Psychotomimetic Cannabinoid Hyperlocomotion Involves GSK-3β Signaling at Striatopallidal Neurons in Male Mice.

Tomaselli G.; Bellocchio L.; Raux P.; Roullot-Lacarrière V.; Busquets-Garcia A.; Lalanne V.; Mariani Y.; Cathala A.; Zanese M.; Cannich A. et al. · Biological psychiatry global open science · 2026

**Background & Methods** This 2026 preclinical study used a multidisciplinary approach combining pharmacological and genetic manipulations in cultured cells and adult male mice to investigate the cellular mechanisms of cannabinoid-induced hyperlocomotion. Methodologies included locomotor activity testing (n=10-12 mice/group), alphaLISA signaling detection, cell transfection studies, viral genetic strategies, fluorescence in situ hybridization, qPCR, and mass spectrometry. **Key Findings** • Low-dose Δ9-tetrahydrocannabinol (THC) at 0.3 mg/kg induces hyperlocomotion in male mice through CB1 receptor activation on dopamine D2 receptor-positive striatopallidal neurons, serving as a proxy for positive psychotic-like symptoms. • The psychomotor stimulation involves a specific intracellular signaling cascade: CB1R activation → β-arrestin 1-dependent inhibition of GSK-3β phosphorylation → hyperlocomotor effect within the cerebello-basal ganglia pathway. • Signaling-specific CB1R inhibitors pregnenolone and its clinical analog AEF0117 successfully prevented GSK-3β-dependent psychomotor stimulation induced by THC, suggesting potential therapeutic targets for cannabinoid-associated psychotic disorders. **Dosage & Administration** THC administered at 0.3 mg/kg in male mice. Route of administration not specified in abstract. Pregnenolone and AEF0117 doses not reported. **Safety & Adverse Effects** Not reported. Study focused on mechanism of action rather than comprehensive safety profiling. **Evidence Quality** This is a preclinical mechanistic study with significant limitations: (1) findings are from male mice only, limiting generalizability to females or humans; (2) no human clinical validation provided; (3) small sample sizes per group (n=4-12); (4) uses animal models of psychotic-like behavior rather than direct human psychosis assessment; (5) single-dose THC administration may not reflect chronic cannabis use patterns. Strengths include multiple complementary methodologies and identification of a specific neurobiological pathway. The work represents hypothesis-generating basic science requiring translational validation before clinical application.

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