NEUROBIOLOGICAL FACTORS IN VULNERABILITY TO OPIOID ABUSE

本提案的目的是描述行为和 神经基质，决定个体差异的功效 吗啡作为一种麻醉剂和对阿片类药物强化行为的脆弱性。 有待检验的具体假设是， 中脑边缘μ阿片受体存在个体差异 浓度和吗啡作为主要麻醉剂的功效。 的 该提案中概述的项目将利用基因工程 动物模型与行为遗传学和神经解剖学技术， 探讨区域μ阿片受体与神经元凋亡的关系 浓度和吗啡强化的行为。 继承的差异 区域μ阿片受体浓度（基因工程和 自然发生的）将被用作独立变量，以确定 如果μ-阿片受体分布的差异， 中脑边缘系统显著影响吗啡作为 - 好的 静脉注射吗啡的自我管理行为将 在两组基因工程小鼠中进行了研究， μ-阿片受体，两种常用的重组近交系， 高和低阿片受体浓度和两个亲本近交系 用于转基因动物生产的菌株。 中枢μ阿片受体 所有基因型中的分布将通过放射自显影进行表征 技术. μ-阿片类药物与脑卒中关系的多因素分析 受体浓度在特定的神经解剖区域和自我- 管理行为将决定特定区域或 区域的组合解释了在自我中看到的遗传变异， 行政行为 总的来说，这些项目将直接测试 基因工程改变对中枢神经系统阿片受体的影响 浓度对静脉注射吗啡的增强作用 注射和测试的假设，μ阿片受体浓度 中边缘系统的一个或多个区域中的细胞的数目预测 吗啡自我给药行为的基因型依赖性差异。 如果多变量分析的结果识别出一个区域或 占世界人口很大一部分的区域的组合 在自我管理行为中看到的差异，这些结果将提供 这是识别参与神经系统疾病的特定神经区域的重要一步， 阿片类药物易感性的神经生物学基础 成瘾

This objective of this proposal is to characterize the behavioral and neural substrates that determine individual differences in the efficacy of morphine as a reinforcer and vulnerability to opioid-reinforced behavior. The specific hypothesis to be tested is that a significant relationship exists between individual differences in mesolimbic mu-opiate receptor concentration and the efficacy of morphine as a primary reinforcer. The projects outlined in this proposal will utilize genetically engineered animal models with behavior genetic and neuroanatomical techniques to investigate the relationship between regional mu-opiate receptor concentration and morphine-reinforced behavior. Inherited differences in regional mu-opiate receptor concentration (genetically engineered and naturally occurring) will be used as the independent variable to determine if differences in the distribution of mu-opiate receptors within the mesolimbic system significantly affect the efficacy of morphine as a reinforcer. Intravenous morphine self-administration behavior will be investigated in two sets of genetically engineered mice that overexpress the mu-opiate receptor, two commonly used recombinant inbred strains with high and low opiate receptor concentration and the two parental inbred strains used for transgenic animal production. Central mu-opiate receptor distribution in all genotypes will be characterized via autoradiographic techniques. Multivariate analysis of the relationship between mu-opiate receptor concentration in specific neuroanatomical regions and self- administration behavior will determine if a particular region or combination of regions accounts for the genetic variance seen in self- administration behavior. Overall, these projects will directly test the effect of genetically engineered alterations in CNS opiate-receptor concentration on the reinforcing effects of intravenous morphine injections and test the hypothesis that mu-opiate receptor concentration in one or more regions of the mesolimbic system are predictive of genotype-dependent differences in morphine self-administration behavior. if the results of the multivariate analysis identify a region or combination of regions that account for a significant portion of the variance seen in self-administration behavior, these results will provide a significant step towards identifying specific neural regions involved in the neurobiological substrates underlying vulnerability to opioid addiction.