Increased Presynaptic Dopamine Synthesis Capacity Is Associated With Aberrant Dopamine Neuron Activity in the Methylazoxymethanol Acetate Rodent Model Used to Study Schizophrenia-Related Pathologies.
Increased Presynaptic Dopamine Synthesis Capacity Is Associated With Aberrant Dopamine Neuron Activity in the Methylazoxymethanol Acetate Rodent Model Used to Study Schizophrenia-Related Pathologies.
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DOI：
10.1093/schizbullopen/sgac067
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发表时间：
2022-01
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多巴胺系统功能异常被认为是导致精神分裂症阳性症状的原因之一。临床影像研究表明，患者中最大的多巴胺异常似乎是突触前多巴胺活性的增加。事实上，利用[18F]DOPA正发射断层扫描的研究可靠地报告了患者突触前多巴胺生物利用度的增加，并可能作为治疗反应的生物标志物。导致人类患者突触前活动增加的机制尚不完全清楚，这就需要使用临床前模型。利用活体电生理学可以直接检测实验动物的多巴胺系统功能。在用于研究分裂样神经病理学的啮齿动物模型的临床前研究中，一个一致的发现是腹侧被盖区(VTA)中自发活跃的多巴胺神经元的数量增加了2倍，称为群体活动。我们推测纹状体多巴胺合成能力的增强归因于VTA多巴胺神经元群体活动的增强。在这里，我们直接使用[~3H]DOPA体外放射自显影来验证这一假设，以量化纹状体多巴胺合成能力，在甲基氮氧基甲醇醋酸酯(MAM)模型中，这是一个经过验证的啮齿动物模型，显示出与精神分裂症样症状一致的神经生理和行为变化。与人类成像研究一致，MAM处理的大鼠背侧和腹侧纹状体亚区(包括尾壳核和伏隔核)的多巴胺合成能力显著增加，并与多巴胺神经元群体活动的特异性增加有关。综上所述，这些数据提供了啮齿动物模型的机制研究和人类受试者突触前多巴胺功能增加的临床研究之间的联系。
Aberrant dopamine system function is thought to contribute to the positive symptoms of schizophrenia. Clinical imaging studies have demonstrated that the largest dopamine abnormality in patients appears to be an increase in presynaptic dopamine activity. Indeed, studies utilizing [18F]DOPA positive emission tomography reliably report increases in presynaptic dopamine bioavailability in patients and may serve as a biomarker for treatment response. The mechanisms contributing to this increased presynaptic activity in human patients is not yet fully understood, which necessitates the use of preclinical models. Dopamine system function can be directly examined in experimental animals using in vivo electrophysiology. One consistent finding from preclinical studies in rodent models used to study schizophrenia-like neuropathology is a 2-fold increase in the number of spontaneously active dopamine neurons in the ventral tegmental area (VTA), termed population activity. We posit that increased striatal dopamine synthesis capacity is attributed to an augmented VTA dopamine neuron population activity. Here, we directly test this hypothesis using [3H]DOPA ex vivo autoradiography, to quantify striatal dopamine synthesis capacity, in the methylazoxymethanol acetate (MAM) model, a validated rodent model displaying neurophysiological and behavioral alterations consistent with schizophrenia-like symptomatologies. Consistent with human imaging studies, dopamine synthesis capacity was significantly increased in dorsal and ventral striatal subregionis, including the caudate putamen and nucleus accumbens, of MAM-treated rats and associated with specific increases in dopamine neuron population activity. Taken together, these data provide a link between mechanistic studies in rodent models and clinical studies of increased presynaptic dopamine function in human subjects.