COCAINE & MATERNAL AGGRESSION--OXYTOCINERGIC MECHANISMS

描述(申请人摘要)：人类母亲滥用可卡因的情况 这与儿童忽视和虐待的高发生率有关。妊娠期 可卡因(COC)治疗已被证明增加了对 侵入者(母体攻击)和降低体内催产素(Oxy)水平 产后6-10天大鼠杏仁核。阻断细胞内的Oxy受体 中央杏仁核导致攻击性增加，与所见结果平行 在COC治疗后。COC可能减少杏仁核中的Oxy，并增加 通过抑制多巴胺和5-羟色胺的再摄取而产生的母亲攻击 5-羟色胺(5-HT)和去甲肾上腺素(NE)。这些研究旨在阐明 COC可能通过的特定机制来改变氧和母体 对老鼠的攻击性。 具体目标1将确定联合使用妊娠期治疗 选择性多巴胺和5-羟色胺摄取抑制剂的治疗将增加母亲 像COC一样咄咄逼人。为了验证这一假设，一组老鼠水坝将 妊娠期(第1-20天)使用COC、对照车辆缓冲液(VCB)、 选择性多巴胺、5-羟色胺或去甲肾上腺素再摄取抑制剂或选择性多巴胺、5-羟色胺或去甲肾上腺素 抑制剂。大坝将在PPD 6接受母性攻击测试。 具体目标2将确定联合应用 选择性多巴胺和5-羟色胺摄取抑制剂将改变氧动力学，COC也是如此。至 检验这一假设，一组大鼠将被妊娠期治疗(天 1-20)具有车辆缓冲液(VCB)、COC、选择性DA、5-羟色胺或去甲肾上腺素再摄取 抑制剂或选择性抑制剂的组合，并在PPD 6上牺牲。 氧水平和受体结合将用放射免疫分析法原位测定。 杏仁核、视前内侧区和大脑皮质的杂交和放射自显影 下丘脑室旁核，所有这些都被牵连 在Oxy对母性攻击的调控中。 具体目标3将确定妊娠期COC治疗是否减少氧含量 视前内侧区和室旁核的合成与催产素 杏仁核、视前内侧区和大脑皮质的受体(OTR)合成 室旁核。为了验证这一假设，将对老鼠坝进行治疗 妊娠合并VCB或COC，并将这些脑区切除原位 杂交法和放射自显影技术评价Oxy和OTR信使 PPD 6上的核糖核酸。 具体目标4将确定产前暴露于COC并由 接受COC治疗的母亲与接受对照治疗的母亲抚养的母亲的比较 车辆增加了雌性后代表现出的母性攻击性 成年后减少子代杏仁核中的氧含量。为了测试这一点 假说，用COC或对照组孕育的母鸡后代 车辆缓冲器(2组，无对喂缓冲器和有对缓冲器 觅食)，将由它们的天然水坝或养育水坝饲养， 车辆处理(成对饲养和非成对饲养)或COC，然后饲养和测试 母体在PPD 6.Oxy水平上对自己的幼崽的攻击 在行为测试之后，将对杏仁核进行评估。

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.