Equipe Région INSERM ERI 24, Groupe de Recherche sur l'Alcool et les Pharmacodépendances, Université de Picardie Jules Verne, Faculté de Pharmacie, Amiens, France.
Neuropsychopharmacology. 2011 Jun;36(7):1518-30. doi: 10.1038/npp.2011.37. Epub 2011 Mar 23.
A few clinical studies have shown that dual antidepressants (serotonergic (5-HT) and noradrenergic (NE) transporter inhibitors, SNRIs) may be effective in alcoholism treatment. We studied the effect of the dual antidepressant milnacipran on ethanol operant self-administration in acutely withdrawn ethanol-dependent and in -non-dependent Wistar rats, and used fluoxetine and desipramine to dissect both 5-HT and NE components, respectively, in the effect of milnacipran. Milnacipran was also tested for relapse after protracted abstinence and on ethanol-induced (1.0 g/kg) conditioned place preference in control rats and ethanol-induced locomotor sensitization in DBA/2J female mice. Milnacipran dose dependently (5-40 mg/kg) attenuated the increased ethanol self-administration observed during early withdrawal and was more potent in preventing reinstatement in dependent rats after protracted abstinence as compared with non-dependent rats. Desipramine and fluoxetine (10 mg/kg) blocked ethanol self-administration during early withdrawal, and recovery was delayed in dependent animals, indicating a potent effect. Ethanol self-administration was also reduced 1 day after treatment with desipramine and fluoxetine but not with milnacipran. Finally, milnacipran prevented ethanol-induced place preference in ethanol-naive rats and reduced the magnitude of ethanol-induced sensitization associated with a delayed induction in mice. Desipramine (20 mg/kg) countered sensitization development and reduced its expression at 1 week after treatment; fluoxetine (10 mg/kg) reduced sensitization expression. Thus, 5-HT and NE transmissions during sensitization expression may mediate the effect of milnacipran on sensitization induction. These results support that SNRIs may have a potential use in alcoholism treatment.
一些临床研究表明，双重抗抑郁药（血清素能（5-HT）和去甲肾上腺素能（NE）转运体抑制剂，SNRIs）可能对治疗酒精中毒有效。我们研究了双重抗抑郁药米那普仑对急性戒断的乙醇依赖和非依赖 Wistar 大鼠乙醇操作性自我给药的影响，并分别使用氟西汀和去甲丙咪嗪来剖析米那普仑作用中的 5-HT 和 NE 成分。还在对照大鼠中测试了米那普仑在延长戒断后的复发以及在 1.0 g/kg 乙醇诱导的条件性位置偏好中的作用，以及在 DBA/2J 雌性小鼠中的乙醇诱导的运动敏化作用。米那普仑剂量依赖性（5-40 mg/kg）减弱了早期戒断期间观察到的乙醇自我给药增加，并且在延长戒断后对依赖大鼠的复燃的预防作用比非依赖大鼠更有效。去甲丙咪嗪和氟西汀（10 mg/kg）在早期戒断期间阻断了乙醇的自我给药，并且依赖动物的恢复延迟，表明作用很强。去甲丙咪嗪和氟西汀治疗后 1 天，乙醇自我给药也减少，但米那普仑没有。最后，米那普仑防止了乙醇诱导的乙醇-naive 大鼠的位置偏好，并减少了与小鼠中诱导延迟相关的乙醇诱导的敏化。去甲丙咪嗪（20 mg/kg）抵消了敏化发展并减少了治疗后 1 周的表达；氟西汀（10 mg/kg）减少了敏化表达。因此，敏化表达期间的 5-HT 和 NE 传递可能介导了米那普仑对敏化诱导的作用。这些结果支持 SNRIs 可能在治疗酒精中毒方面具有潜在用途。
