SSRI TREATMENT OF PRENATAL COCAINE-INDUCED 5HT DEFICITS

描述(申请者摘要)：各种情绪障碍 在子宫内暴露于可卡因的后代中越来越多地被确诊。在人类身上， 5-羟色胺(5-羟色胺)功能受损与以下疾病有关 焦虑、抑郁、冲动和攻击性增加。在.期间 最初的资助期，我们确定了长期的神经化学和功能 孕期接触铅对子代大鼠脑5-羟色胺系统的损伤 可卡因。因此，这项研究的长期目标是确定 临床处方5-羟色胺选择性再摄取抑制剂的疗效观察 (SSRIs)用于治疗产前暴露所致子代的情绪障碍 为了可卡因。SSRIs的临床疗效与它们的能力有关 在5-羟色胺系统中产生神经适应性变化。此续订申请将 确定临床使用的SSRI，如帕罗西汀(帕罗西汀)是否将 有效逆转胎鼠5-羟色胺能神经功能缺陷 接触可卡因。我们的假设是SSRI将有效地恢复 脑5-羟色胺功能与5-羟色胺受体信号的神经适应性变化 胎儿期接触可卡因的子代的转导。这项提议将 确定5-羟色胺损伤和修复的机制 用生化、神经化学和生物化学方法研究SSRIs在后代中的5-羟色胺功能 5-羟色胺突触前和突触后成分的神经内分泌研究 小路。每个目标都将研究神经适应性变化的机制 胎儿期5-羟色胺信号转导通路的不同组成部分 可卡因和随后的产后SSRI治疗。目标1将专注于 突触前5-羟色胺终末功能；目标2将研究 5-羟色胺胞体上的体树突状5-HT1a自身受体；AIMS 3和4将 5-HT1A和5-HT2A受体信号突触后功能的研究 分别是转导系统。因为神经内分泌挑战也可以 用于人类，大脑中神经化学变化之间的对应关系 5-羟色胺介导的神经内分泌反应的诱导变化将提供 评估产前可卡因对人体5-羟色胺功能影响的基础 后代。此外，我们的研究将确定调解机制 SSRI诱导5-羟色胺系统的神经适应性改变 产前吸食可卡因。从拟议的研究中获得的数据将在 预测SSRIs在治疗个体疾病方面的潜在疗效 以前在子宫里接触过可卡因。据我们所知，这些研究是 首先确定SSRIs治疗5-羟色胺功能损害的效用 因为出生前接触了可卡因。

DESCRIPTION (applicant's abstract): Various mood disorders are being increasingly diagnosed in offspring exposed to cocaine in utero. In humans, impairments in serotonin (5-HT) function are associated with disorders such as anxiety, depression and increased impulsivity and aggression. During the initial funding period, we identified long-term neurochemical and functional impairments in brain 5-HT systems in rat offspring exposed prenatally to cocaine. Thus, the long-term objective of this research is to determine the effectiveness of clinically prescribed serotonin-selective reuptake inhibitors (SSRIs) to treat mood disorders in offspring resulting from prenatal exposure to cocaine. The clinical efficacy of SSRIs is related to their ability to produce neuroadaptive changes in 5-HT systems. This renewal application will determine if clinically used SSRIs, such as paroxetine (Paxil), will be effective in reversing the serotonergic deficits in rats produced by prenatal cocaine exposure. Our HYPOTHESIS is that SSRIs will be effective in restoring brain 5-HT function and producing neuroadaptive changes in 5-HT receptor signal transduction in prenatal cocaine-exposed offspring. This proposal will determine the mechanisms responsible for 5-HT impairments and the restoration of 5-HT function by SSRIs in offspring using biochemical, neurochemical and neuroendocrine measures to study pre- and postsynaptic components of 5-HT pathways. Each aim will study the mechanism of neuroadaptive changes in different components of the 5-HT signal transduction pathway due to prenatal cocaine and subsequent postnatal SSRI treatment. Aim 1 will focus on presynaptic 5-HT terminal function; aim 2 will investigate the sensitivity of somatodendritic 5-HT1A autoreceptors on 5-HT cell bodies; and aims 3 & 4 will investigate postsynaptic function of 5-HT1A and 5-HT2A receptor signal transduction systems, respectively. Because neuroendocrine challenge can also be used in humans, the correspondence between neurochemical changes in brain induced changes in 5-HT-mediated neuroendocrine responses will provide the foundation to assess prenatal cocaine-induced changes in 5-HT function in human offspring. In addition, our studies will identify the mechanisms mediating SSRI-induced neuroadaptive changes in 5-HT systems in offspring impaired by prenatal cocaine. Data obtained from the proposed studies will be important in predicting the potential efficacy of SSRIs in treating disorders in individuals previously exposed to cocaine in utero. To our knowledge, these studies are the first to determine the utility of SSRIs to treat impairments in 5-HT function due to prenatal cocaine exposure.