Cross tolerance between anorectic action and induction of Fos-ir with dexfenfluramine and 5HT1B/2C agonists in rats
Cross tolerance between anorectic action and induction of Fos-ir with dexfenfluramine and 5HT1B/2C agonists in rats
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DOI：
10.1007/s002130100749
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发表时间：
2001-06-01
影响因子：
3.4
通讯作者：
Rema, E
中科院分区：
文献类型：
--
作者：
Rowland, NE;Robertson, K;Rema, E
理由：我们已经证明，右芬氟拉明 (DFEN) 是一种可急剧增加突触可用性的血清素 (5-HT) 的药物，在使用急性喂养方案和低剂量时，在预先使用 2-3 次后显示出完全耐受性。这不太可能是由于累积体重减轻或突触前 5-HT 消耗所致。在这项研究中，我们通过测试 DFEN 和 5-HT1B/2C 受体激动剂、间氯和三氟甲基取代的苯基哌嗪（mCPP 和 TFMPP）之间的交叉耐受性，研究了 5-HT1B/2C 受体对行为耐受性的可能贡献。此外，我们通过研究离散大脑区域中 Fos 样免疫反应性 (ir) 的诱导来寻找行为变化的神经元相关性。方法：Sprague-Dawley 大鼠以 2 天的间隔接受两次或三次预注射 2 mg/kg DFEN 或载体。然后将大鼠禁食 24 小时，并在 1-h 喂养测试前 30 分钟接受皮下注射。注射 DFEN、TFMPP (1 mg/kg) 或 mCPP (2 mg/kg)。其他组接受 mCPP 预注射并测试注射 DFEN 或 mCPP。 Fos-ir 研究中的大鼠接受了类似的注射方案，但没有剥夺食物，并在测试注射后 1.5 小时进行灌注。结果：DFEN 预处理的大鼠对 DFEN、TFMPP 和 mCPP 表现出完全的厌食耐受。然而，接受这种 mCPP 预处理方案的大鼠对 mCPP 和 DFEN 均不耐受。 DFEN 在每个检查的大脑区域中诱导的 Fos-ir 被先前的 DFEN 注射显着减少或消除。 TFMPP 在这些区域诱导的 Fos-ir 比 DFEN 少，并且这被之前的 DFEN 减弱。结论：行为数据表明对 DFEN 厌食症的耐受部分或完全是由 5-HT1B 和/或 5-HT2C 受体的功能性亚敏感性介导的。涉及的大脑区域包括室旁下丘脑、内侧纹状体、外侧臂旁核和孤束核。
Rationale: We have shown that the anorectic effect of dexfenfluramine (DFEN), an agent that acutely increases synaptic availability of serotonin (5-HT), shows complete tolerance after 2-3 prior applications when using acute feeding protocols and low dosages. It is unlikely this is due to either accumulative weight loss or presynaptic 5-HT depletion. In this study, we examined the possible contribution of 5-HT1B/2C receptors to behavioral tolerance by testing for cross tolerance between DFEN and the 5-HT1B/2C receptor agonists,,m-chloro- and trifluoromethyl-substituted phenylpiperazines (mCPP and TFMPP). Additionally, we sought neuronal correlates of the behavioral changes by study of the induction of Fos-like immunoreactivity (ir) in discrete brain regions. Methods: Sprague-Dawley rats received two or three pre-injections, at 2-day intervals, of 2 mg/kg DFEN or vehicle. The rats were then food deprived for 24 h and, 30 min prior to a I-h feeding test, received a s.c. injection of either DFEN, TFMPP (I mg/kg), or mCPP (2 mg/kg). Additional groups received mCPP preinjections and test injection of either DFEN or mCPP. Rats in Fos-ir studies received similar injection regimens but were not food deprived and were perfused 1.5 h after the test injection. Results: DFEN-pretreated rats showed complete anorectic tolerance to DFEN, TFMPP, and mCPP. However, rats given this regimen of mCPP pretreatment were tolerant to neither mCPP nor DFEN. Fos-ir induced by DFEN in each brain region examined was either significantly reduced or abolished by prior DFEN injections. TFMPP induced less Fos-ir in these regions than DFEN and this was attenuated by prior DFEN. Conclusions: The behavioral data indicate that tolerance to DFEN anorexia is mediated partially or completely by functional subsensitivity at 5-HT1B and/or 5-HT2C receptors. The brain regions implicated include the paraventricular hypothalamus, medial striatum, lateral parabrachial nucleus, and nucleus of the solitary tract.