东莨菪碱与乙醇联合治疗会产生一种运动兴奋反应，提示存在不受多巴胺受体拮抗剂阻断的协同作用。
Combined scopolamine and ethanol treatment results in a locomotor stimulant response suggestive of synergism that is not blocked by dopamine receptor antagonists.
作者信息
Scibelli Angela C, Phillips Tamara J
机构信息
Portland Alcohol Research Center and Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon, USA.
出版信息
Alcohol Clin Exp Res. 2009 Mar;33(3):435-47. doi: 10.1111/j.1530-0277.2008.00854.x. Epub 2008 Dec 13.
BACKGROUND
Muscarinic acetylcholine receptors (mAChRs) are well positioned to mediate ethanol's stimulant effects. To investigate this possibility, we examined the effects of scopolamine, a receptor subtype nonselective mAChR antagonist, on ethanol-induced stimulation in genotypes highly sensitive to this effect of ethanol. We also investigated whether the dopamine D1-like receptor antagonist, SCH-23390 or the dopamine D2-like receptor antagonist, haloperidol, could block the extreme stimulant response found following co-administration of scopolamine and ethanol.
METHODS
Scopolamine (0, 0.0625, 0.125, 0.25, or 0.5 mg/kg) was given 10 minutes prior to saline or ethanol (0.75 to 2 g/kg) to female FAST (Experiment I) or DBA/2J (Experiment II) mice that were then tested for locomotion for 30 minutes. In Experiments III and IV, respectively, SCH-23390 (0, 0.015, or 0.03 mg/kg) was given 10 minutes prior, and haloperidol (0, 0.08, or 0.16 mg/kg) was given 2 minutes prior, to scopolamine (0 or 0.5 mg/kg), followed 10 minutes later by saline or ethanol (1.5 g/kg) and female DBA/2J mice were tested for locomotion for 30 minutes.
RESULTS
FAST and DBA/2J mice displayed a robust enhancement of the locomotor effects of ethanol following pretreatment with scopolamine that was suggestive of synergism. SCH-23390 had no effect on the response to the scopolamine + ethanol drug combination, nor did it attenuate ethanol- or scopolamine-induced locomotor activity. Haloperidol, while attenuating the effects of ethanol, was not able to block the effects of scopolamine or the robust response to the scopolamine-ethanol drug combination.
CONCLUSIONS
These results suggest that while muscarinic receptor antagonism robustly enhances acute locomotor stimulation to ethanol, dopamine receptors are not involved in the super-additive interaction of scopolamine and ethanol treatment. They also suggest that in addition to cautions regarding the use of alcohol when scopolamine is clinically prescribed due to enhanced sedative effects, enhanced stimulation may also be a concern.
背景
毒蕈碱型乙酰胆碱受体（mAChRs）很可能介导乙醇的兴奋作用。为了探究这种可能性，我们研究了东莨菪碱（一种受体亚型非选择性mAChR拮抗剂）对乙醇诱导的兴奋作用在对乙醇此效应高度敏感的基因型中的影响。我们还研究了多巴胺D1样受体拮抗剂SCH-23390或多巴胺D2样受体拮抗剂氟哌啶醇是否能阻断东莨菪碱和乙醇联合给药后出现的极端兴奋反应。
方法
在给雌性FAST小鼠（实验I）或DBA/2J小鼠（实验II）注射生理盐水或乙醇（0.75至2 g/kg）前10分钟给予东莨菪碱（0、0.0625、0.125、0.25或0.5 mg/kg），然后对其运动进行30分钟测试。在实验III和IV中，分别在给予东莨菪碱（0或0.5 mg/kg）前10分钟给予SCH-23390（0、0.015或0.03 mg/kg），以及在给予东莨菪碱前2分钟给予氟哌啶醇（0、0.08或0.16 mg/kg），10分钟后再给予生理盐水或乙醇（1.5 g/kg），对雌性DBA/2J小鼠的运动进行30分钟测试。
结果
FAST和DBA/2J小鼠在预先给予东莨菪碱后，乙醇的运动效应显著增强，提示存在协同作用。SCH-23390对东莨菪碱+乙醇药物组合的反应无影响，也未减弱乙醇或东莨菪碱诱导的运动活性。氟哌啶醇虽然减弱了乙醇的作用，但无法阻断东莨菪碱的作用或对东莨菪碱-乙醇药物组合的强烈反应。
结论
这些结果表明，虽然毒蕈碱受体拮抗作用能显著增强对乙醇的急性运动兴奋作用，但多巴胺受体不参与东莨菪碱和乙醇联合治疗的超相加相互作用。它们还表明，除了由于镇静作用增强在临床开具东莨菪碱处方时要谨慎使用酒精外，兴奋作用增强也可能是一个问题。
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