Effects of topiramate and other anti-glutamatergic drugs on the acute intoxicating actions of ethanol in mice: modulation by genetic strain and stress.
Effects of topiramate and other anti-glutamatergic drugs on the acute intoxicating actions of ethanol in mice: modulation by genetic strain and stress.
复制标题
DOI：
10.1038/npp.2008.182
复制
发表时间：
2009-05
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
具有抗谷氨酸能特性的化合物目前在临床用于各种适应症（如阿尔茨海默病、癫痫、精神病、情绪障碍），具有作为酒精中毒新疗法的潜在效用。增强对酒精的某些急性中毒作用（共济失调，镇静）的敏感性可能是抗谷氨酸能药物调节酒精使用的一种机制。我们研究了六种化合物（美刚、右美沙芬、氟哌啶醇、拉莫三嗪、奥卡西平、托吡酯）对C57BL/6J小鼠急性酒精中毒（失调性、低温、镇静/催眠）敏感性的影响。对托吡酯的分析扩展到确定遗传背景（通过比较129S1、BALB/cJ、C57BL/6J、DBA/2J自交系）和先前应激史（通过C57BL/6J长期暴露于游泳应激）对托吡酯对乙醇诱导的镇静/催眠作用的影响。结果表明，一种n -甲基- d -天冬氨酸受体（NMDAR）拮抗剂美金刚，而另一种右美沙芬，增强了乙醇的失调性作用，但没有降低体温或镇静/催眠作用。氟哌啶醇增加乙醇诱导的共济失调和镇静/催眠的程度与典型的NMDAR拮抗剂MK-801相似。在抗惊厥药物测试中，拉莫三嗪加强了乙醇诱导的镇静/催眠，而奥卡西平没有效果。在C57BL/6J的基线条件下，托吡酯本身没有作用，但与MK-801在乙醇诱导的镇静/催眠中具有协同作用。比较近交系，托吡酯能显著增强乙醇对BALB/cJ的镇静/催眠作用，而对129S1、C57BL/6J和DBA/2J没有作用。托吡酯还增加慢性应激暴露后C57BL/6J的乙醇诱导的镇静/催眠作用。目前的数据表明，除了MK-801和氟哌啶醇外，在C57BL/6J的基线条件下，测试的化合物对急性乙醇的敏感性没有显着或测定选择性影响。然而，托吡酯的显著作用与NMDAR阻滞剂、遗传背景或先前的应激史共同作用。这些发现提出了托吡酯和其他抗谷氨酸能药物可能在遗传或生活史定义的特定亚群中促进乙醇急性中毒作用的可能性。
Compounds with anti-glutamatergic properties currently in clinical use for various indications (e.g., Alzheimer's disease, epilepsy, psychosis, mood disorders) have potential utility as novel treatments for alcoholism. Enhanced sensitivity to certain acute intoxicating effects (ataxia, sedative) of alcohol may be one mechanism by which anti-glutamatergic drugs modulate alcohol use. We examined the effects of six compounds (memantine, dextromethorphan, haloperidol, lamotrigine, oxcarbazepine, topiramate) on sensitivity to acute intoxicating effects of ethanol (ataxia, hypothermia, sedation/hypnosis) in C57BL/6J mice. Analysis of topiramate was extended to determine the influence of genetic background (via comparison of the 129S1, BALB/cJ, C57BL/6J, DBA/2J inbred strains) and prior stress history (via chronic exposure of C57BL/6J to swim stress) on topiramate's effects on ethanol-induced sedation/hypnosis. Results showed that one N-methyl-D-aspartate receptor (NMDAR) antagonist, memantine, but not another, dextromethorphan, potentiated the ataxic but not hypothermic or sedative/hypnotic effects of ethanol. Haloperidol increased ethanol-induced ataxia and sedation/hypnosis to a similar extent as the prototypical NMDAR antagonist MK-801. Of the anticonvulsants tested, lamotrigine accentuated ethanol-induced sedation/hypnosis, while oxcarbazepine was without effect. Topiramate was without effect per se under baseline conditions in C57BL/6J, but had a synergistic effect with MK-801 on ethanol-induced sedation/hypnosis. Comparing inbred strains, topiramate was found to significantly potentiated ethanol's sedative/hypnotic effects in BALB/cJ, but not 129S1, C57BL/6J or DBA/2J strains. Topiramate also increased ethanol-induced sedation/hypnosis in C57BL/6J after exposure to chronic stress exposure. Current data demonstrate that, with the exception of MK-801 and haloperidol, the compounds tested had either no significant or assay-selective effects on sensitivity to acute ethanol under baseline conditions in C57BL/6J. However, significant effects of topiramate were revealed as a function of co-treatment with a NMDAR blocker, genetic background or prior stress history. These findings raise the possibility that topiramate and possibly other anti-glutamatergic drugs could promote the acute intoxicating effects of ethanol in specific subpopulations defined by genetics or life history.
登录
查看更多内容
影响因子：
2.9
作者：
Boyce-Rustay, Janel M.;Cameron, Heather A.;Holmes, Andrew
通讯作者：
Holmes, Andrew
影响因子：
2.7
作者：
Boyce-Rustay, Janel M.;Janos, Alicia L.;Holmes, Andrew
通讯作者：
Holmes, Andrew
影响因子：
1.7
作者：
Cagetti, E;Baicy, KJ;Olsen, RW
通讯作者：
Olsen, RW
影响因子：
2.9
作者：
CRABBE, JC;MERRILL, CD;BELKNAP, JK
通讯作者：
BELKNAP, JK
DOI：
10.1124/jpet.105.090449
发表时间：
2005-11-01
影响因子：
3.5
作者：
Cowen, MS;Djouma, E;Lawrence, AJ
通讯作者：
Lawrence, AJ