ESTROGEN EFFECTS ON DOPAMINE AUTORECEPTOR ACTIVITY

描述：(逐字摘自申请者摘要)临床观察 都表明卵巢激素调节了糖尿病的症状。 精神分裂症..。因为中脑边缘多巴胺(DA)系统已被牵连 在促进情绪、动机和认知行为方面 与这种疾病有关；已有研究表明卵巢类固醇可能 作用于多巴胺能神经元，导致神经元活动和 最终导致行为表达的变化。而神经元的调制 类固醇激素的活性被很好地记录下来；对类固醇激素的活性知之甚少 准确的动作场地(S)。我们假设卵巢类固醇激素 雌激素通过调节伏隔核内DA的可用性 D2DA受体敏感性的调节以及这种调节是重要的 在相关的病理条件下维持正常的神经元活动 有皮质下多巴胺能亢进，如精神分裂症。激活 突触前D2受体的改变导致细胞外DA的减少 DA转运体的激活和DA释放的抑制 综合。而负责自身受体介导的机制 抑制DA的释放和合成已经得到了广泛的研究，它 目前尚不清楚自身受体如何调节转运蛋白的活动。我们建议 多巴胺自身受体的激活通过改变 第二信使介导的转运蛋白的磷酸化 对这一机制的研究将提供一个工具，通过它来调节雌激素 可以调查DA的可用性。 自身受体介导的~3H-DA摄取和转运体磷酸化的变化 将在由细胞核制备的突触小体准备中进行检查 去卵巢(OVX)雌性大鼠伏隔核。类固醇对多巴胺的影响 运输将在服用生理学药物后确定 相应剂量的苯甲酸雌二醇(EB-primed)。三个主要问题将是 地址。1)D2类多巴胺自身受体负责 DA转运的增强？2)自身受体是否介导DA的激活 运输通过一种涉及第二信使变化的机制进行 级联和/或蛋白质磷酸化？3)EB启动是否产生 DA受体敏感性的功能调节，导致改变 调节多巴胺供应的能力？这些问题的答案是 问题将提供有关多巴胺释放能力的详细信息 从突触前终末调节自身的细胞外可用性 通过突触前自身感受器的作用。此外，他们还将 阐明雌激素调节细胞功能敏感性的能力。 DA自身受体。这些类型的研究对于阐明 雌激素可能在卵巢癌的病理条件下提供生理保护 增加了DAR能活性。

DESCRIPTION: (Verbatim from the Applicant's Abstract) Clinical observations have suggested that ovarian hormones modulate the symptomology of schizophrenia.. Because the mesolimbic dopamine (DA) system has been implicated in the facilitation of emotional, motivational and cognitive behaviors associated with this disorder; it has been suggested that ovarian steroids may act on dopaminergic neurons to produce alterations in neuronal activity and ultimately changes in behavioral expression. While modulation of neuronal activity by steroid hormones is well documented; very little is known about the precise site(s) of action. We hypothesize that the ovarian steroid hormone estrogen regulates DA availability within the nucleus accumbens through a modulation of D2 DA receptor sensitivity and that this modulation is important in maintaining normal neuronal activity in pathological conditions associated with subcortical dopaminergic hyperactivity such as schizophrenia. Activation of the presynaptic D2 receptor results in a decrease in extracellular DA though an activation of the DA transporter and an inhibition of DA release and synthesis. While the mechanisms responsible for autoreceptor mediated inhibition of DA release and synthesis have been extensively investigated, it is not known how the autoreceptor regulates transporter activity. We propose that DA autoreceptor activation potentiates DA uptake through a change in second messenger mediated phosphorylation of the transporter and that examination of this mechanism will provide a tool by which estrogen modulation of DA availability can be investigated. Autoreceptor mediated changes in 3H-DA uptake and transporter phosphorylation will be examined in a synaptosomal preparation prepared from the nucleus accumbens of ovariectomized (OVX) female rats. Steroid mediated changes in DA transport will be determined following administration of a physiologically relevant dose of estradiol benzoate (EB-primed). Three main questions will be addressed. 1) Is the D2 class of dopamine autoreceptors responsible for potentiation of DA transport? 2) Does autoreceptor mediated activation of DA transport proceed by a mechanism which involves alterations in second messenger cascades and/or protein phosphorylation? 3) Does EB-priming produce a functional modulation of DA receptor sensitivity which results in an alteration in the ability to regulate dopamine availability? The answers to these questions will provide detailed information on the ability of dopamine released from the presynaptic terminal to regulate its own extracellular availability through an action at the presynaptic autoreceptor. In addition, they will clarify the ability of estrogen to modulate the functional sensitivity of the DA autoreceptor. These types of studies are critical for elucidating how estrogen may provide physiological protection under pathological conditions of increased DAergic activity.