Fenfluramine-induced increase in preproenkephalin mRNA levels in the striatum: Interaction between the serotonergic, glutamatergic, and dopaminergic systems

Fenfluramine (FE) is a halogenated amphetamine derivative that has been use d in the treatment of obesity. It has been suggested that the effects of FE on the striatum are mediated by serotonergic mechanisms. However, several. major afferent systems may be involved, and administration of FE may be us eful to study interactions between these systems. In this work, the effects of FE on striatopallidal neurons and the possible involvement of the major striatal afferent systems were studied in rats by determination of FE-indu ced changes in striatal levels of preproenkephalin (PPE) mRNA using in situ hybridization. Injection of FE induced a significant increase (60%) in str iatal levels of PPE mRNA. This increase was blocked by pretreatment with th e D-1 dopamine receptor antagonist SCH-23390 or with the NMDA glutamate rec eptor antagonist MK-801, or by lesion of the serotonergic system with 5,7-d ihydroxytryptamine or p-chlorophenylalanine. In 6-hydroxydopamine lesioned rats, the les ion-induced increase in PPE mRNA levels was not affected by i njection of FE, but was reduced by simultaneous serotonergic deafferentatio n. The results suggest that the serotonergic, glutamatergic, and dopaminerg ic system interact to increase striatal PPE mRNA levels after FE administra tion. (C) 2000 Wiley-Liss, Ins.