Psychotomimetic cannabinoid hyperlocomotion involves GSK3β signaling at striatopallidal neurons in male mice

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.