Estrogen effects on dopamine autoreceptor activity

雌激素对多巴胺自身受体活性的影响

基本信息

批准号：
6596363
负责人：
TINA L THOMPSON
金额：
$ 13.87万
依托单位：
MERCER UNIVERSITY MACON
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-12-07 至 2008-02-29
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Schizophrenia is a catastrophic neuropsychiatric disorder that routinely presents in late adolescence or early adulthood, a time when cortical development is nearing completion and circulating gonadal hormones are approaching their adult levels. Clinical observations have suggested that estrogen provides a neuroprotective influence on the expression of schizophrenic symptoms. Because the mesolimbic dopamine (DA) system has been implicated in the facilitation of behaviors associated with this disorder and mesolimbic DAergic hyperactivity is associated with the expression of symptoms, it has been suggested that estrogen may act on DAergic neurons to produce alterations in neuronal activity and ultimately changes in behavioral expression. We have shown that estrogen regulates DA availability within the nucleus accumbens through an alteration of DA D2 autoreceptor sensitivity and DA transporter (DAT) activity. The cellular mechanisms mediating these types of regulation are not known. We hypothesize that estrogen modulates D2 receptor sensitivity through an alteration of a pertussis (PTX) toxin sensitive G-protein and that this regulation is important in maintaining normal neuronal activity in pathological conditions associated with subcortical DAergic hyperactivity. Furthermore, we propose that the developmental and hormonal changes occurring during periadolescence may influence the subsequent alteration of DA D2 receptor sensitivity observed in the adult and may account for the increased susceptibility to early onset psychiatric disorders. Functional alteration of the D2 autoreceptor activation will be investigated in the nucleus accumbens of periadolescent and adult rats. Three questions will be addressed: 1] Are there age and/or sex dependent alterations in the functional sensitivity of the D2 receptor? 2] Does activation of the D2 receptor alter phosphorylation of the DAT, and if so is this alteration age or sex dependent? 3] Are female rats more susceptible to an impaired ability to clear DA from the extracellular space following a functional loss of D2 receptors? The answers to these questions will provide specific information on the functional association between the D2 receptor and the DAT. In addition, they will clarify how developmental and sex dependent changes in sensitivity of the D2 autoreceptor may alter the responsiveness of the mesolimbic DAergic system and ultimately the symptomology associated with schizophrenia.

描述（由申请人提供）：精神分裂症是一种灾难性的神经精神疾病，通常在青春期或成年早期出现，这是皮质发育接近完成且循环的性腺激素接近其成人水平的时期。临床观察结果表明，雌激素对精神分裂症症状的表达产生了神经保护作用。由于中左右多巴胺（DA）系统已与促进与这种疾病相关的行为的促进，并且中唇糖质的Daergic多动症与症状的表达有关，因此已经提出，雌激素可以作用于DAergic神经元来产生神经元活性的变化，并最终在行为表达中发生变化。我们已经表明，雌激素通过改变DA D2自身受体敏感性和DA转运蛋白（DAT）活性来调节伏隔核内的DA可用性。介导这些类型的调节的细胞机制尚不清楚。我们假设雌激素通过改变百日咳（PTX）毒素敏感的G蛋白来调节D2受体敏感性，并且该调节对于在与皮质下脂肪生效相关的病理条件下维持正常的神经元活性很重要。此外，我们提出，周期期间发生的发育和激素变化可能会影响成年人观察到的DA D2受体敏感性的随后改变，并可能导致对早期发作精神疾病的敏感性增加。 D2自身受体激活的功能改变将在周围和成年大鼠的伏隔核中进行研究。将解决三个问题：1] D2受体功能敏感性的年龄和/或性别依赖性改变？ 2] D2受体的激活会改变DAT的磷酸化，如果是这样，这种改变的年龄或性别依赖性？ 3]雌性大鼠在功能性D2受体丧失后更容易受到从细胞外空间清除DA的能力受损？这些问题的答案将提供有关D2受体与DAT之间功能关联的特定信息。此外，他们将阐明D2自感受器灵敏度的发育和性依赖性变化如何改变中唇脂蛋白DAERGIC系统的反应性以及最终与精神分裂症相关的症状。