mTOR activation is required for the anti-alcohol effect of ketamine, but not memantine, in alcohol-preferring rats.
mTOR activation is required for the anti-alcohol effect of ketamine, but not memantine, in alcohol-preferring rats.
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DOI：
10.1016/j.bbr.2013.02.030
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发表时间：
2013-06-15
影响因子：
2.7
通讯作者：
Cottone, Pietro
中科院分区：
文献类型：
--
作者：
Sabino, Valentina;Narayan, Aditi R.;Zeric, Tamara;Steardo, Luca;Cottone, Pietro
谷氨酸NMDA受体介导酒精的许多分子和行为效应，在过量饮酒的发展中起关键作用。因此，非竞争性NMDA受体拮抗剂可能具有治疗酒精中毒的潜力。第一个目的是比较NMDA拮抗剂美金刚和氯胺酮对酒精偏好大鼠饮用乙醇和糖精的影响。第二个目的是确定两种NMDA受体拮抗剂的作用是否由雷帕霉素的哺乳动物靶蛋白（mTOR）介导。允许TSRI Sardinian酒精偏好大鼠自我施用10%w/v乙醇或0.08%w/v糖精和水。在施用美金刚（0 - 10 mg/kg）或氯胺酮（0 - 20 mg/kg）后评估操作性反应和运动活性。最后，在施用美金刚或氯胺酮但用mTOR抑制剂雷帕霉素（2.5mg/kg）预处理的大鼠中评估乙醇自我施用。非竞争性的NMDA受体拮抗剂美金刚和氯胺酮剂量依赖性地减少了酒精偏好大鼠的酒精饮用量;而美金刚对酒精的优先作用超过糖精，氯胺酮减少了对两种溶液的响应。两种拮抗剂均未诱导不适，如对水摄入量和运动活动缺乏影响所示。mTOR抑制剂雷帕霉素阻断了氯胺酮的作用，但没有阻断美金刚的作用。美金刚和氯胺酮都能减少嗜酒大鼠的饮酒量，但只有美金刚对酒精有选择性。氯胺酮而非美金刚胺的作用由mTOR介导。结果支持非竞争性NMDA受体拮抗剂，特别是美金刚，在酒精成瘾的治疗潜力。
Glutamate NMDA receptors mediate many molecular and behavioral effects of alcohol, and they play a key role in the development of excessive drinking. Uncompetitive NMDA receptor antagonists may, therefore, have therapeutic potential for alcoholism. The first aim was to compare the effects of the NMDA antagonists memantine and ketamine on ethanol and saccharin drinking in alcohol-preferring rats. The second aim was to determine whether the effects of the two NMDA receptor antagonists were mediated by the mammalian target of rapamycin (mTOR). TSRI Sardinian alcohol-preferring rats were allowed to self-administer either 10% w/v ethanol or 0.08% w/v saccharin, and water. Operant responding and motor activity were assessed following administration of either memantine (0–10 mg/kg) or ketamine (0–20 mg/kg). Finally, ethanol self-administration was assessed in rats administered with either memantine or ketamine but pretreated with the mTOR inhibitor rapamycin (2.5 mg/kg). The uncompetitive NMDA receptor antagonists memantine and ketamine dose-dependently reduced ethanol drinking in alcohol-preferring rats; while memantine had a preferential effect on alcohol over saccharin, ketamine reduced responding for both solutions. Neither antagonist induced malaise, as shown by the lack of effect on water intake and motor activity. The mTOR inhibitor rapamycin blocked the effects of ketamine, but not those of memantine. Memantine and ketamine both reduce alcohol drinking in alcohol-preferring rats, but only memantine is selective for alcohol. The effects of ketamine, but not memantine, are mediated by mTOR. The results support the therapeutic potential of uncompetitive NMDA receptor antagonists, especially memantine, in alcohol addiction.
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影响因子：
5
作者：
Bienkowski, P;Krzascik, P;Danysz, W
通讯作者：
Danysz, W
影响因子：
1.7
作者：
Callado, LF;Hopwood, SE;Stamford, JA
通讯作者：
Stamford, JA
影响因子：
2.5
作者：
Blanpied, TA;Boeckman, FA;Johnson, JW
通讯作者：
Johnson, JW
影响因子：
5
作者：
BUBSER, M;KESEBERG, U;SCHMIDT, WJ
通讯作者：
SCHMIDT, WJ
DOI：
10.1097/00000374-199804000-00025
发表时间：
1998-04-01
影响因子：
3.2
作者：
Chester, JA;Risinger, FO;Cunningham, CL
通讯作者：
Cunningham, CL