Central Blockade of Cannabinoid CB1 and CB2 Receptors Increases Force Generation in Reserpine-Treated Mice, but Only CB1 Blockade Extends the Duration of Effort.

Carminati Dos Santos B.; Guedes da Rosa I.; Mazzardo L.; Santos N.; Fabro I.; Nery T.; Bastos Pereira A.; Aguiar A. · ACS pharmacology & translational science · 2026

**Background & Methods** This experimental study investigated the separate roles of cannabinoid CB1 and CB2 receptors in motor function using reserpine-treated adult female Swiss mice, an established model of parkinsonism. Mice received intracerebroventricular (ICV) administration of vehicle, CB1 antagonist AM251, or CB2 antagonist AM630, with subsequent assessment of catalepsy and neuromuscular grip force performance across three trials. **Key Findings** - Both CB1 and CB2 antagonists significantly increased initial force generation at task onset, with AM630 producing a 53.9 gf increase (95% CI 22.5-85.3) and AM251 producing a 41.2 gf increase (95% CI 8.8-73.6), with overlapping confidence intervals suggesting comparable effects. - CB1 antagonism (AM251) uniquely extended grip duration by 619 ms (95% CI 113-1125), whereas CB2 antagonism (AM630) showed no significant duration effect (-70 ms, 95% CI -560 to +421), demonstrating a clear dissociation between receptor subtypes. - CB1 blockade demonstrated additional benefits by reducing cataleptic response odds (OR 0.16, 95% CI 0.03-0.89) and maintaining force-time balance, while CB2 antagonism shifted the force-time balance toward acute force production at the expense of sustained effort. **Dosage & Administration** Specific doses for AM251 and AM630 are not reported in the abstract. Administration was via intracerebroventricular injection, indicating central nervous system delivery. **Safety & Adverse Effects** Not reported. **Evidence Quality** This is a preclinical animal study with significant limitations. The research was conducted exclusively in female Swiss mice using a reserpine-induced parkinsonism model, limiting generalizability to human Parkinson's disease. The study lacks anatomical localization of effects within the brain despite ICV delivery, and findings are restricted to acute motor performance measures. The inability to distinguish between force magnitudes across antagonists due to overlapping confidence intervals reduces precision of comparative conclusions. As a 2026 publication in a translational science journal, this represents emerging evidence but requires substantial validation through dose-response studies, mechanistic investigation, and human translation before clinical application.

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