Perez Stephanie M, Elam Hannah B, Lodge Daniel J
Department of Pharmacology and Center for Biomedical Neuroscience, UT Health San Antonio, San Antonio, TX, USA.
South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, TX, USA.
Schizophr Bull Open. 2022 Oct 21;3(1):sgac067. doi: 10.1093/schizbullopen/sgac067. eCollection 2022 Jan.
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 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 [H]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.
异常的多巴胺系统功能被认为与精神分裂症的阳性症状有关。临床影像学研究表明，患者中最大的多巴胺异常似乎是突触前多巴胺活性增加。事实上，利用正电子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，并且这可能作为治疗反应的生物标志物。导致人类患者这种突触前活性增加的机制尚未完全了解，这就需要使用临床前模型。多巴胺系统功能可以在实验动物中通过体内电生理学直接进行检测。在用于研究精神分裂症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）中自发活动的多巴胺神经元数量增加了两倍，这被称为群体活动。我们假设纹状体多巴胺合成能力的增加归因于VTA多巴胺神经元群体活动的增强。在这里，我们使用[H]多巴离体放射自显影术直接检验这一假设，以量化纹状体多巴胺合成能力，该实验在醋酸甲基氧化偶氮甲醇（MAM）模型中进行，这是一个经过验证的啮齿动物模型，其显示出与精神分裂症样症状一致的神经生理学和行为改变。与人类影像学研究一致，MAM处理的大鼠的背侧和腹侧纹状体亚区域，包括尾壳核和伏隔核，多巴胺合成能力显著增加，并且与多巴胺神经元群体活动的特定增加相关。综上所述，这些数据在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建立了联系。
