The Case for TAAR1 as a Modulator of Central Nervous System Function

Abstract

TAAR1 is widely expressed across the mammalian brain, particularly in limbic and monoaminergic areas, allegedly involved in mood, attention, memory, fear, and addiction. However, the subcellular distribution of TAAR1 is still unclear, since TAAR1 signal is largely intracellular. In vitro, TAAR1 is activated with nanomolar to micromolar affinity by some endogenous amines, particularly p-tyramine, beta-phenylethylamine, and 3-iodothyronamine (T1AM), the latter representing a novel branch of thyroid hormone signaling. In addition, TAAR1 responds to a number of psychoactive drugs, i.e., amphetamines, ergoline derivatives, bromocriptine and lisuride. Trace amines have been identified as neurotransmitters in invertebrates, and they are considered as potential neuromodulators. In particular, beta-phenylethylamine and p-tyramine have been reported to modify the release and/or the response to dopamine, norepinephrine, acetylcholine and GABA, while evidence of cross-talk between TAAR1 and other aminergic receptors has been provided. Systemic or intracerebroventricular injection of exogenous T1AM produced prolearning and antiamnestic effects, reduced pain threshold, decreased non-REM sleep, and modulated the firing rate of adrenergic neurons in locus coeruleus. However each of these substances may have additional molecular targets, and it is unclear whether their endogenous levels are sufficient to produce significant TAAR1 activation in vivo. TAAR1 knock out mice show a worse performance in anxiety and working memory tests, and they are more prone to develop ethanol addiction. They also show increased locomotor response to amphetamine, and decreased stereotypical responses induced by apomorphine. Notably, human genes for TAARs cluster on chromosome 6 at q23, within a region whose mutations have been reported to confer susceptibility to schizophrenia and bipolar disorder. For human TAAR1, around 200 non-synonymous and 400 synonymous single nucleotide polymorphisms have been identified, but their functional consequences have not been extensively investigated yet. In conclusion, the bulk of evidence points to a significant physiological role of TAAR1 in the modulation of central nervous system function and a potential pharmacological role of TAAR1 agonists in neurology and/or psychiatry. However, the specific effects of TAAR1 stimulation are still controversial, and many crucial issues require further investigation.

SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D2Receptor Mechanism of Action

“…TAAR1 is a GPCR activated by trace amines and expressed in multiple regions of the mammalian brain, including the limbic system, DRN and VTA (Borowsky et al, 2001;Burchett and Hicks, 2006;Lindemann et al, 2008;Rutigliano et al, 2018). Recent studies have extensively characterized TAAR1 functions, elucidating its important role in modulating dopaminergic circuitry and its potential implications in neuropsychiatric disorders (Borowsky et al, 2001; Leo et al, 2014; Fig.…”

Tyramine action on motoneuron excitability and adaptable tyramine/octopamine ratios adjust Drosophila locomotion to nutritional state

“…Although TA acts as an independent transmitter (31) to affect numerous behaviors in nematodes (32), insects (15,33), and mammals (34), the cellular sites and molecular mechanisms of TA action remain incompletely understood. We provide evidence that TA is released from central arbors of TDC2 neurons into motor neuropils of the Drosophila larval CNS to directly modulate MN excitability.…”

An injectable refrigerated hydrogel for Inducing local hypothermia and neuroprotection against traumatic brain injury

“…T1AM can stimulate TAAR1-expressing cells to produce cAMP, which induces profound hypothermia within minutes (28). Neurons and astrocytes in the brain both express TAAR1 (30). Therefore, we speculated that local administration of free T1AM in the brain would achieve local hypothermia ( Fig.2A).…”

“…T1AM has been used in animal models to protect against stroke-induced brain injury and is able to provide marked neuroprotection because TAAR1 is enriched in neurons and astrocytes in the brain (29). However, T1AM given by intraperitoneal injection is associated with some side effects, which is because TAAR1 is widely distributed in various organs such as the heart, aorta, kidney, stomach, and small intestine (30).…”