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

Abstract

Motor impairment in parkinsonism extends beyond the classical triad to weakness and a reduced capacity to sustain motor output, whose neuromodulatory control is poorly resolved. The endocannabinoid system is a candidate regulator, but CB1 and CB2 receptors have not been separated within one preparation. Reserpine-treated adult female Swiss mice received vehicle, the CB1 antagonist AM251, or the CB2 antagonist AM630 into the lateral ventricle; catalepsy was recorded across three trials and neuromuscular performance in a grip force task. Both antagonists increased the force generated at task onset, by amounts these data cannot distinguish: AM630 by 53.9 gf (95% CI 22.5–85.3) and AM251 by 41.2 gf (95% CI 8.8–73.6). They separated on duration. AM251 increased grip time by 619 ms (95% CI 113–1125), whereas AM630 did not (−70 ms, 95% CI −560 to +421). An interaction contrast on the force–time balance followed from that difference: AM630 shifted the balance toward force (−2.03 SD, P = 0.008), AM251 did not (−0.36 SD, P = 0.66), and the two differed from each other by 1.67 SD (P = 0.022). AM251 also reduced the odds of a cataleptic response (OR 0.16, 95% CI 0.03–0.89). Adjusting for body mass left both force effects unchanged. The dissociation is therefore in the duration of effort rather than in its force: both antagonists raise force, and only CB1 blockade also extends the time over which it is maintained. Delivered intracerebroventricularly, these effects are central in origin but not anatomically localized.