IN UTERO COCAINE-INDUCED 5-HT DYSFUCTION IN PROGENY

子宫内可卡因引起的子代 5-HT 功能障碍

• 批准号: 3214381
• 负责人: GEORGE BATTAGLIA
• 金额: $ 11.18万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-04-01 至 1996-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3214381
• 关键词: adrenocorticotropic hormone; autoradiography; brain mapping; brain metabolism; cocaine; drug abuse; embryo /fetus toxicology; female; gender difference; high performance liquid chromatography; innervation; laboratory rat; male; neuroanatomy; neurochemistry; pregnancy; radioimmunoassay; radiotracer; renin; serotonin; serotonin receptor

The long term objective of this proposal is to understand how cocaine abuse during pregnancy can contribute to the development in offspring, of subsequent clinical disorders involving dysfunction of brain serotonin(5-HT) systems. Dysfunctional 5-HT systems have been implicated in anxiety, depression, suicidal behaviors and preference for alcohol. In adult animals, cocaine perturbs 5-HT neurons by decreasing their firing rate, inhibiting 5-HT synthesis and inhibiting 5-HT uptake. During gestation, 5-HT plays a critical trophic role in the maturation of 5-HT neurons and target cells receiving 5-HT projections. Our hypothesis is that in utero exposure to cocaine produces perturbations of fetal 5-HT systems that result in long-term deficits in the functional status and integrity of brain 5-HT systems in adult progeny. Our preliminary data support our hypothesis of long-term biochemical and functional deficits in progeny brain 5-HT systems following in utero exposure to cocaine. The goal of the present research is to establish the extent of cocaine-induced changes in adult progeny with respect to the following specific aims: (1) To Determine the Functional Status of Brain 5-HT Neurons by measuring (a) 5-HT/5-HIAA content in terminal and cell body regions and the corresponding number and affinity of 5-HT uptake sites in these regions, (b) the viability of 5-HT terminals by the ability of 5-HT releasers to stimulate ACTH and renin secretion, as well as, to reduce (deplete) brain 5-HT content; (2) To Determine the Functional Status of Postsynaptic 5-HT Receptors with respect to cocaine-induced changes in (a) the stimulation of ACTH and renin secretion by directly acting 5-HT1 and 5-HT2/1C serotonin agonists, and (b) the adaptational responsiveness of 5-HT receptors by investigating the dynamics of 5-HT1 and 5-HT2 receptor turnover following receptor inactivation; and (3) To Determine the Neuroanatomic Specificity of In Utero Cocaine-Induced Effects on 5-HT Pathways by measuring regional densities of 5-HT uptake sites, and 5-HT1 & 5-HT2 receptor subtypes using in vitro autoradiographic techniques. These studies should identify discrete brain regions where cocaine- induced receptor alterations may produce functional consequences. Methods: Pregnant rats will be treated b.i.d. from gestational day 13-20 and all progeny fostered at birth. Male and female progeny of pregnant rats from 3 Treatment Groups: (1) Saline-Injected Ad-Lib Fed; (2) Saline-Injected Pair-Fed; and (3) Cocaine-Injected (15 mg/kg) will be compared at a prepubescent time (PD30). Male progeny will also be investigated at postpubescent time (PD70). Significance: Since cocaine ("Crack") abuse among women of childbearing age is becoming increasingly prevalent, these studies will provide timely and important information regarding neurological deficits which may develop in offspring due to in utero cocaine-induced dysfunction of 5-HT systems. In this regard, changes in the stimulation of plasma hormones in response to 5-HT drugs may provide an important clinical marker for in utero cocaine-induced central 5-HT dysfunction in humans.

该提议的长期目标是了解可卡因如何 怀孕期间的虐待可能有助于后代的发展， 随后涉及大脑功能障碍的临床疾病 5-羟色胺（5-HT）系统。 功能失调的5-HT系统已被牵涉到 在焦虑，抑郁，自杀行为和对酒精的偏爱中。 在成年动物中，可卡因通过降低其5-HT神经元的神经元 发射速率，抑制5-HT合成并抑制5-HT摄取。 在妊娠期间，5-HT在成熟中起关键的营养作用 接受5-HT投影的5-HT神经元和靶细胞。 我们的 假设是在子宫中暴露于可卡因会产生扰动 胎儿5-HT系统，导致功能长期缺陷 大脑5-HT系统在成人后代的状态和完整性。 我们的 初步数据支持我们的长期生化和 后代大脑5-HT系统的功能缺陷以后在子宫内 暴露于可卡因。 本研究的目的是建立 相对于可卡因引起的成年后代变化的程度 以下具体目的： （1）通过测量确定脑5-HT神经元的功能状态 （a）末端和细胞体区域的5-HT/5-HIAA含量以及 这些区域中5-HT吸收位点的相应数字和亲和力， （b）通过5-HT释放器的能力，5-HT终端的生存能力 刺激ACTH和肾素分泌，并减少（耗尽）大脑 5-HT内容； （2）确定突触后5-HT的功能状态 受体有关可卡因诱导的（a）刺激的变化的受体 直接作用5-HT1和5-HT2/1C，ACTH和肾素分泌 5-羟色胺激动剂和（b）5-HT的适应性反应能力 通过研究5-HT1和5-HT2受体的动力学通过受体 受体失活后的营业额； （3）确定 子宫内可卡因诱导的5-HT作用的神经解剖学特异性 通过测量5-HT吸收位点的区域密度和5-HT1的途径 ＆5-HT2受体亚型使用体外放射自显影技术。 这些研究应确定可卡因的离散大脑区域 诱导的受体改变可能会产生功能后果。 方法：孕妇将接受B.I.D.治疗从妊娠日13-20 所有后代在出生时都养育了。 男性和女性后代怀孕 来自3个治疗组的大鼠：（1）注入盐水的AD-LIB喂养； （2） 注射盐水的成对喂养； （3）可卡因注射（15 mg/kg）将是 比较在青春期时间（PD30）。 男性后代也会 在青春期时间（PD70）进行了研究。 意义：自可卡因以来 （“裂缝”）妇女虐待育龄的年龄越来越多 这些研究很普遍，将提供及时，重要的信息 关于由于IN的后代可能出现的神经功能缺陷 子宫可卡因诱导的5-HT系统功能障碍。 在这方面， 响应5-HT药物的血浆激素刺激变化 可以为子宫可卡因诱导的重要临床标记提供重要的临床标记 人类中央5-HT功能障碍。