PSYCHOBIOLOGY OF ESTROGEN RECEPTOR MODULATORS

雌激素受体调节剂的心理生物学

基本信息

批准号：
6615129
负责人：
Mark E Wilson
金额：
$ 36万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-01 至 2005-08-31
项目状态：
已结题

项目摘要

Estradiol (E2) is essential for the health, estradiol (E2) also normalizes behavioral systems related to mood and sexuality. Although E2 replacement prevents bone loss and reduces the risk of cardiovascular disease in hypo- estrogenic women, such treatments may adversely affect the breast uterus, despite co-treatment with progestins. Consequently, non-steroidal estrogens have been developed with specific targeted effects as E2 agonists in some tissues and antagonists in others. Since these tissue- specific actions are likely mediated through subtypes of the estrogen receptor (ER), the compounds are described as selective estrogen receptor modulators (SERMs). Despite their well-documented efficacy in peripheral target tissues, it is not known whether these SERMs act as E2 agonists or antagonists within the CNS regulating neuro-chemical mechanisms subserving complex social behavior. This project will determine if the SERMs, tamoxifen and raloxifene, are E2 agonists or antagonists in the neuroendocrine regulation of behavior in female rhesus monkeys. Using ovariectomized females, each Specific Aims will test the hypothesis that SERMs, in the absence of E2, act as agonists whereas, in the presence of E2, are antagonists. Preliminary studies will determine the pharmacokinetics of the SERMs to set the parameters of the treatment protocol. Specific Aim 1 will determine if SERMs mimic E2 and increase affiliative behavior mediated by increased central serotonergic (5HT) activity, assessed from concentrations of 5HT and its metabolite in cerebrospinal fluid, quantitative receptor autoradiography, and in situ hybridization for the 5HT re- uptake transporter. Subsequent studies will test the hypothesis that these SERMs antagonize endogenous E2, diminishing 5HT activity and increasing aggressiveness. Specific Aim 2 will determine if SERMs, in the absence of E2, induce female sexual motivation and coordinate gonadotropin synthesis and secretion. Additional studies will test the hypothesis that these SERMs antagonize endogenous E2, blocking the induction of sexual motivation and regulation of gonadotropin synthesis and release. These data will provide not only a better understanding of the biology of SERMs but will also help clinicians and patients evaluate of these compounds on behavioral health.

雌二醇（E2）对于健康至关重要，雌二醇（E2）也使与情绪和性行为有关的行为系统正常化。尽管E2的替代可防止骨质流失并降低低源性妇女心血管疾病的风险，但尽管与孕激素共同治疗，这种治疗可能会对乳房子宫产生不利影响。因此，已经开发出非甾体类雌激素在某些组织中具有E2激动剂，在其他组织中具有特定的靶向作用。由于这些组织特异性作用可能是通过雌激素受体（ER）的亚型介导的，因此化合物被描述为选择性雌激素受体调节剂（SERMS）。尽管它们在外围靶组织中有据可查的功效，但尚不清楚这些Serm在中枢神经系统中是否充当E2激动剂或拮抗剂，从而调节神经化学机制扩展了复杂的社会行为。该项目将确定Serms，他莫昔芬和雷昔芬是否是雌性恒河猴行为的神经内分泌调节中的E2激动剂或拮抗剂。使用卵巢切除的女性，每个特定的目标都将检验以下假设：在没有E2的情况下Serm充当激动剂，而在E2存在的情况下，Serm是拮抗剂。初步研究将确定SERM的药代动力学设置治疗方案的参数。具体目标1将确定SERMS是否模仿E2并增加由中枢性血清素能（5HT）活性介导的，并根据5HT浓度及其代谢物在脑脊液中的浓度及其代谢物，定量受体自显增生以及5HT重新升压转运剂的原位杂交评估。随后的研究将检验以下假设：这些Serm拮抗内源性E2，减少5HT活性并增加攻击性。具体目标2将确定Serm在没有E2的情况下是否诱导女性性动机并协调促性腺激素的合成和分泌。其他研究将检验以下假设：这些Serms拮抗内源E2，阻止了性动机的诱导和促性腺激素合成和释放的调节。这些数据不仅可以更好地了解SERM的生物学，还将帮助临床医生和患者评估这些化合物的行为健康。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Gonadal steroid modulation of the limbic-hypothalamic- pituitary-adrenal (LHPA) axis is influenced by social status in female rhesus monkeys.

雌性恒河猴的边缘-下丘脑-垂体-肾上腺（LHPA）轴的性腺类固醇调节受到社会地位的影响。

DOI：
10.1385/endo:26:2:089
发表时间：
2005
期刊：
Endocrine
影响因子：
3.7
作者：
Wilson,MarkE;Legendre,Ariadne;Pazol,Karen;Fisher,Jeffrey;Chikazawa,Kathy
通讯作者：
Chikazawa,Kathy

Tamoxifen is an estrogen antagonist on gonadotropin secretion and responsiveness of the hypothalamic-pituitary- adrenal axis in female monkeys.

他莫昔芬是一种雌激素拮抗剂，可抑制雌性猴体内促性腺激素的分泌和下丘脑-垂体-肾上腺轴的反应。

DOI：
10.1385/endo:22:3:305
发表时间：
2003
期刊：
Endocrine
影响因子：
3.7
作者：
Wilson,ME;Mook,D;Graves,F;Felger,J;Bielsky,IF;Wallen,K
通讯作者：
Wallen,K

Chronic subcutaneous leptin infusion diminishes the responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis in female rhesus monkeys.

长期皮下注射瘦素会降低雌性恒河猴下丘脑-垂体-肾上腺（HPA）轴的反应性。

DOI：
10.1016/j.physbeh.2005.01.013
发表时间：
2005
期刊：
Physiology & behavior.
影响因子：
0
作者：
Wilson,MarkE;Fisher,Jeffrey;Brown,Juliet
通讯作者：
Brown,Juliet

Progesterone and medroxyprogesterone acetate differentially regulate alpha4 subunit expression of GABA(A) receptors in the CA1 hippocampus of female rats.

DOI：
10.1016/j.physbeh.2009.01.021
发表时间：
2009-04-20
期刊：
PHYSIOLOGY & BEHAVIOR
影响因子：
2.9
作者：
Pazol, Karen;Northcutt, Katharine V.;Patisaul, Heather B.;Wallen, Kim;Wilson, Mark E.
通讯作者：
Wilson, Mark E.

Immediate and residual effects of tamoxifen and ethynylestradiol in the female rat hypothalamus.

他莫昔芬和乙炔雌二醇对雌性大鼠下丘脑的立即和残留影响。