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: 6200931
• 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: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6200931
• 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.

怀孕期间的酗酒被认为是一个重大风险 胎儿生长和发育正常的因素。 产前酒精 暴露会导致胎儿酒精综合征和与酒精有关的出生 与认知障碍相关的缺陷（ARBD） 智力低下。 这些神经行为疾病是最大的 严重且最不适合治疗。 而机制 负责任的效果尚未确定，结果 用动物模型的研究表明，在子宫乙醇中暴露 明显损害了大多数神经递质的发展。 产前乙醇降低大脑中多巴胺的浓度 包含DA神经元细胞体的区域及其投影 区域和不利影响DA再摄取地点的发展。 DA受体编号也发生了变化，但是慢性的净效应 治疗未明确定义。 拟议的经验将调查多巴胺的作用 ARDB病因中的受体亚型。 怀孕的sprague- Dawley率将喂入含有35％乙醇的液体饮食 妊娠期11-21（ETOH）的卡路里。 血液酒精水平将是 在GDS 15和19的大坝中测量。配对（PF）大坝将是 喂养相同的液体饮食，但用葡萄蛋白麦芽糖取代 在乙醇上等应寄养。 实验室Chow控件（LC）将有自动 单独或在 组合，具有D1，D2和D3 DA受体的特异性 亚型测试产前酒精是否改变了行为敏感性 化合物。 受体亚型刺激和/或阻断 特定的行为反应，将监视30 分钟，使用药物注射后使用时间采样技术。 作为 这些药物引起的行为既剂量又依赖性， 男性和 女后代。 对多巴胺D1，D2和D3的治疗作用 在纹状体，尾状核和前额叶皮质中结合为 以及DA的浓度及其主要代谢物Dopac将会 也可以在21-22天大的后代确定。 由于具有独特的药理特性，不同 每种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 有关特定赤字及其在大脑中的本地化的信息。 产前暴露于药物的后代对药物的差异反应 专门在这些受体上起作用的可能表明 DisruptionInt他在特定神经过程中起作用，并且可能具有 对治疗方案的影响，以预防和/或减轻ARBD。