A role for the subthalamic nucleus in 5-HT2C-induced oral dyskinesia

The 5-hydroxytryptamine2C serotonin receptor is broadly distributed in brain, however, its functional role is unknown. Peripheral administration of drugs acting at the 5-hydroxytryptamine2C receptor induces abnormal oral dyskinesias, hyperkinetic motor disorders that often result from dysfunction of the basal ganglia. The subthalamic nucleus, a brain region anatomically and functionally related to the basal ganglia, has been implicated in oral dyskinesia. The subthalamic nucleus contains messenger RNA encoding 5-hydroxytryptamine2C receptors, suggesting its potential role in 5-hydroxytryptamine2C-mediated oral dyskinesia. Both systemic administration and local unilateral infusion of the 5-hydroxytryptamine2C/1B agonist, 1-(m-chlorophenyl)piperazine into the subthalamic nucleus increased orofacial movements. Oral movements following subthalamic infusion of 1-(m-chlorophenyl)piperazine were blocked by systemic administration of the 5-hydroxytryptamine2C/2A antagonists mianserin, ketanserin and mesulergine but were not altered by systemic pretreatment with either the 5-hydroxytryptamine1A/2A and dopamine antagonist spiperone or the 5-hydroxytryptamine1A/1B antagonist pindolol. Co-infusion of mesulergine with 1-(m-chlorophenyl)piperazine into the subthalamic nucleus blocked 1-(m-chlorophenyl)piperazine-stimulated oral movements. Oral bouts following systemically administered 1-(m-chlorophenyl)piperazine were markedly reduced following bilateral subthalamic infusion of either mesulergine or the selective 5-hydroxytryptamine2C antagonist SDZ SER 082. The findings indicate that stimulating 5-hydroxytryptamine2C receptors in the subthalamic nucleus elicits orofacial dyskinesia in the rat. These data are novel in providing a behavioral model for central 5-hydroxytryptamine2C receptor stimulation attributed to a specific anatomical location, and suggest that antagonists at the 5-hydroxytryptamine2C receptor could be useful in treating hyperkinetic motor disorders.