ESTROGEN EFFECTS ON DOPAMINE AUTORECEPTOR ACTIVITY

描述：（逐字摘自申请人摘要）临床观察结果 已经表明卵巢激素调节了 精神分裂症。由于中脑边缘多巴胺（DA）系统与 在促进情绪、动机和认知行为方面， 与这种疾病有关;已经表明，卵巢类固醇可能 作用于多巴胺能神经元以产生神经元活性的改变， 最终改变行为表达。虽然神经元的调制 类固醇激素的活性是有据可查的;对类固醇激素的活性知之甚少。 精确的作用部位。我们假设卵巢类固醇激素 雌激素调节多巴胺的可用性，在核内通过一个 D2 DA受体敏感性的调节，这种调节是重要的 在病理条件下维持正常的神经元活性， 皮质下多巴胺能亢进症的患者比如精神分裂症激活 突触前D2受体的减少导致细胞外DA的减少， 激活DA转运蛋白并抑制DA释放， 合成.虽然负责自身受体介导的机制 DA释放和合成抑制已经被广泛研究， 尚不清楚自身受体如何调节转运蛋白活性。我们提出 DA自身受体激活通过改变 第二信使介导的转运蛋白磷酸化， 对这种机制的研究将提供一种工具， 可以调查DA可用性。 自身受体介导的~ 3 H-DA摄取和转运蛋白磷酸化的变化 将在从细胞核制备的突触体制剂中进行检查 卵巢切除（OVX）雌性大鼠的睾丸。类固醇介导的DA变化 将在施用生理上可接受的药物后测定转运。 苯甲酸雌二醇（EB-primed）的相关剂量。三个主要问题将是 处理。1)D2类多巴胺自身受体是否负责 DA转运增强？2)自身受体介导的DA激活 通过第二信使改变的机制进行运输 级联反应和/或蛋白质磷酸化3)EB预充是否会产生 DA受体敏感性的功能调节，其导致改变 调节多巴胺分泌的能力的答案 问题将提供有关多巴胺释放能力的详细信息， 从突触前末梢来调节其自身的细胞外可用性 通过突触前自身感受器的作用。此外，他们将 阐明雌激素调节功能敏感性的能力， DA自身受体。这些类型的研究对于阐明 雌激素可在以下病理条件下提供生理保护： DA能活性增加。

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.