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-HT(2C) receptors in the subthalamic nucleus [Neuroscience 72 (1996) 117]. The present studies examined this effect after serotonin depletion to determine whether removal of endogenous serotonin affected this behavioral response and/or subthalamic 5-HT(2C) receptors. Rats received an intraventricular infusion of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT, 100 mg/10 ml) or vehicle 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 sham-operated controls 4 and 8 but not 12 days after the lesion. A subset of lesioned rats that displayed transient seizures after m-CPP injection did not prevent the measurement of oral dyskinesia during the observation period. No differences in 5-HT(2C) receptor levels were found with ligand-binding autoradiography in the subthalamic nucleus, or in other brain regions that express this receptor, in rats sacrificed 5 days following 5,7-DHT lesions. The data indicate that lesion of serotonergic neurons in adult rats induces a transient increase in motor responses mediated by subthalamic 5-HT(2C) receptors. These data suggest that functional alterations in serotonergic transmission in the subthalamic nucleus may be involved in the pathophysiology of hyperkinetic movement disorders.
Department of Neurology, UCLA School of Medicine, Los Angeles, CA 90095, USA.
A
A
Mehta
K
K
Eberle-Wang
M F
MF
Chesselet
D015116:5,7-Dihydroxytryptamine; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism*; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000378:metabolism*; D018490:Serotonin Agents; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D020531:Subthalamic Nucleus / Q000293:injuries / Q000378:metabolism*
D010879:Piperazines; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D018490:Serotonin Agents; D017366:Serotonin Receptor Agonists; D015116:5,7-Dihydroxytryptamine; C015068:1-(3-chlorophenyl)piperazine