摘要
Objective To investigate the effect of M5 muscarinic receptor subtype on the locomotor sensitization induced by heroin priming, and it＇s effect on the FosB expression in the nucleus accumbens （NAc） and the hippocampus in the heroin sensitized rats. Methods Locomotor activity was measured every 10 min for 1 h after subcutaneous injection of heroin. FosB expression was assayed by immunohistochemistry, and the antisense oligonucleotides （AS-ONs） targeting M5 muscarinic receptor was transferred with the lipofectin. Results Microinjection of AS-ONs targeting M5 muscarinic receptor in the ventral tegmental area （VTA） blocked the expression of behavioral sensitization induced by heroin priming in rats. Meanwhile, the expression of FosB-positive neurons in either the NAc or the dentate gyrus （DG） of the hippocam- pus increased in heroin-induced locomotor sensitized rats. The enhancement of FosB-positive neurons in the NAc or DG could be inhibited by microinjection of M5 muscarinic receptor AS-ONs into the VTA before the heroin-induced locomotor sensitization was performed. In contrast, microinjection of M5 muscarinic receptor sense oligonucleotide （S-ONs） into the VTA did not block the expression of behavioral sensitization or the expression of FosB in the NAc or DG in the heroin sensitized rats. Conclusion Blocking M5 muscarinic receptor in the VTA inhibits the expression of heroin-induced locomotor sensitization, which is associated with the regulation of FosB expression in the NAc and hippocampus neurons. M5 muscarinic receptor may be a useful pharmacological target for the treatment of heroin addiction.
目的探讨M5毒蕈碱受体亚型对海洛因诱导的大鼠行为敏化以及敏化后大脑伏隔核(NAc)和海马中FosB蛋白表达的影响。方法建立海洛因诱导的大鼠行为敏化模型,测定大鼠的自主活动量(locomotor activity,LA),观察M5毒蕈碱受体反义寡核苷酸(M5AS-ONs)对行为敏化表达的影响。用免疫组化法测定大鼠 NAc及海马齿状回(DG)FosB蛋白表达。结果海洛因处理组与盐水处理组相比,大鼠在1小时内的LA显著增加,表明这些大鼠已稳定建立了海洛因诱导的敏化。中脑腹侧被盖区(VTA)中注射M5AS-ONs能抑制大鼠海洛因行为敏化的表达。海洛因诱导的行为敏化大鼠中NAc及DG中的FosB免疫反应阳性神经元的表达增加,而在VTA内注射M5AS-ONs能明显抑制NAc及DG中FosB阳性神经元表达的增加;但VTA中注射有义寡核苷酸(M5S-ONs)不能明显抑制大鼠行为敏化的表达,也不能抑制海洛因敏化大鼠NAc和DG中FosB蛋白的表达。结论阻断VTA中M5毒蕈碱受体可抑制海洛因诱导的行为敏化的表达,其机制可能和抑制大脑NAc和DG神经元中FosB蛋白的激活有关。M5毒蕈碱受体可作为改变海洛因行为学效应的有效药理学靶点之一。
基金
This work was supported by the National Nature Science Foundation of China （No.30470554）
the National Basic Research Development Program of China（No.2003CB515404）.
