PRENATAL ALCOHOL--EFFECTS ON CENTRAL DOPAMINE RECEPTOR SUBTYPES

产前酒精——对中枢多巴胺受体亚型的影响

• 批准号: 6347172
• 负责人: Sonya K Sobrian
• 金额: $ 16.86万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6347172
• 关键词: behavior test; biological signal transduction; brain mapping; congenital nervous system disorder; developmental neurobiology; disease /disorder etiology; dopamine receptor; embryo /fetus toxicology; ethanol; fetal alcohol syndrome; gender difference; gestational age; laboratory rat; neurotoxicology; receptor binding; receptor expression

Alcohol abuse during pregnancy is recognized as a significant risk factor to normal fetal growth and development. Prenatal alcohol exposure can result in fetal alcohol syndrome and alcohol-related birth defects (ARBD) which are associated with cognitive disabilities and mental retardation. These neurobehavioral disorders are the most severe and least amenable to treatment. While the mechanism(s) responsible fo rthese effects has not been definitely determine, results of studies with animal model indicate that in utero ethanol exposure markedly impairs the development of most neurotransmitters. Prenatal ethanol decreases concentrations of dopamine in brain regions which contain cell bodies of DA neurons and their projection areas and adversely impacts the development of DA reuptake sites. DA receptor number is also altered, but the net effect of chronic treatment is not clearly defined. The proposed experiements will investigate the role of dopamine receptor subtypes in the etiology of ARDB. Time-pregnant Sprague- Dawley rates will be fed a liquid diet containing 35% ethanol-derived calories on gestation days 11-21 (ETOH). Blood alcohol levels will be measured in the dams on Gds 15 and 19. Pair-Fed (PF) dams will be fed an identical liquid diet, but with dextrin-maltose substituted isocalorically for ethanol. Lab chow controls (LC) will have ad libitum access to standard laboratory and antagonists, either alone or in combination, with specificity for the D1, D2 and D3 DA receptor subtypes to test if prenatal alcohol alters behavioral sensitivity to these compounds. Stimulation and/or blockade of receptor subtypes induced a specific behavioral responses, which will be monitored for 30 minutes, using a time-sampling technique, following drug injection. As behaviors elicited by these drugs are both dose and gender dependent, complete dose-response curves will be generated in both male and female offspring. Treatment effects on dopamine D1, D2 and D3 binding in the striatum, caudate nucleus and the prefrontal cortex as well as concentration of DA and its major metabolite, DOPAC, will also be determined in 21-22 day old offspring. Because of the distinct pharmacological properties, different anatomical distributions and signal transduction mechanisms of each receptors, alterations in a particular DA receptor subtype can provide information about a specific deficit and its localization in the brain. Differential responses by prenatal alcohol-exposed offspring to drugs that act specifically at these receptors may be indicative of a disruptionint he function of a specific neural process and may have implication for treatment regimes to prevent and/or alleviate ARBD.

怀孕期间酗酒被认为是一个重大风险 影响胎儿正常生长和发育的因素。 产前酒精 接触酒精可导致胎儿酒精综合征和与酒精有关的分娩 与认知障碍相关的缺陷（ARBD）， 智力迟钝。 这些神经行为障碍是 严重且最不适合治疗。 虽然机制 对这些影响的责任尚未明确确定，结果 的动物模型研究表明，子宫内乙醇暴露 会明显损害大多数神经递质的发育。 产前乙醇降低大脑中多巴胺的浓度 含有DA神经元胞体及其投射的区域 地区并对DA再吸收点的发展产生不利影响。 DA受体数量也发生了变化，但长期的净效应 治疗没有明确的定义。 本实验将研究多巴胺在 受体亚型在ARDB病因学中的作用。 时间怀孕的斯普拉格- 道利大鼠将喂食含有35%乙醇衍生的 妊娠第11 - 21天的卡路里（ETOH）。 血液酒精含量会 在Gds 15和19的母鼠中测量。 双馈（PF）大坝将 喂食相同的流质食物，但用糊精-麦芽糖替代 等热量地形成乙醇。 实验室饲料对照组（LC）将自由进食 获得标准的实验室和拮抗剂，无论是单独或 对D1、D2和D3 DA受体具有特异性的组合 亚型，以测试产前酒精是否会改变对这些亚型的行为敏感性， 化合物. 刺激和/或阻断诱导的受体亚型 a特定的行为反应，将被监测30 分钟，使用时间采样技术，药物注射后。 作为 由这些药物引起的行为既依赖于剂量又依赖于性别， 将在雄性和雌性动物中生成完整的剂量-反应曲线， 雌性后代 对多巴胺D1、D2和D3的治疗效果 结合在纹状体，尾状核和前额皮质， 以及DA及其主要代谢产物DOPAC的浓度， 也可在21 - 22日龄的子代中测定。 由于不同的药理学特性， 每一种的解剖分布和信号转导机制 受体，特定DA受体亚型的改变可以提供 关于特定缺陷及其在大脑中的定位的信息。 产前酒精暴露后代对药物的不同反应 特异性作用于这些受体可能表明 破坏特定神经过程的功能，并可能具有 对预防和/或缓解ARBD治疗方案的意义。