Psychotomimetic Cannabinoid Hyperlocomotion Involves GSK-3β Signaling at Striatopallidal Neurons in Male Mice
Year: 2026
Type: article
Abstract: ABSTRACT BACKGROUND Hyperlocomotion induced by psychotomimetic agents is considered a proxy for positive psychotic-like symptoms, and is used in antipsychotic drug screenings with rodents. Cannabinoids are psychotomimetic drugs in humans, and low doses of cannabinoid type-1 (CB1R) agonists induce hyperlocomotion in rodents. However, the cellular and molecular mechanisms underlying this effect remain unexplored so far. METHODS We used a combination of pharmacological and genetic manipulations in cultured cells and adult male mouse models, together with an intracellular signaling detection method. Our multidisciplinary approach included locomotor activity (n= 10-12 mice/group), alphaLISA technology (n= 4-12 mice/group), transfection of the β-Arrestin 1 protein in STH dh Q7/Q7 cells (n= 4-6/ group) and viral strategy in transgenic lines to selectively blocked GSK3β phosphorylation (n= 8-10 mice/group). We also used fluorescence in situ hybridization, real-time quantitative and droplet digital PCR, and tandem mass spectrometry. RESULTS We show that the hyperlocomotion induced by a low dose (0.3 mg/kg) of the cannabinoid Δ 9 -tetrahydrocannabinol (THC) depends on the activation of plasma membrane CB1R located at dopamine receptor (D2)-positive striatopallidal projecting neurons. This activation regulates the β-arrestin 1/Akt/GSK3β signaling pathway, which is required for the hyperlocomotor effect. The signaling-specific CB1R inhibitors (CB1-SSi), pregnenolone and its clinically developed analog, AEF0117, prevent GSK3β-dependent psychomotor stimulation induced by THC. CONCLUSIONS This work highlights an intracellular mechanism of CB1R expressed by a selective key neuronal pathway mediating the psychotomimetic effect of THC and by extension low dose cannabis consumption. This discovery will likely help the development of unprecedented therapeutic modalities for the treatment of psychotic conditions.
Authors: Giovanni Tomaselli, Luigi Bellocchio, Pierre-Louis Raux, Valérie Roullot-Lacarrière, Arnau Busquets-Garcia, Valérie Lalanne, Yamuna Mariani, Adeline Cathala, Marion Zanese, Astrid Cannich, Agnès Grel, Doriane Gisquet, Miguel Mondesir, Mathilde Metna-Laurent, Guillaume Drutel, Giovanni Marsicano, Pier Vincenzo Piazza, Jean-Michel Revest, Monique Vallée
Institutions: Université de Bordeaux, Neurocentre Magendie, Aelis Farma (France)
Language: English
Subfield: Pharmacology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,700
Funders: “la Caixa” Foundation, Ministère de l'Enseignement supérieur, de la Recherche et de l'Innovation, Human Frontier Science Program, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Fondation pour la Recherche Médicale, Centre National de la Recherche Scientifique, Université de Bordeaux, Conseil Régional Aquitaine, LabEx BRAIN, European Research Council, Seventh Framework Programme
Awards: G1511890951, G1702859470, G195474297, G2099415532, G2141684770, G2559004560, G2745121931, G2780345700, G286281421, Involvement of the insula in the Autism neurodevelopmental disorder, G3010527862, G3324962957, Role of hippocampal endocannabinoid system in obesity-induced memory deficits, G388644520, G4534217532, G4684214170, G4694349194, G4721901553, G4856472145, G5566077812, G5630952182, CB1 receptors, bioenergetics and memory: a new metabolic interaction between lactate and serine, Investigating the cellular and molecular mechanisms underlying the PREG-CB1R regulatory loop in physiological and pathological conditions, Role of adipose mitochondrial CB1 signaling in the regulation of energy balance, G6069939831, G7080048889, G7240651115, G7376787254, G7378943556, G7878646764, G996255883
OpenAlex ID: W7204525679