Rowland N E, Robertson K, Lo J, Rema E
Department of Psychology, University of Florida, Gainesville 32611-2250, USA.
Psychopharmacology (Berl). 2001 Jun;156(1):108-14. doi: 10.1007/s002130100749.
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.
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 1-h feeding test, received a s.c. injection of either DFEN, TFMPP (1 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.
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.
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.
我们已经表明，右芬氟拉明（DFEN）具有食欲抑制作用，该药物可急性增加血清素（5-HT）的突触可用性，在使用急性喂食方案和低剂量时，在预先应用2-3次后会出现完全耐受性。这不太可能是由于累积体重减轻或突触前5-HT耗竭所致。在本研究中，我们通过测试DFEN与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作用。此外，我们通过研究离散脑区中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。
Sprague-Dawley大鼠每隔2天接受两次或三次2mg/kg DFEN或赋形剂的预注射。然后将大鼠禁食24小时，并在1小时喂食试验前30分钟接受皮下注射DFEN、TFMPP（1mg/kg）或mCPP（2mg/kg）。其他组接受mCPP预注射并测试注射DFEN或mCPP。Fos-ir研究中的大鼠接受类似的注射方案，但不禁食，并在测试注射后1.5小时进行灌注。
DFEN预处理的大鼠对DFEN、TFMPP和mCPP表现出完全的食欲抑制耐受性。然而，接受这种mCPP预处理方案的大鼠对mCPP和DFEN均无耐受性。在每个检测的脑区中，DFEN诱导的Fos-ir在先前注射DFEN后显著降低或消失。TFMPP在这些区域诱导的Fos-ir比DFEN少，并且这被先前的DFEN减弱。
行为数据表明，对DFEN厌食的耐受性部分或完全由5-HT1B和/或5-HT2C受体的功能性亚敏感性介导。涉及的脑区包括室旁下丘脑、内侧纹状体、外侧臂旁核和孤束核。
