Kinase 2; D054774:G-Protein-Coupled Receptor Kinase 5; D054768:G-Protein-Coupled Receptor Kinases; C517897:Grk5 protein, rat; D048049:Extracellular Signal-Regulated MAP Kinases; D003024:Clozapine; D006220:Haloperidol