Psychotomimetic Cannabinoid Hyperlocomotion Involves GSK-3β Signaling at Striatopallidal Neurons in Male Mice.
- 1University of Bordeaux, French National Institute of Health and Medical Research, Neurocentre Magendie, U1215, Bordeaux, France.
- 2Aelis Farma, Bordeaux, France.
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 CB₁ receptor (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 STHdh Q7/Q7 cells (n = 4-6/group) and a viral strategy in transgenic lines to selectively block GSK-3β (glycogen synthase kinase-3β) phosphorylation (n = 8-10 mice/group). We also used fluorescence in situ hybridization, real-time quantitative and droplet digital polymerase chain reaction, and tandem mass spectrometry.Results
We showed that the hyperlocomotion induced by a low dose (0.3 mg/kg) of cannabinoid Δ⁹-tetrahydrocannabinol depends on the activation of plasma membrane CB1R located on dopamine D₂ receptor-positive striatopallidal projecting neurons. This activation regulates the β-arrestin 1/Akt/GSK-3β signaling pathway, which is required for the hyperlocomotor effect. The signaling-specific CB1R inhibitors, pregnenolone and its clinically developed analog, AEF0117, prevent GSK-3β-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 aid the development of unprecedented therapeutic modalities for the treatment of psychotic conditions.
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BibTeX
@article{tomaselli2026psychotomimetic,
title = {{Psychotomimetic Cannabinoid Hyperlocomotion Involves GSK-3β Signaling at Striatopallidal Neurons in Male Mice.}},
author = {Giovanni Tomaselli and Luigi Bellocchio and Pierre-Louis Raux and Valérie Roullot-Lacarrière and Arnau Busquets-Garcia and Valérie Lalanne and Yamuna Mariani and Adeline Cathala and Marion Zanese and Astrid Cannich and Agnès Grel and Doriane Gisquet and Miguel Mondesir and Mathilde Metna-Laurent and Guillaume Drutel and Giovanni Marsicano and Pier Vincenzo Piazza and Jean-Michel Revest and Monique Vallée},
journal = {Biological psychiatry global open science},
year = {2026},
month = aug,
doi = {10.1016/j.bpsgos.2026.100816},
url = {https://europepmc.org/article/MED/42909990},
note = {CC BY},
}
RIS
TY - JOUR
TI - Psychotomimetic Cannabinoid Hyperlocomotion Involves GSK-3β Signaling at Striatopallidal Neurons in Male Mice.
AU - Giovanni Tomaselli
AU - Luigi Bellocchio
AU - Pierre-Louis Raux
AU - Valérie Roullot-Lacarrière
AU - Arnau Busquets-Garcia
AU - Valérie Lalanne
AU - Yamuna Mariani
AU - Adeline Cathala
AU - Marion Zanese
AU - Astrid Cannich
AU - Agnès Grel
AU - Doriane Gisquet
AU - Miguel Mondesir
AU - Mathilde Metna-Laurent
AU - Guillaume Drutel
AU - Giovanni Marsicano
AU - Pier Vincenzo Piazza
AU - Jean-Michel Revest
AU - Monique Vallée
PY - 2026
DA - 2026/08/28
JO - Biological psychiatry global open science
DO - 10.1016/j.bpsgos.2026.100816
UR - https://europepmc.org/article/MED/42909990
AB - 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 CB₁ receptor (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 STHdh Q7/Q7 cells (n = 4-6/group) and a viral strategy in transgenic lines to selectively block GSK-3β (glycogen synthase kinase-3β) phosphorylation (n = 8-10 mice/group). We also used fluorescence in situ hybridization, real-time quantitative and droplet digital polymerase chain reaction, and tandem mass spectrometry.Results We showed that the hyperlocomotion induced by a low dose (0.3 mg/kg) of cannabinoid Δ⁹-tetrahydrocannabinol depends on the activation of plasma membrane CB1R located on dopamine D₂ receptor-positive striatopallidal projecting neurons. This activation regulates the β-arrestin 1/Akt/GSK-3β signaling pathway, which is required for the hyperlocomotor effect. The signaling-specific CB1R inhibitors, pregnenolone and its clinically developed analog, AEF0117, prevent GSK-3β-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 aid the development of unprecedented therapeutic modalities for the treatment of psychotic conditions.
SN - 2667-1743
ER -