Institute of Translational Biomedicine, St. Petersburg State University, 199034 St. Petersburg, Russia.
Valdman Institute of Pharmacology, Pavlov First St. Petersburg State Medical University, 197022 St. Petersburg, Russia.
Pharmacol Biochem Behav. 2024 Sep;242:173817. doi: 10.1016/j.pbb.2024.173817. Epub 2024 Jul 11.
Most cases of anxiety are currently treated with either benzodiazepines or serotonin reuptake inhibitors. These drugs carry with them risks for a multitude of side effects, and patient compliance suffers for this reason. There is thus a need for novel anxiolytics, and among the most compelling prospects in this vein is the study of the TAARs. The anxiolytic potential of ulotaront, a full agonist at the human TAAR1, is currently being investigated in patients with generalized anxiety disorder. Irrespective of whether this compound succeeds in clinical trials, a growing body of preclinical literature underscores the relevance of modulating the TAARs in anxiety. Multiple behavioral paradigms show anxiolytic-like effects in rodents, possibly due to increased neurogenesis and plasticity, in addition to a panoply of interactions between the TAARs and other systems. Crucially, multiple lines of evidence suggest that the TAARs, particularly TAAR1, TAAR2, and TAAR5, are expressed in the extended amygdala and hippocampus. These regions are central in the actuation of anxiety, and are particularly susceptible to neurogenic and neuroplastic effects which the TAARs are now known to regulate. The TAARs also regulate the dopamine and serotonin systems, both of which are implicated in anxiety. Ligands of the TAARs may thus constitute a new class of anxiolytics.
目前，大多数焦虑症病例采用苯二氮䓬类药物或 5-羟色胺再摄取抑制剂进行治疗。这些药物存在多种副作用风险，因此患者的依从性受到影响。因此，需要新型的抗焦虑药物，而在这方面最有前途的是 TAARs 的研究。人类 TAAR1 的完全激动剂 ulotaront 的抗焦虑潜力目前正在广泛性焦虑症患者中进行研究。无论这种化合物在临床试验中是否成功，越来越多的临床前文献强调了调节 TAARs 在焦虑症中的相关性。多种行为范式在啮齿动物中显示出抗焦虑样作用，这可能是由于神经发生和可塑性增加，以及 TAARs 与其他系统之间的多种相互作用所致。至关重要的是，多条证据表明，TAARs，特别是 TAAR1、TAAR2 和 TAAR5，在扩展的杏仁核和海马体中表达。这些区域是引发焦虑的核心，特别容易受到神经发生和神经可塑性的影响，而 TAARs 现在被认为可以调节这些影响。TAARs 还调节多巴胺和 5-羟色胺系统，这两者都与焦虑有关。因此，TAARs 的配体可能构成一类新型的抗焦虑药物。
