Trace Amine-associated Receptor 1 Agonist Reduces Aggression in Brain Serotonin-deficient Tryptophan Hydroxylase 2 Knockout Rats

Overview

Journal Front Psychiatry

Specialty Psychiatry

Date 2025 Jan 3

PMID 39748904

Authors

Ilya S Zhukov

Yazen Alnefeesi

Natalya A Krotova

Vsevolod V Nemets

Konstantin A Demin

Marina N Karpenko

Evgeny A Budygin

Evgeny V Kanov

Allan V Kalueff

Petr D Shabanov

Michael Bader

Natalia Alenina

Raul R Gainetdinov

Affiliations

Soon will be listed here.

Abstract

Introduction: 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.

Methods: 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.

Results: 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.

Discussion: 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.

References

Leger M, Quiedeville A, Bouet V, Haelewyn B, Boulouard M, Schumann-Bard P . Object recognition test in mice. Nat Protoc. 2013; 8(12):2531-7. DOI: 10.1038/nprot.2013.155. View

Wang L, Clark E, Hanratty L, Koblan K, Foley A, Dedic N . TAAR1 and 5-HT receptor agonists attenuate autism-like irritability and aggression in rats prenatally exposed to valproic acid. Pharmacol Biochem Behav. 2024; 245():173862. DOI: 10.1016/j.pbb.2024.173862. View

Bielefeldt A, Danborg P, Gotzsche P . Precursors to suicidality and violence on antidepressants: systematic review of trials in adult healthy volunteers. J R Soc Med. 2016; 109(10):381-392. PMC: 5066537. DOI: 10.1177/0141076816666805. View

Sharma T, Guski L, Freund N, Gotzsche P . Suicidality and aggression during antidepressant treatment: systematic review and meta-analyses based on clinical study reports. BMJ. 2016; 352:i65. PMC: 4729837. DOI: 10.1136/bmj.i65. View

Chen G, Miller G . Advances in tryptophan hydroxylase-2 gene expression regulation: new insights into serotonin-stress interaction and clinical implications. Am J Med Genet B Neuropsychiatr Genet. 2012; 159B(2):152-71. PMC: 3587664. DOI: 10.1002/ajmg.b.32023. View

Cisneros I, Ghorpade A . Methamphetamine and HIV-1-induced neurotoxicity: role of trace amine associated receptor 1 cAMP signaling in astrocytes. Neuropharmacology. 2014; 85:499-507. PMC: 4315503. DOI: 10.1016/j.neuropharm.2014.06.011. View

Shemiakova T, Efimova E, Gainetdinov R . TAARs as Novel Therapeutic Targets for the Treatment of Depression: A Narrative Review of the Interconnection with Monoamines and Adult Neurogenesis. Biomedicines. 2024; 12(6). PMC: 11200894. DOI: 10.3390/biomedicines12061263. View

Lagerberg T, Fazel S, Sjolander A, Hellner C, Lichtenstein P, Chang Z . Selective serotonin reuptake inhibitors and suicidal behaviour: a population-based cohort study. Neuropsychopharmacology. 2021; 47(4):817-823. PMC: 8882171. DOI: 10.1038/s41386-021-01179-z. View

Angoa-Perez M, Kane M, Briggs D, Francescutti D, Kuhn D . Marble burying and nestlet shredding as tests of repetitive, compulsive-like behaviors in mice. J Vis Exp. 2014; (82):50978. PMC: 4108161. DOI: 10.3791/50978. View

10.

Welch J, Lu J, Rodriguiz R, Trotta N, Peca J, Ding J . Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. Nature. 2007; 448(7156):894-900. PMC: 2442572. DOI: 10.1038/nature06104. View

11.

Newman-Tancredi A, Conte C, Chaput C, Spedding M, Millan M . Inhibition of the constitutive activity of human 5-HT1A receptors by the inverse agonist, spiperone but not the neutral antagonist, WAY 100,635. Br J Pharmacol. 1997; 120(5):737-9. PMC: 1564555. DOI: 10.1038/sj.bjp.0701025. View

12.

Shmelkov S, Hormigo A, Jing D, Proenca C, Bath K, Milde T . Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive-like behaviors in mice. Nat Med. 2010; 16(5):598-602, 1p following 602. PMC: 2907076. DOI: 10.1038/nm.2125. View

13.

Black S, Schwartz M, Chen T, Hoener M, Kilduff T . Trace Amine-Associated Receptor 1 Agonists as Narcolepsy Therapeutics. Biol Psychiatry. 2016; 82(9):623-633. PMC: 5395352. DOI: 10.1016/j.biopsych.2016.10.012. View

14.

Leo D, Targa G, Espinoza S, Villers A, Gainetdinov R, Ris L . Trace Amine Associate Receptor 1 (TAAR1) as a New Target for the Treatment of Cognitive Dysfunction in Alzheimer's Disease. Int J Mol Sci. 2022; 23(14). PMC: 9318502. DOI: 10.3390/ijms23147811. View

15.

Jannini T, Lorenzo G, Bianciardi E, Niolu C, Toscano M, Ciocca G . Off-label Uses of Selective Serotonin Reuptake Inhibitors (SSRIs). Curr Neuropharmacol. 2021; 20(4):693-712. PMC: 9878961. DOI: 10.2174/1570159X19666210517150418. View

16.

Mahadevia D, Saha R, Manganaro A, Chuhma N, Ziolkowski-Blake A, Morgan A . Dopamine promotes aggression in mice via ventral tegmental area to lateral septum projections. Nat Commun. 2021; 12(1):6796. PMC: 8610979. DOI: 10.1038/s41467-021-27092-z. View

17.

Gilbert P, McEwan K, Irons C, Bhundia R, Christie R, Broomhead C . Self-harm in a mixed clinical population: the roles of self-criticism, shame, and social rank. Br J Clin Psychol. 2010; 49(Pt 4):563-76. DOI: 10.1348/014466509X479771. View

18.

Alnefeesi Y, Sukhanov I, Gainetdinov R . Ligands of the trace amine-associated receptors (TAARs): A new class of anxiolytics. Pharmacol Biochem Behav. 2024; 242():173817. DOI: 10.1016/j.pbb.2024.173817. View

19.

Brummelte S, Mc Glanaghy E, Bonnin A, Oberlander T . Developmental changes in serotonin signaling: Implications for early brain function, behavior and adaptation. Neuroscience. 2016; 342:212-231. PMC: 5310545. DOI: 10.1016/j.neuroscience.2016.02.037. View

20.

Euston D, Gruber A, McNaughton B . The role of medial prefrontal cortex in memory and decision making. Neuron. 2012; 76(6):1057-70. PMC: 3562704. DOI: 10.1016/j.neuron.2012.12.002. View