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.
Mehta
A
A
Department of Neurology, UCLA School of Medicine, Los Angeles, CA 90095, USA.
Eberle-Wang
K
K
Chesselet
M F
MF
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