The role of beta-arrestin2 in shaping fMRI BOLD responses to dopaminergic stimulation

Kristoffer Sahlholm, Giovanna D. Ielacqua, Jinbin Xu, Lynne A. Jones, Felix Schlegel, Robert H. Mach, Markus Rudin, Aileen Schroeter

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Rationale: The dopamine D2 receptor (D2R) couples to inhibitory Gi/o proteins 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. Objectives: 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.

Original languageEnglish
Pages (from-to)2019-2030
Number of pages12
JournalPsychopharmacology
Volume234
Issue number13
DOIs
StatePublished - Jul 1 2017

Keywords

  • Arrestin3
  • Dopamine
  • Dopamine agents
  • Dopamine receptor
  • Eticlopride

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