NEUROADAPTATION TO COCAINE--ROLE OF STEROID RECEPTORS

可卡因的神经适应——类固醇受体的作用

基本信息

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
项目类别：
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

项目摘要

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.

该项目的目标是描述可卡因对人的影响大脑中的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胞质孕激素的强烈、组织特异性抑制下丘脑视前区 (HPOA) 和前部受体 (cPR) 结合完整雌性大鼠的垂体（AP）和卵巢切除/肾上腺切除、雌二醇治疗的大鼠。孕激素受体是 HPOA 和 AP 以及可卡因中的雌激素诱导蛋白诱导的结合抑制似乎是由于性别特异性雌二醇-受体-DNA相互作用的某些方面受损组织。这些神经内分泌异常是明显的，即使只是给予单次中等高剂量的可卡因，并且 18 小时后进行 cPR 测量；即在某个时间点超出了通常与可卡因的急性作用相关的范围。这些可卡因的作用特别有趣，因为类固醇激素受体不仅充当信号传感器，更重要的是作为转录因子。因此，可卡因可以获得功能性访问基因组并通过效应调节特定基因的转录对类固醇受体。我们的具体目标是： 1) 描述可卡因的特征对 cPR 的影响并探索可卡因的可能机制可能影响 cPR 结合； 2) 确定可卡因对人体的影响 HPOA 中的孕激素受体； 3）确定是否可卡因诱发抑制 HPOA 和 AP 中 cPR 的结合具有生理意义； 4) 表征可卡因对核雌激素受体 (nER) 的影响 HPOA 和 AP 中的结合，并确定是否除了损害在雌二醇-受体-DNA相互作用的某些方面，可卡因会导致不依赖雌二醇的 ER 激活； 5) 确定影响正常内分泌条件下可卡因对雌激素受体的影响； 6) 至确定可卡因对类固醇受体系统的影响是否与性别有关具体的。拟议的项目可能具有重要的临床相关性。尽管人们清楚地认识到可卡因的有害作用滥用，人们对与滥用相关的神经元适应知之甚少可卡因成瘾。我们成功建立了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作用上转录因子。由于类固醇受体可能调节大量的调节（早期）和结构（晚期）基因，它们具有显着增强可卡因作用的潜力引发一系列基因组修饰，这可能持久的行为和生理后果可以很好地延续除了体内存在可卡因之外。