Antidepressant-like effect of cannabidiol injection into the ventral medial prefrontal cortex-Possible involvement of 5-HT1A and CB1 receptors

Behav Brain Res. 2016 Apr 15;303:218-27. doi: 10.1016/j.bbr.2016.01.033. Epub 2016 Jan 20.


Rationale: Systemic administration of cannabidiol (CBD), the main non-psychotomimetic constituent of Cannabis sativa, induces antidepressant-like effects. The mechanism of action of CBD is thought to involve the activation of 5-HT1A receptors and the modulation of endocannabinoid levels with subsequent CB1 activation. The brain regions involved in CBD-induced antidepressant-like effects remain unknown. The ventral medial prefrontal cortex (vmPFC), which includes the infralimbic (IL) and prelimbic (PL) subregions, receives dense serotonergic innervation and plays a significant role in stress responses.

Objective: To test the hypothesis that the administration of CBD into the IL or PL would induce an antidepressant-like effect through 5-HT1A and CB1 activation.

Methods: Rats received intra-IL or -PL microinjections of CBD (10-60 nmol/side), 8-OH-DPAT (5-HT1A agonist, 5-10 nmol/side), anandamide (AEA, 0.5 pmol/side) or vehicle (0.2 μl/side) and were submitted to the forced swimming (FST) or to the open field (OFT) tests. Independent CBD-treated groups were pre-treated with WAY100635 (10, 30 nmol/side, 5-HT1A antagonist) or AM251 (10 pmol/side, CB1 antagonist) and submitted to the same tests. An additional group was treated with WAY100635 followed by anandamide.

Results: CBD (PL: 10-60 nmol; IL:45-60 nmol) and 8-OH-DPAT (10 nmol) administration significantly reduced the immobility time in the FST, without changing locomotor activity in the OFT. WAY100635 (30 nmol) did not induce effect per se but blocked CBD, 8-OH-DPAT and AEA effects. Additionally, AM251 blocked CBD-effects.

Conclusion: administration of CBD into the vmPFC induces antidepressant-like effects possibly through indirect activation of CB1 and 5-HT1A receptors.

Keywords: 5HT1A; Antidepressant; Cannabidiol; Forced swimming test; vmPFC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8-Hydroxy-2-(di-n-propylamino)tetralin / administration & dosage
  • Animals
  • Antidepressive Agents / administration & dosage*
  • Arachidonic Acids / administration & dosage
  • Behavior, Animal / drug effects*
  • Cannabidiol / administration & dosage*
  • Endocannabinoids / administration & dosage
  • Male
  • Motor Activity / drug effects
  • Piperazines
  • Piperidines / administration & dosage
  • Polyunsaturated Alkamides / administration & dosage
  • Prefrontal Cortex / drug effects*
  • Prefrontal Cortex / physiology*
  • Pyrazoles / administration & dosage
  • Pyridines
  • Rats
  • Rats, Wistar
  • Receptor, Cannabinoid, CB1 / agonists
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors
  • Receptor, Cannabinoid, CB1 / physiology*
  • Receptor, Serotonin, 5-HT1A / physiology*
  • Serotonin 5-HT1 Receptor Agonists / administration & dosage
  • Serotonin Antagonists / administration & dosage


  • Antidepressive Agents
  • Arachidonic Acids
  • Endocannabinoids
  • Piperazines
  • Piperidines
  • Polyunsaturated Alkamides
  • Pyrazoles
  • Pyridines
  • Receptor, Cannabinoid, CB1
  • Serotonin 5-HT1 Receptor Agonists
  • Serotonin Antagonists
  • Receptor, Serotonin, 5-HT1A
  • Cannabidiol
  • AM 251
  • N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
  • 8-Hydroxy-2-(di-n-propylamino)tetralin
  • anandamide