Ciproxifan, a histamine H3-receptor antagonist/inverse agonist, modulates methamphetamine-induced sensitization in mice
Ciproxifan, a histamine H3-receptor antagonist/inverse agonist, modulates methamphetamine-induced sensitization in mice
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DOI：
10.1111/j.1460-9568.2011.07618.x
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发表时间：
2011-04-01
影响因子：
3.4
通讯作者：
Arrang, Jean-Michel
中科院分区：
文献类型：
--
作者：
Motawaj, Mouhammad;Arrang, Jean-Michel
组胺神经元在精神分裂症和精神刺激剂滥用中的作用尚不清楚。对精神刺激剂的行为敏感化是这些障碍的一个基本特征。在此，我们探讨了免疫调节剂和环丙沙芬(CPX)对甲基苯丙胺(MET)诱导的小鼠运动敏化的调节作用。MET(2 mg/kg)前2 h分别给予生理盐水、环磷酰胺(3 mg/kg)或免疫球蛋白(3 mg/kg)，每日1次，连续12天，洗净2天后处死。Imetit没有作用，但CPX导致MET诱导的运动活性下降，在第5天变得明显，在第10天更明显。在致敏小鼠中使用定量聚合酶链式反应来定量脑源性神经营养因子(BDNF)和N-甲基-D-天冬氨酸(NMDA)受体亚单位1(NR1)mRNAs，这两个因素在精神分裂症和药物滥用中都会改变。IMEITT和CPX单独使用对任何标志物均无影响。MET致敏可使海马区BDNFmRNAs减少40%。这一下降被CPX逆转。MET致敏后，大脑皮层、海马区和纹状体NR1mRNAs表达显著减少，但下丘脑未见明显变化。这些下降也被CPX逆转。CPX对甲硫氨酸致敏小鼠的强调制作用可能与其对大脑皮层和纹状体NR1mRNAs的调制作用有关。CPX逆转致敏动物海马区BDNF和NR1mRNAs，进一步增强了H-3受体反向激动剂长期治疗精神分裂症患者认知障碍的兴趣。
The role of histamine neurons in schizophrenia and psychostimulant abuse remains unclear. Behavioural sensitization to psychostimulants is a cardinal feature of these disorders. Here, we have explored the ability of imetit and ciproxifan (CPX), a reference H-3-receptor agonist and inverse agonist, respectively, to modulate locomotor sensitization induced in mice by methamphetamine (MET). Mice received saline, CPX (3 mg/kg) or imetit (3 mg/kg) 2 h before MET (2 mg/kg), once daily for 12 days, and were killed after a 2-day wash out. Imetit had no effect, but CPX induced a decrease of MET-induced locomotor activity, which became significant at Day 5, and even more at Day 10. Quantitative polymerase chain reaction was used in the sensitized mice to quantify brain-derived neurotrophic factor (BDNF) and N-methyl-d-aspartate (NMDA)-receptor subunit 1 (NR1) mRNAs, two factors that are altered in both schizophrenia and drug abuse. Imetit and CPX used alone had no effect on any marker. Sensitization by MET decreased BDNF mRNAs by 40% in the hippocampus. This decrease was reversed by CPX. Sensitization by MET also induced strong decreases of NR1 mRNAs in the cerebral cortex, hippocampus and striatum, but not hypothalamus. These decreases were also reversed by CPX. The strong modulator effect of CPX in mice sensitized to MET may result from its modulator effect on NR1 mRNAs in the cerebral cortex and striatum. The reversal by CPX of BDNF and NR1 mRNAs in the hippocampus of sensitized animals further strengthens the interest of H-3-receptor inverse agonists for the long-term treatment of cognitive deficits of patients with schizophrenia.