Queensland Brain Institute, University of Queensland, Brisbane, QLD, 4072, Australia.
MRS London Institute of Medical Sciences, Hammersmith Hospital, London, UK.
Sci Rep. 2021 Feb 22;11(1):4294. doi: 10.1038/s41598-021-83681-4.
An increase in dopamine (DA) synthesis capacity in the dorsal striatum (DS) during the prodromal stage of schizophrenia becomes more pronounced as patients progress to the full disorder. Understanding this progression is critical to intervening in disease course. We developed an animal model-Enhanced Dopamine in Prodromal Schizophrenia (EDiPS)-which uses a genetic construct to increase DA synthesis capacity in the DS of male rats. We assessed pre-pulse inhibition (PPI) and amphetamine (AMPH)-induced locomotion (0.6 mg/kg) in EDiPS animals longitudinally after post-natal day 35 (when the EDiPS construct is administered). We also assessed their response to repeated acute restraint stress. In adult EDiPS animals, we measured baseline and evoked extracellular DA levels, and their stereotyped responses to 5 mg/kg AMPH. AMPH-induced hyperlocomotion was apparent in EDiPS animals 6-weeks after construct administration. There was an overall PPI deficit in EDiPS animals across all timepoints, however the stress response of EDiPS animals was unaltered. Adult EDiPS animals show normal baseline and potassium-evoked DA release in the DS. These findings suggest that key behavioural phenotypes in EDiPS animals show a progressive onset, similar to that demonstrated by patients as they transition to schizophrenia. The EDiPS model could therefore be used to investigate the molecular mechanisms underlying the prodrome of schizophrenia.
在精神分裂症前驱期，背侧纹状体（DS）中的多巴胺（DA）合成能力增加，随着患者进展为完全障碍，这种增加变得更加明显。了解这种进展对于干预疾病过程至关重要。我们开发了一种动物模型——前驱期精神分裂症中的增强多巴胺（EDiPS），该模型使用一种遗传构建体来增加雄性大鼠 DS 中的 DA 合成能力。我们在出生后第 35 天（给予 EDiPS 构建体后）对 EDiPS 动物进行纵向评估，以评估预脉冲抑制（PPI）和安非他命（AMPH）诱导的运动（0.6mg/kg）。我们还评估了它们对反复急性束缚应激的反应。在成年 EDiPS 动物中，我们测量了基线和诱发的细胞外 DA 水平，以及它们对 5mg/kg AMPH 的刻板反应。在构建体给药后 6 周，EDiPS 动物出现明显的 AMPH 诱导的过度运动。EDiPS 动物在所有时间点都存在总体 PPI 缺陷，但 EDiPS 动物的应激反应没有改变。成年 EDiPS 动物在 DS 中显示出正常的基线和钾诱发的 DA 释放。这些发现表明，EDiPS 动物的关键行为表型呈进行性发作，类似于患者向精神分裂症转变时的表现。因此，EDiPS 模型可用于研究精神分裂症前驱期的分子机制。
