THC and CBD produce divergent effects on perception and panic behaviours via distinct cortical molecular pathways

Prog Neuropsychopharmacol Biol Psychiatry. 2021 Jan 10:104:110029. doi: 10.1016/j.pnpbp.2020.110029. Epub 2020 Jul 2.


Clinical and pre-clinical evidence demonstrates divergent psychotropic effects of THC vs. CBD. While THC can induce perceptual distortions and anxiogenic effects, CBD displays antipsychotic and anxiolytic properties. A key brain region responsible for regulation of cognition and affect, the medial prefrontal cortex (PFC), is strongly modulated by cannabinoids, suggesting that these dissociable THC/CBD-dependent effects may involve functional and molecular interplay within the PFC. The primary aim of this study was to investigate potential interactions and molecular substrates involved in PFC-mediated effects of THC and CBD on differential cognitive and affective behavioural processing. Male Sprague Dawley rats received intra-PFC microinfusions of THC, CBD or their combination, and tested in the latent inhibition paradigm, spontaneous oddity discrimination test, elevated T-maze and open field. To identify local, drug-induced molecular modulation in the PFC, PFC samples were collected and processed with Western Blotting. Intra-PFC THC induced strong panic-like responses that were counteracted with CBD. In contrast, CBD did not affect panic-like behaviours but blocked formation of associative fear memories and impaired latent inhibition and oddity discrimination performance. Interestingly, these CBD effects were dependent upon 5-HT1A receptor transmission but not influenced by THC co-administration. Moreover, THC induced robust phosphorylation of ERK1/2 that was prevented by CBD, while CBD decreased phosphorylation of p70S6K, independently of THC. These results suggest that intra-PFC infusion of THC promotes panic-like behaviour associated with increased ERK1/2 phosphorylation. In contrast, CBD impairs perceptive functions and latent inhibition via activation of 5-HT1A receptors and reduced phosphorylation of p70S6K.

Keywords: Cannabinoids; Latent inhibition; Panic; Prefrontal cortex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticonvulsants / administration & dosage
  • Cannabidiol / administration & dosage*
  • Discrimination Learning / drug effects
  • Discrimination Learning / physiology
  • Dronabinol / administration & dosage*
  • Infusions, Intraventricular
  • Inhibition, Psychological*
  • Male
  • Panic / drug effects*
  • Panic / physiology
  • Perception / drug effects*
  • Perception / physiology
  • Prefrontal Cortex / drug effects*
  • Prefrontal Cortex / physiology
  • Psychotropic Drugs / administration & dosage
  • Rats
  • Rats, Sprague-Dawley


  • Anticonvulsants
  • Psychotropic Drugs
  • Cannabidiol
  • Dronabinol

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