Morphine administration modulates expression of Argonaute 2 and dopamine-related transcription factors involved in midbrain dopaminergic neurons function
Morphine administration modulates expression of Argonaute 2 and dopamine-related transcription factors involved in midbrain dopaminergic neurons function
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DOI：
10.1111/bph.12083
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发表时间：
2013-04-01
影响因子：
7.3
通讯作者：
Milanes, M. V.
中科院分区：
文献类型：
--
作者：
Garcia-Perez, D.;Saez-Belmonte, F.;Milanes, M. V.
背景与目的调节多巴胺（DA）神经元发育和维持的转录因子（如Nurr 1和Pitx 3）的改变在成瘾性疾病的发病机制中起重要作用。本实验观察了急性和慢性吗啡及吗啡戒断对大鼠腹侧被盖区（VTA）和延髓核（NAc）TH表达和活性以及Nurr 1、Pitx 3和Ago 2表达的影响。实验方法大鼠急性注射吗啡，1或2 h后断头。另一组大鼠通过植入两个吗啡丸来依赖吗啡。注射纳洛酮诱导戒断反应。采用免疫印迹法、高效液相色谱法和免疫荧光法测定VTA和/或NAc中Ago 2、Pitx 3、Nurr 1、总TH（tTH）、Ser 31和Ser 40磷酸化TH、3，4-二羟基苯乙酸和DA含量。关键结果急性吗啡产生了显着增加TH活性和DA营业额的NAc，伴随着增加Nurr 1和Pitx 3的VTA的表达。与此相反，吗啡催促戒断减少TH激活，TH的表达，并没有增加DA营业额在NAc。这些作用包括降低Ago 2表达，同时增加Nurr 1和Pitx 3，TH活性和VTA中TH蛋白水平的正常化。结论和影响-Ago 2的减少和Nurr 1和Pitx 3的增加可能代表了一些机制，这些机制可以防止吗啡戒断大鼠中观察到的多巴胺TH调节，这可能是DA生物利用度影响行为的关键。
Background and Purpose Alterations in transcription factors that regulate the development and maintenance of dopamine (DA) neurons (such as Nurr1 and Pitx3) play an important role in the pathogenesis of addiction diseases. We have examined the effects of acute and chronic morphine and morphine withdrawal on TH expression and activity as well as expression of Nurr1, Pitx3 and Ago2 in the ventral tegmental area (VTA) and nucleus accumbens (NAc) of the rat. Experimental Approach Rats were injected acutely with morphine and decapitated 1 or 2h later. Another set of rats were made dependent on morphine by implantation of two morphine pellets. Precipitated withdrawal was induced by injection of naloxone. Ago2, Pitx3, Nurr1, total TH (tTH), TH phosphorylated at Ser31 and at Ser40, and 3,4-Dihydroxyphenylacetic acid, and DA determination in the VTA and/or NAc were measured using immunoblotting, HPLC and immunofluorescence. Key Results Acute morphine produced a marked increase in TH activity and DA turnover in the NAc, concomitantly with increased Nurr1 and Pitx3 expression in the VTA. In contrast, precipitated morphine withdrawal decreased TH activation, TH expression and did not increase DA turnover in the NAc. These effects paralleled decreases in Ago2 expression, which was accompanied by increased Nurr1 and Pitx3, TH activity and normalized TH protein levels in the VTA. Conclusions and Implications The combined decrease in Ago2 and increases in Nurr1 and Pitx3 might represent some of the mechanisms that served to protect against accumbal TH regulation observed in morphine withdrawn rats, which may be critical for DA bioavailability to influence behaviour.