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.
Bishop
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Department of Anatomy and Cell Biology, Wayne State University, School of Medicine, Detroit, MI 48201, USA.
Walker
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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