吗啡诱发的大鼠强迫性觅药动机及中脑神经元活动性改变

摘要

目的 考察不同剂量吗啡用药模式下大鼠的行为敏感化表达是否受到前期用药环境的调控,探索行为敏感化表达不受前期用药环境影响的动物模型及其中脑区域神经元的活动性改变.方法 按吗啡给药方式将大鼠分为3组:累加大剂量吗啡前处理组(HD组)、固定小剂量吗啡前处理组(LD组)和盐水前处理组(S组).戒断后,在"非用药环境"中考察大鼠经吗啡点燃后的水平运动和刻板运动.随后进行腹侧被盖区(VTA)和黑质(SN)的Fos蛋白和酪氨酸羟化酶(Tyrosine hydroxylase,TH)双重免疫组织化学染色.结果 10mg/kg吗啡点燃后,HD组水平运动和刻板运动均显著高于S组(水平运动和刻板运动,HD组:26907±2003和129.6±6.5;S组:14962±1888和89.9±10.9,均P＜0.01).与S组比较,HD组在SNr整体及SNr外侧部Fos蛋白阳性神经元均显著增高(SNr和SNr外侧部Fos阳性神经元,HD组:29.14±5.27和9.83±2.84;S组:17.29±1.51和2.06±0.45;均P＜0.05).结论 相对于固定小剂量吗啡用药,累加大剂量吗啡用药诱导的大鼠行为敏感化不受前期用药环境调控;SNr尤其是其外侧部的神经元活动性增加与累加大剂量吗啡用药大鼠的觅药动机表达有重要关系.%Objective To probe the different expression of psychomotor in different model of pretreatment and the influence of pretreatment context on the expression of psychomotor.And to compare dopaminergic and non-dopaminergic neuron activity in midbrain after different pretreatment.Methods Rats were pretreated by escalated high-dose morphine( HD group) ,fixed low-dose morphine( LD group) and saline as control(S group).After withdrawal, rats were challenged by morphine in non-drug used environment.Locomotor behavior and stereotypy behavior were monitored as the index of compulsive drug-seeking motivation.By double labeling immunohistochemistry of tyrosine hydroxylase (TH) and Fos protein, the plasticity of neuronal activity in ventral tegmental area and substantia nigra of rats response to morphine challenge were disclose after pretreated with morphine or saline.Results After 10 mg/kg morphine challenge in non-drug used environment,the locomotor behavior and the stereotypy behavior of HD group were both significant higher than that of S group ( Locomotor behavior and Stereotypy behavior,HD group: 26907 ± 2003 and 129.6 ± 6.5; S group: 14962 ± 1888 and 89.9 ± 10.9, all P ＜ 0.01 ).The results of immunohistochemistry showed that Fos protein expressed in the SNr and in lateral SNr was significantly higher in the HD group compared to S groups ( Fos expression in SNr and lateral SNr,HD group: 29.14 ±5.27 and 9.83 ± 2.84; S group: 17.29 ± 1.51 and 2.06 ±0.45; all P＜0.05 ).Conclusion The sensitization behavior expression of the rat pretreated by escalated high-dose morphine is not modulated by drug using enviroment compared with fixed low-dose morphine pretreatment.The neuroplasticity of SNr,especially lateral SNr might be one of the mechanisms underlying the uncontroled sensitization behavior expression.