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.

Ioannis Mantas,Xiaoqun Zhang,Marc Bertrand,Lucianne Groenink,Mark J Millan,Sylvie Veiga,Per Svenningsson,Mauricette Brocco,Benjamin Di Cara,Laetitia Cistarelli

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.

Highlights

Trace amines (TAs) are a diverse group of aminergic compounds that, in mammals, are either derived from the intake of food such as cheese, from the metabolism of thyroid hormone or from enzymatic pathways of synthesis in nervous tissue [1,2]
We focused on readouts relevant to the influence of Trace Amine-Associated Receptor 1 (TAAR1) on DAergic neurotransmission and their potential role in the response to antidepressants
The TAAR1-KO mice used in the present study, lack the coding sequence of TAA1 which is replaced by the LacZ reporter gene (Figure 1A)

Summary

Introduction

Trace amines (TAs) are a diverse group of aminergic compounds that, in mammals, are either derived from the intake of food such as cheese, from the metabolism of thyroid hormone or from enzymatic pathways of synthesis in nervous tissue [1,2]. In contrast to classical monoamines, such as noradrenaline (NA) and serotonin (5-HT), these and other. It has been hypothesized that a disruption of their activity may contribute to the pathophysiology of multiple classes of metabolic, 4.0/). The notion that trace amines exert neuromodulatory effects, themselves, via specific classes of receptors [8] was concretized with the discovery of receptors that bind TAs in rodents [9,10], followed by the identification of a whole family of G protein-coupled “Trace Amine-Associated Receptors”

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Results

Discussion

Conclusion