Topiramate moderately reduces the motivation to consume alcohol and has a marked antidepressant effect in rats
Topiramate moderately reduces the motivation to consume alcohol and has a marked antidepressant effect in rats
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DOI：
10.1111/j.1530-0277.2007.00485.x
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发表时间：
2007-11-01
影响因子：
3.2
通讯作者：
McGregor, Iain S.
中科院分区：
文献类型：
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作者：
Hargreaves, Garth A.;McGregor, Iain S.
背景：在最近的人体研究中，抗惊厥药物托吡酯(TPM)在治疗酒精渴求和情绪障碍方面显示出疗效。然而，支持这种效应的临床前证据令人惊讶地稀少。在实验1中，大鼠在家中自由饮用食物、水和啤酒(4.44%乙醇v/v)或“准啤酒”(热量匹配的无酒精啤酒，0.44%乙醇)。然后，他们被限制在每天1小时的操作过程中，在舔舔水和啤酒或接近啤酒的过程中，他们在舔口器中按照渐进的比率计划进行强化。然后评估了TPM对消费啤酒或接近啤酒的动机的急性影响。在TPM检测后，还评估了纳洛酮的效果(作为阳性对照)。在实验2中，大鼠被给予11周的自由在家笼子里获得食物、水和啤酒。然后，他们每天重复注射TPM，并监测在临时家庭笼子进入条件下对啤酒消费的影响。结果：托吡酯(10、20、40 mg/kg)能显著降低小鼠舔啤酒的动机，但与纳洛酮(10 mg/kg)相比作用不大。然而，与TPM不同的是，纳洛酮也减少了对接近啤酒的反应，这表明TPM具有酒精特异性效应。在实验2中，TPM(40 mg/kg和80 mg/kg)倾向于在自由接触条件下暂时减少家庭笼子中的酒精消耗量，但这种作用随着反复给药而消失。TPM(10-80 mg/kg，在测试前4小时内两次给药)在强迫游泳测试中可显著减少不动和增加主动应对策略，与地昔帕明(2×20 mg/kg)相似。结论：TPM急性给药对Wistar大鼠的饮酒冲动有一定的抑制作用，且有一定的选择性。与纳洛酮相比，这种抗酒精作用是温和的，在长期治疗和临时酒精接触的情况下似乎会消失。在强迫游泳试验中有明显的抗抑郁药样作用，在其他动物模型中有部分缓解焦虑的作用，这表明TPM可能是一种有益的情感障碍治疗方法。这些初步结果表明，有必要进行进一步的研究，以解决TPM调节情绪和饮酒的机制。
Background: In recent human studies, the anticonvulsant drug topiramate (TPM) has shown efficacy in treating alcohol craving and mood disorders. However, preclinical evidence supporting such effects is surprisingly sparse. Three experiments were conducted here to assess possible anticraving and antidepressant effects of TPM using animal models.Methods: In Experiment 1, rats were given 23 weeks ad libitum access to food, water, and either beer (4.44% ethanol v/v) or "near-beer" (a calorie-matched nonalcoholic beer, 0.44% ethanol) in their home cages. They were then restricted to daily 1 hour operant sessions in which they licked for water and either beer or near-beer under a progressive ratio schedule of reinforcement in a lickometer apparatus. The acute effects of TPM on the motivation to consume beer or near-beer were then assessed. The effects of naloxone were also assessed (as a positive control) after TPM testing. In Experiment 2, rats were given 11 weeks of ad libitum home-cage access to food, water, and beer. They then received repeated daily injections of TPM and effects on beer consumption under ad libitum home cage access conditions were monitored. In Experiment 3, the effects of TPM were assessed in the modified Porsolt forced swim test, emergence test, and elevated plus-maze (EPM) using alcohol naive rats.Results: Topiramate (10, 20, and 40 mg/kg) significantly reduced the motivation to lick for beer, although the maximal effect was moderate in comparison with naloxone (10 mg/kg). However, naloxone, unlike TPM, also reduced responding for near-beer suggesting an alcohol-specific effect of TPM. In Experiment 2, TPM (40 and 80 mg/kg) tended to transiently reduce alcohol consumption in the home cage under ad libitum access but this effect disappeared with repeated administration of the drug. TPM (10 to 80 mg/kg, given twice over 4 hours before test) produced a robust dose-dependent decrease in immobility and increase in active coping strategies in the forced swim test similar to that seen with desipramine (2 x 20 mg/kg). There were modest anxiolytic effects of TPM on the EPM and emergence tests.Conclusions: With acute administration, TPM is moderately effective and relatively selective in reducing the drive to consume alcohol in Wistar rats. This anti-alcohol effect is modest in comparison with naloxone and appears to dissipate under conditions of chronic treatment and ad libitum alcohol access. A marked antidepressant-like effect in the forced swim test and partial anxiolytic effects in other animal models suggests that TPM may be a beneficial treatment for affective disorders. These preliminary results suggest further research is warranted to resolve the mechanisms involved in TPM modulation of both mood and alcohol consumption.