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

Per Svenningsson¹  Xiaoqun Zhang¹  Ioannis Mantas¹  Lucianne Groenink²  Sylvie Veiga³  Mark J. Millan³  Mauricette Brocco³  Benjamin Di Cara³  Laetitia Cistarelli³  Marc Bertrand⁴ 

[1]Department of Clinical Neuroscience, Karolinska Institute, 17177 Stockholm, Sweden

[2]Department of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, 3584 CS Utrecht, The Netherlands

[3]Neuroscience and Inflammation Therapeutic Area, Institut de Recherches SERVIER, 78290 Croissy-sur-Seine, France

[4]Technologie Servier, 45000 Orléans, France

关键词: TAAR1;    o-PIT;    DA;    antidepressants;   

DOI  :  10.3390/ijms22168907

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown