ETHANOL SELECTION: COMPARATIVE NEUROCHEMISTRY

现在人们普遍认识到， 乙醇的影响，以及对 对乙醇的依赖是遗传和环境的共同作用。 调控 然而，乙醇产生其 基因型因素调节的反应， 动物对乙醇的反应仍然知之甚少。 调查这些问题的一个策略涉及 小鼠品系的选择育种， 对乙醇的行为反应及其相关性研究 行为和神经化学反应。 找到一个 相关的神经化学反应意味着 反应一定受到某些基因的影响，这些基因与 选择性反应，并表明改变的神经化学物质 途径可能参与乙醇的作用机制。 我们 目前正在培育的小鼠品系在两种反应上不同， 急性剂量的乙醇：低温（TEMP）线， 对乙醇的影响敏感（冷）和抵抗（热） 体温和活动（OFA）线（FAST） 并且对由乙醇引起的活性增加具有抗性（SLOW）。 的 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。 该提案的目标是确定和系统化 具体和相关的相关反应研究 神经递质系统在选择过程中的温度 OFA线。 该提案的一个主要假设是， 生理学和药理学数据， 儿茶酚胺能和肾上腺素能系统介导乙醇的作用 在TEMP细胞系中，儿茶酚胺能途径介导 OFA线的差异。 最初，我计划测量 DA、NE、5-HT及其代谢产物的水平，并表征 它们的受体在小鼠体内的结合特性 注射了急性剂量的乙醇 这些实验应该 提供了一个快速和敏感的措施发生的变化，在每个 通路 根据这些研究的结果，我将设计 更详细地集中在特定系统中的实验 尤其是第二信使和神经递质 release. 这项提案的顺利完成将增加 我们对乙醇如何导致其行为影响的理解， 基因型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.