Investigation of the involvement of adenosinergic neurotransmission in the behavioral effects of cannabidiol: participation of serotoninergic 5-HT1A and CB1 cannabinoid receptors.

Abstract

Cannabidiol is the main non-psychotomimetic constituent of the Cannabis sativa plant and has broad therapeutic potential for neuropsychiatric disorders, including anxiety and depression. However, the mechanisms involved in these effects have not been fully elucidated yet. In vitro results suggest that, among the different mechanisms described, CBD is capable of inhibiting adenosine uptake. Studies suggest that adenosinergic signaling is also involved in the aforementioned psychiatric disorders. For example, agonism or antagonism of adenosinergic receptors produces anxiolytic or anxiogenic effects, respectively. However, to date, the involvement of adenosinergic receptors in the antidepressant and anxiolytic-like effects of cannabidiol has not been fully investigated. In an initial study in our laboratory, we verified that the administration of a sub-effective dose of caffeine, a non-selective antagonist of adenosinergic receptors, does not alter the behavioral effect induced by the acute administration of cannabidiol in animals submitted to the forced swimming test. However, the combination of a selective A2A receptor antagonist with cannabidiol, at ineffective doses, reduced immobility time in forced swimming, considered an antidepressant-like effect. In this sense, the present work proposes to investigate the possible involvement of serotoninergic 5-HT1A and cannabinoid CB1 receptors in the antidepressant-like and/or anxiolytic behavioral effect observed by the co-administration of cannabidiol and adenosinergic antagonists in male and female mice submitted to different behavioral models, sensitive to antidepressant and anxiolytic drugs. For this, the animals will receive an acute systemic injection of SCH-58261 (selective adenosinergic A2A receptor antagonist: 0.1, 0.5, and 1 mg/kg), CPT (selective adenosinergic A1 receptor antagonist; 1 and 10 mg/kg ), cannabidiol (3, 10 and 30 mg/kg), imipramine (30 mg/kg) and vehicle (10 ml/kg) and will be submitted to open field, forced swimming, elevated plus maze, tail suspension, and light-dark transition tests. From this first experiment, the mice will receive a combination of ineffective doses of adenosinergic antagonists and cannabidiol, then submitted to open field, forced swimming, elevated plus maze, tail suspension, and light-dark transition tests. Finally, before the combination of adenosinergic antagonists and cannabidiol, an additional group of animals will be treated with WAY-100635 (5-HT1A serotonin receptor antagonist) or AM251 (CB1 cannabinoid receptor antagonist) and subjected to the aforementioned behavioral tests.