Nye H E, Nestler E J
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA.
Mol Pharmacol. 1996 Apr;49(4):636-45.
Previous studies have shown that repeated exposure to cocaine or to several other stimuli induces novel 35-37 kDa Fos-related antigens (chronic Fras) in specific brain regions. Induction of these proteins is associated with prolonged increases in AP-1 DNA binding activity that parallel the long half-life of the chronic Fras in brain. In the current study, we characterized regulation of the chronic Fras in response to prolonged exposure to morphine. After 5 days of morphine treatment, we observed increased levels of the chronic Fras and of AP-1 binding activity in rat striatum and nucleus accumbens, effects that were not seen in most other brain regions that we studied. Concomitant administration of naltrexone, an opioid receptor antagonist, prevented the induction of these proteins. Two-dimensional gel analysis showed that the chronic Fras induced by chronic morphine administration are identical to those induced after chronic cocaine and other treatments. A time course study indicated that chronic Fra induction was first apparent after 3 days of morphine treatment and peaked between 5 and 7 days of treatment in both the striatum and nucleus accumbens. Withdrawal studies demonstrated robust induction of several known acute Fras, including c-Fos, FosB, Fra-1, Fra-2, and delta FosB, at 6 hr after naltrexone precipitation of withdrawal in the striatum, nucleus accumbens, and several other brain regions. Levels of these proteins returned to basal values by 72 hr. In contrast, no further induction of the chronic Fras was evident after 6 hr of withdrawal in the striatum and nucleus accumbens, but levels of the proteins increased beyond their already elevated chronic morphine values after longer periods (72 hr) of withdrawal, even though physical withdrawal symptoms had resolved at this time point. Chronic Fras were also induced after these prolonged withdrawal periods in several other brain regions, where the proteins were not induced by chronic morphine alone. We discuss the possible roles played by the chronic Fras in the adaptive responses of the brain to chronic opiate exposure and opiate withdrawal.
先前的研究表明，反复接触可卡因或其他几种刺激物会在特定脑区诱导产生新的35 - 37 kDa Fos相关抗原（慢性Fras）。这些蛋白质的诱导与AP - 1 DNA结合活性的长期增加相关，这与慢性Fras在脑中的长半衰期平行。在本研究中，我们对长期接触吗啡后慢性Fras的调节进行了表征。吗啡治疗5天后，我们观察到大鼠纹状体和伏隔核中慢性Fras水平和AP - 1结合活性增加，而在我们研究的大多数其他脑区未观察到这种效应。同时给予阿片受体拮抗剂纳曲酮可阻止这些蛋白质的诱导。二维凝胶分析表明，慢性吗啡给药诱导的慢性Fras与慢性可卡因及其他处理后诱导的相同。时间进程研究表明，慢性Fras的诱导在吗啡治疗3天后首次明显，在纹状体和伏隔核中于治疗5至7天达到峰值。撤药研究表明，在纹状体、伏隔核和其他几个脑区，纳曲酮诱发撤药6小时后，几种已知的急性Fras，包括c - Fos、FosB、Fra - ⅰ、Fra - 2和δFosB，有强烈诱导。这些蛋白质的水平在72小时后恢复到基础值。相比之下，在纹状体和伏隔核撤药6小时后，慢性Fras没有进一步诱导，但在撤药较长时间（72小时）后，蛋白质水平超过了其已升高的慢性吗啡值，尽管此时身体撤药症状已消退。在其他几个脑区，经过这些长时间撤药后也诱导出了慢性Fras，而这些脑区单独使用慢性吗啡时不会诱导这些蛋白质。我们讨论了慢性Fras在大脑对慢性阿片暴露和阿片撤药的适应性反应中可能发挥的作用。
