Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats

Psychopharmacology (Berl). 2008 Aug;199(2):223-30. doi: 10.1007/s00213-008-1168-x. Epub 2008 May 1.


Rationale: Cannabidiol (CBD) is a non-psychotomimetic constituent of Cannabis sativa plant that induces anxiolytic effects. However, the brain sites and mechanisms of these effects remain poorly understood. The dorsolateral periaqueductal gray (dlPAG) is a midbrain structure related to anxiety that contains receptors proposed to interact with CBD such as 5HT1A. In addition, since CBD has been shown to inhibit anandamide metabolism, CB1 receptors could also be involved in the effects of this cannabinoid.

Objectives: To investigate if the dlPAG could be a possible site of the anxiolytic effects induced by CBD and if these effects depend on CB1 or 5HT1A receptors.

Materials and methods: Male Wistar rats with cannulae aimed at the dlPAG were tested in the elevated plus maze (EPM) and the Vogel conflict test (VCT).

Results: CBD injected into the dlPAG produced anxiolytic-like effects in the EPM with a bell-shaped dose-response curve. The anxiolytic effect of CBD was confirmed in the VCT. These effects were prevented by WAY100635, a 5HT1A receptor antagonist, but not by AM251, an antagonist of CB1 receptors.

Conclusion: These results suggest the CBD interacts with 5HT1A receptors to produce anxiolytic effects in the dlPAG.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Anxiety Agents*
  • Cannabidiol / administration & dosage
  • Cannabidiol / pharmacology*
  • Dose-Response Relationship, Drug
  • Male
  • Microinjections
  • Periaqueductal Gray* / anatomy & histology
  • Piperazines / pharmacology
  • Piperidines / pharmacology
  • Pyrazoles / pharmacology
  • Pyridines / pharmacology
  • Rats
  • Rats, Wistar
  • Receptor, Cannabinoid, CB1 / drug effects
  • Receptor, Serotonin, 5-HT1A / drug effects*
  • Serotonin Antagonists / pharmacology


  • Anti-Anxiety Agents
  • Piperazines
  • Piperidines
  • Pyrazoles
  • Pyridines
  • Receptor, Cannabinoid, CB1
  • Serotonin Antagonists
  • Receptor, Serotonin, 5-HT1A
  • Cannabidiol
  • AM 251
  • N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide