Adenosine and schizophrenia: mechanisms and therapies

描述(申请人提供)：腺苷和精神分裂症：机制和治疗项目摘要：精神分裂症(SZ)是一种令人衰弱的精神疾病，给社会带来巨大的人力、社会和经济代价。不幸的是，由于对这种疾病的生物学基础缺乏了解，现有的治疗方法并不令人满意，目前的发展仍然停滞不前。有两种观点强调了大脑中两种神经化学信使--多巴胺和谷氨酸--的紊乱，它们与不同的SZ症状有关。这项提议将研究第三种信使--腺苷(ADO)，作为联合SZ的多巴胺和谷氨酸假说的潜在纽带。腺苷可以通过具有相反作用的受体(A1和A2A腺苷受体)来调节多巴胺和谷氨酸的神经传递。因此，ADO作为这两个神经递质系统之间的上游协调器/调节器具有独特的地位。因此，基于ADO的治疗可能是一个有吸引力的替代方案，对谷氨酸和多巴胺系统具有双重纠正作用，从而实现对选定的SZ症状的有效控制。我们的中心假设是，腺苷能神经调节的微妙干扰可以引起与SZ有关的特定行为内表型；因此，针对ADO系统的相应纠正性干预应该会赋予针对这些SZ内表型的治疗潜力，从而验证我们的假设。我们的假设将通过三个具体目标进行检验。首先，我们将在通过腺苷激酶基因操作实现脑ADO过度或低表达的转基因小鼠中，表征选定的SZ相关内表型以及它们的相反表型的出现。第二，我们的目标是确定腺苷调节多巴胺能和谷氨酸能神经传递的分子机制。这将通过对A1R和A2AR基因敲除小鼠的行为和生化检查来实现。第三，我们的目标是剖析ADO-多巴胺相互作用和ADO-谷氨酸相互作用有助于调节特定SZ相关内表型的大脑区域。为了实现这一目标，ADO将通过移植分泌ADO的干细胞和作用于ADO受体的药物进行局部修饰。该项目的预期结果包括：(I)对SZ的一种新的神经化学理论进行生物学验证，以及(Ii)一种基于ADO的新策略的可行性测试，以产生具有治疗潜力的行为调整。

DESCRIPTION (provided by applicant): Adenosine and schizophrenia: mechanisms and therapies Project Summary: Schizophrenia (SZ) is a debilitating mental illness with tremendous human, social and financial costs to society. Unfortunately, existing treatments are unsatisfactory and current development remains stagnant due to poor understanding of the biological bases of the disease. Two perspectives have emphasized disturbances in two neurochemical messengers in the brain -dopamine and glutamate, in relation to disparate SZ- symptoms. This proposal will examine a third messenger -adenosine (ADO), as a potential link uniting the dopamine and glutamate hypotheses of SZ. ADO can regulate both dopamine and glutamate neurotransmission via receptors with opposing actions (A1 vs. A2A adenosine receptors). ADO is therefore uniquely positioned as an upstream coordinator/regulator between these two neurotransmitter systems. Hence, ADO-based treatment may be an attractive alternative with dual corrective actions on the glutamate and dopamine systems, thereby achieving effective control over selected SZ symptoms. Our central hypothesis is that subtle disturbances in adenosinergic neuromodulation can give rise to selected behavioral endophenotypes implicated in SZ; thus corresponding corrective interventions targeting at the ADO system should confer therapeutic potential against such SZ endophenotypes, and thereby validate our hypothesis. Our hypothesis will be tested by three specific aims. First, we will characterize the emergence of selected SZ-related endophenotypes as well as their opposing phenotypes in transgenic mice with either over- or under- expression of brain ADO achieved by genetic manipulation of adenosine kinase. Second, we aim to identify the molecular mechanisms of adenosine-based modulation of dopaminergic and glutamatergic neurotransmission. This will be achieved by behavioral and biochemical examination of A1R and A2AR knockout mice. Third, we aim to dissect the brain regions in which ADO-dopamine interactions and ADO-glutamate interactions contribute to the regulation of specific SZ-related endophenotypes. To achieve this, ADO will locally be modified by transplantation of ADO-secreting stem cells and by focal infusion of drugs acting on ADO-receptors. The expected outcomes of this project include: (i) the biological validation of a novel neurochemical theory of SZ, and (ii) the feasibility-test of a novel ADO-based strategy to produce behavioral adjustment with therapeutic potential.