Kabbaj M, Evans S, Watson S J, Akil H
Department of Biomedical Sciences, College of Medicine, Florida State University, 520 Building 127, Tallahassee, FL 32306-4300, USA.
Neuropharmacology. 2004;47 Suppl 1:111-22. doi: 10.1016/j.neuropharm.2004.07.021.
Basic neurobiological studies have led to great progress in our understanding of the mechanisms of action of drugs of abuse. Much has been learned about the brain response from the moment a psychoactive drug enters the organism onwards, including the psychological, neurobiological and peripheral effects of repeated drug administration, withdrawal and re-exposure. However, to relate this knowledge to the human experience requires further research on the antecedents of drug-taking behavior and the factors that predispose particular individuals to drug seeking and drug abuse. Thus, it is important to address several issues at the fundamental level: (1) Why are some individuals more vulnerable to drugs of abuse more than others? Is there a broader dimension or dimensions of emotional reactivity that contribute to this difference in vulnerability? (2) What is the effect of psychosocial stress on drug-seeking and drug-taking behavior, and are the effects distinct across individuals? (3) Since both drug-taking behavior and stress have sustained and pervasive effects on the brain, can we use microarrays to discern the "neural signature" or "neural phenotype" associated with these processes, and can we distinguish this signature across individuals with differing propensities to taking drugs? In the present paper, we summarize some of our early attempts at addressing these questions. We rely on animal studies aimed at characterizing the emotional and stress reactivity of rats with different propensities to self-administer drugs (high responders and low responders); we briefly describe the effect of a psychosocial stressor on these animals; we then detail a study using microarray technology aimed at investigating the "neural phenotype" associated with social defeat stress in the high vs. low responder animals. This "discovery" approach is used as a starting place for identifying novel mechanisms that might alter the vulnerability of different individuals to drug-seeking behavior. The power and limits of this approach, and its future directions, are discussed within this general framework.
基础神经生物学研究在我们对滥用药物作用机制的理解方面取得了巨大进展。从精神活性药物进入机体的那一刻起，人们对大脑反应已经有了很多了解，包括重复给药、戒断和再次接触药物的心理、神经生物学及外周效应。然而，要将这些知识与人类体验联系起来，还需要进一步研究吸毒行为的前因以及使特定个体易染上觅药和滥用药物行为的因素。因此，在基础层面解决几个问题很重要：（1）为什么有些人比其他人更容易染上滥用药物？是否存在更广泛的情绪反应维度导致这种易感性差异？（2）心理社会压力对觅药和吸毒行为有什么影响，这些影响在个体间是否不同？（3）由于吸毒行为和压力都会对大脑产生持续且广泛的影响，我们能否使用微阵列来辨别与这些过程相关的“神经特征”或“神经表型”，以及我们能否区分有不同吸毒倾向个体的这种特征？在本文中，我们总结了我们早期尝试解决这些问题的一些情况。我们依赖旨在表征具有不同自我给药倾向（高反应者和低反应者）的大鼠情绪和应激反应的动物研究；我们简要描述心理社会应激源对这些动物的影响；然后我们详细介绍一项使用微阵列技术的研究，该研究旨在调查高反应者和低反应者动物中与社会挫败应激相关的“神经表型”。这种“发现”方法被用作识别可能改变不同个体对觅药行为易感性的新机制的起点。在此总体框架内讨论了这种方法的优势和局限性及其未来方向。
