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 serotoninerg ic systems in the striatum to the effects of d-fenfluramine, an indirect se rotonin receptor agonist, we assessed the expression of Fos/Jun proteins in duced by d-fenfluramine given alone or in the presence of dopaminergic or s erotoninergic agents. To determine the neuronal targets of d-fenfluramine i n the striatum, we identified the phenotypes of striatal neurons in which d -fenfluramine induced Fos expression. Our results demonstrated that d-fenfl uramine evokes nuclear expression of Fos/Jun B proteins in the striatum, an d that the Fos expression was dose-dependent and accompanied by transient i nduction of c-fos mRNA. Fos expression was blocked by p-chloroamphetamine, a serotoninergic neurotoxin. Pretreatment with SCH 23390, a D-1-dopamine re ceptor 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 expressio n completely in the cortex and only partially in the caudoputamen, The expr ession of Fos/Jun B in the striatum occurred mainly in dynorphin-containing neurons and in a subpopulation of striatal interneurons that exhibited NAD PH-diaphorase activity. Most of the enkephalin-containing neurons of the st riatum did not show Fos/Jun B staining. These results suggest that the mech anism 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 sy stem by serotonin.