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Pregnenolone blocks cannabinoid-induced acute psychotic-like states in mice

Abstract

Cannabis-induced acute psychotic-like states (CIAPS) represent a growing health issue, but their underlying neurobiological mechanisms are poorly understood. The use of antipsychotics and benzodiazepines against CIAPS is limited by side effects and/or by their ability to tackle only certain aspects of psychosis. Thus, safer wide-spectrum treatments are currently needed. Although the blockade of cannabinoid type-1 receptor (CB1) had been suggested as a therapeutical means against CIAPS, the use of orthosteric CB1 receptor full antagonists is strongly limited by undesired side effects and low efficacy. The neurosteroid pregnenolone has been recently shown to act as a potent endogenous allosteric signal-specific inhibitor of CB1 receptors. Thus, we tested in mice the potential therapeutic use of pregnenolone against acute psychotic-like effects of Δ9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis. We found that pregnenolone blocks a wide spectrum of THC-induced endophenotypes typically associated with psychotic-like states, including impairments in cognitive functions, somatosensory gating and social interaction. In order to capture THC-induced positive psychotic-like symptoms (e.g. perceptual delusions), we adapted a behavioral paradigm based on associations between different sensory modalities and selective devaluation, allowing the measurement of mental sensory representations in mice. Acting at hippocampal CB1 receptors, THC impaired the correct processing of mental sensory representations (reality testing) in an antipsychotic- and pregnenolone-sensitive manner. Overall, this work reveals that signal-specific inhibitors mimicking pregnenolone effects can be considered as promising new therapeutic tools to treat CIAPS.

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Acknowledgements

We thank Delphine Gonzales, Nathalie Aubailly and all the personnel of the Animal Facility of the NeuroCentre Magendie for mouse care. We also thank all the members of Marsicano’s lab for useful discussions and Virginie Morales for the unvaluable help. This work was supported by INSERM (to GM), EU–FP7 (PAINCAGE, HEALTH-603191 to GM and FP7-PEOPLE-2013-IEF-623638 to AB-G), European Research Council (Endofood, ERC-2010-StG-260515; CannaPreg, ERC-2014-PoC-640923 to GM), Fondation pour la Recherche Medicale (DRM20101220445 and DPP20151033974 to GM), Human Frontiers Science Program (to GM), Region Aquitaine (to GM), French State/Agence Nationale de la Recherche/LabEx BRAIN (ANR-10-LABX-0043 to GM), Fyssen Foundation (to ES-G), CONACyT (to ES-G), French State/Agence Nationale de la Recherche/IdEx (ANR-10-IDEX-03-02 to AB-G), French State/Agence Nationale de la Recherche/Blanc (NeuroNutriSens ANR-13-BSV4-0006-02 to GM).

Author contributions

AB-G, GF, P-VP and GM designed research; AB-G, ES-G, BR, YM and FC performed research; AB-G, GF, P-VP and GM supervised research; MV helped with some experiments; AB-G, ES-G, GF and GM analyzed data; and AB-G, GF and GM wrote the manuscript. All authors edited the manuscript.

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Correspondence to G Marsicano.

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PVP and GM are founders, stakeholders and consultants for the start-up company Aelis Farma. The remaining authors declare no conflicts of interest.

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Busquets-Garcia, A., Soria-Gómez, E., Redon, B. et al. Pregnenolone blocks cannabinoid-induced acute psychotic-like states in mice. Mol Psychiatry 22, 1594–1603 (2017). https://doi.org/10.1038/mp.2017.4

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