Ethanol Discrimination in Transgenic Mice

转基因小鼠的乙醇歧视

• 批准号: 6479592
• 负责人: KEITH L SHELTON
• 金额: $ 7.25万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6479592
• 关键词: GABA receptor; NMDA receptors; alcoholic beverage consumption; alcoholism /alcohol abuse; animal population genetics; behavior test; behavioral /social science research tag; ethanol; genetic susceptibility; genetically modified animals; inbreeding; injection /infusion; laboratory mouse; ligands; neurotransmitter receptor; operant conditionings; preference; psychopharmacology; receptor binding; receptor sensitivity; serotonin; serotonin receptor; stimulus /response; substance abuse related behavior

Alcohol abuse and alcoholism are serious societal problems. Genetics play a major role in determining the risk for developing alcohol abuse disorders. Inbred and transgenic mice are powerful tools for examining the genetic and molecular basis of the effects of alcohol. Some transgenic and inbred mice have altered responses to the physiological and reinforcing effects of ethanol. It has not been determined if the subjective discriminative effects of ethanol are different across strains of inbred mice or altered in transgenic mice. We propose to examine the discriminative stimulus properties of ethanol in two inbred mouse strains (C57BL/6 and DBA/2J) and one transgenic mouse line which over-expresses 5-HT3 receptors. The C57BL/6 mouse strain is characterized by high levels of ethanol drinking and decreased sensitivity to ethanol. The DBA/2J and 5-HT3 over-expressing strains drink less ethanol than controls and have increased responses to the motor activating effects of low dose ethanol. The first specific aim of this proposal is to train an ethanol discrimination in 5-HT3 over- expressers, B6SJL control mice, C57BL/6 mice and DBA/2J mice. It is hypothesized that all four strains will be capable of discriminating ethanol from vehicle but will differ in sensitivity to ethanol's discriminative stimulus effects. The second specific aim is to determine if test drug substitution patterns for ethanol systematically differ between transgenic and inbred mouse strains. It is hypothesized that genetic alterations of the 5-HT3 receptor system will effect not only the ability of 5-HT3 ligands to substitute for ethanol, but also drugs which act via the GABAA and NMDA receptor systems. It is also hypothesized that C57BL/6 and DBA/2J mice will differ from one another in the substitution patterns of the test drugs for ethanol. These studies will characterize the discriminative stimulus effects of ethanol in transgenic and inbred strains of mice. These experiments will also explore the direct consequences of alterations of the 5-HT3 receptor systems to the discriminative stimulus effects of ethanol anal the contribution of genetic. background to the ethanol's discriminative ctimnlnc effects.

酗酒和酗酒是严重的社会问题。遗传学在确定酒精滥用障碍的风险方面起着重要作用。近亲繁殖和转基因小鼠是研究酒精影响的遗传和分子基础的有力工具。一些转基因和近交系小鼠对乙醇的生理和强化作用的反应发生了改变。尚未确定乙醇的主观辨别效应是否在近交系小鼠中不同或在转基因小鼠中改变。我们建议检查的歧视性刺激特性的乙醇在两个近交系小鼠（C57 BL/6和DBA/2 J）和一个转基因小鼠品系，过表达5-HT 3受体。C57 BL/6小鼠品系的特征在于高水平的乙醇饮用和对乙醇的敏感性降低。DBA/2 J和5-HT 3过表达菌株比对照饮用更少的乙醇，并且对低剂量乙醇的运动激活作用的反应增加。该建议的第一个具体目的是在5-HT 3过表达者、B6 SJL对照小鼠、C57 BL/6小鼠和DBA/2 J小鼠中训练乙醇辨别。据推测，所有四种菌株将能够区分乙醇从车辆，但将不同的敏感性，乙醇的歧视性刺激效应。第二个具体目标是确定乙醇的试验药物替代模式在转基因和近交系小鼠品系之间是否存在系统性差异。假设5-HT 3受体系统的遗传改变不仅影响5-HT 3配体取代乙醇的能力，而且影响通过GABAA和NMDA受体系统起作用的药物。还假设C57 BL/6和DBA/2 J小鼠在供试药物对乙醇的替代模式方面彼此不同。这些研究将描述乙醇在转基因和近交系小鼠中的区别性刺激效应。这些实验还将探讨5-HT 3受体系统的改变对乙醇的辨别刺激效应的直接后果以及遗传因素的贡献。乙醇的区别性CTIMNNNC效应的背景。