5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats

Br J Pharmacol. 2009 Jan;156(1):181-8. doi: 10.1111/j.1476-5381.2008.00046.x.


Background and purpose: Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa which induces anxiolytic- and antipsychotic-like effects in rodents. These effects could be mediated by facilitation of the endocannabinoid system or by the activation of 5-HT(1A) receptors. As either of these mechanisms could promote adaptation to inescapable stress, the aim of the present work was to test the hypothesis that CBD would attenuate the autonomic and behavioural consequences of restraint stress (RS). We also investigated if the responses to CBD depended on activation of 5-HT(1A) receptors.

Experimental approach: Male Wistar rats received i.p. injections of vehicle or CBD (1, 10 or 20 mg kg(-1)) and 30 min later were submitted to 60 min of restraint where their cardiovascular responses were recorded. The protocol of the second experiment was similar to the first one except that animals received i.p. injections of the 5-HT(1A) receptor antagonist WAY100635 (0.1 mg kg(-1)) before CBD treatment and exposure to restraint. 24 h later they were also tested in the elevated plus-maze (EPM), an animal model of anxiety.

Key results: Exposure to RS increased blood pressure and heart rate and induced an anxiogenic response in the EPM 24 h later. These effects were attenuated by CBD. WAY100635 by itself did not change the cardiovascular and anxiogenic response to RS, but blocked the effects of CBD.

Conclusion and implications: The results suggest that CBD can attenuate acute autonomic responses to stress and its delayed emotional consequences by facilitating 5-HT(1A) receptor-mediated neurotransmission.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Anxiety Agents / administration & dosage
  • Anti-Anxiety Agents / pharmacology*
  • Anti-Anxiety Agents / therapeutic use
  • Behavior, Animal / drug effects*
  • Blood Pressure / drug effects
  • Cannabidiol / administration & dosage
  • Cannabidiol / pharmacology*
  • Cannabidiol / therapeutic use
  • Dose-Response Relationship, Drug
  • Heart Rate / drug effects
  • Hemodynamics / drug effects*
  • Injections, Intraperitoneal
  • Male
  • Maze Learning / drug effects
  • Piperazines / pharmacology
  • Pyridines / pharmacology
  • Rats
  • Rats, Wistar
  • Receptor, Serotonin, 5-HT1A / physiology*
  • Restraint, Physical
  • Serotonin 5-HT1 Receptor Agonists
  • Serotonin Antagonists / pharmacology
  • Stress, Psychological / drug therapy*
  • Stress, Psychological / physiopathology
  • Stress, Psychological / psychology


  • Anti-Anxiety Agents
  • Piperazines
  • Pyridines
  • Serotonin 5-HT1 Receptor Agonists
  • Serotonin Antagonists
  • Receptor, Serotonin, 5-HT1A
  • Cannabidiol
  • N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide