Dopamine/Adenosine interaction in depression: Therapeutic role of A2A antagonism

多巴胺/腺苷在抑郁症中的相互作用：A2A 拮抗作用的治疗作用

基本信息

批准号：
8359164
负责人：
Mariana Pereira Arboleya
金额：
$ 7.75万
依托单位：
RUTGERS THE STATE UNIV OF NJ NEWARK
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8359164
关键词：
Adenosine Adenosine A2A Receptor Affect Area Attention Attenuated Behavioral Brain Clinical Cognitive Corpus striatum structure Data Development Dimensions Dopamine Dopamine Antagonists Dopamine Receptor Emotional Face Family Female Functional disorder Genetic Health Health Care Costs Impairment Infant Lead Literature Maternal Behavior Medial Mental Depression Microdialysis Modeling Mothers Neurobiology Neuromodulator Nucleus Accumbens Outcome Output Parenting behavior Personal Satisfaction Phase Postpartum Depression Postpartum Period Prefrontal Cortex Productivity Public Health Publishing Rattus Risk Role Sampling Site Structure Symptoms Testing Therapeutic Treatment Efficacy Woman Work base depressive symptoms dopamine system flexibility in vivo male motivational processes neurobiological mechanism neurochemistry neurotransmission new therapeutic target novel novel strategies novel therapeutics pre-clinical progenitor pup receptor research study response severe mental illness social treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Postpartum depression is a serious condition that, if not recognized and treated timely, not only has deleterious effects on the mother but also poses a serious risk for the mother-infant relationship and ultimately infant developmental outcome. Recent evidence shows that the clinical features of postpartum depression differ from depression that occurs outside the postpartum period, with the former being characterized primarily by cognitive and motivational disturbances, including impairments in attention and cognitive flexibility, as well as reduced behavioral activation and effort-related functions. Although the clinical literature consistently relates postpartum depression to compromised parenting, to date, no studies have examined the neurobiological mechanisms by which parenting is disrupted in postpartum depression. A substantial body of work implicates a role for altered mesocorticolimbic dopamine (DA) neurotransmission in the pathophysiology of cognitive and motivational symptoms of depression. The studies in the present proposal will examine whether alterations in mesocorticolimbic DA function underlie the cognitive and motivational impairments in postpartum depression that lead to deficits in parenting. These studies will use the Wistar-Kyoto (WKY) genetic rat model of depression. Preliminary data demonstrate that the WKY strain recapitulates, with considerable face validity, the major clinical features of depression in new mothers, including the cognitive, motivational and parenting disturbances. The first group of experiments will use maternal behavior analysis with simultaneous microdialysis sampling to examine whether alterations in DA release in discrete cortical and striatal structures critically involved in cognitive and motivational processes, are related to the deficient maternal response of WKY females. The second group of experiments will use a symptom-based approach to dissect the specific contribution of cognitive and motivational dysfunctions to parenting disturbances. These studies will use site- specific DA receptor blockade within cortical and striatal structures in control strains and behavioral tasks that specifically assess cognitive and effort-related symptom domains, in combination with detailed analysis of maternal behavior. The third group of experiments will evaluate the therapeutic efficacy of adenosine A2A receptor antagonism as a novel treatment strategy for postpartum depression. Emerging evidence indicates that the neuromodulator adenosine, particularly through actions on adenosine A2A receptors, modulates behavioral functions associated with the mesocorticolimbic DA system, including cognitive and motivational processes. My published work supports the potential of the A2A receptor as a novel therapeutic target by demonstrating that adenosine A2A receptor antagonism reversed the disruptive effects of DA receptor blockade on the effort-related instrumental output of male rats and on the maternal behavior of postpartum rats. PUBLIC HEALTH RELEVANCE: Postpartum depression is one of the most prevalent and severe mental illnesses affecting women, and is of serious public health concern because of its demonstrated adverse impact on the mother's health and parenting capacities, with effects on the infant's socio-emotional and cognitive developmental outcome. The potential impacts of postpartum depression affect not only the well-being of the mother, her infant, and her family, but also have consequences for social productivity and health care costs. The proposed studies represent the first preclinical attempt to examine the neurobiological underpinnings of the cognitive and motivational symptom dimensions that are central to postpartum depression and likely lead to deficits in parenting, as well as to test a novel treatment that is specifically tareted toward ameliorating them.

描述（申请人提供）：产后抑郁症是一种严重的疾病，如果不及时识别和治疗，不仅对母亲产生有害影响，而且还会对母婴关系以及最终婴儿的发育结果构成严重风险。最近的证据表明，产后抑郁症的临床特征与产后期间以外发生的抑郁症不同，前者主要表现为认知和动机障碍，包括注意力和认知灵活性受损，以及行为激活和努力相关的减少。功能。尽管临床文献一致将产后抑郁症与养育方式受损联系起来，但迄今为止，还没有研究探讨产后抑郁症中养育方式被破坏的神经生物学机制。大量研究表明中皮质边缘多巴胺（DA）神经传递的改变在抑郁症认知和动机症状的病理生理学中发挥着重要作用。本提案中的研究将探讨中皮质边缘 DA 功能的改变是否是产后抑郁症中认知和动机障碍的基础，从而导致养育缺陷。这些研究将使用 Wistar-Kyoto (WKY) 遗传性抑郁症大鼠模型。初步数据表明，WKY 菌株以相当大的表面效度概括了新妈妈抑郁症的主要临床特征，包括认知、动机和养育障碍。第一组实验将使用母体行为分析和同时微透析采样来检查与认知和动机过程密切相关的离散皮质和纹状体结构中 DA 释放的变化是否与 WKY 女性的母性反应不足。第二组实验将使用基于症状的方法来剖析认知和动机功能障碍对养育障碍的具体影响。这些研究将在皮质和纹状体结构中使用位点特异性 DA 受体阻断来控制应变和行为任务，专门评估认知和努力相关的症状领域，并结合对母亲行为的详细分析。第三组实验将评估腺苷A2A受体拮抗剂作为产后抑郁症新治疗策略的治疗效果。新的证据表明，神经调节剂腺苷，特别是通过对腺苷 A2A 受体的作用，调节与中皮质边缘 DA 系统相关的行为功能，包括认知和动机过程。我发表的论文通过证明腺苷 A2A 受体拮抗作用逆转了 DA 受体阻断对雄性大鼠与努力相关的工具输出和产后大鼠母性行为的破坏性影响，支持了 A2A 受体作为新型治疗靶点的潜力。公共健康相关性：产后抑郁症是影响妇女的最普遍和最严重的精神疾病之一，由于它对母亲的健康和养育能力产生不利影响，并影响婴儿的社会情感和认知能力，因此受到严重的公共健康关注。发展成果。产后抑郁症的潜在影响不仅影响母亲、婴儿和家庭的福祉，还会对社会生产力和医疗保健成本产生影响。拟议的研究代表了首次临床前尝试，以检查认知和动机症状维度的神经生物学基础，这些症状是产后抑郁症的核心，并可能导致育儿缺陷，并测试一种专门针对改善这些症状的新疗法。