可乐定对吗啡依赖小鼠催促戒断后行为的影响

目的:研究吗啡依赖小鼠在纳洛酮催促戒断时可乐定治疗对稽延性戒断症状相关行为的影响。方獉法獉:采用剂量递增法使小鼠对吗啡产生依赖;每天sc盐酸吗啡3次,共3d,剂量由50mg·kg-1逐步上升到125mg·kg-1。d4sc注射50mg·kg-1吗啡1h后,可乐定治疗组小鼠ig0.6mg·kg-1可乐定,对照组ig等体积的去离子水;sc吗啡2h后各组小鼠均ip5mg·kg-1的纳洛酮进行催促戒断,观察30min内小鼠的跳跃反应和体重变化。在催促戒断后5h和24-30h通过洞板试验、悬尾试验、十字迷宫试验和自发活动试验,观察小鼠的探究行为、抑郁样行为、焦虑行为及活动性。部分小鼠在第一次戒断后10h及次日重新给予吗啡(100-125mg·kg-1)使之再次产生依赖,在d6依d4操作进行二次戒断,但不给予可乐定治疗。结果:在催促戒断试验中,可乐定可以显著降低吗啡依赖小鼠的跳跃次数和体重减轻(P<0.01);催促戒断5h后,可乐定组小鼠在洞板试验中的探洞次数比对照组少(P<0.01);在悬尾试验中的不动时间比对照组长(P<0.01);在十字迷宫试验中进入开臂的时间和次数与对照组比较差异无显著性;在自发活动试验中,前5min自发活动计数低于对照组(P<0.01),但30min内活动量与对照组比较差异无显著性;催促戒断24-30h后,两组之间的各项行为学指标差异均无显著性;在二次戒断实验中,可乐定组小鼠跳跃次数高于对照组(P<0.05),但两组小鼠体重变化差异无显著性。结论:用于拮抗吗啡依赖小鼠急性戒断症状的可乐定对戒断后的抑郁样行为有加重趋势,对焦虑行为没有影响;可乐定上述作用的行为药理学机制可能是抑制逃脱动机。

BEHAVIORAL EFFECTS OF CLONIDINE ON MORPHINE-DEPENDENT MICE AFTER NALOXONE-PRECIPITATED WITHDRAWAL

Objective:To study the behavioral effects of clonidine after naloxone-precipitated withdrawal in morphine-dependent mice.Methods:Morphine dependence of mice was established by dose-increasing(50 to 125 mg·kg-1,sc) administration of morphine three times per day for 3 days.On the fourth day,all mice were sc injected with 50 mg·kg-1 morphine.One hour later,one group of mice were ig administered with 0.6 mg·kg-1 clonidine,another group of mice were ig administered with vehicle of same volume.Two hours later after morphine administration,all mice were ip injected with 5 mg·kg-1naloxone to induce withdrawal.Jumping and body weight loss of mice in the following 30 min were measured.Hole-board test,tail suspension test,elevated plus maze test,and locomotion test were performed to assay novelty exploration,depression-like,anxiety-like behaviors and general activity after 5 h and 24-30 h of naloxone injection.Parts of mice in the two groups received more morphine injections(100-125 mg·kg-1) to keep morphine dependence after 10 h and on the next day.On Day 6,steps on Day 4 were repeated to induce withdrawal without administration of clonidine.Results:Clonidine significantly reduced jumping and body weight loss in the naloxone-precipitated withdrawal of mice(P <0.01) ;5 h after withdrawal,clonidine-treated mice had lower head-dipping counts(P < 0.01) in the hole-board test,longer immobility time in tail suspension test(P <0.01),and similar stay time and entrance of open arm in plus maze test,lower locomotion during first 5-min(P <0.01) and no significant difference in 30 min in the locomotion test,as compared with mice in the control group;24 30 h after withdrawal,no significant difference was found between clonidine treated and non-treated mice.In the repeated withdrawal experiment,clonidine-treated mice had higher jumping counts than rats in the control group(P <0.05) ;while clonidine-treated mice expressed similar body weight loss as compared with mice in control groups.Conclusion:Clonidine used for reduction of naloxone precipitated withdrawal in mice augments the depression-like behavior,has no effects on anxiety-like behaviors.Inhibition of escape motivation is proposed as a behavioral mechanism underlying the effects of clonidine.