Rouillard C, Bovetto S, Gervais J, Richard D
Department of Pharmacology, Laval University, Québec, Canada.
Brain Res Mol Brain Res. 1996 Apr;37(1-2):105-15. doi: 10.1016/0169-328x(95)00284-y.
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.
右旋芬氟拉明是一种5-羟色胺（5-HT）释放剂，可诱导纹状体以及其他接受密集5-HT神经支配的脑区快速表达Fos样免疫反应性（Fos-LI）。芬氟拉明诱导的纹状体Fos-LI表达可能直接源于5-HT受体的激活，也可能是多巴胺（DA）和5-HT神经递质系统之间相互作用的结果。为了区分这两种可能性，在给予芬氟拉明前20分钟，用不同的5-HT拮抗剂或DA D1拮抗剂对不同组的大鼠进行预处理。60分钟后处死动物。在纹状体中，芬氟拉明诱导的Fos-LI表达几乎完全被SCH 23390、麦角酰二乙胺和S(-)-普萘洛尔阻断。5-HT2A/2C拮抗剂利坦色林预处理对芬氟拉明诱导的即刻早期基因反应影响较小。还对假手术大鼠和单侧6-羟基多巴胺（6-OHDA）损伤大鼠给予芬氟拉明。在6-OHDA损伤大鼠中，与完整侧和假手术大鼠相比，芬氟拉明诱导的Fos-LI在DA去神经侧降低了60%。为了进一步探究5-HT受体亚型直接激活Fos-LI的可能性，我们评估了给予不同5-HT激动剂后Fos-LI的表达。我们的结果表明，8-OH-DPAT、CGS-12066B、RU 24969和苯基双胍均不能重现芬氟拉明的作用。只有高剂量的DOI（8.5mg/kg）在纹状体背内侧部分产生了中等程度的Fos-LI表达。这与其他脑区的Fos-LI表达形成对比，在其他脑区8-OH-DPAT和DOI（2.5和8.5mg/kg）重现了5-HT释放剂的作用。我们的结果表明，芬氟拉明释放5-HT主要在与联合功能相关的纹状体区域诱导Fos-LI表达，并且这种c-fos反应可能受5-HT和DA的共同控制。此外，芬氟拉明在纹状体中诱导c-fos表达的机制与其他脑区不同。
