Trace Amine-Associated Receptor 1 contributes to diverse functional actions of o-phenyl-iodotyramine in mice but not to the effects of monoamine-based antidepressants

Mantas, I., Millan, M. J., Di Cara, B., Groenink, L., Veiga, S., Cistarelli, L., Brocco, M., Bertrand, M., Svenningsson, P. and Zhang, X. (2021) Trace Amine-Associated Receptor 1 contributes to diverse functional actions of o-phenyl-iodotyramine in mice but not to the effects of monoamine-based antidepressants. International Journal of Molecular Sciences, 22(16), 8907. (doi: 10.3390/ijms22168907)

Abstract

Trace Amine-Associated Receptor 1 (TAAR1) is a potential target for the treatment of depression and other CNS disorders. However, the precise functional roles of TAAR1 to the actions of clinically used antidepressants remains unclear. Herein, we addressed these issues employing the TAAR1 agonist, o-phenyl-iodotyramine (o-PIT), together with TAAR1-knockout (KO) mice. Irrespective of genotype, systemic administration of o-PIT led to a similar increase in mouse brain concentrations. Consistent with the observation of a high density of TAAR1 in the medial preoptic area, o-PIT-induced hypothermia was significantly reduced in TAAR1-KO mice. Furthermore, the inhibition of a prepulse inhibition response by o-PIT, as well as its induction of striatal tyrosine hydroxylase phosphorylation and elevation of extracellular DA in prefrontal cortex, were all reduced in TAAR1-KO compared to wildtype mice. O-PIT was active in both forced-swim and marble-burying tests, and its effects were significantly blunted in TAAR1-KO mice. Conversely, the actions on behaviour and prefrontal cortex dialysis of a broad suite of clinically used antidepressants were unaffected in TAAR1-KO mice. In conclusion, o-PIT is a useful tool for exploring the hypothermic and other functional antidepressant roles of TAAR1. By contrast, clinically used antidepressants do not require TAAR1 for expression of their antidepressant properties.

• Item Type: Articles
• Additional Information: This study was financially supported by Institut de Recherches SERVIER, Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse and the KI-NIH PhD programme.
• Keywords: TAAR1, o-PIT, DA, antidepressants.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Millan, Dr Mark

Creator Roles

Millan, M. J.: Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Validation, Writing – original draft, Writing – review and editing

• Authors: Mantas, I., Millan, M. J., Di Cara, B., Groenink, L., Veiga, S., Cistarelli, L., Brocco, M., Bertrand, M., Svenningsson, P., and Zhang, X.
• College/School: College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
• Journal Name: International Journal of Molecular Sciences
• Publisher: MDPI
• ISSN: 1661-6596
• ISSN (Online): 1422-0067
• Published Online: 18 August 2021
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in International Journal of Molecular Sciences 22(16): 8907
• Publisher Policy: Reproduced under a Creative Commons License