3,4-methylenedioxymethamphetamine induces differential regulation of tryptophan hydroxylase 2 protein and mRNA levels in the rat dorsal raphe nucleus
3,4-methylenedioxymethamphetamine induces differential regulation of tryptophan hydroxylase 2 protein and mRNA levels in the rat dorsal raphe nucleus
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DOI：
10.1016/j.neuroscience.2008.03.086
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发表时间：
2008-07-31
期刊：
影响因子：
3.3
通讯作者：
Austin, M. C.
中科院分区：
文献类型：
--
作者：
Bonkale, W. L.;Austin, M. C.
先前对3,4-亚甲基二氧基甲基苯丙胺（MDMA）的研究表明，该药物的使用导致5-HT神经末段的变性和随后的5-HT神经传递的改变。然而，只有有限的研究检查了MDMA对中缝背核的影响。本研究旨在通过测定大鼠中背核（DR）中色氨酸羟化酶（TPH2）蛋白和mRNA水平，评估MDMA对5-HT生物合成限速酶色氨酸羟化酶（TPH）的影响。给大鼠注射MDMA （20 mg/kg, s.c）或生理盐水，每天2次，连续4 d， 14 d后处死。对DR组织切片进行定量免疫自显影和原位杂交组织化学处理，以测量TPH2免疫反应性（IR）和TPH2 mRNA的水平。为了评估MDMA处理后5-HT轴突末端的完整性，使用[125I]RTI-55 ((-)-2 β -氨基甲氧基-3 β -（4-碘苯基）tropane) （(125)I-RTI-55）作为配体，通过定量放射自显像测量5-HT转运体（SERT）结合位点的密度。与盐水注射大鼠相比，mdma治疗大鼠的TPH2-IR水平在DR中期显著降低45%，在DR尾侧显著降低40%。相比之下，TPH2 mRNA水平在DR中期显著升高24%，在DR尾期显著升高12%。MDMA治疗显著降低纹状体、伏核和扣带皮层中（125）个I-RTI-55标记的SERT结合位点，显示5-HT终端的缺失。mdma处理大鼠DR中期和尾侧TPH2 mRNA水平升高可能反映了损伤的5-HT神经元增加TPH2蛋白合成的代偿机制。综上所述，我们的研究结果表明，MDMA给药后，DR中TPH2的生物合成出现了严重缺陷。(c) 2008 ibro。Elsevier Ltd.出版。版权所有。
Previous investigations with 3,4-methylenedioxy-methamphetamine (MDMA) have suggested that administration of this drug results in a degeneration of 5-HT nerve terminals and subsequent alterations in 5-HT neurotransmission. However, only limited investigations have examined the effects of MDMA on the dorsal raphe nucleus. The present study was designed to assess the effect of MDMA on the rate-limiting enzyme in 5-HT biosynthesis, tryptophan hydroxylase (TPH), by measuring TPH2 protein and mRNA levels in rat dorsal raphe (DR) nucleus. Rats were administered MDMA (20 mg/kg, s.c.) or saline twice daily for 4 days and killed 14 days later. Tissue sections of the DR were processed for quantitative immunoautoradiography and in situ hybridization histochemistry for measurements of the levels of TPH2-immunoreactivity (IR) and TPH2 mRNA. To assess 5-HT axon terminal integrity after MDMA treatment, the density of 5-HT transporter (SERT) binding sites was measured by quantitative autoradiography using [125I]RTI-55 ((-)-2betacarbomethoxy-3 beta-(4-iodophenyl) tropane) ((125)I-RTI-55) as a ligand. TPH2-IR levels were significantly decreased by 45% in the mid DR and by 40% in the caudal DR in the MDMA-treated rats compared with saline-injected rats. In contrast, TPH2 mRNA levels were significantly increased by 24% in the mid DR and by 12% in the caudal DR. MDMA treatment significantly decreased (125)I-RTI-55 labeled SERT binding sites in the striatum, nucleus accumbens and cingulate cortex demonstrating a loss of 5-HT terminals. The increase in TPH2 mRNA levels in both the mid DR and caudal DR of MDMA-treated rats may reflect a compensatory mechanism in the injured 5-HT neurons to increase TPH2 protein synthesis. Taken together, our results suggest that a serious defect occurs in the biosynthesis of TPH2 in the DR following MDMA administration. (C) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.