Involvement of serotonin-mediated neurotransmission in the dorsal periaqueductal gray matter on cannabidiol chronic effects in panic-like responses in rats

Psychopharmacology (Berl). 2013 Mar;226(1):13-24. doi: 10.1007/s00213-012-2878-7. Epub 2012 Sep 25.


Rationale: Cannabidiol (CBD) is a non-psychotomimetic constituent of Cannabis sativa plant that promotes antianxiety and anti-panic effects in animal models after acute systemic or intra-dorsal periaqueductal gray (DPAG) administration. However, the effects of CBD repeated administration, and the possible mechanisms involved, in animal models of anxiety- and panic-related responses remain poorly understood.

Objective: The present study evaluates the role of the serotonergic neurotransmission within the DPAG in the modulation of escape responses of rats chronically treated with CBD.

Methods: Male Wistar rats received acute or repeated (5 mg/Kg/daily/21 days) administration of CBD and were submitted to the elevated T-maze (ETM). We also investigated if CBD effects on the ETM depend on facilitation of 5-HT1A-mediated neurotransmission in the DPAG. To this latter aim, we verified if these effects would be prevented by intra-DPAG injection of the 5-HT1A receptor antagonist WAY100635 (0.37 nmol/0.2 μL). Also, we verified, by in vivo microdialysis, if CBD chronic treatment increases serotonin (5-HT) release and, by quantitative polymerase chain reaction, if there are changes in 5HT-1A or 5HT-2C mRNA expression in DPAG.

Results: The results showed that repeated but not acute peripheral administration of CBD decreases escape responses in the ETM, suggesting a panicolytic effect. This treatment did not change 5HT-1A or 5-HT-2C receptor mRNA expression nor modify serotonin extracellular concentrations in the DPAG. CBD effects were prevented by DPAG injection of the 5-HT1A receptor antagonist.

Conclusions: Together, these findings suggest that repeated treatment with CBD induces anti-panic effects by acting on 5-HT1A receptors in DPAG.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects*
  • Brain Mapping
  • Cannabidiol / administration & dosage
  • Cannabidiol / pharmacology*
  • Cannabidiol / therapeutic use
  • Dose-Response Relationship, Drug
  • Male
  • Maze Learning / drug effects
  • Microdialysis
  • Panic Disorder / physiopathology
  • Panic Disorder / prevention & control*
  • Panic Disorder / psychology
  • Periaqueductal Gray / drug effects*
  • Periaqueductal Gray / metabolism
  • Periaqueductal Gray / physiopathology
  • Polymerase Chain Reaction
  • Rats, Wistar
  • Receptor, Serotonin, 5-HT1A / metabolism
  • Serotonin / metabolism*
  • Synaptic Transmission / drug effects*


  • Receptor, Serotonin, 5-HT1A
  • Cannabidiol
  • Serotonin