Morrison Paul D, Murray R M
Institute of Psychiatry, King's College London, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.
Schizophr Bull. 2009 Jul;35(4):668-74. doi: 10.1093/schbul/sbp049. Epub 2009 Jun 1.
The earliest stages of delusion are characterized by an overabundance of meaningful coincidences impinging on the sufferer's existing worldview. Successive events are seen by him as pointing to, and then confirming, a fundamentally new reality that takes him over and engulfs his everyday life. Research over the last 4 decades has revealed the importance of dopamine (DA), D2 receptors, and the basal ganglia in psychotic thinking. Recent work has implicated the aberrant reward learning initiated by the excess release of striatal DA in the attribution of excessive importance or "salience" to insignificant stimuli and events. But our knowledge of what is happening beyond D2 receptors has remained scant. The gap is especially apparent at the cellular and microcircuit levels, encompassing the plastic changes, which are believed to be essential for new learning, and whose processes may go awry in major mental illness. Now new pharmacological findings are advancing our understanding of information processing and learning within the striatum. DA has an important role in setting the strength of individual striatal connections, but it does not act in isolation. Two other modulator systems are critical, the endocannabinoids and adenosine. Thus, at medium spiny neurons belonging to the indirect pathway, D2 stimulation evokes endocannabinoid-mediated depression of cortical inputs. Adenosine acting at A2A receptors elicits the opposite effect. Remarkably, drugs that target the endocannabinoid and purinergic systems also have pro- or antipsychotic properties. Here, we discuss how the 3 modulators regulate learning within the striatum and how their dysfunction may lead to delusional thinking.
妄想的最初阶段的特征是大量有意义的巧合冲击着患者现有的世界观。他将连续发生的事件视为指向并随后证实了一个全新的现实，这个现实掌控并吞噬了他的日常生活。过去40年的研究揭示了多巴胺（DA）、D2受体和基底神经节在精神病性思维中的重要性。最近的研究表明，纹状体DA过度释放引发的异常奖励学习，会导致对无关紧要的刺激和事件赋予过度的重要性或“显著性”。但我们对D2受体之外所发生情况的了解仍然很少。这一差距在细胞和微回路层面尤为明显，其中包括被认为对新学习至关重要的可塑性变化，而这些过程在重大精神疾病中可能会出现异常。现在，新的药理学发现正在推动我们对纹状体内信息处理和学习的理解。DA在设定单个纹状体连接的强度方面起着重要作用，但它并非单独起作用。另外两个调节系统也很关键，即内源性大麻素和腺苷。因此，在属于间接通路的中等棘状神经元中，D2刺激会引发内源性大麻素介导的皮质输入抑制。作用于A2A受体的腺苷则会产生相反的效果。值得注意的是，针对内源性大麻素和嘌呤能系统的药物也具有促精神病或抗精神病特性。在此，我们讨论这三种调节剂如何调节纹状体内的学习，以及它们的功能障碍如何导致妄想思维。
