药物成瘾是全球性的公害，被认为是一种慢性复发性的脑疾病。长时间用药引起的神经系统长时程的适应性改变，是成瘾现象的生物学基础。在成瘾研究领域，从不同个体具有不同的成瘾易感性这一经验事实出发的成瘾行为的“个体中心理论”C individual-centered vision，为成瘾行为的发生、发展和对成瘾脑机制的研究提供了一个全新的视角。该理论认为，如果我们能够发现高、低成瘾易感性个体特定的行为学表现，确认那些导致不同成瘾易感性的特异的生理、生化改变，便可以有效地揭示成瘾现象的生物学基础，为成瘾行为的治疗提供科学依据。
    论文围绕着成瘾易感性这一研究主题，对高、低成瘾易感性大鼠的先天行为学特征，不同成瘾易感性大鼠的精神兴奋性效应、精神奖赏效应、行为敏感化效应、条件性行为敏感化效应等不同成瘾效应进行了系列研究。同时，应用高通量、同时性的基因芯片技术，对高、低精神奖赏CPP效应大鼠脑内基因的差异表达进行了研究。尝试应用多巴胺系统的药物(多巴胺D1受体拮抗剂SCH23390 )对吗啡精神奖赏CPP效应进行行为层面及基因调控层面的干预，以期在行为与基因表达和调控层面建立联结，为成瘾行为的脑机制研究及成瘾行为的药物干预提供一定的实验依据。
    研究结果如下:
    1.青龄大鼠的新颖寻求行为可以预测其吗啡精神奖赏CPP效应，此二者至少在部分程度上具有相同的生物学基础，同时，此效应与动物的旷场活动量无关;
    2.青龄期新颖寻求水平不同的大鼠，成龄后其吗啡精神奖赏CPP效应存在显著差异，大鼠青龄期的新颖寻求行为可以预测其成龄后的吗啡精神奖赏CPP效应;
    3.吗啡可以诱发大鼠形成行为敏感化及条件性行为敏感化效应，先天具有高运动特征的大鼠较低运动特征的大鼠具有更高的条件信号应答能力，而低运动性大鼠对药物的无条件敏感化效应较高运动特征大鼠更为显著;
    4.在吗啡精神奖赏CPP效应易感性不同的大鼠之间，其脑内基因表达存在显著差异。研究显示，45条基因序列参与高、低不同的CPP易感性的表达。多巴胺Dl受体拮抗剂SCH23390可以直接从行为层面消退高易感性大鼠的CPP效应，同时发现上述45条基因序列中的29条受到药物调控。在这29条基因序列中，一类为编码细胞结构及非免疫类功能相关蛋白的序列，另一类为编码免疫功能相关蛋白的序列。这提示吗啡作为外源性物质，至少作为一种途径，可能通过免疫系统作用，引起相应的神经内分泌系统发生改变，进而表现出对吗啡精神奖赏CPP效应的不同易感性。
    上述研究结果表明，在吗啡诸种不同的成瘾效应中，在行为和基因表达两个不同的层面，发生同时性改变，这种改变在不同个体之间的差异，直接制约了生物体对成瘾药物的不同易感性，其中长时程的生物学改变，有可能成为长时性的成瘾行为和强迫性的觅药行为的生物学基础。

    Addiction has been considered as a reoccurred brain disease characterized by persistent abnormal neuroadaptations in the brain. Conceptualized from the empirical phenotype of abusive drug use, the individual-centered theory of addiction provided a new vision for the study the mechanism of drug abuse, which has been proved valuable in identifying the specific neural and hormonal substrates in determining the ultimate susceptibility to the compulsive use of abusive drugs. In these series of studies presented here, the related behavioral characteristics leading to the vulnerability to the use of drugs and corresponding gene expression profile in the rat's brain have been concentrated. Main results are listed as follows:
    1.On distinct ontogenetic period, novelty-seeking behavior possessed a common pathway with the rewarding effect of morphine and predicted the propensity to this effect.
    2.Stress-related neural and hormonal activation was not critically involved in the rewarding effect of morphine.
    3.Novelty-seeking behavior and open-field activity in juvenile rats differentially related the rewarding effect of morphine in their adulthood.
    4.Morphine-induced behavioral sensitization and conditioned sensitization could be readily acquired  by rats, with  HR animals showing  more significant conditioned activation and LR animals expressing more robust sensitization to the drug effect.
    5. With cDNA microarray analysis, 45 unigenes or in the differential expression of high and low effect of morphine, among which 29 sequences antagonist SCH23390. ESTs were found to be involved susceptibility to the rewarding were regulated by D1-receptor antagonist SCH23390.
6.Two groups of unigenes or ESTs were found to be involved in regulating the differential vulnerability to rewarding effect of morphine. One group related to sequences encoding cellular functional proteins. The other related to that encoding immunity-related proteins.
  The above results demonstrated that series of concurrent changes were involved in the expression of differential susceptibility to the abusive drugs, which exsit from behavioral to molecular and genetic level. Differentials and speficities expressed in this aspect may lead to the ultimate propensity to the use of abusive drugs, among which the long-term neuroadaptation process could account for the persistence and compulsivity of drug craving.