SELECTION FOR ALCOHOL PREFERENCE AND PHENOTYPING

该IRPG研究计划的长期目标是确定 基因和神经生物学底物的基础上酒精寻求 通过动物模型的研究。 1976年，我们开始 高、低度酒精品系的选育 消耗/偏好来自Wistar大鼠的基础种群。 的 随后显示所得的优选P线满足 酒精中毒动物模型的标准。 比较P和 非偏好NP系揭示了先天的神经生物学差异 以及对酒精反应的差异。 等 神经生物学知识的进步为我们提供了 酒精中毒的药物研发 1984年，我们开始挑选 HAD（高度饮酒）和LAD（低度饮酒）线 来自遗传异质性N/Nih大鼠。 他们现在大约在 S2 O世代 本研究项目（IRPG 1）的具体目标是： 未来5年将是：l）继续开发复制 HAD_1/LAD_1和HAD_2/LAD_2品系的稳定选择限; 通过反向选择已经达到该选择限制，并且 近亲繁殖;和3）冷冻保存来自HAD和LAD系的胚胎， 当它们达到选择限制时。 HAD和LAD动物将 然后进行比较，以确定是否行为，神经化学和 神经解剖学差异之间发现P和NP线是-看到 也在HAD和LAD之间。 这些研究将在 与IRPG 5、7和8合作。 行为测量（具体 目标4）将包括自发运动活动，焦虑，操作性 对乙醇的反应，乙醇的抗焦虑作用，乙醇诱导 对运动障碍的厌恶和耐受，以及对 乙醇 神经化学措施（具体目标5）将包括： 脑局部5-羟色胺（5-HT）、多巴胺（DA）含量及 代谢产物，以及5-HT，DA，GABA，NMDA，阿片样物质， 和烟碱受体。 神经解剖学测量（具体目标6） 将是DA和5 HT纤维密度在选定的大脑区域。 最后， 饮酒与其他行为之间的遗传相关性 在P/NP线中发现的酒精偏好的关联将是 在近交系P和NP大鼠的F2后代中确定， 酒精偏好和相关特征的研究将在这些 F2动物（具体目标7），与IRPG 2合作。

The long-term objective of this IRPG research program is to identify the genes and the neurobiological substrates underlying alcohol-seeking behavior through studies in animal models. In 1976, we began the selective breeding of rat lines for high and low alcohol consumption/preference from a foundation stock of Wistar rats. The resultant preferring P line was subsequently shown to satisfy the criteria for an animal-model of alcoholism. Comparisons of the P and the nonpreferring NP lines have revealed innate neurobiological differences between the lines as well as differences in responses to alcohol. Such gains in neurobiological knowledge have led to promising avenues of medications development for alcoholism. In 1984, we began the selection of the HAD (high-alcohol-drinking) and LAD (low-alcohol-drinking) lines from the genetically heterogeneous N/Nih rat. They are now at about the S2O generation. The specific aims of this research project (IRPG 1) in the next 5 years will be: l) to continue developing the replicate HAD1/LAD1 and HAD2/LAD2 lines to stable selection limits; 2) to ascertain that selection limit has been reached by means of reverse selection and inbreeding; and 3) to cryopreserve embryos from the HAD and LAD lines, when they have reached selection limits. The HAD and LAD animals will then be compared to ascertain whether the behavioral, neurochemical and neuroanatomical differences found between-the P and NP lines are- seen also between the HAD and LAD lines. These studies will be performed in collaboration with IRPGs 5, 7 and 8. The-behavioral measures (specific aim 4) will include spontaneous motor activity, anxiety, operant responding to ethanol, the anxiolytic effect of ethanol, ethanol-induced aversion, and tolerance to the motor-impairment and aversive effects of- ethanol. The neurochemical measures (specific aim 5) will include the brain regional contents of serotonin (5HT), dopamine (DA) and their metabolites, and the regional densities of 5HT, DA, GABA, NMDA, opioid, and nicotinic receptors. The neuroanatomical measures (specific aim 6) will be DA and 5HT fiber densities in selected brain regions. Finally, genetic correlations between alcohol consumption and other behavioral associations of alcohol preference discovered in the P/NP lines will be ascertained in the F2 offspring of inbred P and NP rats, and QTL napping of alcohol preference and correlated traits will be performed in these F2 animals (specific aim 7), in collaboration with IRPG 2.