Department of Biomedical Sciences, Grand Valley State University, Allendale, MI, USA.
Department of Biology, Minot State University, Minot, ND, USA.
Neuropsychopharmacology. 2023 Sep;48(10):1446-1454. doi: 10.1038/s41386-023-01578-4. Epub 2023 Apr 13.
Drugs that stimulate the trace amine-associated receptor 1 (TAAR1) are under clinical investigation as treatments for several neuropsychiatric disorders. Previous studies in a genetic mouse model of voluntary methamphetamine intake identified TAAR1, expressed by the Taar1 gene, as a critical mediator of aversive methamphetamine effects. Methamphetamine is a TAAR1 agonist, but also has actions at monoamine transporters. Whether exclusive activation of TAAR1 has aversive effects was not known at the time we conducted our studies. Mice were tested for aversive effects of the selective TAAR1 agonist, RO5256390, using taste and place conditioning procedures. Hypothermic and locomotor effects were also examined, based on prior evidence of TAAR1 mediation. Male and female mice of several genetic models were used, including lines selectively bred for high and low methamphetamine drinking, a knock-in line in which a mutant form of Taar1 that codes for a non-functional TAAR1 was replaced by the reference Taar1 allele that codes for functional TAAR1, and their matched control line. RO5256390 had robust aversive, hypothermic and locomotor suppressing effects that were found only in mice with functional TAAR1. Knock-in of the reference Taar1 allele rescued these phenotypes in a genetic model that normally lacks TAAR1 function. Our study provides important data on TAAR1 function in aversive, locomotor, and thermoregulatory effects that are important to consider when developing TAAR1 agonists as therapeutic drugs. Because other drugs can have similar consequences, potential additive effects should be carefully considered as these treatment agents are being developed.
刺激微量胺相关受体 1（TAAR1）的药物正在作为几种神经精神疾病的治疗方法进行临床研究。在自愿摄入甲基苯丙胺的遗传小鼠模型中的先前研究确定，由 Taar1 基因表达的 TAAR1 是一种对阿片样甲基苯丙胺作用的关键调节剂。甲基苯丙胺是 TAAR1 的激动剂，但也对单胺转运体具有作用。在我们进行研究时，尚不清楚是否仅激活 TAAR1 会产生厌恶作用。使用味觉和位置条件反射程序测试了选择性 TAAR1 激动剂 RO5256390 的厌恶作用。根据先前关于 TAAR1 介导的证据，还检查了致冷和运动作用。使用了几种遗传模型的雄性和雌性小鼠，包括选择性繁殖用于高和低甲基苯丙胺摄入的品系，一种 Taar1 的敲入系，其中突变形式的 Taar1 编码非功能性 TAAR1 被编码功能性 TAAR1 的参考 Taar1 等位基因取代，以及它们的匹配对照系。RO5256390 具有强烈的厌恶、致冷和运动抑制作用，仅在具有功能性 TAAR1 的小鼠中发现。在通常缺乏 TAAR1 功能的遗传模型中，敲入参考 Taar1 等位基因挽救了这些表型。我们的研究提供了 TAAR1 在厌恶、运动和体温调节作用中的功能的重要数据，在开发 TAAR1 激动剂作为治疗药物时应考虑这些作用。由于其他药物可能具有类似的后果，因此在开发这些治疗剂时应仔细考虑潜在的附加作用。
