ETHANOL SELECTION: COMPARATIVE NEUROCHEMISTRY

现在人们普遍认识到，对 乙醇的影响，以及对酒精和酒精的耐受性的发展 对乙醇的依赖既是遗传的，也是环境的。 监管。然而，乙醇生产其 影响和基因因素调节反应的方式 动物对乙醇的反应仍然知之甚少。 调查这些问题的一种策略涉及 不同特异性小鼠品系的选育 乙醇的行为反应及其相关研究 对选择的行为和神经化学反应。查找一个 相关的神经化学反应将意味着相关的 反应一定受到某些基因的影响，这些基因与 选定的反应，并表明改变的神经化学物质 乙醇的作用机制可能与其作用途径有关。我们是 目前培育的两个反应不同的小鼠品系 急性剂量的乙醇：体温过低(TEMP)线 对乙醇的影响敏感(冷)和抗(热) 体温和活动(OFA)线俯卧(快速) 对乙醇引起的活性增加具有抵抗力(缓慢)。这个 相关神经化学反应的平行研究 行为反应的选择从未被报道过。 这项建议的目标是识别和系统化 特定反应和相关反应的相关研究 临时工选拔过程中的神经递质系统 和OFA线路。这一提议的一个主要假设，基于 生理和药理学数据，是不是 儿茶酚胺能和5-羟色胺能系统介导乙醇的作用 在临时线上，儿茶酚胺能通路 OFA系列之间的差异。首先，我计划测量 多巴胺、去甲肾上腺素、5-羟色胺及其代谢物的水平 它们的受体在小鼠体内的结合特性 接受了急性剂量的乙醇注射。这些实验应该 快速而灵敏地衡量每个项目中发生的变化 路径。根据这些研究的结果，我将设计 在特定系统中进行更详细的实验 受影响，特别是第二信使和神经递质 放手。这项提案的成功完成将增加 我们对乙醇如何引起其行为影响的理解 基因如何调节对乙醇的敏感性。

It is now generally recognized that differences in sensitivity to the effects of ethanol, and the development of tolerance to and dependence on ethanol is under genetic as well as environmental regulation. However, the mechanism by which ethanol produces its effects and the way genotypic factors modulates the response of animals to ethanol is still poorly understood. One strategy for investigating these questions involves the selective breeding of mouse lines which differ in specific behavioral responses to ethanol and the study of correlated behavioral and neurochemical responses to selection. Finding a correlated neurochemical response would imply that the correlated response must be influenced by some genes in common with the selected response and suggest that the altered neurochemical pathway may be involved in ethanol's mechanism of action. We are currently breeding lines of mice which differ in two responses to an acute dose of ethanol: hypothermia (TEMP) lines which are susceptible (COLD) and resistant (HOT) to the effect of ethanol on body temperature, and activity (OFA) lines which are prone (FAST) and resistant (SLOW) to increased activity caused by ethanol. The parallel study of correlated neurochemical responses during selection for a behavioral response has never been reported. The goal of this proposal is the identification and systematic study of correlated responses in specific and relevant neurotransmitter systems during the selection process for the TEMP and OFA lines. One main hypothesis of this proposal, based on physiological and pharmacological data, is that the catecholaminergic and serotonergic systems mediate ethanol's effect in the TEMP lines, and that the catecholaminergic pathways mediate the differences in the OFA lines. Initially, I plan to measure the levels of DA, NE, 5-HT and their metabolites, and characterize the binding properties of their receptors in mice that have received an acute dose of ethanol. These experiments should provide a rapid and sensitive measure of changes occurring in each pathway. Based on the outcome of these studies I will design experiments focussing in more detail in the specific systems affected, particularly the second messengers and neurotransmitter release. The successful completion of this proposal will increase our understanding of how ethanol causes its behavioral effects and how genotype regulates sensitivity to ethanol.