Increased m-CPP-induced oral dyskinesia after lesion of serotonergic neurons

Peripheral administration of the 5-hydroxytryptamine (5-HT)(2C/1B) agonist 1-(m-chlorophenyl)piperazine (m-CPP) produces abnormal orofacial movements in rats. We have previously shown that this behavior is mediated by 5-HT2C receptors in the subthalamic nucleus [Neuroscience 72 (1996) 117]. The pres ent studies examined this effect after serotonin depletion to determine whe ther removal of endogenous serotonin affected this behavioral response and/ or subthalamic 5-HT2C receptors. Rats received an intraventricular infusion of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT, 100 mg/10 mi) or vehic le after desipramine pretreatment (25 mg/kg ip). The efficacy of serotonin depletion was confirmed by a decrease in serotonin uptake sites measured by autoradiography. Oral dyskinesia induced by peripheral administration of m -CPP (1.0 mg/kg ip) was markedly increased in lesioned rats compared to sha m-operated controls 4 and 8 but not 12 days after the lesion. A subset of l esioned rats that displayed transient seizures after m-CPP injection did no t prevent the measurement of oral dyskinesia during the observation period. No differences in 5-HT2C receptor levels were found with ligand-binding au toradiography in the subthalamic nucleus, or in other brain regions that ex press this receptor, in rats sacrificed 5 days following 5,7-DHT lesions. T he data indicate that lesion of serotonergic neurons in adult rats induces a transient increase in motor responses mediated by subthalamic 5-HT2C rece ptors. These data suggest that functional alterations in serotonergic trans mission in the subthalamic nucleus may be involved in the pathophysiology o f hyperkinetic movement disorders. (C) 2001 Elsevier Science Inc. All right s reserved.