Open Access Peer-reviewed Research Article

TAAR1 as a new target for the treatment of bipolar disorder: Anti-manic and anti-depressant activity of the novel agonist PCC0105004

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Submitted   Jan 2, 2024
Published   Mar 25, 2024
Issue    Vol 5 No 1 (2023)
DOI   10.25082/JPBR.2023.01.004

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Linyao Yu
School of Pharmacy, Yantai University, Yantai 264005, China
Wei Zhang
School of Pharmacy, Yantai University, Yantai 264005, China
Yaoqin Shi
School of Pharmacy, Yantai University, Yantai 264005, China
Yingtian Zhang
School of Pharmacy, Yantai University, Yantai 264005, China
Min Xu
School of Pharmacy, Yantai University, Yantai 264005, China
Yang Xu
School of Pharmacy, Yantai University, Yantai 264005, China
Chunmei Li
School of Pharmacy, Yantai University, Yantai 264005, China
Jingwei Tian corresponding author
School of Pharmacy, Yantai University, Yantai 264005, China

Abstract

Background: Bipolar disorder (BD) is a deleterious psychiatric disorder, and the available pharmacotherapies have limited efficacy with significant side effects. Trace amine-associated receptor 1 (TAAR1) is an emerging drug target for neuropsychiatric disorders such as schizophrenia and substance user disorders. However, it is unknown whether TAAR1 is involved in the pathogenesis of BD. This study examined the effects and underlying mechanisms of a novel TAAR1 agonist, PCC0105004, in a rat model of ouabain (OUA)-induced BD.
Methods: Intracerebroventricular (ICV) administration of OUA-induced BD model was established. The in vitro cell-based cAMP assay was used to examine TAAR1 agonism of PCC0105004. The receptor specificity of PCC0105004 was determined by an off-target panel assay that included radioligand binding and enzymatic assays. The effects of PCC0105004 on manic-like and depressive-like behaviors were evaluated in the rat BD model. TAAR1-mediated signaling and oxidative stress parameters were biochemically determined in the prefrontal cortex and the hippocampus of rats.
Results: Western blotting revealed reduced TAAR1 expression level in the prefrontal cortex but unchanged in the hippocampus in model rats. PCC0105004, a TAAR1 agonist with the agonism EC50 value of 0.06182 μM, attenuated the manic-like behaviors on the 7th day and the depressive-like behaviors on the 14th day at doses that did not affect locomotor activity in the BD rats. Mechanistically, PCC0105004 exerted its behavioral effects via the reduction of ROS damage through the phosphorylation activation of the TAAR1/Akt/GSK3β/BDNF signaling pathway.
Conclusion: These results demonstrated the potential antimanic-like and antidepressant-like efficacy of a novel TAAR1 agonist PCC0105004 in rats and revealed its underlying molecular basis, which supports the possibility of TAAR1 agonists as candidate pharmacotherapeutics for BD.

Keywords
bipolar disorder, TAAR1, PCC0105004, prefrontal cortex, oxidative stress

Article Details

Supporting Agencies
This work was supported by the Natural Science Foundation of Shandong Province (No. ZR2020MH411).
How to Cite
Yu, L., Zhang, W., Shi, Y., Zhang, Y., Xu, M., Xu, Y., Li, C., & Tian, J. (2024). TAAR1 as a new target for the treatment of bipolar disorder: Anti-manic and anti-depressant activity of the novel agonist PCC0105004. Journal of Pharmaceutical and Biopharmaceutical Research, 5(1), 396-411. https://doi.org/10.25082/JPBR.2023.01.004
Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

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