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:
  • 金额:
    $ 13.87万
  • 依托单位:
  • 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,通常出现在青春期后期或成年早期,此时皮质发育接近完成,循环性腺激素接近成年水平。临床观察表明,雌激素对精神分裂症症状的表达具有神经保护作用。由于中脑边缘多巴胺(DA)系统与这种疾病相关的行为的促进有关,中脑边缘DA能亢进与症状的表达有关,因此有人认为雌激素可能作用于DA能神经元,以改变神经元的活动,并最终改变行为表达。我们已经表明,雌激素通过改变DA D2自身受体的敏感性和DA转运体(DAT)的活性来调节多巴胺在丘脑核内的可用性。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)毒素敏感性G蛋白来调节D2受体敏感性,并且这种调节在与皮质下DA能亢进相关的病理条件下维持正常神经元活性方面是重要的。此外,我们建议,在青春期发生的发育和激素的变化可能会影响随后的DA D2受体的敏感性在成人中观察到的改变,并可能占早发性精神疾病的易感性增加。D2自身受体激活的功能改变将在青春期前和成年大鼠的丘脑核中进行研究。将解决三个问题:1]在D2受体的功能敏感性中是否存在年龄和/或性别依赖性改变?2]D2受体的激活是否会改变DAT的磷酸化,如果是的话,这种改变是否取决于年龄或性别?3]在D2受体功能丧失后,雌性大鼠是否更容易从细胞外间隙清除DA的能力受损?这些问题的答案将提供具体的信息之间的D2受体和DAT的功能关联。此外,他们将澄清如何发展和性别依赖性的D2自身受体的敏感性变化可能会改变的反应性的中脑边缘DA能系统,并最终与精神分裂症相关的神经病学。

项目成果

期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Alteration of dopamine transport in the striatum and nucleus accumbens of ovariectomized and estrogen-primed rats following N-(p-isothiocyanatophenethyl) spiperone (NIPS) treatment.
N-(p-异硫氰酸苯乙基)螺哌隆 (NIPS) 治疗后,去卵巢和雌激素引发的大鼠纹状体和伏核中多巴胺转运的改变。
  • DOI:
    10.1016/s0361-9230(01)00472-5
  • 发表时间:
    2001
  • 期刊:
  • 影响因子:
    3.8
  • 作者:
    Thompson,TL;Bridges,SR;Weirs,WJ
  • 通讯作者:
    Weirs,WJ
Modulation of dopamine uptake in rat nucleus accumbens: effect of specific dopamine receptor antagonists and sigma ligands.
大鼠伏隔核多巴胺摄取的调节:特异性多巴胺受体拮抗剂和西格玛配体的作用。
  • DOI:
    10.1016/s0304-3940(01)02209-1
  • 发表时间:
    2001
  • 期刊:
  • 影响因子:
    2.5
  • 作者:
    Thompson,TL;Bridges,S;Miller,C
  • 通讯作者:
    Miller,C
Estrogen priming modulates autoreceptor-mediated potentiation of dopamine uptake.
雌激素启动调节自身受体介导的多巴胺摄取增强。
  • DOI:
    10.1016/s0014-2999(00)00432-5
  • 发表时间:
    2000
  • 期刊:
  • 影响因子:
    5
  • 作者:
    Thompson,TL;Moore,CC;Smith,B
  • 通讯作者:
    Smith,B
Estrogen mediated inhibition of dopamine transport in the striatum: regulation by G alpha i/o.
雌激素介导的纹状体多巴胺转运抑制:G α i/o 的调节。
  • DOI:
    10.1016/j.ejphar.2005.02.005
  • 发表时间:
    2005
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Thompson,TinaL;Certain,MatthewE
  • 通讯作者:
    Certain,MatthewE
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TINA L THOMPSON其他文献

TINA L THOMPSON的其他文献

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{{ truncateString('TINA L THOMPSON', 18)}}的其他基金

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:
    6024164
  • 财政年份:
    1999
  • 资助金额:
    $ 13.87万
  • 项目类别:
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
  • 财政年份:
    1999
  • 资助金额:
    $ 13.87万
  • 项目类别:

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