Selective Breeding for Drinking in the Circadian Dark

描述（由申请人提供）：NOT-OD-09-058，NIH宣布为竞争性修订申请提供恢复法案资金。我们正在生产重复的小鼠品系，这些小鼠是根据它们在黑暗中大量饮酒的倾向（HDID）而选择性繁殖的。我们在其昼夜黑暗周期的第3小时开始，在每天2次暴露于20%乙醇2-4小时/天的第二天饲养小鼠以获得高（>150 mg-%）巴尔斯。选择已经成功，并且大多数小鼠现在饮酒至醉酒（Crabbe等人，2009：App MS #2）。现有拨款的一个目的是检查微注入INIA靶向脑回路（最初是侧隔和海马）的药物对DID的影响。我们在最近的一项实验中表明，巴氯芬/蝇蕈醇微量输注到隔减少酒精DID，而不影响饮水。 酒精性饮酒的特征是对酒精的渴望，一旦开始饮酒就失去控制。这些特征，分别被称为食欲和消费，有不同的生物学基础（一个很好的审查见（参孙和霍奇。1996年：ADD MS #3）。人类和啮齿动物都倾向于在集中的会议或回合中喝酒。彻底描述饮酒行为至少需要考虑回合数、平均回合间隔和平均回合幅度。相关的，homeostaticallv调节过程周围的水摄入量和摄食行为也必须进行研究。使用配备lickometer的笼子，我们发现C57 BL/6 J小鼠开始较少的饮酒回合。但他们摄入乙醇的速度是摄入水的两倍。没有关于食物摄入模式的信息（舔食计系统无法做到这一点）。 我们建议获得一个计算机化系统（BioDAQ情景摄入监测笼），使我们能够在DID会话期间以精细的时间分辨率评估液体和食物摄入。我们将能够评估回合频率。回合间间隔、回合持续时间（大小）以及饮酒是否与进食（即正餐）在时间上相关联。此外，我们将能够将这些微观结构行为分析应用于对传递到大脑中的神经化学物质的反应。一些人类研究表明，某些饮酒模式比其他模式更容易受到改善药物治疗的影响（Anton et al. 2004年）。因此，不同的化合物可能会对饮用水的微观结构产生不同的影响。为了完成这些额外的实验，我们将聘请一名博士后水平的人和一名额外的研究助理，并保留一名兼职员工。 公共卫生相关性：这个补充项目将研究饮酒行为的微观结构，其与食物和水消费模式的关系，以及直接微注入特定脑区的药理学试剂对饮酒不同方面的影响（例如，食欲与消费）。这些研究将有助于进一步预测酒精滥用、酒精中毒和特定酒精相关健康问题的风险。我们正在研究的遗传风险和保护性标志物将在未来用于预防和治疗酒精中毒。

DESCRIPTION (provided by applicant): NOT-OD-09-058, NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications. We are producing replicated lines of mice selectively bred for their propensity to high drinking in the dark (HDID). We are breeding mice for their high (>150 mg-%) BALs on the second day of 2 daily exposures to 20% ethanol for 2-4 h/day, starting in hr 3 of their circadian dark cycle. Selection has succeeded, and most mice now drink to intoxication (Crabbe et al. 2009: App MS #2). One aim of the existing grant is to examine the effects on DID of drugs microinfused into INIA-targeted brain circuits, initially the lateral septum and the hippocampus. We have shown in a recent experiment that baclofen/muscimol microinfusions into septum reduced alcohol DID while not affecting water drinking. Alcoholic drinking is characterized bv preoccupation with obtaining access to alcohol (craving) and loss of control over drinking once initiated. These features, termed appetitive and consummatory, respectively, have different biological underpinnings (for an excellent review see (Samson and Hodge. 1996: ADD MS #3). Humans and rodents both tend to drink in focused sessions, or bouts. Thorough description of drinking behavior requires at least consideration of number of bouts, their average inter-bout interval, and the average bout magnitude. The related, homeostaticallv-regulated processes surrounding water intake and feeding behavior must also be studied. Using lickometer-equipped cages, we found that C57BL/6J mice initiated fewer drinking bouts for ethanol. but they ingested ethanol twice as quickly as they did water. No information is available about pattern of food ingestion (lickometer systems cannot do this). We propose to acquire a computerized system (BioDAQ Episodic Intake Monitor cages) that will allow us to assess liquid and food intake with fine temporal resolution during DID sessions. We will be able to assess bout frequency. inter-bout interval, bout duration (size), and whether or not ethanol drinking is temporally coupled with eating (i.e. prandial). Furthermore, we will be able to apply these micro structural behavioral analyses to the response to neurochemicals delivered into the brain. Some human studies suggest that certain patterns of drinking are more susceptible to ameliorative pharmacotherapy than others (Anton et al.. 2004). Thus, different compounds may exert different effects on drinking microstructure. In order to accomplish these additional experiments, we will hire a post-doctoral level person and an additional research assistant, and retain a part-time employee. PUBLIC HEALTH RELEVANCE: This Supplementary project will examine the microstructure of alcohol drinking behavior, its relationship to food and water consumption patterns, and the effects of pharmacological agents microinfused directly into specific brain areas on different aspects of alcohol drinking (e.g., appetitive vs. consummatory). These studies will help further the goals of prediction of risk of alcohol abuse, alcoholism, and specific alcohol-related health problems. The genetic risk and protective markers that we are studying will be of utility in the future for prevention and treatment of alcoholism.