Pregnenolone and AEF0117 block cannabinoid-induced hyperlocomotion through GSK3β signaling at striatopallidal neurons

Tomaselli, G.; Bellocchio, L.; Raux, P.-L.; Roullot-Lacarriere, V.; Busquets-Garcia, A.; Lalanne, V.; Mariani, Y.; Cathala, A.; Zanese, M.; Cannich, A.; Grel, A.; Gisquet, D.; Mondesir, M.; Metna-Laurent, M.; Drutel, G.; Marsicano, G.; Piazza, P.-V.; Revest, J.-M.; Vallee, M.

doi:10.1101/2025.03.07.641990

bioRxiv · 10.1101/2025.03.07.641990

Pregnenolone and AEF0117 block cannabinoid-induced hyperlocomotion through GSK3β signaling at striatopallidal neurons

Tomaselli, G.·Bellocchio, L.·Raux, P.-L.·Roullot-Lacarriere, V.·Busquets-Garcia, A.·Lalanne, V.·Mariani, Y.·Cathala, A.·Zanese, M.·Cannich, A.·Grel, A.·Gisquet, D.·Mondesir, M.·Metna-Laurent, M.·Drutel, G.·Marsicano, G.·Piazza, P.-V.·Revest, J.-M.·Vallee, M.

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Abstract

Administration of {Delta}9-tetrahydrocannabinol (THC), the main psychoactive component of the plant Cannabis sativa, can induce psychotic symptomatology in humans and a large spectrum of acute psychotic-like behaviors in mice, including hyperlocomotion observed at low dose of THC (0.3 mg/kg). The cellular and molecular substrates of this effect have not been fully identified yet. Here we demonstrate that THC-induced hyperlocomotion depends on plasma membrane CB1R, which regulate the {beta}-arrestin 1/Akt/GSK3{beta} signaling pathway in D2R-positive neurons of the dorsal striatum forming the striatopallidal pathway of the basal ganglia. Pregnenolone (PREG) and its clinically developed analog, AEF0117, which are signaling specific inhibitors of CB1R (CB1-SSi), prevented GSK3{beta}-dependent psychomotor stimulation induced by THC. Overall, this work highlights a novel intracellular mechanism of CB1R, thereby revealing a neuronal pathway underlying an important but still underexplored effect of THC and cannabis consumption, which could help the development of innovative therapeutic concepts against psychotic conditions.

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Tomaselli, G., Bellocchio, L., Raux, P.-L., Roullot-Lacarriere, V., Busquets-Garcia, A., Lalanne, V., Mariani, Y., Cathala, A., Zanese, M., Cannich, A., Grel, A., Gisquet, D., Mondesir, M., Metna-Laurent, M., Drutel, G., Marsicano, G., Piazza, P.-V., Revest, J.-M., Vallee, M.. 2025-03-10. Pregnenolone and AEF0117 block cannabinoid-induced hyperlocomotion through GSK3β signaling at striatopallidal neurons. https://doi.org/10.1101/2025.03.07.641990

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