Psychotomimetic Cannabinoid Hyperlocomotion Involves GSK-3β 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 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.