Cocaine-induced sensitization is associated with altered dynamics of transcriptional responses of the dopamine transporter, tyrosine hydroxylase, and dopamine D2 receptors in C57Bl/6J mice
Cocaine-induced sensitization is associated with altered dynamics of transcriptional responses of the dopamine transporter, tyrosine hydroxylase, and dopamine D2 receptors in C57Bl/6J mice
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DOI：
10.1007/s00213-007-0790-3
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发表时间：
2007-09-01
影响因子：
3.4
通讯作者：
Jaber, M.
中科院分区：
文献类型：
--
作者：
Belin, D.;Deroche-Gamonet, V.;Jaber, M.
行为敏感化是一种长期存在的现象，被认为与药物成瘾有关。尽管可卡因诱导的敏化的表达与中脑多巴胺能神经元的活性有关，目的研究可卡因刺激后多巴胺能神经元3个主要调控元件mRNA水平的时程变化，并探讨其在多巴胺能神经元中的作用机制（15 mg/kg，ip，每2天一次，共21天）。材料和方法将小鼠置于活动室中45 min，并在激发注射后45 min、2 h或24 h处死。结果与溶剂对照组相比，溶剂对照组小鼠多巴胺转运蛋白（DAT）mRNA表达迅速增加（+208%），随后延迟下降（-70%）（24 h），D2自身受体（D2）mRNA表达显著下降（-70%），D2受体mRNA表达显著下降（-70%），而D2受体mRNA表达显著下降（-70%）。而TH和D2 mRNA在攻击后24 h均增加（+45%）。在可卡因预处理的小鼠，可卡因诱导的DAT mRNA水平的短期增加和长期减少放大（+328%）和减少（-40%），respectively.Conclusions重复暴露于可卡因改变DA神经元的转录反应，一个新的可卡因的挑战后，长期停止重复暴露于药物。他们指出DAT mRNA是可卡因新呈现的主要反应元件。
Rationale Behavioural sensitization is a long lasting phenomenon that has been proposed to be involved in drug addiction. Although the expression of cocaine-induced sensitization has been associated with the activity of the mesencephalic dopaminergic neurons, little is known about the transcriptional adaptations of these neurons to a new challenge with cocaine long after cessation of repeated exposure to the drug.Objectives We studied the time course of the mRNA levels of three main regulatory elements of dopaminergic transmission after a challenge with cocaine (15 mg/kg) that followed 21 days of withdrawal from a cocaine pretreatment (20 mg/kg, ip, every 2 days for 21 days) in C57Bl/6J mice.Materials and methods Mice were placed 45 min in activity chambers and were killed 45 min, 2 h or 24 h after the challenge injection. Dopamine transporter (DAT), D2 auto-receptor (D2) and tyrosine hydroxylase (TH) mRNA levels were assessed by in situ hybridization in the ventral tegmental area and the substantia nigra compacta.Results As compared to vehicle challenge, cocaine challenge in vehicle pretreated mice induced a rapid increase (+208%) in DAT mRNA (45 min) followed by a delayed decrease (-70%) (24 h), while TH and D2 mRNA were both increased (+45%) 24 h after the challenge. In cocaine pretreated mice, cocaine-induced short-term increase and long-term decrease in DAT mRNA levels were amplified (+328%) and reduced (-40%), respectively.Conclusions Repeated exposure to cocaine alters the transcriptional response of DA neurons to a new cocaine challenge long after cessation of repeated exposure to the drug. They point to the DAT mRNA as a major responsive element to a new presentation of cocaine.