DL-Fenfluramine, a serotonin (5-HT) releasing agent, induces rapid expression of Fos-like immunoreactivity (Fos-LI) in the striatum as well as in other brain structures receiving a dense 5-HT innervation. Fenfluramine-induced Fos-LI expression in the striatum may result directly from the activation of 5-HT receptors or may be the result of interactions between dopamine (DA) and 5-HT neurotransmitter systems. To discriminate between these two possibilities, various groups of rats were pretreated with different 5-HT antagonists or a DA D1 antagonist, 20 min before fenfluramine administration. Animals were killed 60 min later. In the striatum, fenfluramine-induced expression of Fos-LI was almost completely blocked by SCH 23390, methysergide and S(-)-propranolol. The immediate-early gene response to fenfluramine was only slightly affected by pretreatment with the 5-HT2A/2C antagonist ritanserin. Fenfluramine was also administered to sham-operated and to unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats. In the 6-OHDA-lesioned rats, fen-fluramine-induced Fos-LI was decreased by 60% on the DA denervated side compared to the intact side and to sham-operated rats. To further probe the possibility of a direct activation of Fos-LI by 5-HT receptor subtypes, we evaluated the expression of Fos-LI after the administration of different 5-HT agonists. Our results demonstrate that neither 8-OH-DPAT, CGS-12066B, RU 24969 nor phenyl-biguanide was able to reproduce 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 the 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 effects of the 5-HT releasing agent. Our results suggest that the release of 5-HT by fenfluramine induced Fos-LI expression predominantly in a striatal region related to associative functions and, that this c-fos response may be under the control of both 5-HT and DA. Moreover, the mechanism by which fenfluramine induces c-fos expression in the striatum differs from other brain regions.