Tolerance to 3,4-methylenedioxymethamphetamine in rats exposed to single high-dose binges
Tolerance to 3,4-methylenedioxymethamphetamine in rats exposed to single high-dose binges
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DOI：
10.1016/j.neuroscience.2008.01.007
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发表时间：
2008-03-27
期刊：
影响因子：
3.3
通讯作者：
Rothman, R. B.
中科院分区：
文献类型：
--
作者：
Baumann, M. H.;Clark, R. D.;Rothman, R. B.
3，4-亚甲二氧基甲基苯丙胺（MDMA或摇头丸）刺激转运蛋白介导的单胺释放，包括5-HT。高剂量暴露于MDMA会导致动物持续性5-HT缺乏（例如脑5-HT耗竭），但这种缺乏的功能和临床相关性尚不明确。在这里，我们研究的功能后果的MDMA诱导的5-HT消耗大鼠。雄性大鼠接受三次MDMA或生理盐水腹腔注射，每2小时注射一次; MDMA以药理学阈值剂量（1.5 mg/kgx 3，低剂量）或5倍剂量（7.5 mg/kgx 3，高剂量）给药。一周后，植入颈静脉导管和脑内引导插管。狂欢后两周，大鼠接受1和3 mg/kg MDMA急性静脉注射激发。静脉注射MDMA（催乳素和皮质酮分泌）诱发的神经内分泌效应通过连续血液采样进行评估，而神经化学效应（5-HT和多巴胺释放）通过脑微透析进行评估。MDMA仅在高剂量组中使核心温度升高，这些大鼠在2周后表现出类似于50%的前脑5-HT损失。既往暴露于MDMA未改变基线血浆激素或透析液单胺，并且静脉注射MDMA的效应在生理盐水组和低剂量组中相似。相比之下，大鼠预处理与高剂量的MDMA显示显着减少诱发激素分泌和5-HT释放时，挑战与i. v. MDMA。由于耐受性仅在暴露于高剂量暴食的大鼠中产生，因此这种现象涉及体温过高和5-HT耗竭。我们的研究结果表明，MDMA耐受性在人类可能反映5-HT赤字，这可能有助于进一步剂量递增。由Elsevier Ltd代表IBRO出版。
3,4-Methylenedioxymethamphetamine (MDMA or ecstasy) stimulates the transporter-mediated release of monoamines, including 5-HT. High-dose exposure to MDMA causes persistent 5-HT deficits (e.g. depletion of brain 5-HT) in animals, yet the functional and clinical relevance of such deficits are poorly defined. Here we examine functional consequences of MDMA-Induced 5-HT depletions in rats. Male rats received binges of three i.p. injections of MDMA or saline, one injection every 2 h; MDMA was given at a threshold pharmacological dose (1.5 mg/kgx3, low dose) or at a fivefold higher amount (7.5 mg/kgx3, high dose). One week later, jugular catheters and intracerebral guide cannulae were implanted. Two weeks after binges, rats received acute i.v. challenge injections of 1 and 3 mg/kg MDMA. Neuroendocrine effects evoked by i.v. MDMA (prolactin and corticosterone secretion) were assessed via serial blood sampling, while neurochemical effects (5-HT and dopamine release) were assessed via microdialysis in brain. MDMA binges elevated core temperatures only in the high-dose group, with these same rats exhibiting similar to 50% loss of forebrain 5-HT 2 weeks later. Prior exposure to MDMA did not alter baseline plasma hormones or dialysate monoamines, and effects of i.v. MDMA were similar in saline and low-dose groups. By contrast, rats pretreated with high-dose MDMA displayed significant reductions in evoked hormone secretion and 5-HT release when challenged with i.v. MDMA. As tolerance developed only in rats exposed to high-dose binges, hyperthermia and 5-HT depletion are implicated in this phenomenon. Our results suggest that MDMA tolerance in humans may reflect 5-HT deficits which could contribute to further dose escalation. Published by Elsevier Ltd on behalf of IBRO.