TY - JOUR

T1 - New Insights into Complex PTSD Treatment: Focus on TAAR1 Agonists

AU - Tseilikman, David Mandl V.

AU - Tseilikman, Vadim E.

AU - Shatilov, Vladislav A.

AU - Obukhova, Daria A.

AU - Zhukov, Ilya S.

AU - Yatsyk, Ivan V.

AU - Maistrenko, Victoria A.

AU - Shipelin, Vladimir A.

AU - Trusov, Nikita V.

AU - Karpenko, Marina N.

AU - Tseilikman, Olga B.

AU - Gainetdinov, Raul R.

AU - Novak, Jurica

N1 - New Insights into Complex PTSD Treatment: Focus on TAAR1 Agonists / D. M. V. Tseilikman, V. E. Tseilikman, V. A. Shatilov [et al.] // Biomedicines. – 2025. – Vol. 13. - No. 12. – P. 2972. – DOI 10.3390/biomedicines13122972. – EDN AZJCAL. This work was supported by the Russian Scientific Foundation, regional grant, Chelyabinsk Region (#23-15-20040). The breeding, genotyping of rats and the synthesis of LK00764 compound were supported by Saint Petersburg State University throuhg research grant 117033714 (to I.S.Z and R.R.G.). The research was supported by research resource center “Molecular and cell technologies” of St. Petersburg State University. Breeding and support of rats were performed by the Resource Center Vivarium of St. Petersburg State University, St. Petersburg, Russia.

PY - 2025/12/3

Y1 - 2025/12/3

N2 - Background/Objectives: The therapeutic potential of selective trace amine-associated receptor 1 (TAAR1) agonists has been established in multiple animal models of depression and anxiety. PTSD is a debilitating psychiatric disorder frequently characterized by anxiety and often comorbid with major depressive disorder. Complex PTSD represents an even more severe clinical presentation, emerging from prolonged or repeated exposure to traumatic events. Recent studies indicate that TAAR1 agonists can attenuate anxiety-like behaviors in experimental models of PTSD; however, the molecular mechanisms underlying this effect remain poorly understood. In this study, we evaluated whether TAAR1 agonism modulates PTSD-related neurochemical and molecular changes within the hippocampus and striatum. Methods: Post-traumatic stress was modeled using predator stress, a validated experimental paradigm relevant to complex PTSD. Treatment consisted of intraperitoneal administration of the TAAR1 agonist LK00764. Monoamine neurotransmitters and their metabolites were quantified, and the expression of genes implicated in noradrenergic, dopaminergic, and serotonergic signaling pathways was assessed. In addition, gene network reconstruction was performed using artificial intelligence to identify TAAR1-dependent regulatory interactions. Results: Treatment with a TAAR1 agonist fully prevented behavioral abnormalities in the experimental model of complex PTSD. Neurochemical analyses revealed decreased 5-HT levels in the hippocampus and reduced dopamine and metabolite concentrations in the striatum following TAAR1 agonism. Moreover, TAAR1 activation was associated with increased expression of the neurotrophic factor BDNF in the striatum. Gene network reconstruction identified a distinct molecular hub within the PTSD network, comprising TAAR1-coexpressed genes, their encoded proteins, and interconnected signaling pathways, suggesting a tightly regulated feedback loop. Conclusions: These findings provide novel evidence that TAAR1 agonists exert protective effects against complex PTSD-related behavioral and neurochemical abnormalities. The reconstructed TAAR1-centered gene network offers mechanistic insight into receptor-dependent regulation of monoaminergic signaling and neuroplasticity, supporting further exploration of TAAR1 agonists as promising therapeutic candidates for PTSD.

AB - Background/Objectives: The therapeutic potential of selective trace amine-associated receptor 1 (TAAR1) agonists has been established in multiple animal models of depression and anxiety. PTSD is a debilitating psychiatric disorder frequently characterized by anxiety and often comorbid with major depressive disorder. Complex PTSD represents an even more severe clinical presentation, emerging from prolonged or repeated exposure to traumatic events. Recent studies indicate that TAAR1 agonists can attenuate anxiety-like behaviors in experimental models of PTSD; however, the molecular mechanisms underlying this effect remain poorly understood. In this study, we evaluated whether TAAR1 agonism modulates PTSD-related neurochemical and molecular changes within the hippocampus and striatum. Methods: Post-traumatic stress was modeled using predator stress, a validated experimental paradigm relevant to complex PTSD. Treatment consisted of intraperitoneal administration of the TAAR1 agonist LK00764. Monoamine neurotransmitters and their metabolites were quantified, and the expression of genes implicated in noradrenergic, dopaminergic, and serotonergic signaling pathways was assessed. In addition, gene network reconstruction was performed using artificial intelligence to identify TAAR1-dependent regulatory interactions. Results: Treatment with a TAAR1 agonist fully prevented behavioral abnormalities in the experimental model of complex PTSD. Neurochemical analyses revealed decreased 5-HT levels in the hippocampus and reduced dopamine and metabolite concentrations in the striatum following TAAR1 agonism. Moreover, TAAR1 activation was associated with increased expression of the neurotrophic factor BDNF in the striatum. Gene network reconstruction identified a distinct molecular hub within the PTSD network, comprising TAAR1-coexpressed genes, their encoded proteins, and interconnected signaling pathways, suggesting a tightly regulated feedback loop. Conclusions: These findings provide novel evidence that TAAR1 agonists exert protective effects against complex PTSD-related behavioral and neurochemical abnormalities. The reconstructed TAAR1-centered gene network offers mechanistic insight into receptor-dependent regulation of monoaminergic signaling and neuroplasticity, supporting further exploration of TAAR1 agonists as promising therapeutic candidates for PTSD.

KW - TAAR1

KW - agonist

KW - anxiety

KW - complex PTSD

KW - depression

KW - hippocampus

KW - monoamines

KW - striatum

UR - https://www.scopus.com/pages/publications/105025979950

UR - https://elibrary.ru/item.asp?id=88074193

UR - https://www.mendeley.com/catalogue/45876344-aa8c-3c93-b8ca-3b87a07dfe2a/

U2 - 10.3390/biomedicines13122972

DO - 10.3390/biomedicines13122972

M3 - Article

VL - 13

JO - Biomedicines

JF - Biomedicines

SN - 2227-9059

IS - 12

M1 - 2972

ER -