۱- Introduction

۲- Materials and methods

۳- Results

۴- Discussion

۵- Conclusions

References

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.

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. The endocannabinoid system consists of the endogenous arachidonate-based lipids referred to as “endocannabinoids” (such as anandamide and 2-arachidonoylglycerol), enzymes responsible for their synthesis (N-acylphosphatidylethanolamine-phospholipase D and diacylglycerol lipase) and degradation (fatty acid amide hydrolase and monoacylglycerol lipase), and the endocannabinoid CB receptors (for review see [1,2]). Thus far, two types of typical CB receptors, encoded by CNR1 and CNR2 genes, have been described. Both CB1 and CB2 receptors bind endogenous and exogenous cannabinoids with high affinity. Due to specific mechanism of action of CB receptors, on the one hand the endocannabinoid system can help to restore the brain balance after exposure to different stressors, but on the other hand, it is involved in the pathogenesis of certain mental disturbances, like anxiety, stress, aggressive behavior, or depression. Until recently, only CB1 receptors were thought to be implicated in the development of mental diseases as the ones that are expressed both in the periphery and the brain. CB2 receptors were mainly considered as the peripheral receptors. It was believed that they were distributed almost exclusively within the immune cells and thus, that they have only the immunomodulatory role (i.e., regulation of cytokines or migration of immune cells) (for review see [1-3]). However, several research team have found out that CB2 receptors are also localized in the rodent [4] and human central nervous system [5-7]. 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 then, they were also identified under physiological conditions [5].