Intrastriatal serotonin 5-HT2 receptors mediate dopamine D1-induced hyperlocomotion in 6-hydroxydopamine-lesioned rats.
Striatal dopamine (DA) and serotonin (5-HT) functions are altered following DA denervation. Previous research indicates that intrastriatal coadministration of D1 and 5-HT2 receptor agonists synergistically increase locomotor behavior in DA-depleted rats. In the present study, we examined whether striatal 5-HT2 mechanisms also account for supersensitive D1-mediated locomotor behavior following DA denervation. Adult male Sprague-Dawley rats were subjected to bilateral striatal cannulation and then received either intracerebroventricular (i.c.v.) or intrastriatal 6-hydroxydopamine (6-OHDA; 200 microg or 20 microg/side, respectively). After at least 3 weeks, i.c.v.-lesioned rats received intrastriatal infusions of the 5-HT2 receptor antagonist ritanserin (2.0 microg/side) or its vehicle (DMSO) followed by systemic SKF 82958, a D1 agonist (1.0 mg/kg, i.p.) and locomotor activity was monitored. In another experiment, intrastriatal sham and 6-OHDA-lesioned rats received bilateral intrastriatal infusions of ritanserin (2.0 microg/side) or its vehicle (DMSO) followed by intrastriatal infusions of SKF 82958 (5.0 microg/side) or vehicle (0.9% saline). Rats with DA loss demonstrated supersensitive locomotor responses to both systemic and intrastriatal SKF 82958. Ritanserin pretreatment blunted systemic SKF 82958-induced hyperlocomotion and returned intrastriatal D1-mediated hyperactivity to sham lesion levels. The results of this study suggest that striatal 5-HT2 receptors contribute to D1-mediated hyperkinesias resulting from DA loss and suggest a pharmacological target for the alleviation of dyskinesia that can develop with continued DA replacement therapy.
Bishop
Christopher
C
Department of Anatomy and Cell Biology, Wayne State University, School of Medicine, Detroit, Michigan 48201, USA.
Kamdar
Dev P
DP
Walker
Paul D
PD
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D003714:Denervation; D004298:Dopamine / Q000172:deficiency; D018491:Dopamine Agonists / Q000494:pharmacology; D004347:Drug Interactions / Q000502:physiology; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D006948:Hyperkinesis / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism* / Q000503:physiopathology; D016627:Oxidopamine; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects* / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000187:drug effects* / Q000378:metabolism; D016713:Ritanserin / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology
D001552:Benzazepines; D018491:Dopamine Agonists; D044402:Receptor, Serotonin, 5-HT2A; D017447:Receptors, Dopamine D1; D012702:Serotonin Antagonists; D016713:Ritanserin; D012701:Serotonin; C071262:SK&F 82958; D016627:Oxidopamine; D004298:Dopamine