Ethanol Discrimination in Transgenic Mice

酒精滥用和酗酒是严重的社会问题。基因在决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作用的遗传和分子基础的有力工具。一些转基因和近亲繁殖的小鼠对乙醇的生理和强化作用的反应发生了改变。目前还没有确定乙醇的主观辨别效应是否在近亲繁殖的小鼠品系中有所不同或在转基因小鼠中有所改变。我们拟研究乙醇对两种近交系小鼠（C57BL/6和DBA/2J）和一种过表达5-HT3受体的转基因小鼠的区别性刺激特性。C57BL/6小鼠品系的特点是高水平的乙醇饮用和对乙醇的敏感性降低。过表达DBA/2J和5-HT3的菌株比对照组摄入更少的乙醇，对低剂量乙醇的运动激活作用的反应增强。本研究的第一个具体目的是培养5-HT3过表达者、B6SJL对照小鼠、C57BL/6小鼠和DBA/2J小鼠的乙醇识别能力。假设这四种菌株都能够区分乙醇和载体，但对乙醇的区分刺激效应的敏感性不同。第二个具体的目的是确定是否测试药物替代模式乙醇系统不同的转基因和近交系小鼠品系。据推测，5-HT3受体系统的遗传改变不仅会影响5-HT3配体替代乙醇的能力，还会影响通过GABAA和NMDA受体系统起作用的药物。我们还假设C57BL/6和DBA/2J小鼠对乙醇的替代模式不同。这些研究将表征乙醇对转基因和近交系小鼠的区别性刺激作用。这些实验还将探讨5-HT3受体系统的改变对乙醇的鉴别刺激效应的直接影响以及基因的贡献。乙醇的区别性刺激效应的背景。

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.