Adenosine and schizophrenia: mechanisms and therapies

腺苷和精神分裂症：机制和治疗

• 批准号: 7789636
• 负责人: Detlev Boison
• 金额: $ 33.15万
• 依托单位: LEGACY EMANUEL HOSPITAL AND HEALTH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-20 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7789636
• 关键词: Address; Adenosine; Adenosine A2A Receptor; Adenosine Kinase; Adverse effects; Affect; Agonist; Animals; Behavioral; Behavioral Assay; Biochemical; Biological; Biological Assay; Brain; Brain region; Corpus striatum structure; Development; Disease; Dopamine; Drug Delivery Systems; Engineering; Evaluation; Financial cost; Functional disorder; Future; Genetic; Glutamates; Hippocampus (Brain); Human; Individual; Infusion procedures; Intervention; Knockout Mice; Lead; Link; Mediating; Mental disorders; Modification; Molecular; Mus; N-Methyl-D-Aspartate Receptors; Neurobehavioral Manifestations; Neuromodulator; Neurotransmitters; Outcome; Outcome Study; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Play; Population; Positioning Attribute; Prosencephalon; Public Health; Purinergic P1 Receptors; Regulation; Relative (related person); Research; Role; Schizophrenia; Signal Transduction; Societies; Stem cells; Symptoms; System; Testing; Therapeutic; Transgenic Mice; Transplantation; Validation; Wild Type Mouse; base; behavior test; clinical efficacy; comparative; dopamine system; endophenotype; genetic manipulation; improved; in vivo; kinase inhibitor; neurochemistry; neuroregulation; neurotransmission; novel; novel strategies; overexpression; psychopharmacologic; public health relevance; receptor; receptor function; relating to nervous system; research study; social; theories

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.

描述（由申请人提供）：腺苷和精神分裂症：机制和疗法项目摘要：精神分裂症（SZ）是一种使社会巨大的人，社会和经济成本的令人衰弱的精神疾病。不幸的是，由于对疾病的生物学基础的了解不足，现有治疗方法不令人满意，并且目前的发展仍然停滞。两种观点强调了大脑 - 多巴胺和谷氨酸的两个神经化学使者的干扰，与不同的SZ-症状有关。该提案将研究第三个信使 - 腺苷（ADO），作为将SZ的多巴胺和谷氨酸假设团结的潜在链接。 ADO可以通过具有相反作用的受体（A1与A2A腺苷受体）调节多巴胺和谷氨酸神经传递。因此，ADO被唯一地定位为这两个神经递质系统之间的上游协调器/调节器。因此，基于ADO的治疗可能是对谷氨酸和多巴胺系统的双重纠正措施的有吸引力的替代方法，从而实现了对选定的SZ症状的有效控制。我们的中心假设是，腺苷能神经调节中的细微障碍会导致与SZ有关的选定行为内表型。因此，针对ADO系统的相应纠正干预措施应赋予这种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特定目标检验。首先，我们将表征选定的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，其通过基因操纵腺苷激酶而实现的脑ADO的表达或不足。第二，我们旨在确定基于腺苷的多巴胺能和谷氨酸神经传递的调节的分子机制。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，我们的目的是剖析大脑区域，其中泛胺相互作用和亚谷氨酸相互作用有助于调节特定的SZ相关内表型。为了实现这一目标，ADO将通过移植Ado分泌干细胞以及通过对ADO受体作用的药物的局部输注来改变本地。该项目的预期结果包括：（i）新型SZ神经化学理论的生物学验证，以及（ii）一种基于ADO的新型策略的可行性测试，以产生具有治疗潜力的行为调整。公共卫生相关性：精神分裂症是个人和社会的毁灭性精神障碍，但目前的药物治疗的功效仍然很差，而且新型药物的发展仅限于阻断多巴胺或增强谷氨酸神经传递。该提案将检查精神分裂症 - 腺苷的新型药物靶标：鉴于腺苷与多巴胺和谷氨酸神经传递并行相互作用的独特位置，假设腺苷调节药物可赋予多种SZ症状的治疗潜力。