Dopamine/Adenpsine 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：
8501613
负责人：
Mariana Pereira Arboleya
金额：
$ 7.35万
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 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8501613
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.

描述（由申请人提供）：产后抑郁症是一种严重的疾病，如果未被及时识别和及时治疗，不仅对母亲产生有害影响，而且对母亲关系和最终是婴儿的发育结果构成了严重的风险。最近的证据表明，产后抑郁症的临床特征与产后时期以外发生的抑郁症不同，前者的特征主要是认知和动机障碍，包括注意力和认知灵活性的障碍，以及降低行为激活和与努力相关的功能。尽管临床文献始终将产后抑郁症与育儿妥协联系在一起，但迄今为止，尚无研究检查在产后抑郁症中育儿的神经生物学机制。大量的工作暗示了抑郁症的认知和动机症状的病理生理学中的中皮质脂蛋白多巴胺（DA）神经传递的作用。本提案中的研究将研究中皮质骨质DA功能的变化是否是产后抑郁症的认知和动机损害的基础，导致育儿缺陷。这些研究将使用抑郁症的Wistar-Kyoto（WKY）遗传大鼠模型。初步数据表明，WKY菌株以相当大的面部有效性概括了新妈妈的抑郁症的主要临床特征，包括认知，动机和育儿障碍。第一组实验将使用同时微透析采样的孕产妇行为分析来检查DA释放中DA释放的变化是否与认知和动机过程非常重要有关 WKY女性的母亲反应不足。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育儿障碍的特定贡献。这些研究将在对照菌株和行为任务中使用皮质和纹状体结构内的位点特异性DA受体阻滞，这些任务专门评估了认知和努力相关的症状领域，并结合对孕产妇行为的详细分析。第三组实验将评估腺苷A2A受体拮抗作用作为产后抑郁症的新型治疗策略。新兴的证据表明，神经调节剂腺苷，特别是通过对腺苷A2A受体的作用，调节与中性皮质胶质的DA系统相关的行为功能，包括认知和动机过程。我发表的工作通过证明腺苷A2A受体拮抗作用逆转了DA受体阻断对雄性大鼠和产后大鼠的母体行为的破坏性影响，支持A2A受体作为新的治疗靶标的潜力。