PHARMACOGENETIC ANALYSIS OF LOW-DOSE ETHANOL EFFECTS

这项提案中概述的研究考察了基因对 对低剂量酒精的行为反应和神经化学事件 这是低剂量乙醇敏感性的基础。重组近交系菌株和 表现出广泛不同行为的选定小鼠品系 对低剂量乙醇的反应将用于产生基因 行为之间以及行为与行为之间的相关分析 神经化学指标。感兴趣的行为包括运动 活动、探索和焦虑指数，即趋色性和加性- 迷宫表演。对低血压感兴趣的特定神经化学机制 剂量酒精行为反应包括多巴胺代谢和 前脑和中脑不连续区域的神经降压素水平。特定的 结构包括伏核、腹侧被盖、尾状核- 壳核和额叶皮质。特异性多巴胺受体激动剂和 拮抗剂[d1和d2]将与以下药物一起集中应用 IP地址。给药剂量的乙醇最大限度地区分 品系/品系相关行为对低剂量乙醇的反应。长的- 这项研究的术语目标是定义基于遗传的神经化学 低剂量乙醇调节作用的机制。最终这些 研究将对了解饮酒行为具有普遍的启发式价值 行为和酗酒。

The research outlined in this proposal examines genetic influences on behavioral responses to low doses of ethanol and neurochemical events which underlie low-dose ethanol sensitivity. Recombinant inbred strains and selected lines of mice which evince widely differential behavioral responses to low doses of ethanol will be used to generate genetic correlational analyses among behaviors and between behavioral and neurochemical measures. The behaviors of interest include locomotor activity, exploration and indices of anxiety, i.e., thigmotaxis and plus- maze performance. Specific neurochemical mechanisms of interest in low- dose ethanol behavioral response include dopamine metabolism and neurotensin levels in discrete areas of the fore and midbrain. Specific structures include the nucleus accumbens, ventral tegmentum, caudate- putamen and frontal cortex. Specific dopamine receptor agonists and antagonists [both D1 and D2] will be applied centrally, concomitantly with i.p. administration of doses of ethanol which maximally differentiate strain/line-related behavioral response to low doses of ethanol. The long- term goal of this research is to define genetically based neurochemical mechanisms mediating effects of low doses of ethanol. Ultimately these studies will have general heuristic value in understanding alcohol-seeking behavior and alcoholism.