Phillips Tamara J, Roy Tyler, Aldrich Sara J, Baba Harue, Erk Jason, Mootz John R K, Reed Cheryl, Chesler Elissa J
Department of Behavioral Neuroscience and Methamphetamine Abuse Research Center, Oregon Health & Science University, Portland, OR, United States.
Veterans Affairs Portland Health Care System, Portland, OR, United States.
Front Psychiatry. 2021 Aug 26;12:725839. doi: 10.3389/fpsyt.2021.725839. eCollection 2021.
Sensitivity to rewarding and reinforcing drug effects has a critical role in initial use, but the role of initial aversive drug effects has received less attention. Methamphetamine effects on dopamine re-uptake and efflux are associated with its addiction potential. However, methamphetamine also serves as a substrate for the trace amine-associated receptor 1 (TAAR1). Growing evidence in animal models indicates that increasing TAAR1 function reduces drug self-administration and intake. We previously determined that a non-synonymous single nucleotide polymorphism (SNP) in predicts a conformational change in the receptor that has functional consequences. A mutant allele existing in DBA/2J mice expresses a non-functional receptor. In comparison to mice that possess one or more copies of the reference allele ( or ), mice with the genotype readily consume methamphetamine, express low sensitivity to aversive effects of methamphetamine, and lack sensitivity to acute methamphetamine-induced hypothermia. We used three sets of knock-in and control mice in which one allele was exchanged with the alternative allele to determine if other methamphetamine-related traits and an opioid trait are impacted by the same SNP proven to affect MA consumption and hypothermia. First, we measured sensitivity to conditioned rewarding and aversive effects of methamphetamine to determine if an impact of the SNP on these traits could be proven. Next, we used multiple genetic backgrounds to study the consistency of allelic effects on methamphetamine intake and hypothermia. Finally, we studied morphine-induced hypothermia to confirm prior data suggesting that a gene in linkage disequilibrium with , rather than , accounts for prior observed differences in sensitivity. We found that a single SNP exchange reduced sensitivity to methamphetamine conditioned reward and increased sensitivity to conditioned aversion. Profound differences in methamphetamine intake and hypothermia consistently corresponded with genotype at the SNP location, with only slight variation in magnitude across genetic backgrounds. Morphine-induced hypothermia was not dependent on genotype. Thus, genotype and TAAR1 function impact multiple methamphetamine-related effects that likely predict the potential for methamphetamine use. These data support further investigation of their potential roles in risk for methamphetamine addiction and therapeutic development.
对奖赏性和强化性药物效应的敏感性在药物初次使用中起关键作用，但初次使用时厌恶药物效应的作用却较少受到关注。甲基苯丙胺对多巴胺再摄取和流出的影响与其成瘾潜力相关。然而，甲基苯丙胺也是痕量胺相关受体1（TAAR1）的作用底物。动物模型中越来越多的证据表明，增强TAAR1功能可减少药物自我给药和摄入量。我们之前确定， 中的一个非同义单核苷酸多态性（SNP）预测了受体会发生构象变化，这具有功能后果。存在于DBA/2J小鼠中的 突变等位基因表达无功能的受体。与拥有一个或多个参考 等位基因（ 或 ）拷贝的小鼠相比，具有 基因型的小鼠很容易摄入甲基苯丙胺，对甲基苯丙胺的厌恶效应表现出低敏感性，并且对急性甲基苯丙胺诱导的体温过低缺乏敏感性。我们使用了三组敲入小鼠和对照小鼠，其中一个 等位基因与另一个等位基因进行了交换，以确定其他与甲基苯丙胺相关的性状以及一种阿片类性状是否会受到已证实影响甲基苯丙胺消耗量和体温过低的同一SNP的影响。首先，我们测量了对甲基苯丙胺条件性奖赏和厌恶效应的敏感性，以确定该SNP对这些性状的影响是否可以得到证实。接下来，我们使用多种遗传背景来研究等位基因对甲基苯丙胺摄入量和体温过低影响的一致性。最后，我们研究了吗啡诱导的体温过低，以证实先前的数据，即与 处于连锁不平衡状态的一个基因，而非 ，解释了先前观察到的敏感性差异出现的原因。我们发现，单个SNP交换降低了对甲基苯丙胺条件性奖赏的敏感性，并增加了对条件性厌恶的敏感性。甲基苯丙胺摄入量和体温过低的显著差异始终与SNP位置的基因型相对应，在不同遗传背景下幅度仅有轻微变化。吗啡诱导的体温过低不依赖于 基因型。因此， 基因型和TAAR1功能影响多种与甲基苯丙胺相关的效应，这些效应可能预示着使用甲基苯丙胺的可能性。这些数据支持进一步研究它们在甲基苯丙胺成瘾风险和治疗开发中的潜在作用。
