Bronstein D M, Pennypacker K R, Lee H, Hong J S
Neuropharmacology Section, National Institute of Environmental Health Scienes, Research Triangle Park, N.C., USA.
Biol Signals. 1996 Nov-Dec;5(6):317-33. doi: 10.1159/000109205.
Activation of D1 dopamine (DA) receptors in the striatum increases the expression of the opioid neuropeptide, dynorphin (DYN). While cAMP is generally accepted as a second messenger in this signal transduction pathway, the role of Fos/FRA proteins and AP-1 binding in mediating D1 receptor-induced changes in DYN expression remains uncertain. In this study, DYN peptide and mRNA levels, as well as Fos/FRA proteins and AP-1 DNA binding activity, were measured in individual animals following acute challenge with the psychostimulant drug methamphetamine (METH). METH caused an initial decrease in striatal levels of DYN A, reflecting increased peptide release. Six hours postinjection, DYN mRNA levels were significantly elevated by METH as compared to vehicle-injected controls. At the same time, these drugs increased the expression of Fos/FRA-ir proteins, in particular the 35- and 40-kDa molecular weight species, and increased binding to the AP-1 DNA element. Analyses of the time course of METH's effects revealed that DYN mRNA levels, Fos/FRA proteins and AP-1 binding activity showed variable increases by 3 h but all were significantly elevated above control levels by 6 h posttreatment. The D1-specific antagonist, SCH 23390, completely blocked the METH-induced changes in DYN peptide and mRNA levels while a D2 receptor antagonist (sulpiride) had little or no effect. These data indicate that stimulant drugs such as METH increase the expression of DYN and AP-1 factors in the striatum via a D1 receptor-mediated mechanism. However, the finding that AP-1 binding merely paralleled, but did not precede, the increase in DYN expression, as would be expected if it were mediating increased gene transcription, suggests these may be correlative, not causally related events.
纹状体内多巴胺D1（DA）受体的激活会增加阿片类神经肽强啡肽（DYN）的表达。虽然cAMP通常被认为是该信号转导途径中的第二信使，但Fos/FRA蛋白和AP-1结合在介导D1受体诱导的DYN表达变化中的作用仍不确定。在本研究中，在使用精神兴奋药物甲基苯丙胺（METH）对个体动物进行急性刺激后，测量了DYN肽和mRNA水平，以及Fos/FRA蛋白和AP-1 DNA结合活性。METH导致纹状体内DYN A水平最初下降，这反映了肽释放增加。注射后6小时，与注射赋形剂的对照组相比，METH使DYN mRNA水平显著升高。同时，这些药物增加了Fos/FRA免疫反应性蛋白的表达，特别是分子量为35 kDa和40 kDa的蛋白，并增加了与AP-1 DNA元件的结合。对METH作用时间进程的分析表明，DYN mRNA水平、Fos/FRA蛋白和AP-1结合活性在3小时时呈现不同程度的增加，但在治疗后6小时均显著高于对照水平。D1特异性拮抗剂SCH 23390完全阻断了METH诱导的DYN肽和mRNA水平的变化，而D2受体拮抗剂（舒必利）几乎没有影响。这些数据表明，诸如METH之类的兴奋药物通过D1受体介导的机制增加纹状体内DYN和AP-1因子的表达。然而，AP-1结合仅仅与DYN表达的增加平行，但并未先于DYN表达的增加（如果它介导基因转录增加，情况应该是这样），这一发现表明这些可能是相关事件，而非因果相关事件。
