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

描述（由申请人提供）：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，而且会对母婴关系和最终的婴儿发育结果造成严重风险。最近的证据表明，产后抑郁症的临床特征不同于产后以外发生的抑郁症，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减少。尽管临床文献一直将产后抑郁症与父母的不良教养联系起来，但迄今为止，还没有研究调查了产后抑郁症中父母教养被破坏的神经生物学机制。大量的研究表明，中皮质边缘多巴胺（DA）神经传递的改变在抑郁症的认知和动机症状的病理生理学中起着重要作用。本研究将探讨中皮质边缘DA功能的改变是否会导致产后抑郁症的认知和动机障碍，从而导致育儿方面的缺陷。这些研究将使用Wistar-Kyoto （WKY）抑郁症遗传大鼠模型。初步数据表明，WKY菌株以相当的面孔效度重现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。第一组实验将使用同时进行微透析取样的母体行为分析，以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释放的改变是否与该疾病有关

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.