Zhukov Ilya S, Alnefeesi Yazen, Krotova Natalya A, Nemets Vsevolod V, Demin Konstantin A, Karpenko Marina N, Budygin Evgeny A, Kanov Evgeny V, Kalueff Allan V, Shabanov Petr D, Bader Michael, Alenina Natalia, Gainetdinov Raul R
Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia.
Institute of Experimental Medicine, Saint Petersburg, Russia.
Front Psychiatry. 2024 Dec 19;15:1484925. doi: 10.3389/fpsyt.2024.1484925. eCollection 2024.
Aggression and self-harm disproportionately occur in youths preoccupied with social status tracking. These pathological conditions are linked to a serotonin (5-HT) deficit in the brain. Ablation of 5-HT biosynthesis by tryptophan hydroxylase 2 knockout (TPH2-KO) increases aggression in rodents. Remarkably, deletion of the trace amine-associated receptor 1 (TAAR1) results in the same consequences. Unlike the nuanced dynamics of social status cues in young people, the social ranks of rats mainly advance when they dominate larger opponents in combat.
This study explored whether the potent TAAR1 agonist RO5263397 reduces aggression caused by 5-HT depletion, and whether social rank advancement motivates this aggression. The resident-intruder paradigm was applied with larger and smaller intruders to evaluate whether social rank advancement motivates aggressive behaviors in TPH2-KO rats.
When a smaller intruder was introduced, 5-HT-deficient rats did not differ from wild type littermates. However, when the intruders were larger, the mutants extended their aggressive efforts, refusing to submit. Importantly, RO5263397 selectively abolished this abnormal form of aggression in TPH2-KO rats.
Results supported social rank advancement as the main incentive. These data also suggest that TAAR1 is a promising target for the development of new treatments for aggression; independent data also support this conclusion.
攻击行为和自我伤害在关注社会地位追踪的青少年中极为常见。这些病理状况与大脑中血清素（5-羟色胺，5-HT）缺乏有关。通过色氨酸羟化酶2基因敲除（TPH2-KO）消除5-HT生物合成会增加啮齿动物的攻击性。值得注意的是，微量胺相关受体1（TAAR1）的缺失也会导致相同的后果。与年轻人中社会地位线索的微妙动态不同，大鼠的社会等级主要在战斗中战胜更大的对手时提升。
本研究探讨了强效TAAR1激动剂RO5263397是否能减少由5-HT耗竭引起的攻击行为，以及社会等级提升是否会引发这种攻击行为。采用常驻-入侵者范式，分别引入较大和较小的入侵者，以评估社会等级提升是否会激发TPH2-KO大鼠的攻击行为。
当引入较小的入侵者时，5-HT缺乏的大鼠与野生型同窝仔鼠没有差异。然而，当入侵者较大时，突变体加大了攻击力度，拒绝屈服。重要的是，RO5263397选择性地消除了TPH2-KO大鼠这种异常形式的攻击行为。
结果支持社会等级提升是主要诱因。这些数据还表明，TAAR1是开发新型攻击行为治疗方法的一个有前景的靶点；独立数据也支持这一结论。
