Influence of the CB1 and CB2 cannabinoid receptor ligands on the activity of atypical antidepressant drugs in the behavioural tests in mice

Ewa Poleszak,Sylwia Wośko,Karolina Sławińska,Elżbieta Wyska,Aleksandra Szopa,Katarzyna Świąder,Andrzej Wróbel,Urszula Doboszewska,Piotr Wlaź,Aleksandra Wlaź,Anna Serefko

doi:10.1016/j.pbb.2019.172833

Abstract

Available data support the notion that cannabinoids, whose therapeutic value is limited due to severe adverse reactions, could be beneficial as adjunctive agents in the management of mood disorders. Polytherapy, which is superior to monotherapy in the terms of effectiveness, usually requires lower doses of the individual components. Therefore, the main objective of our study was to determine whether administration of cannabinoid (CB) receptor ligands would enhance the antidepressant activity of atypical antidepressant drugs, i.e. agomelatine and tianeptine. To evaluate the antidepressant-like potential of the tested combinations, the mouse forced swim test (FST) and the tail suspension test (TST) were used. The HPLC method was applied to assess the brain levels of agomelatine and tianeptine. Both behavioural tests demonstrated that per se an ineffective intraperitoneal dose of oleamide (CB1 receptor agonist, 5 mg/kg) potentiated the anti-immobility activity of tianeptine (15 mg/kg), whereas AM251 (CB1 receptor inverse agonist/antagonist, 0.25 mg/kg) enhanced the antidepressant effects of tianeptine and agomelatine (20 mg/kg). Intraperitoneal co-administration of per se inactive doses of AM630 (CB2 receptor inverse agonist/antagonist) and agomelatine or tianeptine significantly reduced the immobility time of animals only in the FST. CB receptor ligands did not affect the brain levels of the tested atypical antidepressants. In summary, the outcomes of the present study showed that activation and inhibition of CB1 receptors as well as inhibition of CB2 receptors may increase the antidepressant activity of tianeptine, whereas only inhibition of CB1 and CB2 receptors has a potential to augment the antidepressant activity of agomelatine.

Highlights

Since augmentation and combining therapies have become a common practice in management of the difficult-to-treat depression, new treatment strategies are being searched for
To the best of our knowledge this is the first report of a positive interaction between CB1 and CB2 receptor ligands and atypical antidepressant drugs in the forced swim test (FST) and the TST in mice
We demonstrated that the antidepressant effect of tianeptine was augmented by per se an inactive dose of the inverse agonist/antagonist of CB2 receptors (AM630, 0.25 mg/kg), whereas it was not affected by the CB2 receptor agonist (JWH133, 0.25 mg/kg)

Summary

Introduction

Since augmentation and combining therapies have become a common practice in management of the difficult-to-treat depression, new treatment strategies are being searched for. Available data support the notion that adjunctive use of agents modulating different neurochemical pathways involved in depression with antidepressant drugs may alleviate disease symptoms more profoundly than typical antidepressant monotherapy (Ceskova, 2016). Cannabinoids, i.e. ligands of cannabinoid (CB) receptors, belong to these substances. It was confirmed a long time ago that CB receptors play an important role in regulation of the excitatory (glutamate-related) and inhibitory (GABA-related) neurotransmissions in the brain as well as they modulate synthesis and release of monoamines (i.e., dopamine, norephinephrine, serotonin) (Moreira et al, 2009). Under certain conditions, CB receptor ligands display the anxiolytic-like activity (Moreira et al, 2009) and they produce rapid

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