NEUROBIOLOGICAL FACTORS IN VULNERABILITY TO OPIOID ABUSE

这项建议的目标是描述行为和 决定个体差异的神经底物 吗啡作为增强剂和阿片类药物强化行为的脆弱性。 需要检验的具体假设是，一个重要的关系 中脑边缘Mu-阿片受体存在个体差异 作为主要增强剂的吗啡的浓度和有效性。这个 这份提案中概述的项目将利用基因工程 用行为遗传学和神经解剖学技术建立动物模型 探讨地区性Mu-阿片受体之间的关系 浓度和吗啡强化行为。继承的差异 区域Mu-阿片受体浓度(转基因和 自然发生的)将作为自变量来确定 如果Mu-阿片受体在脑内分布的差异 中脑边缘系统显著影响吗啡作为一种 增强剂。静脉注射吗啡自我给药行为会 在两组过表达的基因工程小鼠中进行的研究 Mu-阿片受体，两个常用的重组近交系菌株 高、低阿片受体浓度与两亲本近交系 用于转基因动物生产的菌株。中枢性Mu-阿片受体 所有基因型的分布将通过放射自显影进行表征。 技巧。阿片类药物相关性的多因素分析 特定神经解剖区域的受体浓度和自身 管理行为将决定特定地区或 区域的组合解释了自体遗传差异的原因 行政行为。总体而言，这些项目将直接测试 基因工程改变对中枢阿片受体的影响 浓度对静脉注射吗啡增强效应的影响 注射并验证阿片受体浓度的假设 在中边缘系统的一个或多个区域预测 吗啡自我给药行为的基因相关差异。 如果多变量分析的结果识别出一个区域或 占很大一部分的地区的组合 自我管理行为的差异，这些结果将提供 朝着确定涉及到的特定神经区域迈出的重要一步 阿片类药物易感性的神经生物学基础 上瘾。

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.