Selective Breeding for Drinking in the Circadian Dark

昼夜节律黑暗中饮酒的选择性育种

• 批准号: 7815576
• 负责人: JOHN C. CRABBE
• 金额: $ 44.2万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7815576
• 关键词: Affect; Alcohol abuse; Alcohol consumption; Alcoholism; Alcohols; Animal Model; Anxiety; Area; Baclofen; Behavioral; Biological; Boutos; Brain; Breeding; Chronic; Circadian Rhythms; Clinic; Coupled; Data; Databases; Eating; Employee; Ethanol; Exposure to; Feeding behaviors; Food; Food Patterns; Frequencies; Funding; Future; Genetic Risk; Goals; Grant; Health; Hippocampus (Brain); Human; Illinois; Ingestion; Intake; Intoxication; Laboratories; Lateral; Letters; Liquid substance; Measures; Microdissection; Monitor; Mus; Muscimol; Oral; Pattern; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Postdoctoral Fellow; Prevention; Principal Investigator; Process; Recovery; Research; Research Personnel; Resolution; Risk; Rodent; Self Administration; Site; Structure; System; Testing; Texas; Time; United States National Institutes of Health; Universities; Water; Water consumption; Withdrawal; alcohol availability; alcohol craving; alcoholism therapy; austin; brain tissue; computerized; drinking; drinking behavior; drinking water; feeding; interest; neurochemistry; problem drinker; public health relevance; research study; response

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.

描述（由申请人提供）：NOT-OD-09-058，NIH 宣布恢复法案基金可用于竞争性修订申请。我们正在生产复制品系的小鼠，这些小鼠因其在黑暗中大量饮酒的倾向（HDID）而被选择性培育。我们正在培育小鼠，使其在每天两次暴露于 20% 乙醇 2-4 小时的第二天，从昼夜节律黑暗周期的第 3 小时开始，获得高 (>150 mg-%) BAL。选择成功了，大多数小鼠现在喝得酩酊大醉（Crabbe et al. 2009：App MS #2）。现有拨款的目的之一是检查药物微量注入 INIA 靶向脑回路（最初是侧隔膜和海马体）对 DID 的影响。我们在最近的一项实验中表明，将巴氯芬/蝇蕈醇微量输注到隔膜中确实可以减少酒精，同时不影响饮水。 饮酒的特点是全神贯注于获取酒精（渴望），一旦开始饮酒就会失去控制。这些特征分别被称为“食欲”和“完美”，具有不同的生物学基础（有关优秀评论，请参阅（Samson 和 Hodge。1996：ADD MS #3）。人类和啮齿动物都倾向于在集中会议或回合中饮酒。详细描述饮水行为至少需要考虑发作次数、平均发作间隔以及平均发作幅度，还必须考虑围绕饮水和进食行为的相关稳态调节过程。使用配备舔液计的笼子，我们发现 C57BL/6J 小鼠饮酒次数较少，但它们摄入乙醇的速度是水的两倍（舔液计系统无法做到这一点）。 ）我们建议购买一个计算机化系统（BioDAQ 情景摄入监测笼），该系统将使我们能够在 DID 会话期间以精细的时间分辨率评估液体和食物的摄入量。发作间隔、发作持续时间（大小）以及饮酒是否与进食（即膳食）暂时结合。此外，我们将能够将这些微观结构行为分析应用于对输送到大脑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饮酒模式更容易受到改善药物治疗的影响（Anton 等人，2004 年）。因此，不同的化合物可能对饮料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级别的人员和一名额外的研究助理，并保留一名兼职员工。 公共健康相关性：该补充项目将研究饮酒行为的微观结构、其与食物和水消耗模式的关系，以及直接微量注入特定大脑区域的药物对饮酒不同方面的影响（例如，食欲与完成性） ）。这些研究将有助于进一步实现预测酗酒、酗酒和特定的酒精相关健康问题风险的目标。我们正在研究的遗传风险和保护性标记将在未来用于预防和治疗酗酒。