ESTROGEN EFFECTS ON DOPAMINE AUTORECEPTOR ACTIVITY

雌激素对多巴胺自身受体活性的影响

• 批准号: 6496211
• 负责人: TINA L THOMPSON
• 金额: $ 1.16万
• 依托单位: MERCER UNIVERSITY MACON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-07 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6496211
• 关键词: dopamine; dopamine receptor; dopamine transporter; estradiol; estrogens; female; hormone regulation /control mechanism; laboratory rat; neurotransmitter transport; nucleus accumbens

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.

描述：（申请人摘要的逐字记录）临床观察 已经提出卵巢激素调节 精神分裂症。 促进情感，动机和认知行为 与这种疾病有关；有人建议卵巢类固醇可能 对多巴胺能神经元作用，以产生神经元活性和 最终行为表达的变化。而神经元的调节 类固醇激素的活性已充分记录；关于 精确的动作站点。我们假设卵巢类固醇激素 雌激素调节伏隔核内的DA可用性 D2 DA受体灵敏度的调节，并且该调制很重要 在维持正常神经元活性的病理条件下 皮质下多巴胺能多动症，例如精神分裂症。激活 突触前的D2受体中导致细胞外DA的降低 DA转运蛋白的激活和DA释放的抑制作用和 合成。而负责自身受体介导的机制 对DA释放和合成的抑制已得到广泛研究，IT 尚不清楚自身受体如何调节转运蛋白活性。我们建议 DA自动受体激活通过更改增强了DA的吸收 第二使者介导的转运蛋白的磷酸化和 对该机制的检查将提供雌激素调节的工具 可以调查DA的可用性。 3H-DA摄取和转运蛋白磷酸化的自身受体介导的变化 将在从核制备的突触体制备中检查 卵巢切除术（OVX）雌性大鼠的a伏。类固醇介导的DA变化 在生理上给药后将确定运输 相关剂量的雌二醇苯甲酸酯（EB-primed）。三个主要问题将是 解决。 1）是D2类的多巴胺自身受体 DA运输的增强？ 2）自身受体介导的DA激活 运输通过涉及第二使者改变的机制进行 级联和/或蛋白质磷酸化？ 3）eb播种会产生 DA受体敏感性的功能调制，导致改变 能够调节多巴胺的可用性？这些答案 问题将提供有关释放多巴胺能力的详细信息 从突触前终端调节其自身的细胞外可用性 通过突触前自动受体的动作。此外，他们将 阐明雌激素调节功能灵敏度的能力 DA自动受体。这些类型的研究对于阐明如何 雌激素可以在病理条件下提供生理保护 增强的DAergic活性。