Adenosine and schizophrenia: mechanisms and therapies

项目简介：精神分裂症是一种使人衰弱的精神疾病，给社会带来巨大的人力、社会和经济成本。不幸的是，现有的治疗方法并不令人满意，而且由于对该病的生物学基础了解不足，目前的发展仍然停滞不前。两种观点强调大脑中两种神经化学信使多巴胺和谷氨酸的紊乱与不同的SZ症状有关。本研究将研究第三个信使-腺苷（ADO），作为连接SZ的多巴胺和谷氨酸假说的潜在联系。ADO可以通过具有相反作用的受体（A1和A2A腺苷受体）调节多巴胺和谷氨酸神经传递。因此，ADO是这两种神经递质系统之间的上游协调者/调节器。因此，以ado为基础的治疗可能是一种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，从而有效控制选定的SZ症状。我们的中心假设是腺苷能神经调节的细微干扰可以引起与SZ有关的选择性行为内表型；因此，针对ADO系统的相应矫正干预应具有针对此类SZ内表型的治疗潜力，从而验证了我们的假设。我们的假设将通过三个具体目标来检验。首先，我们将描述通过对腺苷激酶进行基因操作实现脑ADO过表达或过低表达的转基因小鼠中出现的选择性sz相关内表型及其相反表型。其次，我们的目标是确定腺苷为基础的多巴胺能和谷氨酸能神经传递调节的分子机制。这将通过对A1R和A2AR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 -谷氨酸相互作用对特定sz相关的内表型调节的大脑区域。为了实现这一目标，将通过移植分泌ADO的干细胞和局部输注作用于ADO受体的药物来局部修饰ADO。本项目的预期成果包括：(i)新的SZ神经化学理论的生物学验证，以及（ii）新的基于ado的策略的可行性测试，以产生具有治疗潜力的行为调整。公共卫生相关性：精神分裂症对个人和社会都是一种毁灭性的精神障碍，但目前的药物治疗效果仍然很差，新药的开发仅限于阻断多巴胺或增强谷氨酸神经传递。本研究将研究一种新的精神分裂症治疗药物靶点-腺苷：鉴于腺苷与多巴胺和谷氨酸神经传递平行相互作用的独特地位，腺苷调节药物被假设具有治疗多种SZ症状的潜力。

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. PUBLIC HEALTH RELEVANCE: Schizophrenia is a devastating mental disorder to the individual and society alike, yet the efficacy of current drug treatment remains poor, and the development of novel drugs is limited to either blocking dopamine or enhancing glutamate neurotransmission. This proposal will examine a novel drug target for schizophrenia-therapy -adenosine: Given adenosine's unique position to interact in parallel with dopamine and glutamate neurotransmission, adenosine-modulating drugs are hypothesized to confer therapeutic potential against multiple SZ symptoms.