PRENATAL ALCOHOL--EFFECTS ON CENTRAL DOPAMINE RECEPTOR SUBTYPES

怀孕期间酗酒被认为是一种重大风险 影响胎儿正常生长发育的因素。产前饮酒 暴露可导致胎儿酒精综合征和酒精相关分娩 与认知障碍相关的缺陷(ARBD)和 精神发育迟滞。这些神经行为障碍是最严重的 严重的，最不能接受治疗的。而机制(S) 这些影响的责任还没有明确确定，结果是 对动物模型的研究表明，子宫内接触乙醇 明显损害大多数神经递质的发育。 产前酒精降低大脑中的多巴胺浓度 多巴胺能神经元胞体及其投射的区域 并对多巴胺再摄取场所的发展产生不利影响。 DA受体的数量也发生了改变，但慢性 治疗方法没有明确的定义。 建议的实验将研究多巴胺的作用。 ARDB病因学中的受体亚型。怀着时间的斯普拉格- Dawley Rate将被喂以含有35%乙醇衍生的液体日粮 怀孕11-21天的卡路里(无水乙醇)。血液酒精水平将会是 在GDS 15和19上的大坝中进行测量。双馈(PF)大坝将 饲喂相同的流质日粮，但用糊精-麦芽糖替代 乙醇的等量热量。实验室食物控制(LC)将有随意性 可单独或直接接触标准实验室和拮抗剂 结合D_1、D_2和D_3DA受体 测试产前饮酒是否会改变行为对这些的敏感度 化合物。刺激和/或阻断受体亚型 A特定的行为反应，将被监测30年 在注射毒品后，使用时间采样技术，持续数分钟。AS 这些药物引起的行为既与剂量有关，也与性别有关， 完整的剂量-反应曲线将在男性和 雌性后代。多巴胺D_1、D_2、D_3的治疗作用 纹状体、尾状核和前额叶皮质中AS的结合 以及DA及其主要代谢物DOPAC的浓度将 在21-22日龄的子代中也可测定。 由于不同的药理特性，不同的 三者的解剖分布及信号转导机制 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。 产前酒精暴露子代对药物的差异反应 在这些受体上的特异性行为可能表明 干扰特定神经过程的功能，可能有 对预防和/或减轻ARBD的治疗方案的影响。

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.