Department of Psychiatry and Psychotherapy, Division of General Psychiatry, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
Transl Psychiatry. 2020 Jan 8;10(1):2. doi: 10.1038/s41398-019-0681-5.
Schizophrenia is characterized by increased behavioral and neurochemical responses to dopamine-releasing drugs. This prompted the hypothesis of psychosis as a state of "endogenous" sensitization of the dopamine system although the exact basis of dopaminergic disturbances and the possible role of prefrontal cortical regulation have remained uncertain. To show that patients with first-episode psychosis release more dopamine upon amphetamine-stimulation than healthy volunteers, and to reveal for the first time that prospective sensitization induced by repeated amphetamine exposure increases dopamine-release in stimulant-naïve healthy volunteers to levels observed in patients, we collected data on amphetamine-induced dopamine release using the dopamine D receptor agonist radioligand [C]-(+)-PHNO and positron emission tomography. Healthy volunteers (n = 28, 14 female) underwent a baseline and then a post-amphetamine scan before and after a mildly sensitizing regimen of repeated oral amphetamine. Unmedicated patients with first-episode psychosis (n = 21; 6 female) underwent a single pair of baseline and then post-amphetamine scans. Furthermore, T1 weighted magnetic resonance imaging of the prefrontal cortex was performed. Patients with first-episode psychosis showed larger release of dopamine compared to healthy volunteers. After sensitization of healthy volunteers their dopamine release was significantly amplified and no longer different from that seen in patients. Healthy volunteers showed a negative correlation between prefrontal cortical volume and dopamine release. There was no such relationship after sensitization or in patients. Our data in patients with untreated first-episode psychosis confirm the "endogenous sensitization" hypothesis and support the notion of impaired prefrontal control of the dopamine system in schizophrenia.
精神分裂症的特征是对释放多巴胺的药物的行为和神经化学反应增加。这促使人们假设精神病是多巴胺系统的“内源性”敏化状态，尽管多巴胺能紊乱的确切基础和前额皮质调节的可能作用仍不确定。为了证明首发精神病患者在安非他命刺激下释放的多巴胺比健康志愿者多，并首次揭示重复安非他命暴露引起的预期敏化会使兴奋剂-naïve 的健康志愿者释放更多的多巴胺达到患者观察到的水平，我们使用多巴胺 D 受体激动剂放射性配体 [C]-(+)-PHNO 和正电子发射断层扫描收集了安非他命诱导的多巴胺释放数据。健康志愿者（n=28，14 名女性）在基线时接受了扫描，然后在接受轻度敏化方案的重复口服安非他命之前和之后进行了扫描。未经药物治疗的首发精神病患者（n=21；6 名女性）进行了单次基线和随后的安非他命扫描。此外，还进行了前额叶皮质的 T1 加权磁共振成像。首发精神病患者的多巴胺释放明显大于健康志愿者。健康志愿者在敏化后，其多巴胺释放显著放大，与患者所见不再有差异。健康志愿者的前额叶皮质体积与多巴胺释放呈负相关。敏化后或患者中均无此关系。我们对未经治疗的首发精神病患者的数据证实了“内源性敏化”假说，并支持精神分裂症中前额皮质对多巴胺系统控制受损的观点。
