IN UTERO COCAINE-INDUCED 5-HT DYSFUCTION IN PROGENY

这项提案的长期目标是了解可卡因如何 怀孕期间的虐待会影响后代的发育， 随后的临床疾病涉及脑功能障碍 5-羟色胺（5-HT）系统。 功能失调的5-HT系统已经被牵连 焦虑、抑郁、自杀行为和酗酒。 在成年动物中，可卡因通过降低5-HT神经元的 抑制5-HT合成和抑制5-HT摄取。 在妊娠期，5-HT在胚胎发育过程中起着重要的营养作用 5-HT神经元和接受5-HT投射的靶细胞之间的关系。 我们 一种假设是，在子宫内接触可卡因会产生干扰， 胎儿5-羟色胺系统，导致长期的功能缺陷， 成年子代脑5-HT系统状态和完整性。 我们 初步数据支持我们的假设，长期的生化和 子宫内子代脑5-HT系统的功能缺陷 接触可卡因 本研究的目的是建立 可卡因诱导的成年后代在以下方面的变化程度： 具体目标如下： (1)测定脑内5-HT神经元的功能状态 (a)终末区和胞体区5-HT/5-HIAA含量及 这些区域中5-HT摄取位点的相应数量和亲和力， (b)通过5-HT释放物的能力， 刺激ACTH和肾素分泌，以及减少（消耗）大脑 5-HT含量;（2）确定突触后5-HT的功能状态 受体与可卡因诱导的变化（a）刺激 通过直接作用于5-HT 1和5-HT 2/1C的ACTH和肾素分泌 5-羟色胺激动剂，和（B）5-HT的适应性反应 通过研究5-HT 1和5-HT 2受体的动态， 受体失活后的周转;和（3）为了确定 可卡因对5-羟色胺影响的神经解剖学特异性 通过测量5-HT摄取位点的区域密度和5-HT 1 和5-HT 2受体亚型，使用体外放射自显影技术。 这些研究应该确定可卡因- 诱导的受体改变可产生功能性后果。 方法：将对妊娠大鼠进行b.i.d.给药。从妊娠第13-20天 所有的后代都在出生时被抚养。 怀孕的雄性和雌性后代 来自3个处理组的大鼠：（1）盐水注射Ad-Lib进食;（2） 盐水注射配对喂养;和（3）可卡因注射（15 mg/kg） 在青春期前（PD 30）进行比较。 雄性后代也将 在青春期后（PD 70）进行研究。 标签：可卡因 （“快克”）虐待育龄妇女的现象越来越多， 这些研究将提供及时和重要的信息， 关于神经缺陷，可能会在后代发展，由于在 子宫内可卡因诱导的5-HT系统功能障碍。 在这方面，委员会注意到， 5-HT药物对血浆激素刺激的变化 可能为子宫内可卡因诱导的 中枢5-HT功能障碍。

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.