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

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Title: Protease-activated receptor 2 activation induces behavioural changes associated with depression-like behaviour through microglial-independent modulation of inflammatory cytokines.
Authors: Moudio, Serge (AUTHOR), Willis, Ashleigh (AUTHOR), Pytka, Karolina (AUTHOR), Abulkassim, Roua (AUTHOR), Brett, Ros R. (AUTHOR), Webster, Jack F. (AUTHOR), Wozny, Christian (AUTHOR), Barbour, Mark (AUTHOR), Jiang, Hui-Rong (AUTHOR), Watson, David G. (AUTHOR), van Kralingen, Josie C. (AUTHOR), MacKenzie, Scott M. (AUTHOR), Daniels, Michael (AUTHOR), McColl, Barry W. (AUTHOR), Sossick, Sandra (AUTHOR), Nuthall, Hugh N. (AUTHOR), Bushell, Trevor J. (AUTHOR)
Source: Psychopharmacology. Jan2022, Vol. 239 Issue 1, p229-242. 14p. 5 Graphs.
Subjects: Protease-activated receptors, Cognitive therapy, Mental depression, Cytokines, Blood-brain barrier, Thrombin receptors, Sucrose, Animal behavior, Animal experimentation, Human locomotion, Proteolytic enzymes, Cell receptors, Psychological tests, Food preferences, Gene expression, Enzyme-linked immunosorbent assay, Messenger RNA, Neuroglia, Inflammatory mediators, Polymerase chain reaction, Mice, Motor ability
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. [ABSTRACT FROM AUTHOR]
Copyright of Psychopharmacology is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Protease-activated receptor 2 activation induces behavioural changes associated with depression-like behaviour through microglial-independent modulation of inflammatory cytokines.
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– Name: Abstract
  Label: Abstract
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  Data: 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. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Psychopharmacology is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1007/s00213-021-06040-1
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