GENETIC FACTORS IN DRUG SELF-ADMINISTRATION

自然发生的遗传差异和分子遗传学 基因组的操作提供了一种手段， 滥用药物的神经生物学和精神药理学。本实验室 对分子生物学的整合特别感兴趣 行为遗传学和行为药理学作为一种工具， 药物滥用的神经生物学机制 的 本文所述实验的目的是鉴定神经细胞 与吗啡的疗效显著相关的区域 以确定其他药物之间的潜在共性 虐待 到目前为止，我们的实验室已经检查了静脉注射阿片类药物 四种近交系大鼠和几种近交系大鼠的自我给药行为 小鼠的近交系、重组近交系和转基因系。 遗传 简单（固定比率）和要求更高的关系 （累进比率）加固时间表已确定， 所有这些基因型。 多因素分析 神经解剖分布的遗传差异|- 鸦片制剂 受体浓度和前脑啡肽原mRNA及其相关性 阿片类药物强化行为的效力和功效已被用作 暗示与脆弱性相关的潜在神经区域 阿片类药物滥用 这些研究的结果表明：（1） 受试者的基因型显著影响吗啡的疗效 2）基因型显著影响浓度 以及μ阿片受体和前脑啡肽原的区域分布， 3)没有一个区域可以解释吗啡中的遗传变异 自我管理行为和4）相对敏感性 吗啡的运动刺激或镇痛作用不是预测性的 自我给药行为，而条件运动 药物的刺激作用可能是预测行为下， 强化的渐进比率表。 另外的研究已经 建立了测定尼古丁和 可卡因自我管理行为在这些相同的 基因型 初步结果表明，尼古丁和可卡因 在小鼠基因型中作为阳性标记， 注射吗啡 这些研究将有助于确定潜在的 滥用药物的神经生物学机制。

Naturally occurring genetic differences and molecular genetic manipulations of the genome provide a means for investigating the neurobiology and psychopharmacology of abused drugs. Our laboratory is specifically interested in the integration of molecular biology, behavior genetics and behavior pharmacology as a tool to investigate the neurobiological mechanisms in vulnerability to drug abuse. The goal of the experiments described herein has been to identify neural regions significantly associated with the efficacy of morphine as a reinforcer and to determine potential commonalties across other drugs of abuse. To date, our laboratory has examined intravenous opioid self-administration behavior in four inbred rat strains and several inbred, recombinant inbred and transgenic lines of mice. The genetic relationship across simple (Fixed Ratio) and more demanding (Progressive Ratio) schedules of reinforcement has been determined in all these genotypes. Multivariate analysis of the relationship between genetic differences in the neuroanatomical distribution of |-opiate receptor concentration and preproenkephalin mRNA and the relative potency and efficacy of opioid reinforced behavior has been used as a means to suggest potential neural regions associated with vulnerability to opioid drug abuse. Results of these studies demonstrate that 1) The genotype of the subject significantly affects the efficacy of morphine as a reinforcer, 2) Genotype significantly affects the concentration and regional distribution of mu-opiate receptors and preproenkephalin, 3) No one region can account for the genetic variance seen in morphine self-administration behavior and 4) Relative sensitivity to the locomotor stimulant or analgesic effects of morphine are not predictive of drug self-administration behavior whereas the conditioned locomotor stimulant effects of the drug may be predictive of behavior under the progressive ratio schedule of reinforcement. Additional studies have been established to determine the relative level of nicotine and cocaine self-administration behavior across some of these same genotypes. Initial results suggest that nicotine and cocaine will serve as a positive reinforcer in a mouse genotype that readily self- administers morphine. These studies will help to identify potential neurobiological mechanisms common across drugs of abuse.