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

描述(申请人提供)：产后抑郁症是一种严重的疾病，如果不及时发现和治疗，不仅会对母亲产生有害影响，还会对母婴关系和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不同于产后抑郁症，前者的主要特征是认知和动机障碍，包括注意力和认知灵活性的损害，以及行为激活和努力相关功能的降低。尽管临床文献一直将产后抑郁症与父母教养方式的妥协联系在一起，但迄今为止，还没有研究检验产后抑郁症中父母教养方式中断的神经生物学机制。大量工作表明，在抑郁症的认知和动机症状的病理生理学中，改变的皮质边缘多巴胺(DA)神经传递具有一定的作用。本提案中的研究将检验中皮质边缘DA功能的改变是否是导致产后抑郁的认知和动机障碍的基础，这些障碍导致父母养育不足。这些研究将使用Wistar-京都(WKY)抑郁症的遗传大鼠模型。初步数据表明，WKY菌株以相当高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、动机和育儿障碍。第一组实验将使用母亲行为分析和同步微透析采样来检查在认知和动机过程中至关重要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育儿障碍的具体贡献。这些研究将在对照品系和行为任务中使用皮质和纹状体结构中特定部位的DA受体阻断，这些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受体拮抗剂作为一种新的产后抑郁症治疗策略的治疗效果。新的证据表明，神经调节剂腺苷，特别是通过作用于腺苷A2a受体，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。我发表的工作支持A2A受体作为新的治疗靶点的潜力，证明了腺苷A2A受体拮抗逆转了DA受体阻断对雄性大鼠努力相关的工具输出和产后大鼠母体行为的干扰效应。 公共卫生相关性：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，由于其对母亲的健康和育儿能力产生不利影响，并对婴儿的社会情感和认知发展结果产生影响，因此引起严重的公共卫生关切。产后抑郁的潜在影响不仅影响母亲、婴儿和家庭的福祉，而且还会对社会生产力和医疗保健费用产生影响。这项拟议的研究是临床前的第一次尝试，目的是检查认知和动机症状维度的神经生物学基础，这些症状维度是产后抑郁的核心，可能导致父母养育不足，并测试一种专门针对改善产后抑郁和动机症状的新疗法。

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.