Elmer G I, Pieper J O, Goldberg S R, George F R
Behavioral Pharmacology and Genetics Section, National Institute on Drug Abuse, Baltimore, Maryland 21224, USA.
Psychopharmacology (Berl). 1995 Jan;117(1):23-31. doi: 10.1007/BF02245094.
It is commonly thought that mu-receptors play an important role in the reinforcing effects of opioids. In the present study, inbred strains widely divergent in CNS opiate receptor densities were used to investigate the influence of genetic variation in receptor concentration on opioid-reinforced behavior. In particular, the CXBK/ByJ mice were used as an investigative tool because of their significantly lower number of CNS mu opioid receptors. The behavioral pharmacology of opioids in the mu-deficient CXBK/ByJ mice was compared to other commonly used inbred mouse strains, C57BL/6J and BALB/cJ, and the opiate receptor rich CXBH/ByJ mice. Operant opioid reinforced behavior, opioid-induced locomotor stimulation, analgesia and respiratory depression were investigated in all four inbred strains. To assess the acquisition and maintenance of opioid reinforced behavior, oral self-administration of the potent benzimidazole opioid, etonitazene, was determined using an operant fixed-ratio schedule of reinforcement (FR 8). Acquisition of etonitazene-reinforced behavior was established in all four strains including the mu-deficient CXBK/ByJ mice. However, there were significant genetic differences in the amount of drug intake during the maintenance of opioid-reinforced behavior and extinction behavior following vehicle substitution. For example, drug intake was significantly greater in the BK versus BH mice during the maintenance phase and an extinction burst was seen in the BH but not the BK mice following vehicle substitution. Thus, mu-receptor density may not account for individual variability in the acquisition of opioid-reinforced behavior under these conditions. Sensitivity to etonitazene-induced respiratory depression, stimulation of locomotor activity and analgesia were unrelated to drug intake during self-administration sessions across these four inbred strains.(ABSTRACT TRUNCATED AT 250 WORDS)
人们普遍认为μ受体在阿片类药物的强化作用中起重要作用。在本研究中，使用中枢神经系统阿片受体密度差异很大的近交系来研究受体浓度的遗传变异对阿片类药物强化行为的影响。特别是，CXBK/ByJ小鼠因其中枢神经系统μ阿片受体数量显著减少而被用作研究工具。将μ受体缺陷的CXBK/ByJ小鼠与其他常用的近交系小鼠C57BL/6J和BALB/cJ以及阿片受体丰富的CXBH/ByJ小鼠进行阿片类药物行为药理学比较。在所有这四个近交系中研究了操作性阿片类药物强化行为、阿片类药物诱导的运动刺激、镇痛和呼吸抑制。为了评估阿片类药物强化行为的获得和维持，使用操作性固定比率强化程序（FR 8）测定强效苯并咪唑阿片类药物依托尼嗪的口服自我给药。在包括μ受体缺陷的CXBK/ByJ小鼠在内的所有四个品系中都建立了依托尼嗪强化行为的获得。然而，在阿片类药物强化行为维持期间的药物摄入量以及 vehicle替代后的消退行为方面存在显著的遗传差异。例如，在维持阶段，BK小鼠的药物摄入量明显高于BH小鼠，并且在vehicle替代后，BH小鼠出现了消退爆发，而BK小鼠没有。因此，在这些条件下，μ受体密度可能无法解释阿片类药物强化行为获得过程中的个体差异。在这四个近交系中，对依托尼嗪诱导的呼吸抑制、运动活动刺激和镇痛的敏感性与自我给药期间的药物摄入量无关。（摘要截断于250字）
