The novel cannabinoid receptor GPR55 mediates anxiolytic-like effects in the medial orbital cortex of mice with acute stress

Abstract

The G protein-coupled receptor 55 (GPR55) is a novel cannabinoid receptor, whose exact role in anxiety remains unknown. The present study was conducted to explore the possible mechanisms by which GPR55 regulates anxiety and to evaluate the effectiveness of O-1602 in the treatment of anxiety-like symptoms. Mice were exposed to two types of acute stressors: restraint and forced swimming. Anxiety behavior was evaluated using the elevated plus maze and the open field test. We found that O-1602 alleviated anxiety-like behavior in acutely stressed mice. We used lentiviral shRNA to selectively knockdown GPR55 in the medial orbital cortex and found that knockdown of GPR55 abolished the anxiolytic effect of O-1602. We also used Y-27632, a specific inhibitor of ROCK, and U73122, an inhibitor of PLC, and found that both inhibitors attenuated the effectiveness of O-1602. Western blot analysis revealed that O-1602 downregulated the expression of GluA1 and GluN2A in mice. Taken together, these results suggest that GPR55 plays an important role in anxiety and O-1602 may have therapeutic potential in treating anxiety-like symptoms.

O-1602, an Agonist of Atypical Cannabinoid Receptors GPR55, Reverses the Symptoms of Depression and Detrusor Overactivity in Rats Subjected to Corticosterone Treatment

“…Besides, it induced the anti-inflammatory and pain relieving effects in diverse animal models of inflammation ( Schuelert and McDougall, 2011 ; Schicho et al, 2011 ; Li et al, 2013 ) and had a pronociceptive activity in neuropathic pain ( Breen et al, 2012 ). Several authors noted that administration of O-1602 to both normal ( Rahimi et al, 2015 ) and stressed ( Shi et al, 2017 ) rodents resulted in the anxiolytic-like activity and this effect was mediated via GPR55 receptors since it was abolished by GPR55 antagonists (i.e., CID16020046 or ML-193) and GPR55 receptor knock-down ( Rahimi et al, 2015 ; Shi et al, 2017 ). In the presented study, we found that O-1602 has an antidepressant-like potential and the potential against detrusor overactivity.…”

“…We can only assume that its antidepressant-like activity is most probably due to the potent agonism of GPR55 receptors, as it has been confirmed for its anxiolytic effects. Shi and colleagues (2017) suggested that in the emotional-modulating effects of O-1602, the RhoA/RhoA kinase and phospholipase C/protein kinase C signaling along with the extracellular-signal-regulated kinase pathway may be involved. According to the above-mentioned authors ( Shi et al, 2017 ), other transmissions affected by GPR55 receptors, e.g., p38-, NFAT- or Rac-dependent ones, could contribute to the observed results as well.…”

“…Existence of GPR55 receptors has also been detected in different parts of the brain, including the striatum, hippocampus, forebrain, cortex, and cerebellum ( Wu et al, 2013 ). As a consequence, involvement of these receptors in hyperlagesia ( Staton et al, 2008 ), pain perception ( Deliu et al, 2015 ), motor coordination ( Wu et al, 2013 ), anxiety ( Rahimi et al, 2015 ; Shi et al, 2017 ), substance abuse, and neuroprotection has been demonstrated ( Alavi et al, 2016 ; Hill et al, 2019 ). Most probably, GPR55 receptors also participate in the hippocampal plasticity, and may play an important role in the modulation of memory and learning ( Hurst et al, 2017 ) as well as in the control of decision-making ( Garcia-Gutierrez et al, 2018 ).…”

“…Bearing in mind the following facts: (1) localization of GPR55 receptors in the brain areas implicated in the pathophysiology of depression ( Wu et al, 2013 ), (2) reduced GPR55 gene expression in the dorsolateral prefrontal cortex of suicide victims ( Garcia-Gutierrez et al, 2018 ), and (3) anxiolytic-like effect of GPR55 receptor agonism ( Rahimi et al, 2015 ; Shi et al, 2017 ), GPR55 receptors have drawn our attention as a potential target in the treatment of mood disorders. Depression, as a disease that affects over 322 million people worldwide, poses a major global health issue.…”

The endocannabinoidome as a substrate for noneuphoric phytocannabinoid action and gut microbiome dysfunction in neuropsychiatric disorders

“…25 Inhibitors of FAAH and MAGL (as well as the putative EMT) produce anxiolytic actions mostly due to CB 1 receptor activation, although evidence exists for GPR55 also negatively controlling this condition. 26 Conversely, TRPV1 activation by anandamide, or other NAE substrates of FAAH ( Figure 1), can exacerbate anxiety, to the point that dual FAAH/TRPV1 blockers produce more efficacious anxiolytic actions than selective inhibitors of these two proteins. 27 Ca v3.2 channels, which are inhibited by eCBs and several eCB-like mediators, instead can play both anxiogenic and anxiolytic roles depending on context.…”