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, G Marsicano
Mol Psychiatry. 2017-02-21; 22(11): 1594-1603
DOI: 10.1038/mp.2017.4

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1. Mol Psychiatry. 2017 Nov;22(11):1594-1603. doi: 10.1038/mp.2017.4. Epub 2017 Feb

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

Busquets-Garcia A(1)(2), Soria-Gómez E(1)(2), Redon B(1)(2), Mackenbach Y(1)(2),
Vallée M(1)(2), Chaouloff F(1)(2), Varilh M(1)(2), Ferreira G(2)(3), Piazza
PV(1)(2), Marsicano G(1)(2).

Author information:
(1)INSERM, U1215 NeuroCentre Magendie, Bordeaux, France.
(2)University of Bordeaux, Bordeaux, France.
(3)INRA, Nutrition et Neurobiologie Intégrée, UMR 1286, Bordeaux, France.

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.

DOI: 10.1038/mp.2017.4
PMCID: PMC5447368
PMID: 28220044 [Indexed for MEDLINE]

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