Trace amine-associated receptor 1: a multimodal therapeutic target for neuropsychiatric diseases

ABSTRACT

Introduction: The trace amines, endogenous amines closely related to the biogenic amine neurotransmitters, have been known to exert physiological and neurological effects for decades. The recent identification of a trace amine-sensitive G protein-coupled receptor, trace amine-associated receptor 1 (TAAR1), and subsequent development of TAAR1-selective small-molecule ligands, has renewed research into the therapeutic possibilities of trace amine signaling.

Areas covered: Recent efforts in elucidating the neuropharmacology of TAAR1, particularly in neuropsychiatric and neurodegenerative disease, addiction, and regulation of arousal state, will be discussed. Focused application of TAAR1 mutants, synthetic TAAR1 ligands, and endogenous biomolecules such as 3-iodothyronamine (T1AM) has yielded a basic functional portrait for TAAR1, despite a complex biochemistry and pharmacology. The close functional relationship between TAAR1 and dopaminergic signaling is likely to underlie many of its CNS effects. However, TAAR1’s influences on serotonin and glutamate neurotransmission will also be highlighted.

Expert opinion: TAAR1 holds great promise as a therapeutic target for mental illness, addiction, and sleep disorders. A combination of preclinical and translationally driven studies has solidified TAAR1 as a key node in the regulation of dopaminergic signaling. Continued focus on the mechanisms underlying TAAR1’s regulation of serotonin and glutamate signaling, as well as dopamine, will yield further disease-relevant insights.

KEYWORDS:

• Dopamine
• serotonin
• addiction
• schizophrenia
• depression
• sleep
• psychostimulants
• neuropharmacology

Article Highlights

• TAAR1 regulates DA, 5-HT, and glutamate neurotransmission by decreasing basal firing rates and negatively modulating receptor sensitivity.

• Selective full and partial TAAR1 agonists exhibit potent antipsychotic, antidepressant, anti-impulsive and procognitive effects.

• TAAR1 agonism reduces stimulant-induced reward, stimulant self-administration, and relapse to drug seeking.

• T1AM, an endogenous TAAR1 agonist derived from thyroid hormone, modulates food intake, increases wakefulness and improves cognitive performance.

• TAAR1 partial, but not full agonists, promote wakefulness, while both full and partial agonists suppress cataplexy.

• Based on preclinical studies, TAAR1 agonism represents a novel strategy for treating neuropsychiatric diseases involving dysregulated monoaminergic signaling such as schizophrenia, addiction, depression, ADHD, Parkinson’s disease, and OCD.

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Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

M. D. Schwartz is supported by NIH #NS098813, I. Sukhanov is supported by the Russian Science Foundation Grant #17-75-20177 and R. R. Gainetdinov is supported by the Russian Science Foundation Grant #14-50-00069.