Sukhanov Ilya, Caffino Lucia, Efimova Evgeniya V, Espinoza Stefano, Sotnikova Tatiana D, Cervo Luigi, Fumagalli Fabio, Gainetdinov Raul R
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genova, Italy; St. Petersburg State Medical University, 197022 St. Petersburg, Russia.
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy.
Pharmacol Res. 2016 Jan;103:206-14. doi: 10.1016/j.phrs.2015.11.002. Epub 2015 Dec 2.
Given the recent evidence indicating that amphetamine derivatives may also act as direct agonists of the G protein-coupled trace amine-associated receptor 1 (TAAR1), we hypothesized that TAAR1 could contribute to the reinforcing and addictive properties of amphetamines. Accordingly, the present study aimed to investigate the role of TAAR1 in the effects of psychostimulants by analyzing context-dependent sensitization and conditioned place preference (CPP) to d-amphetamine (AMPH) in TAAR1-KO mice. In context-dependent sensitization experiment, TAAR1-KO mice showed higher conditioned locomotor responses compared to wild-type mice. In the CPP test, TAAR1-KO animals were also more sensitive to priming-induced reinstatement of AMPH-induced conditioned place preference (CPP) than wild type mice. Importantly, saline-treated and AMPH-treated mice lacking TAAR1 demonstrated significant alterations in the total levels and phosphorylation of the critical subunit of NMDA glutamate receptors, GluN1, in the striatum, suggesting a role of TAAR1 in the modulation of frontostriatal glutamate transmission; this effect could underlie the observed alterations in conditioning processes. In conclusion, our data suggest that TAAR1 receptors play an inhibitory role with respect to conditioned responses to AMPH by modulating, at least in part, corticostriatal glutamate transmission.
鉴于最近有证据表明苯丙胺衍生物也可能作为G蛋白偶联的痕量胺相关受体1（TAAR1）的直接激动剂，我们推测TAAR1可能促成苯丙胺的强化和成瘾特性。因此，本研究旨在通过分析TAAR1基因敲除（KO）小鼠对d-苯丙胺（AMPH）的情境依赖性敏感化和条件性位置偏爱（CPP），来研究TAAR1在精神兴奋剂作用中的作用。在情境依赖性敏感化实验中，与野生型小鼠相比，TAAR1-KO小鼠表现出更高的条件性运动反应。在CPP测试中，TAAR1-KO动物对引发诱导的AMPH诱导的条件性位置偏爱（CPP）恢复也比野生型小鼠更敏感。重要的是，缺乏TAAR1的生理盐水处理和AMPH处理的小鼠在纹状体中NMDA谷氨酸受体关键亚基GluN1的总水平和磷酸化方面表现出显著变化，表明TAAR1在调节额叶纹状体谷氨酸传递中起作用；这种作用可能是观察到的条件反射过程变化的基础。总之，我们的数据表明，TAAR1受体通过至少部分调节皮质纹状体谷氨酸传递，对AMPH的条件性反应起抑制作用。
