Kapur Shitij, Mizrahi Romina, Li Ming
Centre for Addiction and Mental Health, Toronto, Canada.
Schizophr Res. 2005 Nov 1;79(1):59-68. doi: 10.1016/j.schres.2005.01.003.
How does an excess in a neurochemical lead someone to being paranoid about the intentions of their neighbour? And why does blocking a dopamine receptor improve this symptom? In this article we present a heuristic framework which attempts to link the biology, phenomenology and pharmacology of psychosis. Focussing on dopamine's role in reward prediction and motivational salience we propose that psychosis arises from an aberrant assignment of novelty and salience to objects and associations. Antipsychotics block dopamine receptors and decrease dopamine transmission, which leads to the attenuation of aberrant novelty and salience. This 'salience' framework accounts for existing data and questions several current assumptions about the speed of onset phenomenological effects of antipsychotics and their behavioral effects in animal models. We review new data to show that in contrast to the prevailing idea of a "delayed onset" of antipsychotic action, the improvement is evident in the first few days. Antipsychotics do not eradicate symptoms, but create a state of "detachment" from them. And the actions of antipsychotics in the conditioned avoidance response model, one of the best established animal models for identifying antipsychotic action, are consistent with the idea that they dampen aberrant as well as normal motivational salience. The article discusses the caveats, limitations as well as the clinical implications of the salience framework.
神经化学物质过量是如何导致一个人对邻居的意图产生偏执的呢？为什么阻断多巴胺受体会改善这种症状呢？在本文中，我们提出了一个启发式框架，试图将精神病的生物学、现象学和药理学联系起来。聚焦于多巴胺在奖励预测和动机显著性方面的作用，我们认为精神病源于对物体和关联赋予了异常的新颖性和显著性。抗精神病药物阻断多巴胺受体并减少多巴胺传递，这导致异常的新颖性和显著性减弱。这个“显著性”框架解释了现有数据，并对当前关于抗精神病药物起效速度的现象学效应及其在动物模型中的行为效应的几个假设提出了质疑。我们回顾新的数据以表明，与抗精神病药物作用“延迟起效”的普遍观点相反，在最初几天改善就很明显。抗精神病药物并不能消除症状，而是创造了一种与症状“分离”的状态。并且在条件性回避反应模型（用于识别抗精神病药物作用的最成熟的动物模型之一）中，抗精神病药物的作用与它们抑制异常以及正常动机显著性的观点一致。本文讨论了显著性框架的注意事项、局限性以及临床意义。
