褪黑素抗大鼠吗啡奖赏效应的表达与脑内CREB及其磷酸化

目的:观察褪黑素(melatonin,Mel)对大鼠吗啡诱导的条件性位置偏爱(CPP)效应表达的影响及此过程中脑内cAMP反应元件结合蛋白(CREB)及其磷酸化的变化。方法:(1)大鼠连续6 d给予吗啡(sc,5 mg.kg-1/d)建立CPP模型,于CPP测试前20 min ip Mel(50和25 mg.kg-1),观察Mel对大鼠吗啡诱导的CPP效应表达的影响。(2)大鼠同上建立吗啡CPP模型,d7上、下午,d8上午ip Mel 50 mg.kg-1,共3次,最后一次ip后6 h,采用免疫组化结合计算机图像处理技术测定脑内伏隔核、海马内CREB及磷酸化CREB(p-CREB)的免疫阳性反应强度。结果:Mel 50 mg.kg-1可显著翻转大鼠吗啡诱导的CPP评分升高(P<0.01),同时显著降低吗啡诱导的大鼠伏隔核、海马内p-CREB的上调(P<0.01)。结论:Mel抑制大鼠吗啡奖赏效应的表达,此作用可能与其抑制吗啡诱导的伏隔核、海马内p-CREB蛋白水平上调有关。

MELATONIN REVERSES THE EXPRESSION OF MORPHINE-INDUCED REWARDING EFFECT AND INVOLVEMENT OF CREB AND PHOSPHORYLATION IN BRAIN

Objective:To observe the effect of melatonin(Mel) on the expression of morphine-induced conditioned place preference(CPP) in rats and changes of cAMP response element binding protein(CREB) and CREB in the brain during this process.Methods:(1) The CPP was established by morphine(sc,5 mg·kg-1,once daily for 6 consecutive days) in rats.Mel(50 and 25 mg·kg-1) was administrated 20 min before the CPP testing to observe the effect of melatonin on the expression of morphine-induced CPP.(2) The CPP in rats was established as described above.From d7,Mel(50 mg·kg1,ip) was administrated twice daily(in the morning and the afternoon),and on d8 morning,ip Mel,totally 3 times.6 h after the last administration,the immunoreactivities of CREB and p-CREB in the nucleus accumbens(NAc) and the hippocampus(Hip) were detected by immunohistochemistry analysis.Results:Melatonin 50 mg·kg-1 significantly reversed morphine-induced increase in CPP scores in rats(P<0.01);and decreased the upregulation of p-CREB protein level in the NAc and the Hip induced by morphine during this process(P<0.01).Conclusion:Melatonin may reverse the expression of morphine-induced rewarding effect,and this action may be relevant to its ability to decrease the upregulation of p-CREB protein level in the NAc and the Hip induced by morphine.