Adenosine and schizophrenia: mechanisms and therapies

描述（由申请人提供）：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，现有的治疗方法是不令人满意的，目前的发展仍然停滞不前，由于对疾病的生物学基础的了解不足。两种观点强调了大脑中两种神经化学信使-多巴胺和谷氨酸的干扰，与不同的SZ症状有关。这项建议将审查第三信使腺苷（ADO），作为一个潜在的联系团结多巴胺和谷氨酸假说的SZ。ADO可通过具有相反作用的受体（A1与A2 A腺苷受体）调节多巴胺和谷氨酸神经传递。因此，ADO作为这两种神经递质系统之间的上游协调者/调节者具有独特的地位。因此，基于ADO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，微妙的干扰腺苷能神经调节可以引起选定的行为内源性表型牵连SZ，因此，相应的纠正干预措施，针对ADO系统应赋予治疗潜力，对这种SZ内源性表型，从而验证我们的假设。我们的假设将通过三个具体目标来检验。首先，我们将表征所选SZ相关内表型的出现以及它们在转基因小鼠中的相反表型，所述转基因小鼠具有通过腺苷激酶的遗传操作实现的脑ADO的过度表达或表达不足。第二，我们的目标是确定腺苷为基础的调制多巴胺能和多巴胺能神经传递的分子机制。这将通过A1 R和A2 AR敲除小鼠的行为和生化检查来实现。第三，我们的目标是解剖的大脑区域，其中的ADO-多巴胺的相互作用和ADO-谷氨酸的相互作用有助于特定SZ相关的内表型的调节。为了实现这一点，ADO将通过移植分泌ADO的干细胞和通过作用于ADO受体的药物的局部输注来局部修饰。该项目的预期成果包括：（i）SZ的新神经化学理论的生物学验证，以及（ii）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。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。该提案将研究一种新的药物靶点精神分裂症治疗腺苷：鉴于腺苷的独特地位，相互作用与多巴胺和谷氨酸神经传递平行，腺苷调节药物被假设为赋予治疗潜力，对多种SZ症状。

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.