Dopamine D2 receptor overexpression, adenosine A2A receptors, and motivation

多巴胺 D2 受体过度表达、腺苷 A2A 受体和动机

• 批准号: 8003856
• 负责人: Ryan David Ward
• 金额: $ 5.5万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8003856
• 关键词: Acute; Adenosine A2A Receptor; Adult; Behavioral Genetics; Brain; Chronic; Corpus striatum structure; Dopamine D2 Receptor; Down-Regulation; Impairment; Measures; Motivation; Mus; Neurons; Outcome; Output; Patients; Phenotype; Population; Research; Rewards; Role; Schizophrenia; Therapeutic; Transgenes; Work; feeding; motivated behavior; mouse model; nervous system disorder; neural circuit; overexpression; public health relevance; receptor

DESCRIPTION (provided by applicant): One important aspect of motivation that is compromised in psychiatric/neurological diseases is the ability to overcome effort related obstacles to obtain a valued outcome. Dopaminergic modulation of striatal outputs is crucial to this type of reward motivated behavior. Adenosine A2A receptors, which are coexpressed with dopamine D2 receptors on the same population of striatal neurons, modulate effort related choice by means of a reciprocal antagonistic relationship with D2 receptors. The research in this proposal will use a trangenic mouse model which selectively and reversibly overexpresses the D2 receptor in the striatum (D2OE) to assess the efficacy of targeting A2A receptors for treatment of the motivational deficits associated with schizophrenia. The D2OE mouse models some of the core motivational impairments displayed by patients with schizophrenia, including deficits in a concurrent lever pressing/free feeding task that measures aspects of motivation and effort related choice. In addition, preliminary assessment of brain changes that result from striatal D2 overexpression indicate that the adenosine A2A receptor is significantly downregulated in the D2OE mice. The proposed research will use a combination of behavioral, genetic, and pharmacological approaches to characterize the role of the adenosine A2A receptor in modulating effort related choice in D2OE mice. First, we will more fully characterize the effort related choice phenotype in D2OE mice and see if the deficit is modulated by the work requirement. We will verify downregulation of A2A expression, and determine whether A2A expression can be rescued by turning off the transgene in the adult mouse. We will assess whether the effort related choice phenotype can be rescued by acute and chronic antagonism of D2 receptors. We will also assess the efficacy of A2A agonism as a treatment for the effort related choice phenotype. Finally, we will assess changes in D2 receptors as a function of chronic A2A agonism. PUBLIC HEALTH RELEVANCE: Current treatments for schizophrenia are not successful in treating the motivational deficit. The present research will help to clarify the neural circuits underlying reward motivated behavior, and may suggest therapeutic strategies for treating the motivational deficits in schizophrenia and other psychiatric/neurological diseases.

描述（由申请人提供）：在精神/神经疾病中，动机的一个重要方面是克服与努力相关的障碍以获得有价值的结果的能力。纹状体输出的多巴胺能调节对这种类型的奖励动机行为至关重要。腺苷A2A受体与多巴胺D2受体在同一纹状体神经元上共表达，通过与D2受体的拮抗关系调节与努力相关的选择。本研究将使用一种转基因小鼠模型，该模型在纹状体中选择性和可逆地过表达D2受体（D2OE），以评估靶向A2A受体治疗精神分裂症相关动机缺陷的疗效。D2OE小鼠模拟了精神分裂症患者表现出的一些核心动机障碍，包括同时按压杠杆/自由喂食任务的缺陷，该任务测量动机和努力相关选择的各个方面。此外，对纹状体D2过表达导致的脑变化的初步评估表明，腺苷A2A受体在D2OE小鼠中显著下调。拟议的研究将使用行为学、遗传学和药理学方法的结合来表征腺苷A2A受体在调节D2OE小鼠的努力相关选择中的作用。首先，我们将更全面地表征D2OE小鼠的努力相关选择表型，并观察这种缺陷是否受到工作要求的调节。我们将验证A2A表达下调，并确定在成年小鼠中关闭转基因是否可以挽救A2A表达。我们将评估是否努力相关的选择表型可以抢救急性和慢性拮抗D2受体。我们还将评估A2A激动剂作为努力相关选择表型的治疗效果。最后，我们将评估D2受体的变化作为慢性A2A激动作用的功能。