G.Marsicano, G.Ferreira, P.V Piazza et al. dans Mol.Psy.

A new therapeutic opportunity for cannabis-induced psychotic-like states.

“Pregnenolone blocks cannabinoid-induced acute psychotic-like states in mice”
A Busquets-Garcia, E Soria-Gómez, B Redon, Y Mackenbach, M. Vallée, F Chaouloff, M Varilh, G Ferreira, P-V Piazza, and G Marsicano. Molecular Psychiatry (2017/ February) 00, 1–10 © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 1359-4184/17

Giovanni Marsicano: Team leader – Endocannabinoids and neuroadaptation / Neurocentre Magendie

Cannabis-induced acute psychotic-like states represent a growing health issue, but their underlying neurobiological mechanisms are poorly understood. The use of typical and atypical antipsychotics and benzodiazepines against psychotic-like states is limited by side-effects and/or by their ability to tackle only certain aspects of psychosis. Given these limits of currently used drugs, researchers are now investigating the role of new neurobiological substrates in order to find safer wide-spectrum treatments to tackle the pathophysiology of psychotic-like states. Recently, we demonstrated that the neurosteroid pregnenolone acts as a potent endogenous signal-specific inhibitor of CB1 receptor exerting less undesired behavioral effects compared to classical antagonists.

“In this work, Arnau Busquets-Gracia (Equipe Marsicano, NCM) in collaboration with Guillaume Ferreira (NutriNeuro) and Pier-Vincenzo Piazza (NCM) show that pregnenolone is able to block the THC-induced endophenotypes resembling acute psychotic-like states such as cognitive impairment, alteration of somatosensory gating (i.e. decreased pre-pulse inhibition) and reduction of social interaction in mice. However, positive symptoms (e.g. hallucinations and delusions) are hallmarks of psychotic-like states in humans and are obviously difficult to model in rodents.”

Importantly, systemic and intra-hippocampal pregnenolone is also able to block THC-induced alterations in mental sensory representations (i.e. delusion-like behaviors) that we developed (“reality testing”). Our results show that pregnenolone can block the full range of acute psychotic-like symptoms and related endophenotypes induced by THC, thereby suggesting that drugs mimicking pregnenolone activity could be used to treat cannabis-induced psychotic-like states