MOUSE SELECTION AND PHENOTYPING

描述(申请人提供)：酒精中毒的原因既有遗传因素，也有 环境：最可能的解释是基因和环境之间的相互作用导致了过度饮酒。虽然动物只能模拟酒精中毒的某些方面，但实验者可以控制它们的遗传和环境，从而更好地理解这些变量及其相互作用是如何导致酗酒的。在这项建议中，我们试图维持有选择地饲养的小鼠品系，要么自由饮用相对大量的酒精(高酒精偏好，o1：HAP)，要么戒酒(低酒精偏好，或LAP)。为了能够在高饮酒者和低饮酒者之间进行可靠的比较，将培育出高饮酒者和低饮酒者两个种群。我们还将通过跨越这两条高饮酒线来开发一种新的、非常高的饮酒线。这些小鼠对遗传学和行为学研究都很有用。此前，HAP小鼠被证明比LAP小鼠更有可能在反复经历后对酒精的激活效应产生更高的敏感性。在HAP小鼠中，酒精体验也增加了随后的饮酒。这项提议将寻求更好地理解 酒精敏感性增加的原因和后果，以及为什么HAPS更有可能表现出这一点。首先，这项建议将评估HAPS活性的增加是否可能是由于对酒精的不协调影响的耐受所致。其次，研究将评估酒精经验是否会增加对其他激活药物的敏感性，如可卡因。这样的研究可以模拟为什么许多人类酗酒者经常转向其他滥用药物。第三，将研究HAP小鼠是否比LAP小鼠对酒精以外的药物表现出更多的敏感性，以评估导致酗酒的基因是否会影响大脑对许多滥用药物的适应。这笔拨款的额外工作将开发一种新的行为模型来评估酒精寻求和渴望行为，这被认为是酒精中毒的重要因素。我们将评估被培育成大量饮酒的小鼠，当它们必须努力获得酒精溶液时，是否也会表现出更多的酒精寻求。通过比较这些线，并操纵环境，这项提议将增加对高饮酒基因如何与药物和酒精体验相互作用以促进进一步饮酒的理解。

DESCRIPTION (provided by applicant): The causes of alcoholism are both genetic and environmental: the most likely explanation is an interaction between genes and environment resulting in excessive drinking. Although animals can only model certain aspects of alcoholism, the experimenter can control both their genetics and environment, leading to better understanding of how these variables and their interaction cause high drinking. In this proposal, we seek to maintain lines of mice selectively bred to either freely drink a relatively large amount of alcohol (High Alcohol Preferring, o1:HAP), or abstain (Low Alcohol Preferring, or LAP). To allow reliable comparisons between high and low drinkers, two populations of both high and low drinkers will be bred. We will also develop a new, very high drinking line by crossing the two high drinking lines. These mice will be useful for both genetic and behavioral studies. Previously, HAP mice were shown to be more likely than LAP mice to develop increased sensitivity to activating effects of alcohol following repeated experience. In HAP mice, alcohol experience also increased subsequent alcohol drinking. This proposal will seek to better understand the causes and consequences of increased alcohol sensitivity, and why HAPs are more likely to show it. First, this proposal will assess whether the increase in activity in HAPs might result from tolerance to the incoordinating effects of alcohol. Second, studies will assess whether experience with alcohol increases sensitivity to other activating drugs, such as cocaine. Such studies can model why many human alcoholics often turn to other drugs of abuse. Third will be study of whether HAP mice show more sensitization than LAP mice to drugs other than alcohol, to assess whether the genes which cause high drinking affect how the brain adapts to many drugs of abuse. Additional work in this grant will develop a new behavioral model to assess alcohol seeking and craving behavior, thought to be important in alcoholism. We will assess whether mice bred to drink large quantities of alcohol will also show more alcohol seeking when they must work to gain access to alcohol solutions. By comparing these lines, and manipulating the environment, this proposal will increase understanding of how genes for high drinking interact with drug and alcohol experience to promote further drinking.