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

In rats, THC infused directly into the medial prefrontal cortex (PFC) caused strong panic-like responses, while CBD did not affect panic but blocked the formation of associative fear memories and impaired latent inhibition and oddity discrimination. CBD counteracted THC-induced panic and prevented THC-driven phosphorylation of ERK1/2. CBD's effects on perception and latent inhibition depended on 5-HT1A receptor transmission and were accompanied by reduced phosphorylation of p70S6K, independently of THC. The findings suggest dissociable molecular mechanisms: THC promotes panic via ERK1/2 phosphorylation, while CBD impairs perceptive functions via 5-HT1A receptors and reduced p70S6K phosphorylation.

Study at a glance

Abstract

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.