Reed Cheryl, Baba Harue, Zhu Zhen, Erk Jason, Mootz John R, Varra Nicholas M, Williams Robert W, Phillips Tamara J
Department of Behavioral Neuroscience and Methamphetamine Abuse Research Center, Oregon Health & Science University, Portland, OR, United States.
Department of Genetics, Genomics and Informatics, University of Tennessee Health Sciences Center, Memphis, TN, United States.
Front Pharmacol. 2018 Jan 22;8:993. doi: 10.3389/fphar.2017.00993. eCollection 2017.
Major gene effects on traits associated with substance use disorders are rare. Previous findings in methamphetamine drinking (MADR) lines of mice, bred for high or low voluntary MA intake, and in null mutants demonstrate a major impact of the trace amine-associated receptor 1 () gene on a triad of MA-related traits: MA consumption, MA-induced conditioned taste aversion and MA-induced hypothermia. While inbred strains are fundamentally genetically stable, rare spontaneous mutations can become fixed and result in new or aberrant phenotypes. A single nucleotide polymorphism in that encodes a missense proline to threonine mutation in the second transmembrane domain ( ) has been identified in the DBA/2J strain. MA is an agonist at this receptor, but the receptor produced by does not respond to MA or endogenous ligands. In the present study, we used progeny of the C57BL/6J × DBA/2J F2 cross, the MADR lines, C57BL/6J × DBA/2J recombinant inbred strains, and DBA/2 mice sourced from four vendors to further examine -MA phenotype relations and to define the chronology of the fixation of the mutation. Mice homozygous for were found at high frequency early in selection for high MA intake in multiple replicates of the high MADR line, whereas homozygotes were absent in the low MADR line. The homozygous genotype is causally linked to increased MA intake, reduced MA-induced conditioned taste aversion, and reduced MA-induced hypothermia across models. Genotype-phenotype correlations range from 0.68 to 0.96. This polymorphism exists in DBA/2J mice sourced directly from The Jackson Laboratory, but not DBA/2 mice sourced from Charles River (DBA/2NCrl), Envigo (formerly Harlan Sprague Dawley; DBA/2NHsd) or Taconic (DBA/2NTac). By genotyping archived samples from The Jackson Laboratory, we have determined that this mutation arose in 2001-2003. Our data strengthen the conclusion that the mutant allele, which codes for a non-functional receptor protein, increases risk for multiple MA-related traits, including MA intake, in homozygous individuals.
对与物质使用障碍相关性状产生主要基因效应的情况较为罕见。先前在为高或低自愿甲基苯丙胺（MA）摄入量培育的甲基苯丙胺饮用（MADR）品系小鼠以及基因敲除突变体中的研究结果表明，痕量胺相关受体1（）基因对一组与MA相关的性状具有重大影响：MA消耗、MA诱导的条件性味觉厌恶和MA诱导的体温过低。虽然近交系在基因上基本稳定，但罕见的自发突变可能会固定下来并导致新的或异常的表型。在DBA/2J品系中已鉴定出编码第二个跨膜结构域中脯氨酸错义突变为苏氨酸突变的单核苷酸多态性（）。MA是该受体的激动剂，但由产生的受体对MA或内源性配体无反应。在本研究中，我们使用了C57BL/6J×DBA/2J F2杂交后代、MADR品系、C57BL/6J×DBA/2J重组近交系以及来自四个供应商的DBA/2小鼠，以进一步研究-MA表型关系并确定突变固定的时间顺序。在高MADR品系的多个重复品系中，在早期选择高MA摄入量时，高频发现纯合的小鼠，而在低MADR品系中不存在纯合子。纯合基因型与跨模型中MA摄入量增加、MA诱导的条件性味觉厌恶减少以及MA诱导的体温过低存在因果关系。基因型与表型的相关性范围为0.68至0.96。这种多态性存在于直接来自杰克逊实验室的DBA/2J小鼠中，但不存在于来自查尔斯河（DBA/2NCrl）、Envigo（原哈兰·斯普拉格·道利；DBA/2NHsd）或泰康尼克（DBA/2NTac）的DBA/2小鼠中。通过对来自杰克逊实验室的存档样本进行基因分型，我们确定该突变发生在2001 - 2003年。我们的数据强化了这样的结论，即编码无功能受体蛋白的突变等位基因会增加纯合个体出现多种与MA相关性状（包括MA摄入量）的风险。
