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

J Psychopharmacol. 2018 Dec;32(12):1379-1384. doi: 10.1177/0269881118805495. Epub 2018 Oct 16.


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.

Keywords: Hypothalamus-pituitary-adrenal axis; acute restraint stress; cannabidiol; gene expression; real time polymerase chain reaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amygdala / drug effects
  • Amygdala / metabolism
  • Animals
  • Cannabidiol / administration & dosage
  • Cannabidiol / pharmacology*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation / drug effects
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Hypothalamo-Hypophyseal System / drug effects*
  • Hypothalamo-Hypophyseal System / metabolism
  • Hypothalamus / drug effects
  • Hypothalamus / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Pituitary-Adrenal System / drug effects*
  • Pituitary-Adrenal System / metabolism
  • Receptor, Serotonin, 5-HT1A / drug effects
  • Receptor, Serotonin, 5-HT1A / genetics
  • Receptor, Serotonin, 5-HT1A / metabolism
  • Restraint, Physical
  • Stress, Psychological / drug therapy*
  • Stress, Psychological / physiopathology


  • Receptor, Serotonin, 5-HT1A
  • Cannabidiol