Role of the endogenous cannabinoid system in the regulation of motor activity

One of the prominent pharmacological features of drugs acting at the brain cannabinoid receptor (CB1) is the induction of alterations in motor behavior. Catalepsy, immobility, ataxia, or the impairment of complex behavioral acts are observed after acute administration of either natural and synthetic cannabinoid receptor agonists or the endogenous CB1 ligand anandamide. The dense presence of CB1 receptors in the cerebellum and in the basal ganglia, especially at the outflow nuclei (substantia nigra and the internal segment of the globus pallidus), supports the existence of an endogenous cannabinoid system regulating motor activity. In the basal ganglia, the functionality of the anandamide-CB1 system is poorly understood. Dual effects are often observed after the administration of CB1 ligands in animal models of pharmacological manipulation of basal ganglia transmitter systems, indicating that the activity of the anandamide-CB1 system depends on the ongoing activation of the different elements of the basal ganglia. This finding is in agreement with the proposed activity-dependent release of anandamide from a plasmalemma precursor. Additionally, a potential state-dependent bidirectional coupling of the CB1 receptor to the adenylate cyclase transduction system has also been described. From this perspective, the endogenous cannabinoid system can be proposed as a local regulator of neurotransmission processes within the basal ganglia. This system may serve as a counterregulatory homeostatic mechanism preserving the functional role of basal ganglia circuits in coding the serial order of events that constitute movement.