Department of Psychiatry, University of Oxford Oxford, UK ; Department of Pharmacology, University of Oxford Oxford, UK.
Department of Psychiatry, University of Oxford Oxford, UK.
Front Synaptic Neurosci. 2014 May 2;6:11. doi: 10.3389/fnsyn.2014.00011. eCollection 2014.
D-amino acid oxidase (DAO, DAAO) degrades the NMDA receptor co-agonist D-serine, modulating D-serine levels and thence NMDA receptor function. DAO inhibitors are under development as a therapy for schizophrenia, a disorder involving both NMDA receptor and dopaminergic dysfunction. However, a direct role for DAO in dopamine regulation has not been demonstrated. Here, we address this question in two ways. First, using in situ hybridization and immunohistochemistry, we show that DAO mRNA and immunoreactivity are present in the ventral tegmental area (VTA) of the rat, in tyrosine hydroxylase (TH)-positive and -negative neurons, and in glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes. Second, we show that injection into the VTA of sodium benzoate, a DAO inhibitor, increases frontal cortex extracellular dopamine, as measured by in vivo microdialysis and high performance liquid chromatography. Combining sodium benzoate and D-serine did not enhance this effect, and injection of D-serine alone affected dopamine metabolites but not dopamine. These data show that DAO is expressed in the VTA, and suggest that it impacts on the mesocortical dopamine system. The mechanism by which the observed effects occur, and the implications of these findings for schizophrenia therapy, require further study.
D-氨基酸氧化酶（DAO，DAAO）降解 NMDA 受体共激动剂 D-丝氨酸，调节 D-丝氨酸水平，从而调节 NMDA 受体功能。DAO 抑制剂作为精神分裂症的一种治疗方法正在开发中，精神分裂症是一种涉及 NMDA 受体和多巴胺能功能障碍的疾病。然而，DAO 在多巴胺调节中的直接作用尚未得到证实。在这里，我们通过两种方法来解决这个问题。首先，通过原位杂交和免疫组织化学，我们表明 DAO mRNA 和免疫反应性存在于大鼠腹侧被盖区（VTA）中，存在于酪氨酸羟化酶（TH）阳性和阴性神经元中，以及胶质纤维酸性蛋白（GFAP）免疫反应性星形胶质细胞中。其次，我们表明，将 DAO 抑制剂苯甲酸钠注射到 VTA 中会增加前额皮质细胞外多巴胺，这是通过体内微透析和高效液相色谱法测量的。将苯甲酸钠和 D-丝氨酸联合使用并没有增强这种效果，而单独注射 D-丝氨酸会影响多巴胺代谢物，但不会影响多巴胺。这些数据表明 DAO 在 VTA 中表达，并表明它影响中皮质多巴胺系统。观察到的效应发生的机制，以及这些发现对精神分裂症治疗的意义，需要进一步研究。
