Enhanced Aggression, Reduced Self-Grooming Behavior and Altered 5-HT Regulation in the Frontal Cortex in Mice Lacking Trace Amine-Associated Receptor 1 (TAAR1)

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2022 Nov 26

PMID 36430544

Authors

Ilya S Zhukov

Inessa V Karpova

Nataliya A Krotova

Ilya Y Tissen

Konstantin A Demin

Petr D Shabanov

Evgeny A Budygin

Allan V Kalueff

Raul R Gainetdinov

Affiliations

Soon will be listed here.

Abstract

The Trace Amine-Associated Receptor 1 (TAAR1) is one of the six functional receptors belonging to the family of monoamine-related G protein-coupled receptors (TAAR1-TAAR9) found in humans. However, the exact biological mechanisms of TAAR1 central and peripheral action remain to be fully understood. TAAR1 is widely expressed in the prefrontal cortex and several limbic regions, interplaying with the dopamine system to modulate the reward circuitry. Recent clinical trials suggest the efficacy of TAAR1 agonists as potential novel antipsychotic agents. Here, we characterize behavioral and neurochemical phenotypes of TAAR1 knockout mice, focusing on aggression and self-grooming behavior that both strongly depend on the monoaminergic signaling and cortico-striatal and cortico-limbic circuits. Overall, we report increased aggression in these knockout mice in the resident-intruder test, accompanied by reduced self-grooming behavior in the novelty-induced grooming test, and by higher cortical serotonin (5-HT) tissue levels. Further studies are necessary to explore whether TAAR1-based therapies can become potential novel treatments for a wide range of neuropsychiatric disorders associated with aggression.

Citing Articles

Trace amine-associated receptor 1 agonist reduces aggression in brain serotonin-deficient tryptophan hydroxylase 2 knockout rats.

Zhukov I, Alnefeesi Y, Krotova N, Nemets V, Demin K, Karpenko M Front Psychiatry. 2025; 15:1484925.

PMID: 39748904 PMC: 11693706. DOI: 10.3389/fpsyt.2024.1484925.

Serotonergic Drugs for the Treatment of Attention-Deficit/Hyperactivity Disorder: A Review of Past Development, Pitfalls and Failures, and a Look to the Future.

Chepke C, Brunner E, Cutler A Psychopharmacol Bull. 2024; 54(4):45-80.

PMID: 39263202 PMC: 11385260.

Unlocking the Therapeutic Potential of Ulotaront as a Trace Amine-Associated Receptor 1 Agonist for Neuropsychiatric Disorders.

Kuvarzin S, Sukhanov I, Onokhin K, Zakharov K, Gainetdinov R Biomedicines. 2023; 11(7).

PMID: 37509616 PMC: 10377193. DOI: 10.3390/biomedicines11071977.

Protein Metabolism Changes and Alterations in Behavior of Trace Amine-Associated Receptor 1 Knockout Mice Fed a High-Fructose Diet.

Apryatin S, Zhukov I, Zolotoverkhaya E, Kuvarzin S, Khunagov T, Ushmugina S Neurol Int. 2023; 15(1):339-351.

PMID: 36976665 PMC: 10052549. DOI: 10.3390/neurolint15010022.

Gut Microbiota Alterations in Trace Amine-Associated Receptor 9 (TAAR9) Knockout Rats.

Zhukov I, Vaganova A, Murtazina R, Alferova L, Ermolenko E, Gainetdinov R Biomolecules. 2022; 12(12).

PMID: 36551251 PMC: 9775382. DOI: 10.3390/biom12121823.

References

Gutknecht L, Popp S, Waider J, Sommerlandt F, Goppner C, Post A . Interaction of brain 5-HT synthesis deficiency, chronic stress and sex differentially impact emotional behavior in Tph2 knockout mice. Psychopharmacology (Berl). 2015; 232(14):2429-41. PMC: 4480945. DOI: 10.1007/s00213-015-3879-0. View

Suri D, Teixeira C, Caffrey Cagliostro M, Mahadevia D, Ansorge M . Monoamine-sensitive developmental periods impacting adult emotional and cognitive behaviors. Neuropsychopharmacology. 2014; 40(1):88-112. PMC: 4262911. DOI: 10.1038/npp.2014.231. View

Cromwell H, Berridge K . Implementation of action sequences by a neostriatal site: a lesion mapping study of grooming syntax. J Neurosci. 1996; 16(10):3444-58. PMC: 6579135. View

Couppis M, Kennedy C . The rewarding effect of aggression is reduced by nucleus accumbens dopamine receptor antagonism in mice. Psychopharmacology (Berl). 2008; 197(3):449-56. DOI: 10.1007/s00213-007-1054-y. View

Zhou T, Zhu H, Fan Z, Wang F, Chen Y, Liang H . History of winning remodels thalamo-PFC circuit to reinforce social dominance. Science. 2017; 357(6347):162-168. DOI: 10.1126/science.aak9726. View

Koolhaas J, Coppens C, de Boer S, Buwalda B, Meerlo P, Timmermans P . The resident-intruder paradigm: a standardized test for aggression, violence and social stress. J Vis Exp. 2013; (77):e4367. PMC: 3731199. DOI: 10.3791/4367. View

Revel F, Moreau J, Gainetdinov R, Bradaia A, Sotnikova T, Mory R . TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity. Proc Natl Acad Sci U S A. 2011; 108(20):8485-90. PMC: 3101002. DOI: 10.1073/pnas.1103029108. View

Boulton A . Letter: Amines and theories in psychiatry. Lancet. 1974; 2(7871):52-3. DOI: 10.1016/s0140-6736(74)91390-7. View

Takahashi A, Quadros I, de Almeida R, Miczek K . Brain serotonin receptors and transporters: initiation vs. termination of escalated aggression. Psychopharmacology (Berl). 2010; 213(2-3):183-212. PMC: 3684010. DOI: 10.1007/s00213-010-2000-y. View

10.

Borowsky B, Adham N, Jones K, Raddatz R, Artymyshyn R, Ogozalek K . Trace amines: identification of a family of mammalian G protein-coupled receptors. Proc Natl Acad Sci U S A. 2001; 98(16):8966-71. PMC: 55357. DOI: 10.1073/pnas.151105198. View

11.

Gorlova A, Ortega G, Waider J, Bazhenova N, Veniaminova E, Proshin A . Stress-induced aggression in heterozygous TPH2 mutant mice is associated with alterations in serotonin turnover and expression of 5-HT6 and AMPA subunit 2A receptors. J Affect Disord. 2020; 272:440-451. DOI: 10.1016/j.jad.2020.04.014. View

12.

Zhukov I, Ptukha M, Zolotoverkhaja E, Sinitca E, Tissen I, Karpova I . Evaluation of Approach to a Conspecific and Blood Biochemical Parameters in TAAR1 Knockout Mice. Brain Sci. 2022; 12(5). PMC: 9139149. DOI: 10.3390/brainsci12050614. View

13.

Mohandass A, Krishnan V, Gribkova E, Asuthkar S, Baskaran P, Nersesyan Y . TRPM8 as the rapid testosterone signaling receptor: Implications in the regulation of dimorphic sexual and social behaviors. FASEB J. 2020; 34(8):10887-10906. PMC: 7496617. DOI: 10.1096/fj.202000794R. View

14.

Volavka J . Violence in schizophrenia and bipolar disorder. Psychiatr Danub. 2013; 25(1):24-33. View

15.

Premont R, Gainetdinov R, Caron M . Following the trace of elusive amines. Proc Natl Acad Sci U S A. 2001; 98(17):9474-5. PMC: 55475. DOI: 10.1073/pnas.181356198. 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.

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

18.

Caramaschi D, de Boer S, de Vries H, Koolhaas J . Development of violence in mice through repeated victory along with changes in prefrontal cortex neurochemistry. Behav Brain Res. 2008; 189(2):263-72. DOI: 10.1016/j.bbr.2008.01.003. View

19.

Leo D, Mus L, Espinoza S, Hoener M, Sotnikova T, Gainetdinov R . Taar1-mediated modulation of presynaptic dopaminergic neurotransmission: role of D2 dopamine autoreceptors. Neuropharmacology. 2014; 81:283-91. DOI: 10.1016/j.neuropharm.2014.02.007. View

20.

Bunzow J, Sonders M, Arttamangkul S, Harrison L, Zhang G, Quigley D . Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor. Mol Pharmacol. 2001; 60(6):1181-8. DOI: 10.1124/mol.60.6.1181. View