Hope Bruce T
Molecular Plasticity Section (MPS), National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Building 36, Room 4C23, 36 Convent Drive, MSC-4135, Bethesda, Maryland 20892-4135, USA.
Ann N Y Acad Sci. 1998 May;844(1):1-6. doi: 10.1111/j.1749-6632.1998.tb08216.x.
Cocaine addiction in humans develops gradually with repeated administrations and persists long after cocaine has cleared the body. The mechanisms underlying this persistent form of neuroplasticity are not understood and can involve both structural and biochemical mechanisms. The long time course for cocaine addiction in humans and for development of cocaine self-administration in animal models suggests the involvement of alterations in gene expression leading to altered signaling in the brain. In the striatum (Str) and nucleus accumbens (NAc) of rats, pretreatment with repeated cocaine administrations downregulates the induction of various immediate early genes (IEGs) by a subsequent acute challenge with cocaine. Some of these downregulated IEGs encode Fos-related components of the activator protein-1 (AP-1) complex, which is likely to regulate a number of genes important for neuronal function. Interestingly, repeated cocaine administration induces novel delta FosB-related proteins (called chronic Fos-related antigens (Fras)) in the NAc and Str that replace the downregulated isoforms of Fos. Unlike the acutely induced, short-lasting isoforms of Fos and FosB, the chronic Fras persist long after the last cocaine administration. The known form of delta FosB per se lacks the domain required to activate transcription. If the chronic Fras are similar in structure to delta FosB, then the induction of chronic Fras likely leads to a blockade of AP-1-dependent transcription resulting in altered gene expression. We are presently purifying the chronic Fras to obtain amino acid sequence in order to directly examine our hypothesis about the effects of repeated cocaine administration on AP-1-dependent transcription and gene expression in the brain.
人类对可卡因的成瘾是在反复用药过程中逐渐形成的，并且在可卡因从体内清除后仍会长期存在。这种持续性神经可塑性的潜在机制尚不清楚，可能涉及结构和生化机制。人类可卡因成瘾的漫长过程以及动物模型中可卡因自我给药行为的发展表明，基因表达的改变导致大脑信号传导改变，从而参与其中。在大鼠的纹状体（Str）和伏隔核（NAc）中，预先反复给予可卡因会下调随后可卡因急性刺激所诱导的各种即刻早期基因（IEGs）。其中一些下调的IEGs编码激活蛋白-1（AP-1）复合物中与Fos相关的成分，而该复合物可能调控许多对神经元功能重要的基因。有趣的是，反复给予可卡因会在NAc和Str中诱导出新型的δFosB相关蛋白（称为慢性Fos相关抗原（Fras）），这些蛋白会取代下调的Fos异构体。与急性诱导的、短暂存在的Fos和FosB异构体不同，慢性Fras在最后一次给予可卡因后仍会长期存在。已知形式的δFosB本身缺乏激活转录所需的结构域。如果慢性Fras在结构上与δFosB相似，那么慢性Fras的诱导可能导致AP-1依赖性转录受阻，从而导致基因表达改变。我们目前正在纯化慢性Fras以获得氨基酸序列，以便直接检验我们关于反复给予可卡因对大脑中AP-1依赖性转录和基因表达影响的假设。
