Brodkin E S, Carlezon W A, Haile C N, Kosten T A, Heninger G R, Nestler E J
Laboratory of Molecular Psychiatry and Center for Genes and Behavior, Yale University School of Medicine, New Haven, CT 06508, USA.
Brain Res. 1998 Sep 14;805(1-2):55-68. doi: 10.1016/s0006-8993(98)00663-5.
Previous work has identified inherent behavioral, neuroendocrine, and biochemical differences among inbred rodent strains that have been related to the animals' differential responsiveness to drugs of abuse or stress. In the present study, we sought to determine (1) whether there are genetic correlations among particular phenotypic traits that differ between a pair of inbred rat strains (Lewis and Fischer 344) or a pair of inbred mouse strains (A/J and C57BL/6J); (2) which of these traits might be amenable to quantitative trait locus analysis; and (3) whether additional behavioral or biochemical differences relevant to drug- or stress-responsiveness could be identified in these strains. Specifically, we measured several behavioral, neuroendocrine, and biochemical traits in parental Lewis and Fischer 344 rats and in 298 members of an F2 intercross population, as well as in parental A/J and C57BL/6J mice and in 11 of the AXB/BXA recombinant inbred mouse strains. Traits measured included exploratory locomotor activity in a novel environment; amphetamine-induced locomotor activity; several specific protein levels in striatal regions, including inhibitory G protein subunits, the dopamine transporter, the Fos family member transcription factor DeltaFosB, and the protein phosphatase inhibitor DARPP-32; and late-afternoon plasma corticosterone concentrations. Each of the traits measured in F2 rats or recombinant inbred mice appears to be influenced by multiple genes, as well as by environmental factors. There were statistically significant, albeit relatively weak, correlations among several traits in an F2 intercross population bred from Lewis and Fischer rats. Among the traits studied in Lewis and Fischer rats, one seemed most amenable to quantitative trait locus analysis: the level of the inhibitory G-protein subunit, Galphai, in the nucleus accumbens. We also found a robust genetic correlation between levels of DeltaFosB and levels of the dopamine transporter in striatal regions in AXB/BXA recombinant inbred mouse strains. While these studies demonstrate the likely complexity of the genetic factors that influence the numerous phenotypes associated with altered responsiveness to drugs of abuse and stress, they represent an initial and necessary step toward identifying specific genetic factors involved.
先前的研究已经确定了近交系啮齿动物品系之间存在固有的行为、神经内分泌和生化差异，这些差异与动物对滥用药物或应激的不同反应有关。在本研究中，我们试图确定：（1）在一对近交系大鼠品系（Lewis和Fischer 344）或一对近交系小鼠品系（A/J和C57BL/6J）之间存在差异的特定表型性状之间是否存在遗传相关性；（2）这些性状中的哪些可能适用于数量性状位点分析；以及（3）在这些品系中是否可以识别出与药物或应激反应相关的其他行为或生化差异。具体而言，我们测量了亲代Lewis和Fischer 344大鼠以及F2杂交群体的298个成员的几种行为、神经内分泌和生化性状，以及亲代A/J和C57BL/6J小鼠以及11个AXB/BXA重组近交小鼠品系的这些性状。测量的性状包括在新环境中的探索性运动活动；苯丙胺诱导的运动活动；纹状体区域的几种特定蛋白质水平，包括抑制性G蛋白亚基、多巴胺转运体、Fos家族成员转录因子DeltaFosB和蛋白磷酸酶抑制剂DARPP-32；以及傍晚血浆皮质酮浓度。在F2大鼠或重组近交小鼠中测量的每个性状似乎都受到多个基因以及环境因素的影响。在由Lewis和Fischer大鼠培育的F2杂交群体中，几个性状之间存在统计学上显著的（尽管相对较弱）相关性。在Lewis和Fischer大鼠研究的性状中，有一个似乎最适用于数量性状位点分析：伏隔核中抑制性G蛋白亚基Galphai的水平。我们还在AXB/BXA重组近交小鼠品系的纹状体区域中发现了DeltaFosB水平与多巴胺转运体水平之间存在强烈的遗传相关性。虽然这些研究表明影响与滥用药物和应激反应改变相关的众多表型的遗传因素可能很复杂，但它们代表了朝着识别涉及的特定遗传因素迈出的初步且必要的一步。
