Phillips Tamara J, Shabani Shkelzen
VA Portland Health Care System Portland, OR, USA ; Department of Behavioral Neuroscience and Methamphetamine Abuse Research Center, Oregon Health & Science University Portland, OR, USA.
Department of Biology, Minot State University Minot, ND, USA.
Front Neurosci. 2015 Sep 23;9:327. doi: 10.3389/fnins.2015.00327. eCollection 2015.
The question of whether genetic factors contribute to risk for methamphetamine (MA) use and dependence has not been intensively investigated. Compared to human populations, genetic animal models offer the advantages of control over genetic family history and drug exposure. Using selective breeding, we created lines of mice that differ in genetic risk for voluntary MA intake and identified the chromosomal addresses of contributory genes. A quantitative trait locus was identified on chromosome 10 that accounts for more than 50% of the genetic variance in MA intake in the selected mouse lines. In addition, behavioral and physiological screening identified differences corresponding with risk for MA intake that have generated hypotheses that are testable in humans. Heightened sensitivity to aversive and certain physiological effects of MA, such as MA-induced reduction in body temperature, are hallmarks of mice bred for low MA intake. Furthermore, unlike MA-avoiding mice, MA-preferring mice are sensitive to rewarding and reinforcing MA effects, and to MA-induced increases in brain extracellular dopamine levels. Gene expression analyses implicate the importance of a network enriched in transcription factor genes, some of which regulate the mu opioid receptor gene, Oprm1, in risk for MA use. Neuroimmune factors appear to play a role in differential response to MA between the mice bred for high and low intake. In addition, chromosome 10 candidate gene studies provide strong support for a trace amine-associated receptor 1 gene, Taar1, polymorphism in risk for MA intake. MA is a trace amine-associated receptor 1 (TAAR1) agonist, and a non-functional Taar1 allele segregates with high MA consumption. Thus, reduced TAAR1 function has the potential to increase risk for MA use. Overall, existing findings support the MA drinking lines as a powerful model for identifying genetic factors involved in determining risk for harmful MA use. Future directions include the development of a binge model of MA intake, examining the effect of withdrawal from chronic MA on MA intake, and studying potential Taar1 gene × gene and gene × environment interactions. These and other studies are intended to improve our genetic model with regard to its translational value to human addiction.
遗传因素是否会导致甲基苯丙胺（MA）使用及成瘾风险，这一问题尚未得到深入研究。与人类群体相比，遗传动物模型具有能够控制遗传家族史和药物暴露情况的优势。通过选择性育种，我们培育出了在自愿摄入MA的遗传风险方面存在差异的小鼠品系，并确定了相关基因在染色体上的位置。在10号染色体上鉴定出一个数量性状基因座，它在所选小鼠品系中占MA摄入量遗传变异的50%以上。此外，行为和生理筛查发现了与MA摄入量风险相对应的差异，这些差异催生了可在人类身上进行检验的假说。对MA的厌恶和某些生理效应（如MA引起的体温降低）高度敏感，是为低MA摄入量而培育的小鼠的特征。此外，与回避MA的小鼠不同，偏爱MA的小鼠对MA的奖赏和强化作用以及MA引起的脑细胞外多巴胺水平升高敏感。基因表达分析表明，富含转录因子基因的网络在MA使用风险中具有重要意义，其中一些转录因子基因调节μ阿片受体基因Oprm1。神经免疫因素似乎在高摄入量和低摄入量培育的小鼠对MA的不同反应中发挥作用。此外，10号染色体候选基因研究为痕量胺相关受体1基因Taar1的多态性在MA摄入量风险中的作用提供了有力支持。MA是痕量胺相关受体1（TAAR1）的激动剂，无功能的Taar1等位基因与高MA消耗量相关。因此，TAAR1功能降低有可能增加MA使用风险。总体而言，现有研究结果支持MA饮用小鼠品系作为一种强大模型，用于识别决定有害MA使用风险的遗传因素。未来的方向包括开发MA摄入量的暴饮暴食模型，研究慢性MA戒断对MA摄入量的影响，以及研究潜在的Taar1基因×基因和基因×环境相互作用。这些研究及其他研究旨在提高我们的遗传模型在人类成瘾转化价值方面的水平。
