Abstract
RationaleMajor 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.ObjectivesIn 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.MethodsAC264613-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.ResultsUsing 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.ConclusionsThese 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.
Highlights
Major depressive disorder (MDD) is a major contributor to the global burden of disease (Miller and Raison 2016; Bhattacharya and Drevets 2017; WHO Mental Health Report 2020), and contributing to this burden is the significant number of patients that are treatment-resistant (TRD), whilst other sufferers experience relapses despite being on current therapies (Bhattacharya and Drevets 2017)
We reveal that the proteaseactivated receptor 2 (PAR2) activator, AC, crosses the blood–brain barrier (BBB), impairs locomotor activity, and induces anhedonia
Our finding regarding SLIGRL-NH2 is in contrast to a previous study that showed the presence of SLIGRL-NH2 in the brain when examined in Genetic Absence Epilepsy Rats from Strasbourg (GAERS; Lohman et al 2009)
Summary
Major depressive disorder (MDD) is a major contributor to the global burden of disease (Miller and Raison 2016; Bhattacharya and Drevets 2017; WHO Mental Health Report 2020), and contributing to this burden is the significant number of patients that are treatment-resistant (TRD), whilst other sufferers experience relapses despite being on current therapies (Bhattacharya and Drevets 2017). AC-induced behavioural changes correlate with increased serum IL-6 levels and brain IL-1β mRNA, with these data being analogous to those reported previously in animal models of depression-like behaviour and in MDD (Bhattacharya and Drevets 2017; Dantzer 2017). These novel findings provide further evidence to our previous proposals that PAR2 plays a role in behavioural changes associated with depression-like behaviour and warrants further investigation as a novel target for future therapeutic interventions for the treatment of MDD
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