NEUROADAPTATION TO COCAINE--ROLE OF STEROID RECEPTORS

可卡因的神经适应——类固醇受体的作用

• 批准号: 2430044
• 负责人: Bruce Lane Nock
• 金额: $ 20.12万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-01 至 1999-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2430044
• 关键词: adrenalectomy; brain mapping; cocaine; estradiol; estrogen receptors; female; gender difference; gene induction /repression; genetic transcription; hormone regulation /control mechanism; hypothalamic pituitary axis; hypothalamus; laboratory rat; ovariectomy; pituitary gland; preoptic areas; progestins; receptor binding; receptor expression; steroid hormone receptor; transcription factor; adrenalectomy; brain mapping; cocaine; estradiol; estrogen receptors; female; gender difference; gene induction /repression; genetic transcription; hormone regulation /control mechanism; hypothalamic pituitary axis; hypothalamus; laboratory rat; ovariectomy; pituitary gland; preoptic areas; progestins; receptor binding; receptor expression; steroid hormone receptor; transcription factor

The goal of this project is to characterize the effects of cocaine on intracellular estrogen and progestin receptor systems in brain. The proposed studies are based on preliminary experiments in which cocaine caused a robust, tissue-specific suppression of cytosol progestin receptor (cPR) binding in hypothalamus-preoptic area (HPOA) and anterior pituitary gland (AP) of intact female rats and of ovariectomized/adrenalectomized, estradiol-treated rats. The progestin receptor is an estrogen-inducible protein in HPOA and AP and the cocaine- induced suppression of binding appears to be due to a gender-specific impairment of some aspect of estradiol-receptor-DNA interactions in those tissues. These neuroendocrine abnormalities were evident even though only a single, moderately high dose of cocaine was administered and measurements of cPR were taken 18 hours later; i.e. at a time point beyond that typically associated with acute actions of cocaine. These effects of cocaine are particularly intriguing because steroid hormone receptors function not only as signal transducers but, more importantly, as transcription factors. Thus, cocaine could gain functional access to the genome and modulate transcription of specific genes through effects on steroid receptors. Our specific aims are: 1) To characterize cocaine's effects on cPR and to explore possible mechanisms through which cocaine might affect cPR binding; 2) To localize the effects of cocaine on progestin receptors in HPOA; 3) To determine whether the cocaine-induced suppression of cPR binding in HPOA and AP is physiologically significant; 4) To characterize cocaine effects on nuclear estrogen receptor (nER) binding in HPOA and AP and to determine whether, in addition to impairing some aspect of estradiol-receptor-DNA interaction, cocaine causes an estradiol-independent activation of ER; 5) To establish the impact of cocaine on estrogen receptors under normal endocrine conditions; 6) To establish whether cocaine effects on steroid receptor systems are gender specific. The proposed project could have significant clinical relevancy. Although there is clear recognition of the deleterious effects of cocaine abuse, little is known about the neuronal adaptations associated with cocaine addiction. Our success in establishing an animal model for assessing cocaine's effects on steroid receptor systems could be instrumental in focusing attention on the role of this group of transcription factors. Since steroid receptors are likely to regulate a large number of regulatory (early) and structural (late) genes, they have the potential for markedly amplifying the effects of cocaine and precipitating a cascade of genomic modifications which could have enduring behavioral and physiological consequences that extend well beyond the presence of cocaine in the body.

该项目的目的是表征可卡因对 大脑中细胞内雌激素和孕激素受体系统。这 拟议的研究基于可卡因的初步实验 引起耐用的组织特异性抑制细胞质孕激素 下丘脑苯丙胺流行区（HPOA）和前方的受体（CPR）结合 完整的雌性大鼠的垂体（AP） 卵巢切除/肾上腺素切除，雌二醇治疗的大鼠。孕激素 受体是HPOA和AP中的雌激素诱导蛋白，可卡因 - 诱导的抑制结合似乎是由于特定性别的 雌二醇 - 受体DNA相互作用的某些方面受损这些方面 组织。这些神经内分泌异常是显而易见的 给予一个中度高剂量的可卡因，并 18小时后进行了心肺复苏术的测量；即在一个时间点 除了通常与可卡因的急性作用相关的外。这些 可卡因的影响特别有趣，因为类固醇激素 受体不仅作为信号传感器的功能，而且更重要的是 作为转录因子。因此，可卡因可以获得功能访问 通过影响的基因组和调节特定基因的转录 在类固醇受体上。我们的具体目的是：1）表征可卡因的 对CPR的影响并探索可卡因的可能机制 可能会影响CPR结合； 2）定位可卡因对 HPOA中的孕激素受体； 3）确定可卡因诱导的 HPOA和AP中CPR结合的抑制具有生理意义。 4）表征可卡因对核雌激素受体（NER）的影响 在HPOA和AP中结合，并确定除了损害 雌二醇 - 受体-DNA相互作用的某些方面可卡因导致 ER的雌二醇非依赖性激活； 5）建立影响 在正常内分泌条件下雌激素受体上的可卡因； 6）到 确定可卡因对类固醇受体系统的影响是否是性别 具体的。拟议的项目可能具有很大的临床相关性。 尽管对可卡因的有害影响有明确的认识 虐待，对与之相关的神经元适应知之甚少 可卡因成瘾。我们成功建立动物模型 评估可卡因对类固醇受体系统的影响可能是 有助于将注意力集中在这一群体的角色上 转录因子。由于类固醇受体可能调节 大量调节（早期）和结构（晚期）基因，它们具有 明显放大可卡因和可卡因影响的潜力 沉淀一系列可能具有的基因组修饰 持久的行为和生理后果很好地扩展 超越体内可卡因的存在。