title: The role of beta-arrestin2 in shaping fMRI BOLD responses to dopaminergic stimulation.
abstract: BACKGROUND
  The dopamine D2receptor (D2R) couples to inhibitory Gi/oproteins and is targeted by antipsychotic and antiparkinsonian drugs. Beta-arrestin2 binds to the intracellular regions of the agonist-occupied D2R to terminate G protein activation and promote internalization, but also to initiate downstream signaling cascades which have been implicated in psychosis. Functional magnetic resonance imaging (fMRI) has proven valuable for measuring dopamine receptor-mediated changes in neuronal activity, and might enable beta-arrestin2 function to be studied in vivo.
  
  
  OBJECTIVE
  The present study examined fMRI blood oxygenation level dependent (BOLD) signal changes elicited by a dopamine agonist in wild-type (WT) and beta-arrestin2 knockout (KO) mice, to investigate whether genetic deletion of beta-arrestin2 prolongs or otherwise modifies D2R-dependent responses.
  
  
  METHODS
  fMRI BOLD data were acquired on a 9.4 T system. During scans, animals received 0.2 mg/kg apomorphine, i.v. In a subset of experiments, animals were pretreated with 2 mg/kg of the D2R antagonist, eticlopride.
  
  
  RESULTS
  Following apomorphine administration, BOLD signal decreases were observed in caudate/putamen of WT and KO animals. The time course of response decay in caudate/putamen was significantly slower in KO vs. WT animals. In cingulate cortex, an initial BOLD signal decrease was followed by a positive response component in WT but not in KO animals. Eticlopride pretreatment significantly reduced apomorphine-induced BOLD signal changes.
  
  
  CONCLUSIONS
  The prolonged striatal response decay rates in KO animals might reflect impaired D2R desensitization, consistent with the known function of beta-arrestin2. Furthermore, the apomorphine-induced positive response component in cingulate cortex may depend on beta-arrestin2 signaling downstream of D2R.
authors.affiliation: Institute for Biomedical Engineering, University and ETH Zurich, Wolfgang-Pauli-Str. 27, 8093, Zurich, Switzerland. kristoffer.sahlholm@ki.se.|Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. Kingshighway Blvd, St. Louis, MO, 63110, USA. kristoffer.sahlholm@ki.se.|Department of Neuroscience, Karolinska Institutet, Retzius väg 8, SE-171 77, Stockholm, Sweden. kristoffer.sahlholm@ki.se.
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Sahlholm
authors.affiliation: Institute for Biomedical Engineering, University and ETH Zurich, Wolfgang-Pauli-Str. 27, 8093, Zurich, Switzerland.
authors.forename: Giovanna D
authors.initials: GD
authors.lastname: Ielacqua
authors.affiliation: Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. Kingshighway Blvd, St. Louis, MO, 63110, USA.
authors.forename: Jinbin
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. Kingshighway Blvd, St. Louis, MO, 63110, USA.
authors.forename: Lynne A
authors.initials: LA
authors.lastname: Jones
authors.affiliation: Institute for Biomedical Engineering, University and ETH Zurich, Wolfgang-Pauli-Str. 27, 8093, Zurich, Switzerland.
authors.forename: Felix
authors.initials: F
authors.lastname: Schlegel
authors.affiliation: Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 231 S. 34th St, Philadelphia, PA, 19104, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
authors.affiliation: Institute for Biomedical Engineering, University and ETH Zurich, Wolfgang-Pauli-Str. 27, 8093, Zurich, Switzerland.|Neuroscience Center Zurich, University and ETH Zurich, Winterthurer-Str. 190, 8057, Zurich, Switzerland.|Institute of Pharmacology and Toxicology, University of Zurich, Winterthurer-Str. 190, 8057, Zurich, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Rudin
authors.affiliation: Institute for Biomedical Engineering, University and ETH Zurich, Wolfgang-Pauli-Str. 27, 8093, Zurich, Switzerland.|Neuroscience Center Zurich, University and ETH Zurich, Winterthurer-Str. 190, 8057, Zurich, Switzerland.
authors.forename: Aileen
authors.initials: A
authors.lastname: Schroeter
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000378:metabolism / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000378:metabolism / Q000494:pharmacology*; D001058:Apomorphine / Q000008:administration & dosage* / Q000737:chemistry; D003342:Corpus Striatum / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017072:Neostriatum / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D000071560:beta-Arrestin 2
chemical_list: D000978:Antiparkinson Agents; D014150:Antipsychotic Agents; C581293:DRD2 protein, human; D018491:Dopamine Agonists; D017448:Receptors, Dopamine D2; D000071560:beta-Arrestin 2; D001058:Apomorphine
keywords: Arrestin3; Dopamine; Dopamine agents; Dopamine receptor; Eticlopride