SSRI TREATMENT OF PRENATAL COCAINE-INDUCED 5HT DEFICITS

描述（申请人摘要）：各种情绪障碍正在被 在子宫内接触可卡因的后代中越来越多地被诊断出来。在人类中， 5-羟色胺（5-HT）功能的损伤与以下疾病有关， 焦虑、抑郁、冲动和攻击性增加。期间 在最初的资助期间，我们确定了长期的神经化学和功能 产前暴露于苯并咪唑对大鼠子代脑5-HT系统的影响 可卡因因此，本研究的长期目标是确定 临床处方的选择性重摄取抑制剂的有效性 （SSRIs）治疗产前暴露导致的后代情绪障碍 可卡因。SSRIs的临床疗效与其 在5-HT系统中产生神经适应性变化。此更新申请将 确定临床上使用的SSRIs，如帕罗西汀（Paxil），是否会 有效地逆转大鼠中由产前 可卡因暴露我们的假设是SSRIs将有效地恢复 脑5-HT功能和产生5-HT受体信号的神经适应性变化 在产前可卡因暴露的后代中的转导。这项建议会 确定负责5-HT损伤和恢复的机制 SSRIs在后代中使用生化，神经化学和 神经内分泌措施，研究5-HT的突触前和突触后成分 途径。每个目标将研究神经适应性变化的机制， 5-HT信号转导通路的不同组成部分，由于产前 可卡因和产后SSRI治疗。目标1将侧重于 突触前5-HT末端功能;目的2将研究 5-HT细胞体上的体树5-HT 1A自受体;目标3和4将 5-HT 1A和5-HT 2A受体信号突触后功能研究 换能系统。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-HT介导的神经内分泌反应的诱导变化将提供 评价产前可卡因诱导的人类5-HT功能变化的基础 后代此外，我们的研究将确定介导 SSRI诱导的5-HT系统的神经适应性变化 产前可卡因从拟议的研究中获得的数据将是重要的， 预测SSRIs治疗个体疾病的潜在疗效 曾在子宫内接触过可卡因据我们所知，这些研究是 首先确定SSRIs治疗5-HT功能障碍的效用 因为产前接触可卡因

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.