THE ROLE OF TEMPERATURE, STRESS, AND OTHER FACTORS IN THE NEUROTOXICITY OF THE SUBSTITUTED AMPHETAMINES 3,4-METHYLENEDIOXYMETHAMPHETAMINE AND FENFLURAMINE
THE ROLE OF TEMPERATURE, STRESS, AND OTHER FACTORS IN THE NEUROTOXICITY OF THE SUBSTITUTED AMPHETAMINES 3,4-METHYLENEDIOXYMETHAMPHETAMINE AND FENFLURAMINE
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DOI：
10.1007/bf02740694
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发表时间：
1995-08-01
影响因子：
5.1
通讯作者：
OCALLAGHAN, JP
中科院分区：
文献类型：
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作者：
MILLER, DB;OCALLAGHAN, JP
苯丙胺(AMPs)可导致纹状体多巴胺(DA)和5-羟色胺(5-HT)的长期枯竭，这些减少通常被认为是AMP对纹状体的多巴胺和5-羟色胺能投射造成损害的初步证据。很少有与神经损伤相关的指数用于评估AMP的神经毒性。在此，我们测定了D-亚甲基二氧基甲基苯丙胺(d-MDMA)和d-芬氟拉明(d-fen)两种取代AMPs对群养雌性C57BL6/J小鼠的潜在神经毒性作用。胶质纤维酸性蛋白(GFAP)定量评估星形胶质细胞增生症是d-MDMA所致神经损伤的主要指标。用酪氨酸羟化酶(TH)、多巴胺(DA)和5-羟色胺(5-HT)测定对DA和5-羟色胺系统的影响。由于AMP以其刺激和高温诱导特性而闻名，因此在几个实验中对活性和核心温度进行了监测。为了推广我们的发现，我们在单独饲养的雌性C57BL6/J小鼠以及群养的雄性C57BL6/J或雌性B6C3F1小鼠中检测了d-MDMA处理后的这些相同的终点。D-MDMA(20 mg/kg)(单独饲养的小鼠接受20、30或40 mg/kg的剂量)或d-fen(25 mg/kg)每隔2小时注射一次，总共四次sc。D-MDMA引起体温升高，而d-Fen引起体温降低。D-MDMA使纹状体GFAP显著增加(300%)，TH和DA下降50-75%，3wk时仍明显。d-Fen不影响纹状体的任何参数。D-MDMA是一种纹状体多巴胺能神经毒物，在雄性和雌性C57BL6/小鼠中都有，无论性别，星形胶质细胞增生症和该区域DA的缺乏都证明了这一点。对男性的更大杀伤力表明，他们可能比女性更敏感，至少对d-MDMA的一般毒性更敏感。D-MDMA(20 mg/kg)对单独饲养和成群饲养的小鼠造成相同程度的损伤。在单独饲养的小鼠中，更高的剂量会导致更大的致死率，但不会产生更大的神经毒性。D-MDMA对B6C3F1小鼠也有明显的纹状体损伤作用。D-MDMA诱导的活性显著增加，这种增加不能被MK-801预处理所阻断，尽管这种联合诱导的体温显著降低。降低体温，无论是降低15摄氏度的环境温度(降幅约2摄氏度)，还是预先注射MK-801(第一次和第三次注射d-MDMA之前的1.0 mg/kg，降幅约5-6摄氏度)或限制(降幅约5-6摄氏度)，都有效地阻断d-MDMA对C57BL6/J和B6C3F1的神经毒性。D-MDMA的刺激作用对d-MDMA的神经毒性或MK-801的保护作用影响不大。这些数据表明，在小鼠中，d-mdma的神经毒性效应，以及最有可能的其他amps，与体温的影响有关。
Amphetamines (AMPs) can cause long-term depletions in striatal dopamine (DA) and serotonin (5-HT), and these decrements are often accepted as prima facie evidence of AMP-induced damage to the dopaminergic and serotonergic projections to striatum. Rarely are indices linked to neural damage used to evaluate the neurotoxicity of the AMPs. Here, we determined the potential neurotoxic effects of two substituted AMPs, d-methylenedioxymethamphetamine (d-MDMA) and d-fenfluramine (d-FEN) in group-housed female C57BL6/J mice. Astrogliosis, assessed by quantification of glial fibrillary acidic protein (GFAP), was the main indicator of d-MDMA-induced neural damage. Assays of tyrosine hydroxylase (TH), DA, and 5-HT were used to determine effects on DA and 5-HT systems. Since AMPs are noted for both their stimulatory and hyperthermia-inducing properties, activity, as well as core temperature, was monitored in several experiments. To extend the generality of our findings, these same end points were examined in singly housed female C57BL6/J mice and in group-housed male C57BL6/J or female B6C3F1 mice after treatment with d-MDMA. Mice received either d-MDMA (20 mg/kg) (singly housed mice received dosages of 20, 30, or 40 mg/kg) or d-FEN (25 mg/kg) every 2 h for a total of four sc injections. d-MDMA caused hyperthermia, whereas d-FEN induced hypothermia. d-MDMA cause a large (300%) increase in striatal GFAP that resolved by 3 wk and a 50-75% decrease in TH and DA that was still apparent at 3 wk, d-FEN did not affect any parameters in striatum. d-MDMA is a striatal dopaminergic neurotoxicant in both male and female C57BL6/mice, as evidenced by astrogliosis and depletions of DA in this area in both sexes. The greater lethality to males suggests they may be more sensitive, at least to the general toxicity of d-MDMA, than females. d-MDMA (20 mg/kg) induced the same degree of damage whether mice were housed singly or in groups. Higher dosages in singly housed mice induced greater lethality, but not greater neurotoxicity. d-MDMA was also effective in inducing striatal damage in mice of the B6C3F1 strain. Significant increases in activity were induced by d-MDMA, and these increases were not blocked by pretreatment with MK-801, despite the profound lowering of body temperature induced by this combination. A lowering of body temperature, whether by a 15 degrees C ambient temperature (approx 2 degrees C drop), pretreatment with MK-801 (1.0 mg/kg prior to the first and third d-MDMA injections; approx 5-6 degrees C drop) or restraint (approx 5-6 degrees C drop), was effective in blocking the neurotoxicity of d-MDMA in both C57BL6/J and B6C3F1. The stimulatory effects of d-MDMA appeared to have little impact on the neurotoxicity induced by d-MDMA or the protection conferred by MK-801. These data suggest that in the mouse, the neurotoxic effects of d-MDMA, and most likely other AMPs, are linked to an effect on body temperature.