One of the most robust neurochemical abnormalities reported in patients living with schizophrenia is an increase in dopamine (DA) synthesis and release in the dorsal striatum (DS). Importantly, it appears that this increase progresses as a patient transitions from a prodromal stage to the clinical diagnosis of schizophrenia. Here we have recreated this pathophysiology in an animal model by increasing the capacity for DA synthesis preferentially within the DS. To achieve this we administer a genetic construct containing the rate-limiting enzymes in DA synthesis—tyrosine hydroxylase (TH), and GTP cyclohydrolase 1 (GCH1) (packaged within an adeno-associated virus)—into the substantia nigra pars compacta (SNpc) of adolescent animals. We refer to this model as “Enhanced Dopamine in Prodromal Schizophrenia” (EDiPS). We first confirmed that the TH enzyme is preferentially increased in the DS. As adults, EDiPS animals release significantly more DA in the DS following a low dose of amphetamine (AMPH), have increased AMPH-induced hyperlocomotion and show deficits in pre-pulse inhibition (PPI). The glutamatergic response to AMPH is also altered, again in the DS. EDiPS represents an ideal experimental platform to (a) understand how a preferential increase in DA synthesis capacity in the DS relates to “positive” symptoms in schizophrenia; (b) understand how manipulation of DS DA may influence other neurotransmitter systems shown to be altered in patients with schizophrenia; (c) allow researchers to follow an “at risk”-like disease course from adolescence to adulthood; and (d) ultimately allow trials of putative prophylactic agents to prevent disease onset in vulnerable populations.

精神分裂症患者中最强大的神经化学异常之一是多巴胺（DA）的合成和背侧纹状体（DS）的释放增加。重要的是，这种增加似乎随着患者从前驱阶段过渡到精神分裂症的临床诊断而进行。在这里，我们通过优先增加DS中DA合成的能力，在动物模型中重新创建了这种病理生理学。为实现此目的，我们将包含DA合成中的限速酶（酪氨酸羟化酶（TH）和GTP环水解酶1（GCH1）（包装在腺相关病毒中））的遗传构建体植入到黑质致密性黑斑病（SNpc）中。的青春期动物。我们将此模型称为“前驱性精神分裂症中的多巴胺增强”（EDiPS）。我们首先证实TH酶在DS中优先增加。成年后，EDiPS动物在低剂量的苯丙胺（AMPH）后在DS中释放的DA明显增加，AMPH诱导的运动过度增加，并且在脉冲前抑制（PPI）中显示不足。在DS中，对AMPH的谷氨酸能反应也被改变。EDiPS代表了以下理想的实验平台：（a）了解DS中DA合成能力的优先增加如何与精神分裂症的“阳性”症状相关；（b）了解DS DA的操作如何影响精神分裂症患者表现出改变的其他神经递质系统；（c）允许研究人员遵循从青春期到成年的“处于危险中”的疾病过程；