胍丁胺联合育亨宾对吗啡诱发小鼠行为敏化的影响

Effect of agmatine co-administration with yohimbine on morphine-induced behavioral sensitization in mice

目的：研究胍丁胺单独给药及联合α2-肾上腺素受体特异性拮抗剂育亨宾用药对吗啡致小鼠行为敏化的影响。方法1.观察药物处理对小鼠基础活动性的影响。将雄性C57BL/6J小鼠分为盐水对照组、胍丁胺（1、10、20、40和80 mg/kg）组、育亨宾（0.3、1、2和8 mg/kg）组和育亨宾（2 mg/kg）＋胍丁胺（80 mg/kg）组，给予胍丁胺（sc）或育亨宾（ip）后测试小鼠60 min的水平移动距离；2.观察药物处理对吗啡诱发小鼠高活动性的影响。小鼠分为盐水对照组、吗啡（10 mg/kg）组、胍丁胺（1、20和80 mg/kg）＋吗啡（10 mg/kg）组、育亨宾（2 mg/kg）＋吗啡（10 mg/kg）组和育亨宾（2 mg/kg）＋胍丁胺（80 mg/kg）＋吗啡（10 mg/kg）组，单独给予胍丁胺（sc）或育亨宾（ip）以及两药联合使用后给予吗啡（sc），测试药物处理后小鼠60 min的移动距离；3.观察药物处理对吗啡诱发小鼠行为敏化精神依赖行为的影响。采用连续间断给药方式建立敏化模型，在预适应分组后分别在第1天、第4天和第7天给予吗啡（10 mg/kg），同时检测小鼠60 min的移动距离。实验设计中分为盐水对照组、吗啡（10 mg/kg）组、胍丁胺（1、20和80 mg/kg）＋吗啡（10 mg/kg）组和育亨宾（2 mg/kg）＋胍丁胺（80 mg/kg）＋吗啡（10 mg/kg）组，单独给予胍丁胺（sc）或联合育亨宾（ip）用药后给予吗啡（sc），并在给药当天测试小鼠60 min的移动距离，比较给药组与吗啡模型组的差异。结果1.单独给予胍丁胺（1~80 mg/kg）或育亨宾（0.3~2 mg/kg）的系列剂量后，与盐水对照组比较，小鼠的移动距离无明显差异；2.急性吗啡诱发高活性实验中，伴随给予胍丁胺（1~80 mg/kg）或育亨宾（2 mg/kg）后，与吗啡组比较，小鼠的移动距离均无明显差异，而胍丁胺（80 mg/kg）与育亨宾（2 mg/kg）联合用药后小鼠的移动距离为（22581.6±11694.0）cm，显著低于吗啡组（37577.9±9657.4）cm （P＜0.05）；3.在吗啡诱导小鼠行为敏化模型中，伴随给予胍丁胺（1~80 mg/kg），其测试当天的移动距离与吗啡模型组比较均无明显差异；当胍丁胺（80 mg/kg）与育亨宾（2 mg/kg）联合用药后小鼠在敏化实验第1天、第4天和第7天的移动距离分别为（21112.7±5586.7）cm、（37672.7±10518.8）cm和（47681.0±15845.3）cm，均显著低于吗啡组（31156.4±8010.5）cm（P＜0.01）、（51724.9±11364.51）cm（P＜0.05）和（63572.2±12151.2）cm（P＜0.05），提示胍丁胺和育亨宾联合用药显著抑制吗啡诱导小鼠行为敏化的形成。结论在C57BL/6J小鼠中，胍丁胺与α2-肾上腺素受体拮抗剂育亨宾联合应用具有抗吗啡行为敏化的作用，为吗啡精神依赖的治疗提供可能的新策略。

Objective To investigate the effect of agmatine or agmatine combined with yohimbine on morphine-induced psychological dependence in mice. Methods 1. Testing the effect of agmatine or agmatin combined with yohimbine on basal locomotor activity in 60 minutes. C57BL/6J male mice were divided into four groups：control group, agmatine （1,10,20,40 and 80 mg/kg） groups, yohimbine（0.3,1,2 and 8 mg/kg） groups and yohimbine（2 mg/kg）＋ agmatine（80 mg/kg） group. 2. Testing the effects of drug pretreatment on morphine-induced hyperlocomotion in 60 minutes. Mice were divided into five groups： control group, morphine（10 mg/kg） group, agmatine（1,20 and 80 mg/kg）＋ morphine（10 mg/kg） group,yohimbine（2 mg/kg）＋ morphine（10 mg/kg） group and yohimbine（2 mg/kg）＋ agmatine（80 mg/kg）＋ morphine（10 mg/kg） group. 3. Observing the effects of agmatine or agmatine combined with yohimbine on morphine induced behavioral sensitization. The mice were administrated with morphine（10 mg/kg） on the 1st , 4th and 7th day and the locomotor activity of mice was recorded for 60 minutes. Mice were divided into four groups： control group, morphine（10 mg/kg） group, agmatine（1,20 and 80 mg/kg） ＋ morphine（10 mg/kg） groups and yohimbine （2 mg/kg）＋ agmatine（80 mg/kg）＋ morphine（10 mg/kg） group. Results Our present study showed that agmatine（1-80 mg/kg） or yohimbine （0.3-2 mg/kg）, a selective antagonist of α2-adrenoceptor, had no significant effect on basal locomotor and acute morphine-induced hyperlocomotion compared with those of control group. However, the distance in the group of agmatine combined with yohimbine followed by morphine for 60 min was（22 581.6±11 694.0） cm,which was significantly lower than the acute morphine group（37 577.9±9 657.4）cm（P〈0.05）. In the mophine-induced behavioral sensitization model, agmatine（1,20 and 80 mg/kg） alone had no effect on morphine-induced development of behavioral sensitization in mice. But, the combination of the two drugs significantly attenuated morphine-induced behavioral sensitization. The locomotor activities in the combination treatment groups were （21 112.7±5 586.7）cm,（37 672.7±10 518.8）cm and（47 681.0±15 845.3）cm, which were lower than those of morphine group （31 156.4±8 010.5） cm（P〈0.01）,（51 724.9±11 364.51）cm（P〈0.05） and（63 572.2±12 151.2） cm（P〈0.05） on the 1st , 4th and 7th day of experiment, respectively. Conclusion Our current results demonstrated that agmatine combined with yohimbine could decrease morphine-induced psychological dependence in mice. It may provide a new strategy for psychological dependence of morphine.