title: G protein-coupled receptor kinase 6/β-arrestin 2 system in a rat model of dopamine supersensitivity psychosis.
abstract: In humans, long-term antipsychotic treatment is known to induce movement disorders and a psychosis, called dopamine supersensitivity psychosis (DSP). The mechanism by which chronic administration of antipsychotic(s) causes DSP may be the treatment-induced up-regulation of dopamine D2 receptors (DRD2). G protein-coupled receptor kinase 6 (GRK6) and beta-arrestin 2 (ARRB2) play important roles in the trafficking of DRD2 by phosphorylation and internalization. We investigated the effects of chronic continuous treatment with mini-pump-administered haloperidol (HAL) on the sensitivity of Wistar rats to dopamine, as measured by the locomotor response to methamphetamine (MAP) and the density of striatal DRD2. Chronic continuous treatment with HAL resulted in significantly higher locomotor response to MAP and significantly higher striatal DRD2 density compared with those in rats administered vehicle (VEH). Enzyme-linked immunosorbent assays revealed that striatal ARRB2 in DSP model rats tended to decrease in comparison with that in the VEH group. In addition, the ratio of GRK6/ARRB2 in DSP model rats was significantly higher than that in controls. Our results suggest that alterations of the GRK6 and ARRB2 system could induce both DRD2 up-regulation and impairment of the dopamine signaling pathway, resulting potentially in the development of DSP.
authors.affiliation: Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan odayasunori@chiba-u.jp.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Oda
authors.affiliation: Department of Psychiatry, Shousin-kai Mobara Hospital, Mobara, Japan.
authors.forename: Shigenori
authors.initials: S
authors.lastname: Tadokoro
authors.affiliation: Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takase
authors.affiliation: Division of Medical Treatment and Rehabilitation, Chiba University Center for Forensic Mental Health, Chiba, Japan.
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Kanahara
authors.affiliation: Division of Medical Treatment and Rehabilitation, Chiba University Center for Forensic Mental Health, Chiba, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Department of Psychiatry, Teikyo University Chiba Medical Center, Ichihara, Japan.
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Shirayama
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Hashimoto
authors.affiliation: Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Masaomi
authors.initials: M
authors.lastname: Iyo
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D019390:Arrestins / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D054768:G-Protein-Coupled Receptor Kinases / Q000378:metabolism*; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D008694:Methamphetamine / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D011618:Psychotic Disorders / Q000188:drug therapy / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605254:ARRB2 protein, human; D014150:Antipsychotic Agents; C000605257:Arrb2 protein, rat; D019390:Arrestins; D017448:Receptors, Dopamine D2; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D008694:Methamphetamine; D054768:G-Protein-Coupled Receptor Kinases; C089176:G-protein-coupled receptor kinase 6; D006220:Haloperidol; D004298:Dopamine
keywords: Antipsychotic; dopamine; dopamine D2 receptor (DRD2); locomotor activity; radioligand binding assay; striatum