FENFLURAMINE-INDUCED ACTIVATION OF THE IMMEDIATE-EARLY GENE C-FOS IN THE STRIATUM - POSSIBLE INTERACTION BETWEEN SEROTONIN AND DOPAMINE

DL-Fenfluramine, a serotonin (5-HT) releasing agent, induces rapid exp ression of Fos-like immunoreactivity (Fos-LI) in the striatum as well as in other brain structures receiving a dense 5-HT innervation. Fenfl uramine-induced Fos-LI expression in the striatum may result directly from the activation of 5-HT receptors or may be the result of interact ions between dopamine (DA) and 5-HT neurotransmitter systems. To discr iminate between these two possibilities, various groups of rats were p retreated with different 5-HT antagonists or a DA D-1 antagonist, 20 m in before fenfluramine administration. Animals were killed 60 min late r. In the striatum, fenfluramine-induced expression of Fos-LI was almo st completely blocked by SCH 23390, methysergide and S(-)-propranolol. The immediate-early gene response to fenfluramine was only slightly a ffected by pretreatment with the 5-HT2A/(2C) antagonist ritanserin. Fe nfluramine was also administered to sham-operated and to unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats. In the 6-OHDA-lesioned rats, fenfluramine-induced Fos-LI was decreased by 60% on the DA denervated side compared to the intact side and to sham-operated rats. To furthe r probe the possibility of a direct activation of Fos-LI by 5-HT recep tor subtypes, we evaluated the expression of Fos-LI after the administ ration of different 5-HT agonists. Our results demonstrate that neithe r 8-OH-DPAT, CGS-12066B, RU 24969 nor phenylbiguanide was able to repr oduce the effects of fenfluramine. Only a high dose of DOI (8.5 mg/kg) produced a moderate expression of Fos-LI in the dorsomedial part of t he striatum. This contrasted with the Fos-LI expression in other brain areas where 8-OH-DPAT and DOI (2.5 and 8.5 mg/kg) reproduced the effe cts of the 5-HT releasing agent. Our results suggest that the release of 5-HT by fenfluramine induced Fos-LI expression predominantly in a s triatal region related to associative functions and, that this c-fos r esponse may be under the control of both 5-HT and DA. Moreover, the me chanism by which fenfluramine induces c-fos expression in the striatum differs from other brain regions.