Clozapine reverses increased brown adipose tissue thermogenesis induced by 3,4-methylenedioxymethamphetamine and by cold exposure in conscious rats
Clozapine reverses increased brown adipose tissue thermogenesis induced by 3,4-methylenedioxymethamphetamine and by cold exposure in conscious rats
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DOI：
10.1016/j.neuroscience.2006.05.050
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发表时间：
2006-01-01
期刊：
影响因子：
3.3
通讯作者：
Ootsuka, Y.
中科院分区：
文献类型：
--
作者：
Blessing, W. W.;Zilm, A.;Ootsuka, Y.
氯氮平是一种治疗精神分裂症的非典型抗精神病药物，对交感神经流出到体温调节性皮肤循环有显著的抑制作用。在兔身上，氯氮平逆转了由MDMA(3，4-亚甲基二氧基甲基苯丙胺，摇头丸)或将动物暴露在寒冷环境中而引起的耳廓血管收缩。在大鼠中，已知这两种方法都能增加肩胛间棕色脂肪组织(IBAT)的交感神经激活产热，这对大鼠的产热很重要。在目前的研究中，我们在清醒的大鼠身上确定了氯氮平是否减少了MDMA和寒冷暴露所诱导的MAT产热。我们设计了我们的研究，以便我们也可以确定氯氮平对由S.C.注射。MDMA提高了iBAT温度(90分钟后+1.7+/-0.2摄氏度，P<；0.01，n=14)。氯氮平显著逆转了MDMA引起的iBAT温度升高(MDMA后氯氮平治疗60分钟后-1.3+/-0.2摄氏度，与MDMA后赋形剂治疗后60分钟+0.3+/-0.2摄氏度相比，P<；0.01，n=7)。氯氮平还减少了压力引起的iBAT温度升高，以及将大鼠暴露在寒冷(5摄氏度)环境中引起的升高。结合我们之前的发现，结果表明MDMA激活交感体温调节输出(包括到iBAT的输出)，以保护体温免受寒冷暴露，并因应环境压力而提高体温。氯氮平对iBAT产热的显着抑制可能为其用于治疗包括精神分裂症在内的精神障碍患者时导致肥胖的显着倾向提供了线索。我们在大鼠身上的证明是，氯氮平降低了交感介导的MDMA引起的iBAT温度升高，增加了氯氮平和氯氮平类药物对MDMA引起的人类威胁生命的体温升高具有治疗效果的可能性。(C)2006年IBRO。爱思唯尔有限公司出版。保留所有权利。
Clozapine, an atypical antipsychotic agent important for the treatment of schizophrenia, has marked inhibitory effects on sympathetic outflow to the thermoregulatory cutaneous circulation. In rabbits clozapine reverses ear pinna vasoconstriction induced either by administration of MDMA (3,4-methylenedioxymethamphetamine, ecstasy) or by exposing the animal to a cold environment. In rats, both these procedures are known to increase sympathetic activation of interscapular brown adipose tissue (iBAT) thermogenesis, important for heat production in the rat. In the present study in conscious rats we determined whether clozapine reduces MAT thermogenesis induced by MDMA and by exposure to cold. We designed our study so that we could also determine effects of clozapine on the acute (stress-induced) increases in iBAT thermogenesis initiated by the process of s.c. injection. MDMA increased iBAT temperature (+1.7 +/- 0.2 degrees C after 90 min, P < 0.01, n=14 measurements from seven rats each studied on two occasions). Clozapine acutely reversed the MDMA-elicited increase in iBAT temperature (-1.3 +/- 0.2 degrees C 60 min after clozapine treatment following MDMA versus +0.3 +/- 0.2 degrees C for 60 min after vehicle treatment following MDMA, P < 0.01, n=7). Clozapine also reduced stress-induced increases in iBAT temperature, as well as increases elicited by exposing rats to a cold (5 degrees C) environment. Results, taken together with our previous findings, suggest that MDMA activates the sympathetic thermoregulatory outputs (including the output to iBAT) that defend body temperature against cold exposure and that increase body temperature in response to environmental stress. Clozapine's marked inhibition of iBAT thermogenesis may provide a clue to its marked tendency to cause obesity when used to treat humans with mental disorders including schizophrenia. Our demonstration in rats that clozapine decreases sympathetically-mediated increases in iBAT temperature elicited by MDMA adds to the likelihood that clozapine and clozapine-like agents might be therapeutically effective in life threatening hyperthermia induced by MDMA in humans. (c) 2006 IBRO. Published by Elsevier Ltd. All rights reserved.