Interaction between the serotoninergic and dopaminergic systems in d-fenfluramine-induced activation of c-fos and jun B genes in rat striatal neurons.
To test for the relative contributions of the dopaminergic and serotoninergic systems in the striatum to the effects of d-fenfluramine, an indirect serotonin receptor agonist, we assessed the expression of Fos/Jun proteins induced by d-fenfluramine given alone or in the presence of dopaminergic or serotoninergic agents. To determine the neuronal targets of d-fenfluramine in the striatum, we identified the phenotypes of striatal neurons in which d-fenfluramine induced Fos expression. Our results demonstrated that d-fenfluramine evokes nuclear expression of Fos/Jun B proteins in the striatum, and that the Fos expression was dose-dependent and accompanied by transient induction of c-fos mRNA. Fos expression was blocked by p-chloroamphetamine, a serotoninergic neurotoxin. Pretreatment with SCH 23390, a D1-dopamine receptor antagonist, led to a marked decrease in Fos/Jun B expression in the caudoputamen, but not in the cortex, whereas pretreatment with methiothepin, a nonselective serotonin 5-HT1 receptor antagonist, blocked Fos expression completely in the cortex and only partially in the caudoputamen. The expression of Fos/Jun B in the striatum occurred mainly in dynorphin-containing neurons and in a subpopulation of striatal interneurons that exhibited NADPH-diaphorase activity. Most of the enkephalin-containing neurons of the striatum did not show Fos/Jun B staining. These results suggest that the mechanism by which d-fenfluramine induces c-fos and jun B expression in the rat caudoputamen depends at least in part on activation of the dopaminergic system by serotonin.
Gardier
A M
AM
Laboratoire de Neuropharmacologie UPRES EAD MENRT, IFR-ISIT Institut de Signalisation et Innovation Thérapeutique, Amiens, France.
Moratalla
R
R
Cuéllar
B
B
Sacerdote
M
M
Guibert
B
B
Lebrec
H
H
Graybiel
A M
AM
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D003342:Corpus Striatum / Q000166:cytology; D004298:Dopamine / Q000502:physiology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004399:Dynorphins / Q000032:analysis / Q000502:physiology; D005277:Fenfluramine / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D008719:Methiothepin / Q000494:pharmacology; D009474:Neurons / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D010641:Phenotype; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis / Q000235:genetics*; D016755:Proto-Oncogene Proteins c-jun / Q000032:analysis / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012701:Serotonin / Q000502:physiology*; D018490:Serotonin Agents / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects; D010133:p-Chloroamphetamine / Q000494:pharmacology
D001552:Benzazepines; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018490:Serotonin Agents; D012702:Serotonin Antagonists; D005277:Fenfluramine; D012701:Serotonin; D008719:Methiothepin; D010133:p-Chloroamphetamine; D004399:Dynorphins; D003042:Cocaine; D004298:Dopamine