Espinoza Stefano, Leo Damiana, Sotnikova Tatyana D, Shahid Mohammed, Kääriäinen Tiina M, Gainetdinov Raul R
Fondazione Istituto Italiano di Tecnologia, Department of Neuroscience and Brain Technologies, Genoa, Italy.
Department of Neurosciences, University of Mons, Mons, Belgium.
Front Pharmacol. 2018 Jun 21;9:645. doi: 10.3389/fphar.2018.00645. eCollection 2018.
Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor, which signals through elevating intracellular cAMP levels, and expressed in most vertebrates, including rodents and humans. In recent years, several lines of evidence indicated the role of TAAR1 in the regulation of dopaminergic system and its importance in physiological processes such as locomotion, control of emotional states and cognition. In our study, we used RO5263397, a selective TAAR1 agonist, as a tool and characterized its pharmacology in HEK293 cells and its effects in tests assessing potential antidepressant and antipsychotic actions. We found that RO5263397 not only increases cAMP levels at very low concentrations but also can induce the phosphorylation of ERK and CREB in a concentration- and time-dependent manner. Like other TAAR1 agonists, RO5263397 potently suppressed high dopamine-dependent hyperactivity in mice lacking the dopamine transporter. Moreover, RO5263397 produced a strong antidepressant-like effect in the forced swim test comparable to fluoxetine. Furthermore, the antidepressant-like activity was blocked by pretreatment with SCH23390 (dopamine D1 receptor antagonist) or NBQX (glutamate AMPA receptor antagonist) but only in part by WAY100635 (serotonin 5HT1A receptor antagonist). In conclusion, our study confirms some previous and findings in relation to the pharmacological effects of RO5263397 but more importantly provides new insight on intracellular signaling pathway and other neurotransmitter receptors modulated by TAAR1 receptor activation.
痕量胺相关受体1（TAAR1）是一种G蛋白偶联受体，通过提高细胞内cAMP水平来传递信号，在包括啮齿动物和人类在内的大多数脊椎动物中均有表达。近年来，多项证据表明TAAR1在多巴胺能系统调节中的作用及其在诸如运动、情绪状态控制和认知等生理过程中的重要性。在我们的研究中，我们使用了选择性TAAR1激动剂RO5263397作为工具，在HEK293细胞中对其药理学特性进行了表征，并在评估潜在抗抑郁和抗精神病作用的试验中研究了其效果。我们发现，RO5263397不仅在极低浓度下就能提高cAMP水平，还能以浓度和时间依赖性方式诱导ERK和CREB的磷酸化。与其他TAAR1激动剂一样，RO5263397能有效抑制缺乏多巴胺转运体的小鼠中高多巴胺依赖性的多动。此外，RO5263397在强迫游泳试验中产生了与氟西汀相当的强烈抗抑郁样效果。此外，抗抑郁样活性可被SCH23390（多巴胺D1受体拮抗剂）或NBQX（谷氨酸AMPA受体拮抗剂）预处理阻断，但仅部分被WAY100635（5-羟色胺5HT1A受体拮抗剂）阻断。总之，我们的研究证实了一些先前关于RO5263397药理作用的发现，但更重要的是为TAAR1受体激活所调节的细胞内信号通路和其他神经递质受体提供了新的见解。
