Ligands of the CB2 cannabinoid receptors augment activity of the conventional antidepressant drugs in the behavioural tests in mice

Ewa Poleszak,Sylwia Wośko,Karolina Sławińska,Elżbieta Wyska,Aleksandra Szopa,Jan Sobczyński,Andrzej Wróbel,Urszula Doboszewska,Piotr Wlaź,Aleksandra Wlaź,Jarosław Szponar,Piotr Skałecki,Anna Serefko

doi:10.1016/j.bbr.2019.112297

Abstract

Although a lot of information can be found on the specific dual role of the endocannabinoid system in the emotional-related responses, little is known whether stimulation or inhibition of the cannabinoid (CB) receptors may affect the activity of the frequently prescribed antidepressant drugs. Our interests have been particularly focused on the potential influence of the CB2 receptors, as the ones whose central effects are relatively poorly documented when compared to the central effects of the CB1 receptors. Therefore, we evaluated the potential interaction between the CB2 receptor ligands (i.e., JWH133 – CB2 receptor agonist and AM630 – CB2 receptor inverse agonist) and several common antidepressant drugs that influence the monoaminergic system (i.e., imipramine, escitalopram, reboxetine). In order to assess the antidepressant-like effects we used two widely recognized behavioural tests, the mouse forced swim test (FST) and the tail suspension test (TST). Brain concentrations of the tested antidepressants were evaluated by the HPLC method. Intraperitoneal co-administration of per se ineffective doses of JWH133 (0.25 mg/kg) or AM630 (0.25 mg/kg) with imipramine (15 mg/kg), escitalopram (2 mg/kg), and reboxetine (2.5 mg/kg) significantly shortened the immobility time of mice in the FST and the TST, whereas it did not disturb their spontaneous locomotor activity. Furthermore, the brain levels of antidepressants were not changed. Summarizing, the results of the present study revealed that both activation and inhibition of the CB2 receptor function have a potential to strengthen the antidepressant activity of drugs targeting the monoaminergic system. Most probably, the described interaction has a pharmacodynamic background.

Highlights

The endocannabinoid system has attracted clinicians attention for decades as an endogenous homeostatic system associated with a large number of neurotransmitters and their pathways, and implicated in numerous physiological functions, including an inflammatory process, pain, or emotions
We evaluated the potential interaction between CB2 receptor ligands (i.e., JWH133 – CB2 receptor agonist and AM630 – CB2 receptor inverse agonist) and three common antidepressant drugs that influence the monoaminergic system
We examined the impact of co-administration of CB2 receptor agonist (JWH133) or CB2 receptor antagonist (AM630) and imipramine, escitalopram, or reboxetine on the depression-related behaviour of mice in the forced swim test (FST) and the TST, i.e. two most widely used animal tests evaluating the antidepressant-like activity

Summary

Introduction

The endocannabinoid system has attracted clinicians attention for decades as an endogenous homeostatic system associated with a large number of neurotransmitters and their pathways, and implicated in numerous physiological functions, including an inflammatory process, pain, or emotions. Several research team have found out that CB2 receptors are localized in the rodent [4] and human central nervous system [5,6,7] At first, their presence in the brain was linked to existence of pathological conditions, like Alzheimer’s disease [8], multiple sclerosis, amyotrophic lateral sclerosis [9], or tumours [10], but they were identified under physiological conditions [5]. CB2 receptors are localized in the spinal nucleus, olfactory nucleus, thalamus, hippocampus, amygdala, cerebral cortex, and cerebellum [11,12] They are mainly distributed post-synaptically, but they can be found in the presynaptic areas. Onaivi et al [4] reported a reduced expression of CB2 receptors in the striatum and midbrain of mice that developed alcohol preference

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