REGULATION OF IMMEDIATE EARLY GENE-EXPRESSION AND AP-1 BINDING IN THE RAT NUCLEUS-ACCUMBENS BY CHRONIC COCAINE
REGULATION OF IMMEDIATE EARLY GENE-EXPRESSION AND AP-1 BINDING IN THE RAT NUCLEUS-ACCUMBENS BY CHRONIC COCAINE
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DOI：
10.1073/pnas.89.13.5764
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发表时间：
1992-07-01
影响因子：
11.1
通讯作者：
NESTLER, EJ
中科院分区：
文献类型：
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作者：
HOPE, B;KOSOFSKY, B;NESTLER, EJ
用可卡因长期治疗大鼠会导致脑桥核（NAc）的长期生化变化，这是一个涉及调节可卡因和其他滥用药物的强化作用的大脑区域。立即早期基因（IEGs）和它们的蛋白质产物似乎在将细胞外刺激转化为细胞基因表达的改变模式，从而转化为细胞功能的长期变化中起着重要作用。因此，我们研究了急性和慢性可卡因治疗大鼠NAc中IEGs c-fos、c-jun、fosB、junB和zif 268 mRNA水平的变化。单次可卡因注射增加了所有IEG的mRNA水平。然而，在慢性可卡因治疗后，IEG表达恢复到对照水平，并且在用可卡因进一步急性激发后没有显著增加，这表明可卡因诱导这些IEG的能力脱敏。同样，Fos样免疫反应性水平，这是增加在NAC的急性可卡因，降低到控制水平在慢性可卡因治疗的大鼠。Fos、Jun和许多相关蛋白质通过与称为AP-1位点的DNA反应元件结合来激活或抑制基因的转录。正如从RNA数据和免疫组织化学所预期的那样，急性可卡因给药增加了NAc中的AP-1结合活性，这种作用在8-12小时内完全恢复到对照水平。相反，用可卡因慢性治疗的动物的NAc中的AP-1结合活性在最后一次慢性注射后18小时仍以急性水平升高，c-fos和c-jun mRNA水平和Fos样免疫反应性恢复到对照值的时间。额外的急性可卡因攻击没有进一步增加AP-1结合。这些数据表明，慢性可卡因治疗导致AP-1结合活性的持续增加，这可能涉及可卡因成瘾的一些生理和行为方面。
Chronic treatment of rats with cocaine leads to long-term biochemical changes in the nucleus accumbens (NAc), a brain region implicated in mediating the reinforcing effects of cocaine and other drugs of abuse. Immediate early genes (IEGs) and their protein products appear to play an important role in transducing extracellular stimuli into altered patterns of cellular gene expression and, therefore, into long-term changes in cellular functioning. We therefore examined changes in the mRNA levels for the IEGs c-fos, c-jun, fosB, junB, and zif268 in the NAc of rats treated acutely and chronically with cocaine. A single cocaine injection increased the mRNA levels of all of the IEGs examined. Following chronic cocaine treatment, however, IEG expression had returned to control levels and was not significantly increased following a further acute challenge with cocaine, suggesting desensitization in the ability of cocaine to induce these IEGs. Similarly, levels of Fos-like immunoreactivity, which are increased in the NAc by acute cocaine, were reduced to control levels in chronic cocaine-treated rats. Fos, Jun, and a number of related proteins activate or repress transcription of genes by binding to DNA response elements called AP-1 sites. As would be expected from the RNA data and immunohistochemistry, acute cocaine administration increased AP-1 binding activity in the NAc, an effect that reverted completely to control levels within 8-12 hr. In contrast, AP-1 binding activity in the NAc of animals treated chronically with cocaine remained elevated at acute levels 18 hr after the last chronic injection, a time at which c-fos and c-jun mRNA levels and Fos-like immunoreactivity had returned to control values. An additional acute cocaine challenge did not further increase AP-1 binding. The data suggest that chronic cocaine treatment leads to a persistent increase in AP-1 binding activity, which may be involved in some of the physiological and behavioral aspects of cocaine addiction.