Molecular mechanisms of drug addiction: adaptations in signal transduction pathways.
Molecular mechanisms of drug addiction: adaptations in signal transduction pathways.
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发表时间：
1996-07
影响因子：
11
通讯作者：
Eric J. Nestler;Melissa T. Berhow;E. Brodkin
中科院分区：
文献类型：
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作者：
Eric J. Nestler;Melissa T. Berhow;E. Brodkin
尽管神经科学在过去十年中取得了惊人的进步，但对精神障碍的病理生理学和发病机制的详细了解仍然严重有限。同样，长期接触精神药物导致其临床相关作用的机制尚不清楚。精神病学研究相对缺乏进展的部分原因是大脑的异常复杂，以及研究中枢神经系统病理学的固有困难。然而，缺乏进展的另一个原因是精神神经科学的范围有限，在很大程度上仍然专注于传统的神经递质及其受体，作为疾病状态下病理生理损害的部位，并作为这些疾病的药物治疗的最终靶点。尽管我们目前知道，这种神经递质和受体实际上只是大脑复杂的神经元间和神经元内调节机制的冰山一角，但这种有限的关注仍然存在。这篇综述的目的是说明我们对神经元调节机制的快速发展的知识如何作为模板，在其中描述更完整的精神药物作用的分子机制模型，以及遗传和环境因素在确定药物反应的个体差异中的作用。审查的重点是吸毒成瘾。反复接触滥用药物已被证明在特定大脑区域的受体后第二信使和蛋白质磷酸化途径中诱导长期适应。越来越多的证据表明，这些适应是上瘾状态的分子基础的一部分。其中一些相同信号蛋白的个体差异也可能导致对药物成瘾易感性的个体差异。最近的研究表明，药物诱导的适应发生在其他非第二信使相关的受体后信号通路中，特别是那些受神经营养因子影响的信号通路。总之，这些研究提供了对复杂机制的洞察，在理解大脑对慢性干扰的总体适应以及神经精神障碍的形成及其治疗时必须考虑这些机制。
Despite staggering advances in the neurosciences over the past decade, detailed knowledge of the pathophysiology and pathogenesis of psychiatric disorders remains severely limited. Similarly, the mechanisms by which long-term exposure to psychotropic drugs leads to their clinically relevant actions are not yet known. This relative lack of progress in psychiatric research is due in part to the extraordinary complexity of the brain and the difficulties inherent in studying central nervous system pathology. However, the lack of progress is also due to the limited scope of psychiatric neuroscience, which remains focused to a great extent on traditional neurotransmitters and their receptors as the site of pathophysiological lesions in a disease state and as the ultimate targets for pharmacological treatments of these disorders. This limited focus persists despite our current knowledge that such neurotransmitters and receptors are truly the tip of the iceberg of the brain's complex inter- and intraneuronal regulatory machinery. The goal of this review is to illustrate how our rapidly evolving knowledge of neuronal regulatory mechanisms can be used as a template within which to delineate more complete models of the molecular mechanisms of psychotropic drug action, as well as the role of genetic and environmental factors in determining individual differences in drug responsiveness. The focus of the review is on drug addiction. Repeated exposure to drugs of abuse has been shown to elicit long-term adaptations in post-receptor second messenger and protein phosphorylation pathways in specific brain regions. There is increasing evidence that these adaptations are part of the molecular basis of an addictive state. Individual differences in some of these same signaling proteins also may contribute to individual differences in vulnerability for drug addiction. More recent research has demonstrated that drug-induced adaptations occur in other, non-second messenger-related, post-receptor signaling pathways, specifically, those influenced by neurotrophic factors. Together, these studies provide insight into the complex mechanisms that must be considered in understanding the brain's adaptations to chronic perturbations in general as well as the formation of a neuropsychiatric disorder and its treatment.