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. Author manuscript; available in PMC: 2022 Jan 25.
Published in final edited form as: CNS Drugs. 2021 Nov 12;35(12):1239–1248. doi: 10.1007/s40263-021-00871-4

Potential of Ligands for Trace Amine-Associated Receptor 1 (TAAR1) in the Management of Substance Use Disorders

Ruyan Wu 1,2, Jun-Xu Li 2,*
PMCID: PMC8787759  NIHMSID: NIHMS1771606  PMID: 34766253

Abstract

Trace amines, including β-phenylethylamine (β-PEA), p-tyramine (TYR), tryptamine (TRP) and p-octopamine (OCT), represent a group of amines expressed at low levels in the mammalian brain. Given the close structural similarities to traditional monoamines, the links between trace amines and the monoaminergic system have long been established. Trace amine associated receptor 1 (TAAR1), the most well characterized receptor in the TAARs family, has been shown to be potently activated by trace amines like TYR and PEA. Meanwhile, catecholamine metabolites and amphetamine analogs are also potent agonists of TAAR1, implicating its role in mediating the monoaminergic system and substance use disorders. In the central nervous system, TAAR1 is expressed in brain regions involved in dopaminergic, serotonergic and glutamatergic transmission. Genetic animal models and electrophysiological studies have revealed that TAAR1 is a potent modulator of the monoaminergic system, and TAAR1 agonists may be potential pharmacotherapies for the treatment of substance use disorders. Selective and potent engineered TAAR1 ligands, including full (RO5166017 and RO5256390) and partial (RO5203648, RO5263397 and RO5073012) agonists and the antagonist EPPTB (N-(3-ethoxyphenyl)-4-(1-pyrrolidinyl)-3-(trifluoromethyl)benzamide, RO5212773), serve as invaluable tools for the investigation of TAAR1 functions and display high potential for the development of TAAR1-based pharmacotherapies for the treatment of substance use disorders. Despite a number of advances that have been made, more clinical studies are warranted in order to test the potential and efficacy of TAAR1 ligands in the treatment of psychiatric disorders, especially substance use disorders.

1. The trace aminergic system and its relevance to substance use disorders

1.1. Trace amines

Trace amines represent a group of amines expressed in the mammalian brain at concentrations that are at least 100-fold below those of traditional neurotransmitters such as dopamine, norepinephrine or serotonin [1]. The strictures of traces amines are highly similar to those of monoamines, examples of traces amines include β-phenylethylamine (β-PEA), p-tyramine (TYR), tryptamine (TRP) and p-octopamine (OCT) [1, 2]. Trace amines are typically formed after precursor amino acids are decarboxylated by aromatic L-amino acid decarboxylase (AADC), rather than tyrosine hydroxylase or tryptophan hydroxylase [3–6]. Therefore, the discovery of a group of neurons that express only AADC – not tyrosine hydroxylase nor serotonin – suggested the existence of a potential trace aminergic neuronal system [7].

Trace amines like PEA, TYP and TRP do not appear to be stored, as they have a remarkably high turnover rate compared with traditional monoamines [8, 9]. They are likely to pass across the cell membranes through a mechanism similar to passive diffusion [8, 10]. However, recent studies suggest that their levels are further modulated by transporters like organic cation transporter 2 (OCT2; Slc22A2) [11]. Although the mechanisms by which trace amines are metabolized and transported are poorly understood, they are known to interact closely with monoaminergic systems [12–14]. Traces amines inhibit reuptake processes and displace monoamines from their storage vesicles, demonstrating indirect sympathomimetic amphetamine-like effects [15, 16]. Moreover, trace amines like PEA have inhibitory effects on dopamine-related hyperactivity [17].

Since PEA has been hypothesized to be an “endogenous amphetamine” [18, 19], links between trace amines and drug reward/substance use disorders have long been suspected. Increased PEA levels were observed in response to Δ9-tetra-hydrocannabinol (Δ9-THC), the primary psychoactive component of marijuana [20]. Furthermore, the synthetic enzyme that breaks down trace amines, AADC, is involved in the neural mechanisms of reward and reinforcement, since altered AADC activity and AADC gene polymorphisms have been associated with alcohol and nicotine dependence [21–23]. Following their discovery during the late 1870s [24], interest in trace amines continued; however, it soon faded away after 1910s as they were viewed as metabolic by-products and emphases were put to the more abundant monoamines. There was a resurgence of interest in trace amines when a new group of G protein-coupled receptors (GPCRs) was identified in 2001, of which two novel receptors (TAAR1 and TAAR4) showed high selectivity to trace amines [25, 26]. In fact, there are 9 members in the trace amine-associated receptors (TAARs) family (TAAR1–9) [2]. The discovery of TAARs, especially TAAR1, has strengthened the suspected connections between trace amines and substance use disorders.

1.2. Trace amine-associated receptor 1 (TAAR1)

In an attempt to find novel GPCRs that are activated by dopamine, serotonin or other related biogenetic amines, TAAR1 was identified by two independent groups who found it to be potently activated by trace amines like TYR and PEA [25, 26]. Interestingly, catecholamine metabolites 3-methoxytyramine (3-MT), normetanephrine, and metanephrine and amphetamine analogs including amphetamine, methamphetamine (METH) and 3,4-Methyl​enedioxy​methamphetamine (MDMA) are also potent agonists of TAAR1 [25, 26]. Previous in situ hybridization experiments indicate that TAAR1 is expressed at low levels in rat brain tissue [26]. However, utilization of a more sensitive reverse transcription-polymerase chain reaction (RT-PCR) showed that TAAR1 is widely distributed in both the peripheral and central nervous system (CNS) [25, 26]. In the periphery, TAAR1 is found in the liver, pancreatic β-cells, stomach and intestinal cells, which may might participate in immune functions and homeostasis [27–33]. However, such effect is generally overlooked because TAAR1 was also found in brain regions involved in the dopaminergic, serotonergic and glutamatergic systems (Figure 1) as TAAR1 mRNA was found in the prefrontal cortex (PFC), amygdala, ventral tegmental area (VTA), substantia nigra (SN), nucleus accumbens (NAc), hippocampus, dorsal raphe (DRN) and the locus coeruleus (LC) [2, 34, 35]. Such a distribution is consistent both in rodents and primates and was later confirmed by a study which replaced a Taar1 coding sequence with a LaZ reporter [36], allowing for a more sensitive examination of TAAR1 tissue distribution. Although it is a GPCR, TAAR1 expression is consistently suggested to be intracellular [25, 26, 28, 32]. Studies have suggested that interaction with the dopamine D2 receptor may provide an avenue for its translocation to the membrane [34, 37] though the mechanism is unclear.

Figure 1.

Figure 1.

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TAAR1 expression in the central nervous system (CNS). TAAR1 is expressed in brain regions involved in dopaminergic, serotonergic and glutamatergic systems, including the prefrontal cortex (PFC), amygdala, ventral tegmental area, nucleus accumbens, hippocampus, and dorsal raphe. TAAR1: trace amine-associated receptor 1; mPFC: medial prefrontal cortex, NAc: nucleus accumbens, Hypo: hypothalamus, Amy: amygdala, VTA: ventral tegmental area, Hippo: hippocampus, DRN: dorsal raphe nucleus.

It is widely suggested that TAAR1 plays an important part in the regulation of serotonergic, glutamatergic and dopaminergic systems. For example, TAAR1 is expressed in the DRN, a key location where serotonin neurons are innervated [36]. Moreover, while deletion of TAAR1 led to increased frequency of spontaneous firing frequency of serotonin neurons in brain slices [36], TAAR1 full agonists significantly inhibited the firing frequency in DRN serotonin neurons [28, 38]. Besides the role of TAAR1 in modulation of the serotoninergic system, recent studies have also implicated a key role of TAAR1 in glutamatergic transmission. Since TAAR1 knockout (TAAR1-KO) mice showed altered glutamatergic transmission in the PFC [39] and TAAR1 agonists significantly blocked hyperlocomotion and cognitive deficits induced by N-methyl-D-aspartate (NMDA) antagonists [28, 38, 40], TAAR1 seems to have a calming effect on hypoglutamatergic-related activities. Furthermore, a recent study indicated that TAAR1 agonist, TYR, and glutamate are associated with the behavioral and neurochemical effects of monoamine oxidase inhibitors (MAOIs) [41], suggesting that it is also involved in the actions of antidepressants. In addition to its role in cognition, wakefulness, schizophrenia and drug reward, TAAR1 exhibits a multifaceted role in the modulation of psychiatric disorders [42]. However, our understanding of the mechanisms by which TAAR1 mediates the serotonergic and glutamatergic systems is lacking, thus more extensive studies are warranted.

Genetic animal models and physiological studies have revealed that TAAR1 is also a potent modulator of dopaminergic transmission. TAAR1-KO mice displayed increased dopamine release and a higher proportion of high-affinity D2 receptors in the striatum compared with their WT counterparts, concomitant with enhanced responses to amphetamine, as shown by augmented amphetamine-induced locomotor activity [36, 43]. In vitro electrophysiological recordings showed a remarkable increase in the spontaneous firing rate of dopamine neurons in the VTA of TAAR1-KO mice [36]. While the endogenous TAAR1 agonist TYR decreased the firing rate of dopamine neurons in slices from WT mice, it had no effect in slices from TAAR1-KO mice [36]. Conversely, TAAR1 overexpression (TAAR1-OE) mice showed hyposensitivity to the psychostimulant effects of amphetamine, as it only produced a weak locomotor activation in these mice, and elicited no changes in extracellular levels of dopamine or norepinephrine in the NAc [44]. Intriguingly, TAAR1-OE mice had enhanced dopamine and serotonin levels in the NAc and PFC, which was associated with an increased spontaneous firing frequency in the monoaminergic system [44]. These findings were unexpected and remain inconclusive, since TAAR1 was also expressed in brain areas that normally do not express this receptor [44].

The role of TAAR1 in the dopaminergic system has been further characterized by studies that examines its interaction with dopamine transporter (DAT) and dopamine receptors. DAT is important for dopamine transmission as it mediates the reuptake of released dopamine back to the presynaptic terminals and thus is closely associated with the psychostimulant effects of METH [45–48]. TAAR1 was found to be co-expressed with DAT in dopamine neurons in both the primates and the mice [49] and in vitro co-expression of TAAR1 with DAT significantly enhanced TAAR1 signaling in a DAT-dependent manner [49, 50]. Furthermore, TAAR1 modulation of dopamine reuptake and efflux may be dependent on the activities of protein kinase C (PKC) and protein kinase A (PKA) [51]. However, in other studies, no changes were observed with respect to dopamine reuptake in TAAR1-KO mice nor after TAAR1 alterations in WT mice [52]. TAAR1 agonists are also able to inhibit dopamine-related hyperlocomotion in DAT-KO mice [38, 40, 53]. Therefore, it appears that the effect of TAAR1 on dopamine transmission may occur in a DAT-independent manner. Indeed, TAAR1 activation may be regulated by D2 receptors as TAAR1-KO mice showed an increased proportion of high-affinity D2 receptors in the striatum [43]. Moreover, D2 receptor antagonists haloperidol, raclopride, and amisulpride selectively enhanced TAAR1 activation [37]. Consistently, cocaine induced dopamine efflux in the NAc requires activation of both D2 receptors and related signaling [54]. It is suggested that TAAR1-D2 heterodimerization increases the membrane expression of TAAR1 [37, 55, 56] and hence alteresTAAR1-mediated effects, although detailed mechanisms for this interplay remain elusive. Nonetheless, it is evident that TAAR1 mediates the dopaminergic system and thus, is involved in drug reward and substance use disorders.

Accumulating evidence suggests that TAAR1 may be a promising therapeutic target for the treatment of substance use disorders given its role in mediating the dopaminergic system. Indeed, initial studies focused on abuse of psychostimulants, since TAAR1-KO animals showed enhanced responses to the amphetamine-type drugs [36, 43]. Animals showed increased amphetamines-induced enhancement of locomotor activity [57], pronounced conditioned place preference (CPP) [57, 58], behavioral sensitization and increased drug taking [59]. Furthermore, when TAAR1 expression levels were decreased through TAAR1 gene mutation or deletion, the animals were insensitive to METH-induced neurotoxicity in models of conditional place aversion (CTA) and hypothermia [60–64]. These results suggest that TAAR1 activation may be beneficial in attenuating the rewarding effects of psychostimulants, and thus TAAR1 agonists could potentially serves as promising pharmacotherapies for treating substance use disorders. In addition to amphetamines, studies have examined the effects of TAAR1 modulation on drugs of abuse like nicotine [65–67], cocaine [68, 69], opioids [57, 70] and ethanol [71] using selective and potent TAAR1 ligands. We will discuss this in detail in the following section. Importantly, these ligands serve as excellent pharmacological tools for investigating the physiological function of TAAR1, in addition to inspiring development of TAAR1-based pharmacotherapies for the treatment of substance use disorders. It should be noted that the data presented in the article are, unless otherwise stated, from animal models not clinical samples.

2. TAAR1 ligands in substance use disorders

Initially, studies of TAAR1 function depended largely on the utilization of nonselective agonists such as trace amines or thyronamine derivatives. Though much progress was made with these agonists, they are not specific to TAAR1, and so there may be TAAR1-independent effects mediated by other targets, such as monoaminergic receptors or transporters [38]. Therefore, the development and characterization of TAAR1 ligands with high potency and selectivity would be particular useful for the identification of TAAR1 specific central functions. Fortunately, several engineered TAAR1 ligands are well characterized and remain outstanding tools for the examination of TAAR1-mediated effects, especially in substance use disorders.

2.1. Full agonists

2.1.1. RO5166017

In 2011, the first TAAR1 full agonist RO5166017 was engineered by Revel and colleagues [38]. RO5166017 showed high potency and efficacy for TAAR1 from different species (such as mice, rats, monkeys, and humans) when these receptors were expressed in HEK293 cells. It was highly selective also for TAAR1, as high concentration of RO5166017 were not found to activate mouse TAAR4, which is the only other TAAR family member activated by trace amines [38]. The highly selective effect of RO5166017 was further demonstrated shown by electrophysiological studies. Similar to TYR, RO5166017 reduced the firing rate of VTA dopamine neurons and DRN serotonin neurons in brain slices from WT but not TAAR1-KO mice, through the activation of K+-mediated outward current, which can be blocked by TAAR1 antagonist EPPTB [38]. RO5166017 was found to have favorable in vivo pharmacokinetic properties, as it is preferentially distributed to the brain rather than the plasma, which allows further explorations [38]. RO5166017 prevented cocaine-induced hyperlocomotion and stereotypies in WT but not TAAR1-KO mice, suggesting its efficacy in blocking the reinforcing effects of psychostimulants [38]. The fact that it prevents the hyperlocomotion induced by NMDA receptor antagonist L-687,414 further suggests its role in modulation of the glutamatergic system [38].

The efficacy of RO5166017 in modulating the rewarding and reinforcing effects of psychostimulants was further examined using animal models of substance use disorders. When examining the effect of RO5166017 on cocaine-induced responses in a CPP model, RO5166017 was found to inhibit the expression of, but not retention of cocaine reward memory [72]. Using an intravenous self-administration model, infusion of RO5166017 in specific sub-regions of the reward system demonstrated distinct effects on the relapse-like behaviors of cocaine addiction [73]. When infused into the VTA and prelimbic cortex, RO5166017 was found to attenuate both cue- and drug-induced cocaine-seeking behaviors at doses that were not found to affect locomotion and food responding [73]. However, when RO5166017 was infused into the NAc core and shell it was found to prevent cue- and drug-induced cocaine-seeking, respectively [73].

Recently, a more systematic study further examined the effects of RO5166017 in nicotine addiction-related behaviors [65]. RO5166017 was shown to significantly reduce nicotine-induced c-Fos expression and dopamine release in the NAc [65], which may underlie the functional role of TAAR1 in regulating nicotine responses. Similar to cocaine, RO5166017 suppressed nicotine intake and reinstatement of nicotine-seeking behavior, suggesting a negative effect of RO5166017 in modulating nicotine addiction [65]. Consistently, RO5166017 in the NAc reduced nicotine relapse-like behaviors [65]. Taken together, these studies suggest that RO5166017 may be a promising therapeutic for the treatment of substance use disorders.

2.1.2. RO5256390

Similar to RO5166017, RO5256390 has high potency and selectivity at TAAR1 [28]. The activation of TAAR1 by RO5256390 results in an increase in Cyclic Adenosine Monophosphate (cAMP) (79 – 107%), which was comparable to that induced by PEA (100%). RO5256390 decreased the firing frequency of VTA dopamine and DRN serotonin neurons in brain slices from WT but not TAAR1-KO mice, and blocked the locomotor-stimulating effects of cocaine and NMDA receptor antagonists (PCP and L-687,414), showing antipsychotic-like effects [28]. This observation led to closer examination into the effects of RO5256390 on drug addiction-related behaviors. RO5256390 attenuated the reinforcing effects of cocaine as demonstrated by decreased cocaine intake and cocaine-induced lowering of intracranial self-stimulation (ICSS) thresholds [74]. Moreover, RO5256390 reduced cocaine-seeking after a prolonged period of withdrawal from chronic cocaine self-administration without affecting responses to natural rewards [69]. Neurochemical data also showed that RO5256390 blocked cocaine-induced inhibition of dopamine clearance, which may underlie its role in regulating the neurochemical actions of cocaine [54].

2.2. Partial agonists

2.2.1. RO5203648

RO5203648, which was the first selective TAAR1 partial agonist to be characterized, has high affinity at rodent and primate TAAR1 expressed in vitro, comparable to that of full agonists RO5166017 and RO5256390 [40]. However, it activates cAMP production with partial efficacy (48%– 73%) compared with RO5166017 and PEA [40]. Intriguingly, unlike TAAR1 full agonists, RO5203648 increased the firing frequency of VTA dopamine neurons and DRN serotonin neurons in vitro, similar to TAAR1 antagonist EPPTB [40]. Nevertheless, it did not affect the firing activity in dopaminergic and serotonergic neurons of TAAR1-KO mice, demonstrating high constitutive activity [40]. Considering the finding that TAAR1-KO mice showed increased frequency of spontaneous firing of dopamine neurons in the VTA [36], it is possible that TAAR1 is tonically activated by endogenous ligands in order to decrease dopamine neuron firing rates. While partial agonists can act as either an agonist or an antagonist depending on the intrinsic activity of the receptor [75], it is possible that TAAR1 partial agonist RO5203648 increased the firing frequency of dopaminergic neurons while the full agonists RO5166017 and RO5256390 inhibited the basal spike frequency of dopamine neurons.

Interestingly, in vivo studies showed that RO5203648 attenuated hyperlocomotion in animals treated with cocaine, amphetamine and L-687,414 [40], similar to the effects of other TAAR1 agonists [28, 38]. Moreover, RO5203648 reduced lever-press behavior for cocaine in a self-administration model [40], indicating its efficacy in modulation of cocaine-induced reinforcement. Consistently, RO5203648 shifted the cocaine dose-effect curve downward in a dose-dependent manner [74] and inhibited drug-induced reinstatement of cocaine-seeking both in withdrawal-reinstatement and extinction-reinstatement models [69]. This effect is drug-specific as RO5203648 did not alter the responses maintained by food [69]. Mechanistically, the prevention of cocaine-induced dopamine overflow in the NAc [69] was thought to contribute to the effect of RO5203648 on cocaine reinforcement. However, it did not alter half-life of dopamine, which suggests the effect is due to a mechanism that is independent of interactions with DAT [69].

2.2.2. RO5263397

RO5263397 is the most well-studied agonist among all engineered TAAR1 ligands, its efficacy has been examined in abuse-related behaviors induced by a variety of substances, including psychostimulants (amphetamines, cocaine, and nicotine), morphine, and alcohol. RO5263397 showed similar pharmacological properties to full agonist RO5263390 in terms of selectivity for TAAR1 with relatively lower efficacy (maximal cAMP level 59 – 85%) [28]. However, it increased the firing frequency of VTA dopamine neurons and DRN serotonin neurons in brain slices [28], consistent with the profiles of other TAAR1 partial agonists. Similar to RO5263390, RO5263397 displays anti-psychotic effects and promotes wakefulness and cognition [28]. In regards to substance use disorders, it shows a robust antagonism to the responses induced by different drugs of abuse.

RO5263397 was shown to reduce the expression of METH-induced behavioral sensitization, METH self-administration, and cue- and drug-induced reinstatement of METH-seeking [76], to decrease the break-point for METH self-administration in a progressive ratio test, and to prevent METH-induced dopamine overflow in the brain slices, while exhibiting no abuse potential [77]. These findings suggest that RO5263397 is efficient in attenuating METH reinforcement and relapse-like behaviors and could be a promising therapeutic for the treatment of METH addiction. Moreover, RO5263397 plays an inhibitory role in METH-induced impulsivity, an important personal trait associated with substance use disorders [78]. RO5263397 significantly decreased the premature responses induced by acute administration of METH and METH discontinuation in the 5-choice serial reaction time task (5-CSRTT). However, RO5263397 had no effect in delay-discounting performance [78], suggesting that RO5263397 is effective in regulation of impulsive action but not impulsive choice.

RO5263397 is essential in modulation of abuse-related responses to other psychostimulants. RO5263397 reduced cocaine- and nicotine-induced behavioral sensitization, self-administration, and reinstatement of drug-seeking and increased elasticity of the drug demand curve [65, 66, 79, 80]. However, TAAR1-KO rats showed significantly higher cue- and drug-induced nicotine-seeking [65]. When an extended-access self-administration model was used to test compulsive cocaine use, RO5263397 was found to attenuate cocaine intake, binge intake after forced abstinence, and cue- and stress-induced cocaine-seeking [68]. Importantly, tolerance to RO5263397 did not develop during this prolonged test [68], indicating a great potential for the development of long-term clinical interventions. Furthermore, RO5263397 was sufficient to block nicotine-induced activation of the NAc and reduce nicotine-induced dopamine release [65]. Taken together, RO5263397 may be a novel pharmacological approach to treat psychostimulant addiction.

The role of RO5263397 in the behavioral effects of opioids is not well characterized. Comparable to its effects on psychostimulants, a recent study demonstrated that RO5263397 reduced morphine intake, morphine break-point, and cue- and drug-induced reinstatement of morphine seeking [70]. However, RO5263397 did not affect morphine-induced CPP [70], which was consistent with previous studies. Interestingly, RO5263397 did not affect naltrexone-induced jumping behavior and conditioned place aversion (CPA) in rodents [70], suggesting RO5263397 has no effect on morphine withdrawal. Moreover, RO5263397 had no effect on the analgesic effects of morphine [70]. These results indicate that RO5263397 may selectively attenuate the reinforcing effects, but not the withdrawal and analgesic effects of morphine, and thus could be useful for the treatment of opioid addiction.

Only one study examined the effect of RO5263397 on ethanol-induced responses [71]. RO5263397 significantly decreased the development and expression of ethanol-induced behavioral sensitization in both female and male mice [71]. However, RO5263397 did not alter this behavioral effect in TAAR1-KO mice, suggesting it is highly selective to the TAAR1receptor [71]. However, currently there are no studies investigating the potential effects of RO5263397 on ethanol-drinking behavior or relapse-like behaviors of ethanol. Moreover, it remains unknown whether RO5263397 could modulate the addictive effects of other depressants like benzodiazepines, and further studies are warranted to better characterize the potential of RO5263397 in regulation of substance use disorders.

In addition to its potential in attenuating the positive reinforcing effects of drugs of abuse, RO5263397 was also able to reduce the withdrawal-related effects of nicotine [67]. In a long-access self-administration model, RO5263397 reduced nicotine withdrawal-induced anxiety-like behavior, reduced mechanical hypersensitivity, and precipitated withdrawal signs in rats [67]. Moreover, in regards to motivational withdrawal effects of nicotine, RO5263397 decreased the motivation for nicotine in a progressive-ratio test [67]. In summary, RO5263397 demonstrates superb activity in alleviating both the positive and negative effects of the drugs of abuse, which may provide the potential for further clinical development.

2.2.3. RO5073012

Among all the TAAR1 agonists, RO5073012 is the least well-characterized, as only one study has examined its pharmacological properties [44]. Consistent with other selective TAAR1 agonists, RO5073012 has high affinity at TAAR1 from different species when expressed ex vivo. It exhibits high potency and selectivity at TAAR1 but has low intrinsic efficacy (maximal cAMP level reached 24–43%), showing a partial agonist profile[44]. However, since it was suggested that partial agonists can act as an antagonist depending on endogenous intrinsic activity of the receptor, it was used to reduce the activity of TAAR1 in TAAR1-OE mice. RO5073012 significantly restored sensitivity to amphetamine in TAAR1-OE mice with amphetamine-induced hypolocomotion, and had no effect on locomotion in the control group [44]. Interestingly, it did not prevent amphetamine-induced increase in locomotor activity in WT mice [44], which is contrary to other TAAR1 partial agonists. However, since we have very limited knowledge of the in vivo pharmacological effects of RO5073012, additional studies are needed to further examine why RO5073012 failed to prevent amphetamine-induced increase in locomotor activity in WT mice while other TAAR1 partial agonists did, as well as to further evaluate its potential in modulating drug abuse-related behaviors.

2.3. Antagonist

2.3.1. EPPTB

Currently, there is only one TAAR1 antagonist engineered for studying the role of TAAR1 in modulating the monoaminergic system. EPPTB was developed in 2009 by Bradaia and colleagues, and showed higher affinity to mouse TAAR1 than rat and human TAAR1 [81]. EPPTB was able to antagonize TAAR1 activation-induced cAMP production in stably transfected HEK293 cells [81]. EPPTB prevented the inhibition of firing frequency of dopamine neurons induced by non-selective TAAR1 agonist TYR in dopamine neurons of WT but not TAAR1-KO mice [81], suggesting a high selectivity. Given that TAAR1 has an inhibitory role in the dopaminergic system, which contributes to the alleviation of substance use disorder, the antagonism of TAAR1 may have minimal effects in drug addiction. However, it shows potential in preventing hypodopaminergic functions and thus may be useful for the treatment of disorders like Parkinson’s disease [56]. Therefore, TAAR1 antagonism may be a promising strategy for treating diseases associated with hypodopaminergic activities.

3. Clinical studies of TAAR1 ligands

Thus far, no clinical studies have tested the efficacy of TAAR1 ligands in treatment of substance use disorders. However, several clinical studies have begun to test the efficacy of TAAR1 agonists in treating other mental disorders. For example, Hoffmann–La Roche has started a phase I clinical study to test the efficacy of RG75351, a TAAR1 partial agonist, in major depressive disorders [56]. Moreover, a more recent randomized, controlled clinical trial showed that SEP-363856, a dual agonist at TAAR1 and serotonin1A receptors, was generally well-tolerated and reduced the psychotic symptoms of schizophrenia based on a significant reduction in the Positive and Negative Symptom Scale (PANSS) [82]. Certainly, future extended clinical trials with larger sample sizes are needed to confirm its efficacy. Nonetheless, it moves us a step closer to the possibility of clinical studies examining the potential of TAAR1 ligands in treating substance use disorders.

Indeed, TAAR1 partial agonist RO5263397 has been tested for its safety and tolerability in a randomized, double-blind, placebo-controlled clinical study [83]. Generally, this compound was found to be safe, however, a 136-fold above-average systemic exposure to the parent compound was found in one participant [83]. Further study showed two more poor metabolizers, all three were of African origin. Unexpectedly, the contribution of the enzyme UGT2B10 to RO5263397 glucuronidation was underestimated. Subsequent DNA database analysis demonstrated the UGT2B10 splice site mutation to be more common in individuals of African origin (45%), in contrast to individuals of Asian (8%) or Caucasian (<1%%) origin. This mutation prevents the assembly of full-length UGT2B10 mRNA and thus functional UGT2B10 protein expression, leading to a >100-fold lower intrinsic clearance of RO5263397 in cells homozygous for the splice site variant allele from 20 individual African donors [83]. This study emphasizes the importance of recruiting individuals of different ethnicities during the drug development process. Furthermore, a new group of potent and selective TAAR1 agonists with refined pharmacokinetic properties will be necessary for future clinical studies.

In addition, the discovery of more promising ligands targeting the human TAAR1 (hTAAR1) orthologue could aid tremendously in the advancement of TAAR1-related clinical trials. Thus, considerable effort has been made to uncover relevant chemical features and structure-activity relationships of TAAR1 ligands [84]. It is reported that a basic core and an aromatic/heteroaromatic moiety are mandatory pharmacophore features and these two units need to be linked by a spacer of variable nature and length in order to modulate the molecular flexibility [84, 85]. In this context, Sara and colleagues developed two quantitative structure-activity relationship (QSAR) models to explore the features of different TAAR1 ligands towards murine and hTAAR1 [86]. Using these models, they found some species specificity preferences and obtained useful information for engineering novel biguanide-based compounds [86]. In fact, based on the application of a combined pharmacophore model/scaffold simplification strategy, Valeria and colleagues synthesized a new series of 1-amidino-4-phenylpiperazine derivatives, showing nanomolar EC50 values at hTAAR1 and low general cytotoxicity [87]. These findings support the development of hTAAR1 agonists, and provide more evidence for moving forward with TAAR1-based clinical trials for treating multiple neuropsychiatric disorders.

4. Conclusion

Trace amines have close interactions with monoaminergic system and are thought to be associated with drug reward and substance use disorders. The identification of TAAR1, the best characterized receptor of TAARs family, has spurred study into the links between trace amines and substance use disorders. TAAR1 is widely involved in modulations of monoaminergic system, such as dopaminergic, serotoninergic and glutamatergic system. Activation of TAAR1 inhibits a broad range of addiction-related behaviors and neurochemical effects, and TAAR1 may serve as an important therapeutic target for the management of substance use disorders. Therefore, selective and potent TAAR1 ligands could potentially be beneficial for the treatment of substance use disorders with respect to reinforcing effects, withdrawal and relapse. Currently, clinical studies of TAAR1 ligands for treatment of substance use disorders remain scarce, yet are warranted. Furthermore, development of TAAR1 ligands with more favorable pharmacokinetic properties remains important for future clinical development. As mechanisms and functions of TAAR1 are further elucidated, TAAR1 ligands may serve as potential lead compounds for treatment of substance use disorders.

Key Points.

Trace amine-associated receptor 1 (TAAR1) is an emerging drug target for the treatment of substance use disorders. This article reviews current preclinical evidence that TAAR1 agonists are powerful drugs against addiction-related effects of several drugs of abuse and have high potential as new treatments of substance use disorders.

Acknowledgements

This work was supported by the National Institutes of Health National Institute on Drug Abuse (Grant number R01DA047967 to J-X.L.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank our colleague Kristen Woodhouse for proofreading this review.

Footnotes

Conflict of interest

The authors declare no conflicts of interest.

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