SELECTION FOR ALCOHOL PREFERENCE AND PHENOTYPING

此IRPG研究计划的长期目标是确定 基因与寻酒的神经生物学基础 通过动物模型研究的行为。1976年，我们开始了 高、低度酒精品系的选育 来自Wistar大鼠基础种群的消费/偏好。这个 所得到的首选P线随后被证明满足 酒精中毒动物模型的标准。P与The的比较 不喜欢NP的品系揭示了先天的神经生物学差异 字里行间的差异以及对酒精反应的差异。是这样的 神经生物学知识的进步导致了有希望的途径 治疗酒精中毒的药物开发。1984年，我们开始了选拔 HAD(高酒精饮酒)和LAD(低酒精饮酒)线 来自遗传异质性的N/NIH大鼠。他们现在大约在 产生S2O。这项研究项目(IRPG 1)的具体目标是 未来5年：L)继续发展复制 HAD1/LAD1和HAD2/LAD2品系稳定的选择下限；2)确定 通过反向选择达到了该选择极限 近亲交配；3)冷冻保存HAD和LAD系的胚胎， 当他们达到选择限制时。哈德和小动物们会 然后进行比较，以确定行为、神经化学和 P线和NP线之间的神经解剖学差异是可见的 也是在HAD和LAD之间。这些研究将在 与IRPG 5、7和8协作。-行为测量(具体 目标4)将包括自发运动活动、焦虑、可操纵性 回应乙醇，乙醇的抗焦虑作用，乙醇诱导 厌恶，以及对运动损伤和厌恶效应的耐受性- 乙醇。神经化学措施(具体目标5)将包括 脑内局部5-羟色胺、多巴胺及其受体的含量 代谢物和5-羟色胺、多巴胺、氨基丁酸、N-甲基-D-天冬氨酸、阿片类药物、 和尼古丁受体。神经解剖学测量(特定目标6) 将是选定大脑区域中DA和5-羟色胺纤维密度。最后， 饮酒与其他行为的遗传相关性 在P/NP品系中发现的酒精偏好的关联将是 近交系P、NP大鼠F2代基因定位及QTL定位 酒精偏好和相关特征的研究将在这些 F2动物(特定目标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.