C. Rouillard et al., FENFLURAMINE-INDUCED ACTIVATION OF THE IMMEDIATE-EARLY GENE C-FOS IN THE STRIATUM - POSSIBLE INTERACTION BETWEEN SEROTONIN AND DOPAMINE, Molecular brain research, 37(1-2), 1996, pp. 105-115
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.