MEMORY COMPONENT OF BEHAVIORAL ETHANOL TOLERANCE

这些实验的目标是检查大脑的记忆成分 对长期服用乙醇的行为耐受性。我们建议 习得的耐受性涉及激活可能调制的系统 小鼠复杂的学习和记忆过程。目前的证据表明 大脑蛋白激酶C可能调节某些形式的学习和 记忆。检测是否参与了蛋白激酶C的激活 在发展对乙醇的耐受性方面，一种遗传方法将是 使用。C57BL/6小鼠对低温耐受性的研究 将腹膜腔内注射乙醇与DBA/2进行比较 对低温效应没有明显耐受性的小鼠 反复给药后的乙醇含量。以前的实验是这样的 实验室研究表明，C57BL/6和DBA/2小鼠的复合体也不同 学习成绩和海马区蛋白激酶C活性。因此，一个 这些参数之间可能存在着关系，并与发展 学会了对乙醇的耐受性。 我们将通过两种不同的途径来检测获得性的乙醇耐受性 在环境提示的复杂性上有所不同的管理 和动物的处理：1)为了最大限度地暗示，乙醇将 通过腹膜内注射和体温 在日常处理的小鼠中进行监测，并在不同的环境中进行测试 2)为了最大限度地减少暗示，小鼠将接受静脉注射 使用微型器持续监测体温的乙醇 系统。将进行剂量-反应和时间-过程实验。 蛋白激酶C与佛波酯结合的生化测定 包括海马体在内的七个大脑区域将在 乙醇处理后。 在选择最佳条件后，潜在蛋白质的变化 激酶C磷酸蛋白底物将作为以下函数进行测量 C57BL/6和DBA/2脑片对乙醇耐受性的研究 最后，将进行BXD重组近交系研究，以评估 共同基因是否调节习得性耐受性的形成 酒精，蛋白激酶C活性，或复杂学习的测量 性能。 这些研究应该提供有关以下方面的新信息 学习和记忆系统在酒精耐受性发展中的作用。

The goal of these experiments is to examine the memory component of behavioral tolerance to chronic administration of ethanol. We propose that learned tolerance involves activation of systems that may modulate complex learning and memory processes in mice. Current evidence suggests that brain protein kinase C may modulate some forms of learning and memory. To examine whether activation of protein kinase C is involved in the development of tolerance to ethanol, a genetic approach will be used. C57BL/6 mice which develop tolerance to the hypothermic effects of ethanol after intraperitoneal administration will be compared to DBA/2 mice which do not show pronounced tolerance to the hypothermic effects of ethanol after repeated administration. Previous experiments from this laboratory have shown that C57BL/6 and DBA/2 mice also differ in complex learning performance and hippocampal protein kinase C activity. Thus a relationship may exist between these parameters and the development of learned tolerance to ethanol. Learned tolerance to ethanol will be examined using two different routes of administration which differ in the complexity of environmental cueing and handling of the animals: 1) to maximize cueing, ethanol will be administered via intraperitoneal injections and body temperature will be monitored in mice handled daily and tested in different environments and 2) to minimize cueing, mice will receive intravenous administration of ethanol with constant monitoring of body temperature using minimitter systems. Dose-response and time-course experiments will be performed. Biochemical measurements of protein kinase C and phorbol ester binding in seven brain regions including hippocampus will be performed during and after ethanol treatment. After optimal conditions are selected, changes in potential protein kinase C phosphoprotein substrates will be measured as a function of ethanol tolerance in C57BL/6 and DBA/2 brain slices. Lastly, a BXD recombinant inbred strain study will be performed to assess whether common genes mediate the development of learned tolerance to ethanol, protein kinase C activity, or measurements of complex learning performance. These studies should provide new information concerning the role of learning and memory systems in the development of ethanol tolerance.