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

Moudio, S. et al. (2022) Protease-activated receptor 2 activation induces behavioural changes associated with depression-like behaviour through microglial-independent modulation of inflammatory cytokines. Psychopharmacology, 239(1), pp. 229-242. (doi: 10.1007/s00213-021-06040-1) (PMID:34888704) (PMCID:PMC8770450)

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.

• Item Type: Articles
• Additional Information: This work was partially supported by a University of Strathclyde PhD CASE studentship with Eli Lilly Ltd to SM, a Ministry of Science and Higher Education, Poland Mobility Grant (Award Number: 1661/ MOB/V/2017/0) to KP.
• Keywords: Inflammation, protease-activated receptor-2, open-field test, sucrose preference, cytokines.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Van Kralingen, Ms Josie and MacKenzie, Dr Scott
• Authors: Moudio, S., Willis, A., Pytka, K., Abulkassim, R., Brett, R. R., Webster, J. F., Wozny, C., Barbour, M., Jiang, H.-R., Watson, D. G., van Kralingen, J. C., MacKenzie, S. M., Daniels, M., McColl, B. W., Sossick, S., Nuthall, H. N., and Bushell, T. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Psychopharmacology
• Publisher: Springer
• ISSN: 0033-3158
• ISSN (Online): 1432-2072
• Published Online: 09 December 2021
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Psychopharmacology 239(1): 229-242
• Publisher Policy: Reproduced under a Creative Commons License