Ethanol Discrimination in Transgenic Mice

酗酒和酗酒是严重的社会问题。遗传学在确定发生酒精滥用障碍的风险方面发挥着重要作用。近亲交配和转基因小鼠是检验酒精影响的遗传和分子基础的有力工具。一些转基因和近亲交配的小鼠已经改变了对乙醇的生理和增强效应的反应。目前还没有确定乙醇的主观辨别效应在不同品系的近交系小鼠中是不同的，还是在转基因小鼠中发生了改变。我们建议在两个近交系小鼠品系(C57BL/6和DBA/2J)和一个过度表达5-HT3受体的转基因小鼠品系中检测乙醇的识别刺激特性。C57BL/6小鼠品系的特点是大量饮酒，对酒精的敏感度降低。过表达DBA/2J和5-HT3的菌株比对照菌株喝更少的乙醇，并对低剂量乙醇的运动激活效应有更高的反应。该方案的第一个具体目标是训练5-HT3过表达小鼠、B6SJL对照小鼠、C57BL/6小鼠和DBA/2J小鼠对乙醇的辨别能力。据推测，所有四种菌株都能够区分车辆中的乙醇，但对乙醇的歧视性刺激作用的敏感度不同。第二个具体目标是确定转基因和近交系小鼠品系之间乙醇的测试药物替代模式是否存在系统差异。假设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受体系统发挥作用的药物。还假设C57BL/6和DBA/2J小鼠在试验药物对乙醇的替代模式上会有所不同。这些研究将描述乙醇对转基因和近交系小鼠的区别刺激作用。这些实验还将探索5-HT3受体系统的改变对乙醇的区别性刺激效应的直接影响，以及遗传的贡献。乙醇的歧视性ctimnnc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.