Cannabidiol regulates the expression of hypothalamus-pituitary-adrenal axis-related genes in response to acute restraint stress

• Published in: Journal of psychopharmacology (Oxford) 2018-12, Vol.32 (12), p.1379-1384
• Main Authors: Viudez-Martínez, Adrián, García-Gutiérrez, María S, Manzanares, Jorge
• Format: Article
• Language: English
• Subjects: Allosteric properties; Amygdala; Amygdala - drug effects; Amygdala - metabolism; Animals; Antidepressants; Arcuate nucleus; Cannabidiol - administration & dosage; Cannabidiol - pharmacology; Corticotropin-releasing hormone; Disease Models, Animal; Dose-Response Relationship, Drug; Gene expression; Gene Expression Regulation - drug effects; Glucocorticoids; Hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; Hypothalamo-Hypophyseal System - drug effects; Hypothalamo-Hypophyseal System - metabolism; Hypothalamus; Hypothalamus - drug effects; Hypothalamus - metabolism; Male; Mice; Mice, Inbred C57BL; Mood; Paraventricular nucleus; Pituitary; Pituitary-Adrenal System - drug effects; Pituitary-Adrenal System - metabolism; Polymerase chain reaction; Proopiomelanocortin; Receptor, Serotonin, 5-HT1A - drug effects; Receptor, Serotonin, 5-HT1A - genetics; Receptor, Serotonin, 5-HT1A - metabolism; Restraint, Physical; Rodents; Serotonin; Stress; Stress, Psychological - drug therapy; Stress, Psychological - physiopathology
• ISSN: 0269-8811; 1461-7285
• DOI: 10.1177/0269881118805495

Background: Research interest has grown around the potential therapeutic use of cannabidiol in mood-related disorders, due to its anxiolytic and antidepressant-like effects. These have been partially attributed to its action as an allosteric modulator of 5-HTR1A. However, the exact mechanism supporting cannabidiol properties remains unclear. Aims: To assess the effects of cannabidiol on different targets of the hypothalamus-pituitary-adrenal axis under baseline and stress conditions. Methods: We administered cannabidiol (5 mg/kg, 15 mg/kg or 30 mg/kg, intraperitoneally) or vehicle to male C57BL/6J mice 90 min before single restraint stress exposure (20 min). Using real-time polymerase chain reaction analysis, we measured alterations in the relative gene expression of corticotropin-releasing factor in the paraventricular nucleus, pro-opiomelanocortin in the arcuate nucleus of the hypothalamus, glucocorticoid receptor in the hippocampus, and serotonin 5-HTR1A receptor in the hippocampus and amygdala. Results: Under baseline conditions, cannabidiol did not modify any element of the hypothalamus-pituitary-adrenal axis. In contrast, all doses induced alterations in 5-HTR1A in the amygdala and hippocampus. Interestingly, cannabidiol at low (5 mg/kg) and intermediate doses (15 mg/kg) successfully blocked the effects induced by acute stress on corticotropin-releasing factor, pro-opiomelanocortin and glucocorticoid receptor gene expression. Also, restraint stress induced the opposite effects in 5-HTR1A gene expression in the hippocampus and amygdala, an effect not seen in mice treated with cannabidiol at low doses. Conclusions: Taken together, these data suggest the ability of cannabidiol to regulate acute stress hypothalamus-pituitary-adrenal axis activation might be explained, at least in part, by its action on 5-HTR1A receptors.