Neuronal Functions and Emerging Pharmacology of TAAR1

Abstract

Trace amine-associated receptor 1 (TAAR1) is a member of TAAR family of G protein-coupled receptors (GPCRs). The members of this class of receptors discovered in 2001 have been found in some tissues ranging from the central nervous system to the olfactory epithelium and in some peripheral organs. The best studied receptor, TAAR1, is activated by a class of compounds named trace amines (TAs) that include compounds such as β-phenylethylamine (PEA), p-tyramine, octopamine, and tryptamine normally present at low levels in the mammalian brain. Although TA levels have been associated with many neuropsychiatric disorders, only the discovery of TAAR1 validated their physiological role. TAAR1 can modulate monoamine neurotransmission and, in particular, dopamine systems. Several studies have demonstrated that TAAR1 knockout (TAAR1-KO) mice display a supersensitive dopaminergic system, while activation of TAAR1 can reduce dopaminergic hyperactivity obtained either with pharmacological tools or present in genetic mouse model. For these reasons, TAAR1 has been proposed as a novel therapeutic target for neuropsychiatric disorders such as schizophrenia, bipolar disorder, and addiction. Moreover, several peripheral functions of TAAR1 have been described recently indicating intriguing novel TAAR1 roles in system physiology. Here we will review brain and peripheral functions mediated by TAAR1 and other TAARs.

TAAR1 modulates cortical glutamate NMDA receptor function

“…TAAR1 knockout (TAAR1-KO) mice display a higher sensitivity to amphetamine and other psychostimulants (Wolinsky et al, 2007;Lindemann et al, 2008;Di Cara et al, 2011), and seem to have a supersensitive dopaminergic system (Wolinsky et al, 2007;Lindemann et al, 2008), making them an interesting model relevant for schizophrenia (Wolinsky et al, 2007). Accordingly, both full and partial TAAR1-selective agonists are efficacious in experimental rodent models of psychosis, such as pharmacologic or genetic mouse models of hyperdopaminergia, further supporting the idea that TAAR1 could represent a novel target for psychiatric diseases (Sotnikova et al, 2009;Espinoza and Gainetdinov, 2014). Although there is evidence suggesting a potential TAAR1 involvement in cognitive functions (Revel et al, 2013), no studies evaluated TAAR1 role in cortical regions so far.…”

TAARs as Novel Therapeutic Targets for the Treatment of Depression: A Narrative Review of the Interconnection with Monoamines and Adult Neurogenesis

“…Starting with RO5256390, new partial or full TAAR1 agonists with high affinity and selectivity for TAAR1 have been created and studied [ 78 ]. Initially, TAAR1 agonists were considered for the treatment of schizophrenia [ 79 , 80 ]. Researchers have already shown their effectiveness against the positive, negative (lack of motivation, anhedonia), and cognitive symptoms of schizophrenia, which are often overlooked by typical antipsychotics [ 64 ].…”

Depressive disorders: Treatment failures and poor prognosis over the last 50 years

“…Multiple mechanisms are likely to account for the clinical response in alleviating depression: (a) receptor downregulation; (b) other components of cellular signaling (eg, biased agonism) that are regulated by cyclic AMP, which are prominent transcription factors in the brain (phosphorylated cAMP response element protein, CREB); and (c) factors controlling cellular plasticity such as brain‐derived neurotrophic factor –, 18KDa translocator protein—TSPO, Trace Amines—TAAR1 …”