Protease-activated receptor 2 activation induces behavioural changes associated with depression-like behaviour through microglial-independent modulation of inflammatory cytokines

Serge Moudio, Ashleigh Willis, Karolina Pytka, Roua Abulkassim, Ros R. Brett, Jack F. Webster, Christian Wozny, Mark Barbour, Hui-Rong Jiang, David G. Watson, Josie C. van Kralingen, Scott M. Mackenzie, Michael Daniels, Barry W. McColl, Sandra Sossick, Hugh N. Nuthall, Trevor J. Bushell

Research output: Contribution to journalArticlepeer-review

Abstract

Rationale: Major depressive disorder (MDD) is a leading cause of disability worldwide but currently prescribed treatments do not adequately ameliorate the disorder in a significant portion of patients. Hence, a better appreciation of its aetiology may lead to the development of novel therapies. Objectives: In the present study, we have built on our previous findings indicating a role for protease-activated receptor-2 (PAR2) in sickness behaviour to determine whether the PAR2 activator, AC264613, induces behavioural changes similar to those observed in depression-like behaviour. Methods: AC264613-induced behavioural changes were examined using the open field test (OFT), sucrose preference test (SPT), elevated plus maze (EPM), and novel object recognition test (NOR). Whole-cell patch clamping was used to investigate the effects of PAR2 activation in the lateral habenula with peripheral and central cytokine levels determined using ELISA and quantitative PCR. Results: Using a blood–brain barrier (BBB) permeable PAR2 activator, we reveal that AC-264613 (AC) injection leads to reduced locomotor activity and sucrose preference in mice but is without effect in anxiety and memory-related tasks. In addition, we show that AC injection leads to elevated blood sera IL-6 levels and altered cytokine mRNA expression within the brain. However, neither microglia nor peripheral lymphocytes are the source of these altered cytokine profiles. Conclusions: These data reveal that PAR2 activation results in behavioural changes often associated with depression-like behaviour and an inflammatory profile that resembles that seen in patients with MDD and therefore PAR2 may be a target for novel antidepressant therapies.

Original languageEnglish
Number of pages14
JournalPsychopharmacology
Early online date9 Dec 2021
DOIs
Publication statusE-pub ahead of print - 9 Dec 2021

Keywords

  • open field test
  • sucrose preference
  • inflammation
  • cytokines
  • protease-activated receptor-2

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