Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Trace Amine-Associated Receptor 1 (TAAR1)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101881

Synonyms

 TA1;  TAAR1;  TAR1;  TRAR1

Historical Background

Trace amines (TAs) are a class of endogenous amines that traditionally include compounds such as β-phenylethylamine (b-PEA), tyramine, tryptamine, octopamine, and synephrine (Fig. 1) (Berry 2004). Trace amines are characterized by their trace levels in the brain, their lack of vesicular storage, and their fast metabolism. These molecules are structurally related to the classic monoamines (dopamine, norepinephrine, and serotonin) and share similar synthetic and degradation pathways. TAs are synthesized by the action of L-amino acid decarboxylase and are degraded primarily by monoamine oxidases (MAO-A and MAO-B) (Fig. 2). TAs were initially discovered over 100 years ago and are present in several organisms (Grandy 2007). In invertebrates, octopamine and tyramine serve as major neurotransmitters, functionally replacing the role of epinephrine and norepinephrine found in vertebrates. However, in vertebrates, in particular in mammals, the precise physiological role of TAs is less clear. While TAs are present in many tissues at low levels, including the brain, they have long been considered side products of the synthesis and metabolism of classic monoamines with little physiological functions. TAs were most commonly described to act as sympathomimetic substances within the brain. Indeed, there is substantial evidence that several TAs can act as “false neurotransmitters” at high concentrations by interacting with the vesicular and plasma membrane monoamine transporters such as the dopamine transporter (DAT) and vesicular monoamine transporter 2 in an amphetamine-like manner. For example, b-PEA, a prototypical TA, can increase extracellular dopamine concentration after systemic administration resulting in increased locomotor activity. For this reason, and the fact that its structure differs from amphetamine by only a methyl group, b-PEA is considered an “endogenous amphetamine.” However, these sympathomimetic effects occur at high concentrations of TAs and in general these effects are not thought to be relevant at physiological concentrations. While the exact role of TAs in mammals has remained elusive for many years, in clinical settings, several studies have reported that dysregulated levels of TAs are associated with several human diseases such as schizophrenia, bipolar disorders, attention deficit hyperactivity disorder, Parkinson’s disease (PD), phenylketonuria, and many others.
Trace Amine-Associated Receptor 1 (TAAR1), Fig. 1

Pathway for Trace Amine and Catecholamine Production. The synthesis of the endogenous neurotransmitters dopamine, norepinephrine, and epinephrine follow the enzymatic modification of phenylalanine. First phenylalanine is P-hydroxylated to tyrosine by phenylalanine hydroxylase. Next L-DOPA is produced by the O-hydroxylation of tyrosine by tyrosine hydroxylase. Decarboxylation of L-DOPA by aromatic L-amino acid decarboxylase (AADC) produces dopamine where further β-hydroxylation of dopamine by dopamine beta hydroxylase (DBH) produces norepinephrine and methylation of the primary amine by phenylethanolamine N-methyltransferase (PNMT) produces epinephrine. The primary trace amines b-PEA and p-tyramine are formed from decarboxylation of phenylalanine and tyrosine by AADC, respectively. Further β-hydroxylation of p-tyramine by DBH produces octopamine, and methylation of the primary amine of tyramine or octopamine produces N-methyltryamine and synephrine, respectively. Methylation of the primary amine of b-PEA by PNMT produces N-methylphenethylamine

Trace Amine-Associated Receptor 1 (TAAR1), Fig. 2

Metabolic pathway of trace amines and catecholamines. The primary pathway for the metabolism for both TA and catecholamines involves the formation of acid derivatives from these compounds. The first step to the metabolism of these compounds involves the conversion of the primary or secondary amine to a short-lived aldehyde intermediary through monoamine oxidase A or B. Further metabolism of these aldehyde intermediaries by aldehyde dehydrogenase produces the acid form of the metabolites, where these acid forms are the primary metabolites for both TA and catecholamines. Secondary metabolites are also formed by the reduction of the aldehyde intermediary to an alcohol through aldehyde reductase. Lastly the acid metabolites of dopamine, norepinephrine, and epinephrine are further metabolized by catechol-O-methyltransferase as their primary metabolite that is excreted through the urine

Although binding sites for TAs had already been reported in rat brain, it was the discovery of a family of GPCRs that were activated by TAs that provided evidence of their potential importance in mediating brain physiology. Indeed, in 2001, two independent groups reported the discovery of a family of GPCRs that were stimulated by various TAs and hence named trace amine receptors (TA1 and TA2) (Borowsky et al. 2001; Bunzow et al. 2001). Since the initial discovery of TA1 and TA2, other receptors with similar structural homology have been discovered leading to the nomenclature of the family being changed to trace amine-associated receptors (TAARs) (Lindemann et al. 2005). Using this nomenclature TAAR1 and TAAR4 (formerly TA1 and TA2) are the only described receptors that bind TAs. There is a substantial diversity in the number of TAARs among different species, with nine genes in human (three pseudogenes), nine in chimpanzee (six pseudogenes), 19 in rats (two pseudogenes), and 16 in mice (one pseudogene). All TAARs cluster in a narrow region of the same chromosome of approximately 100–200 kilobases, and all genes are encoded by a single exon, except TAAR2 which has two exons. In the human genome, TAAR1 is located on chromosome 6 (6.q23.2) and encodes for a protein of 332 amino acid long. Among all TAARs, TAAR1 is the most studied member of the family and rapidly attracted the attention of the researchers because of its expression pattern in the brain and its pharmacological profile.

Expression and Cellular Signaling

TAAR1 expression has been reported in several organisms, in both invertebrates and vertebrates, including zebrafish, rodents, rhesus monkey, and humans (Grandy 2007). While there are conflicting results regarding the precise expression profile of TAAR1 between different studies (probably due to the limitations of different techniques used), there is a certain agreement on TAAR1 expression in certain brain regions and peripheral organs. Interestingly, among the TAAR family of receptors, TAAR1 is the only member of the family that is not expressed in the olfactory epithelium.

TAAR1 expression has been well documented in the mouse, rat, and monkey. Using RT-PCR, in situ hybridization, and LacZ staining in transgenic mice, TAAR1 expression has been reported in the brain, specifically, monoaminergic nuclei (ventral tegmental area (VTA), substantia nigra, and dorsal raphe (DR)) and their projecting areas (striatum, nucleus accumbens, prefrontal cortex, amygdala, subiculum, and parahippocampal region). This expression pattern in key monoaminergic areas suggests a potential role of TAAR1 in regulating dopamine and serotonin neurotransmission. Indeed, as shown by many in vivo studies, TAAR1 is able to modulate aspects linked to monoaminergic neurotransmission such as locomotor activity and emotional and motivated behaviors. In addition to monoaminergic brain regions, TAAR1 is also expressed in the periphery, including the liver, spleen, gastrointestinal tract, thyroid, pancreas, and leukocytes.

While the vast majority of studies have focused primarily on rodent expression of TAAR1, it has been shown that in humans, TAAR1 is indeed expressed in the brain, primarily in the amygdala. Furthermore, in the periphery, TAAR1 is expressed at moderate levels in the stomach, lung, kidney, duodenum, and pancreatic islets (Borowsky et al. 2001). Lastly, expression of TAAR1 is also present in blood leukocytes, particularly in polymorphonuclear T and B cells.

The subcellular localization of TAAR1, in heterologous cell systems, seems to be primarily in the cytoplasm, with poor membrane localization. However, due to technical limitations, the precise localization of TAAR1 protein in an endogenous system, such as neurons, is currently unknown. Therefore, it is possible that in heterologous cells, an essential component needed for the proper expression and trafficking of the receptor to the plasma membrane is missing. Indeed, co-expression of TAAR1 with D2 dopamine receptors resulted in increased plasma membrane expression of TAAR1 leading to formation of heterodimer receptor complexes and induction of biased signaling events (Harmeier et al. 2015). In order to study receptor functions and signaling in vitro, structural modifications to human TAAR1 have been used to improve expression at the plasma membrane. These modifications include human/rat receptor chimeras and the addition of a small N-terminal amino acid sequence from the β2 adrenergic receptor (Barak et al. 2008).

TAAR1 is coupled to the Gαs protein and its stimulation leads to an increase in intracellular cAMP levels. The response of TAAR1 agonists has been found to be quite prolonged compared to other GPCR, and the receptor shows little to no desensitization. This is also confirmed by the poor recruitment of β-arrestin1 or β-arrestin2 to the receptor. In addition to the stimulation of Gαs, TAAR1 activation can also lead to the phosphorylation of extracellular signal-regulated kinase (ERK) and of cAMP response element-binding (CREB) protein both in heterologous cells and in vivo in mouse striatum. Activation of TAAR1 also results in phosphorylation of protein kinase A and PKC in HEK cells. Recently, the involvement of TAAR1 in modulating D2 dopamine-receptor-dependent β-arrestin2/AKT/GSK3 signaling cascade, via formation of heterodimer receptor complexes, has also been reported in vivo (Harmeier et al. 2015).

Accumulating evidence also indicates that TAAR1 can modulate NMDA receptor-mediated glutamate transmission at least in the prefrontal cortical neurons although the molecular mechanism of such modulation presently is not known (Espinoza et al. 2015b).

TAAR1 Ligands

In general, there are multiple classes of ligands that bind to TAAR1. Endogenous ligands that activate TAAR1 include trace amines, thyronamines, and catecholamine metabolites. Synthetic ligands include several groups of monoaminergic and imidazoline ligands, as well as TAAR1-selective compounds developed by Roche (Fig. 3.) (Hu et al. 2009; Cichero et al. 2014).
Trace Amine-Associated Receptor 1 (TAAR1), Fig. 3

Known ligands for human TAAR1. Potent agonists for TAAR1 are found within the following classes of known synthetic ligands: dopaminergic and imidazoline agonists. In addition, it has been shown that catecholamine metabolites and thyronamines are potent TAAR1 agonists. Novel and selective synthetic agonists for TAAR1 have also been developed and discovered by Hoffmann-La Roche (RO compounds) as well as novel chemical scaffolds found from in silico screens (compound 1*, 8+, and 16+). Lastly the only known antagonist for TAAR1 is the synthetic ligand EPPTB (*Cichero et al. 2014; +Lam et al. 2015)

Endogenous b-PEA and tyramine are full TAAR1 agonists, with b-PEA being more potent at the mouse and human form and tyramine being more potent at the rat TAAR1. Conversely, tryptamine and octopamine are having lower potency and are partial agonists for TAAR1. In addition, the O-metabolites of cathecholamines (3-methoxytyramine (3-MT), 4-methoxytyramine, metanephrine, and normetanephrine) are also agonists of TAAR1. Interestingly, these molecules are generally described as biologically inactive, and 3-MT, for example, has been commonly considered as only a reflection of extracellular dopamine in the brain. However, Bunzow et al., and later other studies, showed that these compounds are also TAAR1 full agonists (Bunzow et al. 2001). In particular, 3-MT can produce behavioral and biochemical effects in mice in a dopamine-independent manner that are partly mediated by TAAR1 (Sotnikova et al. 2010).

Another set of interesting endogenous TAAR1 ligands are thyronamines, which are compounds that are structurally related to thyroid hormones. 3-iodothyronamine (T1 AM) and its deiodinated form thyronamine (T0 AM) are potent and full TAAR1 agonists and when injected in rats can produce profound physiological effects, such as hypothermia, cardiac effects, and metabolic and neurological alterations (Scanlan et al. 2004). It should be noted, however, that thyronamines can affect other molecular targets such as α2A adrenergic receptors as well as plasma membrane and vesicular monoamine transporters, and thus contribution of TAAR1 to the physiological effects observed should be carefully evaluated.

Interestingly, TAAR1 can also bind to several known dopaminergic and serotonergic ligands (Fig. 3). One class of these compounds are the amphetamines. D- and L-amphetamine, D-methamphetamine, MDMA, and several other amphetamine derivatives are potent full TAAR1 agonists, increasing the cAMP concentration in HEK cells expressing rat TAAR1. Further studies have confirmed these observations in other cell systems using human, mouse, and rhesus monkey TAAR1. Importantly, the range of concentration necessary to activate human TAAR1 (0.1–1 μM) is within the plasma concentration that is achieved upon administration of these drugs to humans suggesting that these compounds could exert some of their effects by acting on TAAR1. Indeed, it has been postulated that TAAR1 plays an important role in the mechanism of action of amphetamine in humans. Other two interesting known chemicals with TAAR1 activity are apomorphine, a prototypical D1/D2 nonselective agonist, and ractopamine, a food additive used to feed livestock in the USA.

Finally, since both TAs and the other TAAR1 ligands mentioned above are not selective and also bind other biological targets, a significant advancement in understanding TAAR1 physiology in the brain and periphery came from the synthesis of selective TAAR1 ligands by Hoffmann-La Roche. Several full and partial agonists were tested and described in studies that showed potent biological actions of these compounds (Revel et al. 2011; Revel et al. 2013). Unfortunately, only one antagonist has been described so far (EPPTB or N-(3-ethoxyphenyl)-4-(pyrrolidin-1-yl)-3-trifluoromethylbenzamide) with a poor pharmacokinetic profile, making it only useful for in vitro experiments (Bradaia et al. 2009).

TAAR1 Physiology in the Brain

Once TAAR1 expression was discovered in monoaminergic brain regions such as VTA and DR, several studies focused their attention on evaluating TAAR1 regulation of monoaminergic systems, particularly the dopamine system. In general, TAAR1 seems to play a role as a modulator of dopaminergic neurotransmission. Electrophysiological recordings on dopamine neurons in the VTA show that the antagonism or genetic deletion of TAAR1 leads to an increase in the firing rate of these neurons and thus an increase in dopamine tone, while conversely, pharmacological activation of TAAR1 is able to reduce dopaminergic tone. TAAR1-KO mice are more sensitive to the neurochemical and behavioral effect of amphetamine, demonstrating an increased locomotor activation and more pronounced increase of dopamine release in the striatum following amphetamine administration (Wolinsky et al. 2007; Lindemann et al. 2008). It is expected that TAAR1 antagonists would also recapitulate these behaviors seen in the genetic knockout of TAAR1; however a TAAR1 antagonist with proper pharmacokinetic profile for in vivo testing does not yet exist. In contrast, administration of TAAR1-selective agonists can reduce the hyperlocomotion produced pharmacologically by cocaine treatment or naturally present in the hyperdomainergic DAT-KO mouse line (Revel et al. 2011).

TAAR1 influences the dopamine neurons in multiple sites, from their soma to their projections in their afferent areas. As mentioned above TAAR1 can regulate the firing activity of dopaminergic neurons in the VTA, with TAAR1-KO mice showing an increased firing rate. The same effect is obtained with the application of the selective antagonist EPPTB in vitro. On the contrary, full agonists reduce the firing frequency of these same neurons. This effect is independent on cAMP levels, but is mediated by the Gβγ subunits of the activated G protein, and results from changes in K+ current from the Kir3-type K+ channels (Revel et al. 2011). Interestingly, the partial agonist behaves as an antagonist, suggesting that in basal condition, there could be an endogenous tone activating the receptor by TA or other substances (Revel et al. 2012).

In addition, it has been shown that TAAR1 also influences the activity of the dopamine D2 receptors. In the VTA, TAAR1 activation decreases D2 autoreceptor activity and promotes the desensitization of this receptor. Interestingly, the same functional interaction is present in the DR between TAAR1 and serotonergic 5-HT1A autoreceptor (Revel et al. 2011). In vivo microdialysis and fast-scan cyclic voltammetry studies revealed that TAAR1 regulated the dopamine release through the modulation of D2 autoreceptor activity in the nucleus accumbens (Leo et al. 2014). In the TAAR1-KO mice, the basal dopamine release in the nucleus accumbens, but not in dorsal striatum, is increased, and the pharmacological activation or the blockade of TAAR1 can modulate dopamine release. There is substantial evidence that TAAR1 can interact with the D2 dopamine postsynaptic receptors as well. It has been shown that TAAR1-KO mice have an increased expression of D2 receptor in the striatum and a higher proportion of these receptors in the high affinity state. Moreover, one signaling pathway that is mediated by D2 receptor activation, the β-arrestin2/AKT/GSK3 cascade, is basally activated in TAAR1-KO animals (Espinoza et al. 2015a). All these alterations suggest an enhanced sensitivity of the D2 postsynaptic receptor that is manifested also in the locomotor behavior of TAAR1-KO mice. One possible mechanism for this functional interaction between TAAR1 and D2 receptors is direct heterodimerization between the two receptors. In vitro and in vivo studies showed that TAAR1 and D2 receptors form a heterodimer, as demonstrated by co-immunoprecipitation experiments from brain tissue and BRET assays in vitro in HEK cells (Espinoza et al. 2011; Harmeier et al. 2015). The dimerization seems to be important for TAAR1 trafficking in the cells and can also influence signaling of each receptor, for example, TAAR1 signaling becomes biased toward β-arrestin2 signaling rather than the accumulation of cAMP.

Several studies also showed that TAAR1 can bind and regulate monoamine transporters, such as DAT, norepinephrine transporter, and serotonin transporter. Co-expression studies revealed the presence of TAAR1 and DAT in a subset of neurons in the substantia nigra, while synaptosomal preparations show that TAAR1 can modulate DAT activity (Xie and Miller 2007, 2009). It has also been hypothesized that this interaction could provide a mechanism by which TAAR1 ligands could enter inside the cells and bind TAAR1 that is present in intracellular compartments. It should be noted, however, that TAAR1 agonists exert their normalizing effect on hyperactive hyperdopaminergic mice lacking the DAT that directly demonstrates that this effect is not mediated via interaction of TAAR1 with the DAT.

Another brain region where TAAR1 exerts an interesting biological activity is the prefrontal cortex. TAAR1 is expressed in pyramidal neurons of the layer V, and studies using TAAR1-KO animals have shown that TAAR1 is important for NMDA-mediated glutamatergic neurotransmission (Espinoza et al. 2015b). The prefrontal cortex is important for cognitive functions, and TAAR1-KO mice show decreased NMDA receptor expression and phosphorylation in this brain area accompanied with impulsive and perseverative behaviors suggesting impaired cognitive functions. Notably, also TAAR1 agonists effectively antagonize hyperactivity induced by NMDA receptor antagonists. Furthermore, in situ injections of TAAR1 agonists in subregions of the prefrontal cortex reduce compulsive and binge-like eating behaviors in mice, and these agonists can also reduce cocaine self-administration and prevent reinstatement of this aberrant behavior (see section below).

Another central effect of TAAR1 is the regulation of wakefulness and sleep. It has been shown in TAAR1 transgenic animals and by using a pharmacological approach with TAAR1-selective agonists that TAAR1 has a profound action on EGG spectral composition, regulating wakefulness and REM and NREM sleep (Schwartz et al. 2016).

TAAR1 Physiology in the Periphery

While the majority of TAAR1 research has been focused on its action in the brain, there is increasing evidence that TAAR1 has important physiological effects in the periphery. The TA effect on the cardiovascular system is well known (i.e., the “tyramine effect”), but it is evident that most of these actions are attributed to TAs properties as “false neurotransmitters.” However, the fact that some researchers reported the expression of TAAR1 and other TAAR in the heart raised the question whether TAAR1 exerts a role in this organ. The thyronamines T1 AM and T0 AM, when injected in animals, produce a strong behavioral suppression, with locomotor inhibition, ptosis, reduced metabolic rate, hypotension, and hypothermia (Scanlan et al. 2004). Regarding the cardiovascular effects, in mice, T1 AM and T0 AM induce a drop in heart rate and, in rats, a negative ionotropic and chronotropic effect. Although thyronamines are potent full TAAR1 agonists, they are however not selective for TAAR1, thus there is still a debate whether these effects are mediated solely by TAAR1 activation. Another part where thyronamines could activate TAAR1 is the thyrocytes, since TAAR1 has been found in the secretory pathway of mouse and rat thyrocytes, particularly its accumulations in the primary cilium. Regarding temperature control, TAAR1 may have a role in the hypothermic response of some amphetamines, even if more studies are necessary to address this issue.

The fact that some compounds that target the monoamines transporters such as MDMA could affect leukocytes and immune response suggested the idea that TAAR1 could mediate some of those effects. Indeed, TAAR1 transcript and protein have been found in leukocytes from mouse, rhesus monkey, and human blood. TAAR1 presence was also confirmed in normal and malignant B cells derived from healthy subjects and patients with different blood-related diseases. Interestingly, several TAAR1 agonists at high concentrations could induce cytotoxicity of some of these cells, suggesting a potential use for TAAR1 ligands in disease such as leukemia and lymphomas. TAAR1, along with other TAARs, is also expressed in PMN cells, T cells, B cells, NK cells, and monocytes (Babusyte et al. 2013). b-PEA, tyramine, and T1 AM are able to induce different activities on these cells at low concentration, in the nanomolar range, which reflect the endogenous levels of TA in the body. This observation also supports the fact that TAAR1 pharmacology and biochemistry could be very different between artificial heterologous systems and the native one. These data support a potential role of TAAR1 in immune response and could suggest a role for this receptor in other immunological diseases such as food-related allergy.

In the gastrointestinal tract, TAAR1 is present in the pylorus and the jejunum of the stomach, in the duodenum (Raab et al. 2016). The highest level of TAAR1 expression in the body is found in the pancreatic islets. Only recently has it been shown that the activation of TAAR1 showed a beneficial effect on glucose control and body weight, in animal model of type 2 diabetes and obesity, suggesting a potential benefit of TAAR1-based therapies in the control of these two widespread pathologies.

TAAR1 as Therapeutic Target

Neuropsychiatric Disorders

Discovery of TAAR1 and its unique activity within the dopamine system indicates that TAAR1 could have a role in the pathophysiology of neuropsychiatric diseases. Several studies in the last 50 years linked the dysregulated TAs levels to a variety of psychiatric disorders such as schizophrenia, bipolar disorders, depression, migraine, ADHD, and PD. Increased b-PEA levels in the plasma were found in schizophrenic subjects, while increased b-PEA urinary excretion was found in paranoid schizophrenics (Grandy 2007). The so-called b-PEA hypothesis indeed proposed that a decreased levels of endogenous b-PEA could be responsible for a depression symptomatology, while an excess presence of b-PEA could cause manic episodes. Interestingly, MAO inhibitors have been used for treating depression, and it is believed that part of their effects could be due to an increase of TA levels in the brain. Regarding direct causal link between TAAR1 and these diseases, there is little indication of a genetic associations between TAAR1 and any of neuropsychiatric disorders. The only evidence is that the locus where TAAR genes cluster, the chromosome 6q23.1, is on a known susceptible loci that has been associated with schizophrenia.

The recent development of a series of selective TAAR1 ligands highlighted the biological relevance of TAAR1 in brain physiology and demonstrated that TAAR1 could be considered as a new target for treating a range of psychiatric and neurological disorders. Several studies conducted in vitro and in vivo in different animal models of diseases showed that TAAR1 agonists could be employed as possible drugs in the treatment of pathologies such as schizophrenia, depression, bipolar disorder, and drug addiction. Several partial and full agonists have been developed by Hoffmann-La Roche and showed efficacy in preclinical animal models of these disorders.

Particularly, TAAR1 agonists effectively counteracted hyperactivity caused by dopamine receptor stimulation or by the reduction in glutamate NMDA receptor-mediated transmission both pharmacologically and genetically in transgenic mouse models of schizophrenia (Revel et al. 2011; Revel et al. 2013). These behaviors are commonly considered as manifestations related to positive symptoms of schizophrenia, and thus TAAR1 agonism may represent a novel non-dopaminergic approach to treat these symptoms. Interestingly, both full and partial agonists strongly potentiated effects of olanzapine, suggesting a potential advantage of add-on treatment. Moreover, TAAR1 partial agonists also showed procognitive actions in models of impaired cognitive functions, as demonstrated in rats and monkeys (Revel et al. 2013).

While the bulk of the literature focuses on TAAR1 effects on the dopamine system, TAAR1 effects on the serotonergic system are not as well characterized. It is known that the serotonergic system is important for mood and cognition. Indeed, the TAAR1 agonists have also been tested in models of depression, showing an interesting antidepressant and anxiolytic-like activity. Furthermore, TAAR1 seems to regulate the wakefulness and both the REM and NREM sleep, and the recent study demonstrated the beneficial effect of both full and partial agonists in two rodent models of narcolepsy (Black et al. 2016).

Addiction

The initial evidence that amphetamines could activate TAAR1 raised immediately the hypothesis that part of the addictive properties of these compounds were mediated by TAAR1 (Bunzow et al. 2001). However, as demonstrated by multiple studies, the absence of TAAR1 (like in TAAR1-KO mice) induces a hypersensitivity of the dopaminergic system, while TAAR1 activation can counteract dopaminergic activation. Thus amphetamines, by activating TAAR1, can reduce their own activity on dopaminergic system which suggests that TAAR1 could represent a “brake” in amphetamine actions, as an endogenous negative feedback.

Indeed, it has been demonstrated that MDMA, amphetamine, and methamphetamine are more effective in TAAR1-KO animals and can produce higher addictive effects. An interesting study showed that a mouse line obtained by selective breeding that showed a spontaneous high consumption of methamphetamine carried a nonfunctional allele for TAAR1 (Harkness et al. 2015). Based on this evidence, several studies reported a potential use for TAAR1 agonists as new treatment for drug addiction. Using different strategies and experimental models, TAAR1 agonists have been successfully used for reducing the cocaine-abuse-related effects in rodents (such as sensitization, reinforcing and rewarding effects of cocaine) as well as to reduce the drug relapse, an important aspect of drug addiction (Pei et al. 2014; Thorn et al. 2014). Local infusion of TAAR1 agonists showed that the brain regions that could be involved in these effect are the VTA, the nucleus accumbens, and the prefrontal cortex (the prelimbic region) (Liu et al. 2017).

Obesity and Diabetes

There are several reasons to believe that TAAR1 may become an interesting target for obesity and related metabolic disorders. One therapeutic option that can be related to addiction is the compulsive, binge-like eating disorder (Ferragud et al. 2016). As described above, TAAR1 is expressed in the prefrontal cortex and was shown to modulate glutamatergic neurotransmission in this area and potentially to contribute to impulsive and compulsive behavior. The recent study showed that TAAR1 agonist potently reduced the compulsive, binge-like eating in rats, and one region that mediates this biological effect is the prefrontal cortex (the infralimbic subregion).

High levels of TAAR1 expression is found in the β-cells of the pancreas, the stomach, and the intestines. During preclinical evaluation of TAAR1 agonists as novel therapeutics for schizophrenia, it has been noted that the partial TAAR1 agonist prevents olanzapine-induced weight gain. Administration of TAAR1 agonists also causes enhancement of glucose-stimulated insulin secretion in both rat insulinoma cells and isolated human islets and lowers blood glucose excursion in response to an oral glucose challenge in diabetic and diet-induced obese mouse strains.

Thus, TAAR1 agonists may represent a novel therapeutic opportunity for the treatment of type 2 diabetes and obesity originating from both drug- and diet-induced causes by affecting both the centrally mediated overconsumption and subsequent insulin imbalance mechanisms of obesity and associated metabolic disorders.

Summary

Since the discovery of a family of TAARs 15 years ago, a remarkable progress has occurred in understanding their function, biology, and pharmacology. The best studied member of this family, TAAR1, has become a focus of multiple preclinical studies and showed great potential as a novel treatment of various neuropsychiatric disorders, addiction, obesity, diabetes, and related disorders. While results of ongoing clinical studies are eagerly awaited, it is already clear that this important molecule can be involved in multiple physiological functions and with the further development of new tools will continue to attract interest of physiologists and pharmacologists.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Pharmacology and ToxicologyUniversity of TorontoTorontoCanada
  2. 2.Institute of Translational BiomedicineSt. Petersburg State UniversitySt. PetersburgRussia
  3. 3.Skolkovo Institute of Science and Technology (Skoltech)MoscowRussia
  4. 4.Department of Neuroscience and Brain TechnologiesIstituto Italiano di TecnologiaGenoaItaly