Unbalanced Inhibitory/Excitatory Responses in the Substantia Nigra Pars Reticulata Underlie Cannabinoid-Related Slowness of Movements

The substantia nigra pars reticulata (SNr), where the basal ganglia (BG) direct and indirect pathways converge, contains among the highest expression of cannabinoid receptor type 1 (CB1r) in the brain. Hence, SNr is an ideal locus to study path-way interactions and cannabinergic modulations. The objective of this study was to characterize the effects of systemic injec-tions of the CB1r agonist (CP55940) on the balanced activity of the direct/indirect pathways in the SNr and its associated behaviors. To this aim, we recorded somatosensory and pathway-specific representations in the spiking activity of the SNr of male rats under CP55940. CB1r activation mainly decreased the inhibitory, potentially direct pathway component while spar-ing the excitatory, potentially indirect pathway component of somatosensory responses. As a result, cutaneous stimulation produced unbalanced responses favoring increased SNr firing rates, suggesting a potential locus for cannabinergic motor -related effects. To test this hypothesis, we implemented an ad hoc behavioral protocol for rats in which systemic administra-tion of CP55940 produced kinematic impairments that were completely reverted by nigral injections of the CB1r antagonist (AM251). Our data suggest that cannabinoid-related motor effects are associated with unbalanced direct/indirect pathway activations that may be reverted by CB1r manipulation at the SNr.