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

The 5-hydroxytryptamine(2C) serotonin receptor is broadly distributed in brain, however its functional role is unknown. Peripheral administration of drugs acting at the 5-hydroxytryptamine(2C) 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-hydroxytryptamine(2C) receptors, suggesting its potential role in 5-hydroxtryptamine(2C)-mediated oral dyskinesia. Both systemic administration and local unilateral infusion of the 5-hydroxytryptamine(2C/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-hydroxytryptamine(2C/2A) antagonists mianserin, ketanserin and mesulergine but were not altered by systemic pretreatment with either the 5-hydroxytryptamine(1A/2A) and dopamine antagonist spiperone or the 5-hydroxytryptamine(1A/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-hydroxytryptamine(2C) antagonist SDZ SER 082. The findings indicate that stimulating 5-hydroxytryptamine(2C) receptors in the subthalamic nucleus elicits orofacial dyskinesia in the rat. These data are novel in providing a behavioral model for central 5-hydroxytryptamine(2C) receptor stimulation attributed to a specific anatomical location, and suggest that antagonists at the 5-hydroxytryptamine(2C) receptor could be useful in treating hyperkinetic motor disorders.