Combined intrastriatal dopamine D1 and serotonin 5-HT2 receptor stimulation reveals a mechanism for hyperlocomotion in 6-hydroxydopamine-lesioned rats.
Loss of dopaminergic innervation to the striatum increases the sensitivity of dopamine (DA) D1 and serotonin (5-HT) 5-HT2 receptor signaling. Previous work from our laboratory has shown that systemic co-administration of D1 and 5-HT2 receptor agonists leads to the synergistic overexpression of striatal preprotachykinin mRNA levels in the DA-depleted, but not intact animals. In the present study, we examined this mechanism as related to locomotor behavior. Adult male Sprague-Dawley rats were subject to bilateral i.c.v. 6-hydroxydopamine (6-OHDA; 200 microg in 10 microl/side) or vehicle (0.9% saline and 0.1% ascorbic acid). After 3 weeks, rats were tested for locomotor responses to bilateral intrastriatal infusions of vehicle (0.9% NaCl), the D1 agonist SKF82958 [(+/-)6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetra-hydro-(1H)-3-benzazepine hydrobromide; 0.1, 1.0 or 10.0 microg/side], the 5-HT2 agonist DOI [(+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane; 0.1, 1.0 or 10.0 microg/side] or subthreshold doses of DOI and SKF82958 (0.1 microg+0.1 microg in 0.8 microl/side). Rats with DA loss demonstrated supersensitive locomotor responses to SKF82958, but not DOI. Combined administration of subthreshold SKF82958 and DOI doses (0.1 microg+0.1 microg) synergistically increased locomotor behavior only in 6-OHDA-lesioned rats. These effects were blocked by either the D1 antagonist SCH23390 3-methyl-1-phenyl-2,3,4,5-tetrahydro-7-chloro-8-hydroxy-(1H)-3-benzazepine or the 5-HT2 antagonist ritanserin (each 1.0 microg in 0.8 microl/side). The results of this study suggest that the behavioral synergy induced by local co-stimulation of D1 and 5-HT2 receptors within the 6-OHDA-lesioned striatum may lead to hyperkinesias that can occur with continued pharmacological treatment of Parkinson's disease.
Department of Anatomy and Cell Biology, Wayne State University, School of Medicine, Detroit, MI 48201, USA.
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D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001552:Benzazepines / Q000494:pharmacology; D003342:Corpus Striatum / Q000033:anatomy & histology / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007215:Indophenol / Q000031:analogs & derivatives* / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects* / Q000502:physiology; D008297:Male; D016627:Oxidopamine / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000502:physiology*; D044348:Receptors, Serotonin, 5-HT2 / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013239:Stereotyped Behavior / Q000187:drug effects; D013565:Sympatholytics
D001552:Benzazepines; D018491:Dopamine Agonists; D017447:Receptors, Dopamine D1; D044348:Receptors, Serotonin, 5-HT2; D017366:Serotonin Receptor Agonists; D013565:Sympatholytics; C113896:dimethoxy-4-indophenyl-2-aminopropane; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D007215:Indophenol; D006897:Hydroxyindoleacetic Acid; C071262:SK&F 82958; D016627:Oxidopamine; D004298:Dopamine