COCAINE & MATERNAL AGGRESSION--OXYTOCINERGIC MECHANISMS

可卡因

• 批准号: 6286566
• 负责人: Josephine M. Johns
• 金额: $ 28.88万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6286566
• 关键词: aggression; amitriptyline; amygdala; autoradiography; behavioral /social science research tag; cocaine; desipramine; embryo /fetus toxicology; fluoxetine; hormone receptor; hormone regulation /control mechanism; in situ hybridization; laboratory rat; lactation; maternal behavior; oxytocin; paraventricular nucleus; postpartum; pregnancy; preoptic areas; psychopharmacology; radioimmunoassay; receptor binding; tegmentum

DESCRIPTION (applicant's abstract): Cocaine abuse by human mothers is correlated with a high incidence of child neglect and abuse. Gestational cocaine (COC) treatment has been shown to increase aggression towards an intruder (maternal aggression) and reduce the levels of oxytocin (OXY) in the amygdala of rats on postpartum days (PPD) 6-10. Blocking OXY receptors in the central amygdala results in an increase in aggression parallel to that seen following COC treatment. COC likely decreases OXY in the amygdala and increases maternal aggression through its reuptake inhibition of dopamine (DA), serotonin (5-HT) and norepinephrine (NE). These studies are designed to elucidate the specific mechanisms through which COC may work to alter OXY and maternal aggression in rats. Specific Aim 1 will determine if gestational treatment with a combination treatment of selective DA and 5-HT uptake inhibitor will increase maternal aggression as does COC. To test this hypothesis, groups of rat dams will be treated gestationally (days 1-20) with COC, control vehicle buffer (VCB), selective DA, 5-HT, or NE reuptake inhibitors or combinations of selective inhibitors. Dams will be tested for maternal aggression on PPD 6. Specific Aim 2 will determine if gestational treatment with a combination of a selective DA and 5-HT uptake inhibitor will alter OXY dynamics as does COC. To test this hypothesis, groups of rat dams will be treated gestationally (days 1-20) with vehicle buffer (VCB), COC, selective DA, 5-HT, or NE reuptake inhibitors or combinations of the selective inhibitors and sacrificed on PPD 6. OXY levels and receptor binding will be measured by radioimmunoassay, in situ hybridization and autoradiography in the amygdala, medial preoptic area and paraventricular nucleus of the hypothalamus, all of which have been implicated in OXY regulation of maternal aggression. Specific Aim 3 will determine if gestational COC treatment reduces OXY synthesis in the medial preoptic area and paraventricular nucleus and oxytocin receptor (OTR) synthesis in the amygdala, medial preoptic area and paraventricular nucleus. To test this hypothesis, rat dams will be treated gestationally with VCB or COC, and these brain regions removed for in situ hybridization and autoradiography for assessment of OXY and OTR messenger ribonucleic acid on PPD 6. Specific Aim 4 will determine if prenatal exposure to COC and being raised by a COC treated mother as compared to being raised by mothers treated with control vehicle increases maternal aggression displayed by female offspring and decreases OXY in the amygdala of the offspring as adults. To test this hypothesis, female offspring of dams gestationally treated with COC or control vehicle buffer (2 groups, buffer with no pair feeding and buffer with pair feeding), will be raised by their natural dams or foster dams that are vehicle-treated (pair-fed and non-pair-fed) or COC and then bred and tested for maternal aggression in the presence of their own litters on PPD 6. OXY levels in the amygdala will be assessed following the behavioral testing.

描述（申请人摘要）：人类母亲滥用可卡因是 与儿童忽视和虐待的高发生率相关。妊娠期 可卡因 (COC) 治疗已被证明会增加对 入侵者（母亲的攻击性）并降低体内催产素（OXY）的水平 产后第 6-10 天 (PPD) 的大鼠杏仁核。阻断 OXY 受体 杏仁核中央导致攻击性增加，与观察到的情况平行 COC治疗后。 COC 可能会降低杏仁核中的 OXY 并增加 通过抑制多巴胺 (DA)、血清素的再摄取而产生母性攻击行为 （5-HT）和去甲肾上腺素（NE）。这些研究旨在阐明 COC 可能通过特定机制改变 OXY 和母体 老鼠的攻击性。 具体目标 1 将确定是否采用联合妊娠治疗 选择性 DA 和 5-HT 摄取抑制剂治疗会增加母体 与COC一样的侵略性。为了验证这一假设，将进行老鼠坝组 妊娠期（第 1-20 天）用 COC、对照载体缓冲液 (VCB)、 选择性 DA、5-HT 或 NE 再摄取抑制剂或选择性组合 抑制剂。母鼠将在 PPD 6 上接受母性攻击行为测试。 具体目标 2 将确定妊娠治疗是否与 选择性 DA 和 5-HT 摄取抑制剂将像 COC 一样改变 OXY 动力学。到 为了检验这一假设，大鼠母鼠组将接受妊娠处理（天 1-20) 含载体缓冲液 (VCB)、COC、选择性 DA、5-HT 或 NE 再摄取 抑制剂或选择性抑制剂的组合并在 PPD 6 上处死。 OXY 水平和受体结合将通过放射免疫测定法进行原位测量 杏仁核、内侧视前区和的杂交和放射自显影 下丘脑的室旁核，所有这些都与此有关 OXY 对母亲攻击性的调节。 具体目标 3 将确定妊娠期 COC 治疗是否会降低 OXY 内侧视前区和室旁核和催产素的合成 受体（OTR）在杏仁核、内侧视前区和 室旁核。为了检验这一假设，将对大鼠水坝进行处理 妊娠期使用 VCB 或 COC，这些大脑区域被切除用于原位 杂交和放射自显影用于评估 OXY 和 OTR 信使 PPD 6 上的核糖核酸。 具体目标 4 将确定产前是否接触 COC 并由 接受 COC 治疗的母亲与接受对照治疗的母亲抚养长大的情况进行比较 车辆增加了女性后代表现出的母性攻击性 降低后代成年后杏仁核中的 OXY。为了测试这个 假设，母鼠的雌性后代在妊娠期接受 COC 或对照处理 车辆缓冲器（2组，无配对馈送缓冲器和有配对馈送缓冲器 喂养），将由其天然水坝或寄养水坝饲养 经过载体处理（配对喂养和非配对喂养）或 COC，然后进行繁殖和测试 在 PPD 6. OXY 水平上，母体在自己的幼崽面前表现出攻击性 行为测试后将对杏仁核进行评估。