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 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.

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Expert Opinion on Therapeutic Targets
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Trace amine-associated receptor 1: a multimodal
therapeutic target for neuropsychiatric diseases
Michael D. Schwartz, Juan J. Canales, Riccardo Zucchi, Stefano Espinoza, Ilya
Sukhanov & Raul R. Gainetdinov
To cite this article: Michael D. Schwartz, Juan J. Canales, Riccardo Zucchi, Stefano Espinoza,
Ilya Sukhanov & Raul R. Gainetdinov (2018) Trace amine-associated receptor 1: a multimodal
therapeutic target for neuropsychiatric diseases, Expert Opinion on Therapeutic Targets, 22:6,
513-526, DOI: 10.1080/14728222.2018.1480723
To link to this article: https://doi.org/10.1080/14728222.2018.1480723
Accepted author version posted online: 25
May 2018.
Published online: 05 Jun 2018.
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REVIEW
Trace amine-associated receptor 1: a multimodal therapeutic target for
neuropsychiatric diseases
Michael D. Schwartz
a
, Juan J. Canales
b
, Riccardo Zucchi
c
, Stefano Espinoza
d
, Ilya Sukhanov
e
and Raul R. Gainetdinov
f,g
a
Center for Neuroscience, SRI International, Menlo Park, CA, USA;
b
Division of Psychology, School of Medicine, College of Health and Medicine,
University of Tasmania, Hobart, Australia;
c
Department of Pathology, University of Pisa, Pisa, Italy;
d
Fondazione Istituto Italiano di Tecnologia,
Neuroscience and Brain Technologies Dept., Genoa, Italy;
e
Institute of Pharmacology, Pavlov Medical University, St. Petersburg, Russia;
f
Institute of
Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia;
g
Center for Translational Biomedicine, Skolkovo Institute of
Science and Technology, Moscow, Russia
ABSTRACT
Introduction: The trace amines, endogenous amines closely related to the biogenic amine neurotrans-
mitters, 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 neurop-
sychiatric 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.
ARTICLE HISTORY
Received 9 February 2018
Accepted 21 May 2018
KEYWORDS
Dopamine; serotonin;
addiction; schizophrenia;
depression; sleep;
psychostimulants;
neuropharmacology
1. Introduction
1.1. Trace amines and trace amine-associated receptor 1
(TAAR1)
The trace amines, endogenous amines closely related to the bio-
genic amine neurotransmitters (e.g. dopamine (DA), serotonin (5-
hydroxytryptamine; 5-HT) and norepinephrine (NE)), have been
known to exert physiological and neurological effects since the
early twentieth century [1]. However, the lack of an identifiable
endogenous receptor for these molecules, coupled with their
markedly low in vivo concentrations, led in part to the idea that
trace amines were ‘false neurotransmitters’[2]. In 2001, this con-
ventional wisdom was challenged with the identification of a
vertebrate G-protein coupled receptor (GPCR) that preferentially
responded to trace amines [3,4]. This receptor, trace amine-asso-
ciated receptor 1 (TAAR1), is part of a large and evolutionarily
diverse family of TAARs with six functional members in humans
[5]. Several TAARs act as olfactory receptors [6]. In the mammalian
brain, the finding that TAAR1 powerfully modulates monoaminer-
gic neurotransmission [7–9] has rejuvenated research efforts into
the function and therapeutic implications of TAAR1 and its ligands.
1.2. TAAR1 expression and function
In the brain, TAAR1 expression is enriched throughout the
limbic and aminergic systems, encompassing the dopaminer-
gic ventral tegmental area (VTA)/substantia nigra and seroto-
nergic dorsal raphe nucleus (DRN) [1,10,11], and is therefore
ideally positioned to regulate the activity of these neurotrans-
mitter systems. Indeed, transgenic mice lacking TAAR1 exhibit
markedly elevated discharge rates of DA and 5-HT neurons
[12], suggesting that TAAR1 activation down-regulates mono-
aminergic neurotransmission. The strategic neuroanatomical
location of TAAR1 and its remarkable ability to regulate ami-
nergic neurotransmission suggest that this receptor could
serve as a target to develop more effective, new-generation
pharmacotherapies for neuropsychiatric diseases, addiction,
and sleep disorders.
This review will highlight recent efforts in elucidating the
neurological and neurophysiological effects and potential
therapeutic utility of TAAR1 activation via recently developed
TAAR1-specific small molecules, as well as endogenous bio-
molecules such as 3-iodothyronamine. While beyond the
scope of this review, there is also significant peripheral
CONTACT Raul R. Gainetdinov gainetdinov.raul@gmail.com Institute of Translational Biomedicine, St. Petersburg State University, Universitetskaya
embarkment 7-9, 199034 St. Petersburg, Russia
EXPERT OPINION ON THERAPEUTIC TARGETS
2018, VOL. 22, NO. 6, 513–526
https://doi.org/10.1080/14728222.2018.1480723
© 2018 Informa UK Limited, trading as Taylor & Francis Group

TAAR1 expression in pancreas, stomach, and leukocytes, sug-
gesting potential for TAAR1-based drugs in diabetes, obesity,
and possibly immune disorders [2].
1.3. Synthetic TAAR1 agonists and antagonists
Hoffmann-La Roche investigators performed a large-scale effort
to derivatize adrenergic ligands, which were screened for TAAR1
activation by cAMP assays in heterologous cells expressing
TAAR1, and for specificity via radioligand binding experiments
involving over a hundred different proteins. This effort yielded
several full (e.g. RO5166017 and RO5256390) and partial (e.g.
RO5203648 and RO5263397) TAAR1 agonists [11,13,14] that to
date have been successfully used in experimental models of
neurological diseases such as drug addiction, schizophrenia,
and Parkinson’s disease. In general, the ‘RO compounds’are
over 100-fold selective for TAAR1 versus other aminergic recep-
tors, but the Kis for some other receptors –namely α
2
adrener-
gic, 5-HT
2
5-HTergic, µ and κopioid, and I
1
imidazoline receptors
–are in the nanomolar range, and so additional effects on
different targets cannot be excluded in all cases.
Pharmacological research has also aimed at developing
selective TAAR1 antagonists. Screening of about 700,000
Roche compounds led to the identification of N-(3-Ethoxy-
phenyl)-4-pyrrolidin-1-yl-3-trifluoromethyl-benzamide (EPPTB)
[10,15]. This benzamide derivative had high selectivity and
affinity for mouse TAAR1 (Ki = 0.9 nM), although the affinity
for human TAAR1 was in the micromolar range. In particular,
EPPTB was critical in revealing the constitutive background
activity of the TAAR1 system because it caused a significant
increase in the firing rate of mouse VTA DA neurons [10].
2. 3-iodothyronamine: an endogenous TAAR1 ligand
2.1. Biochemistry and pharmacology of T1AM
3-iodothyronamine (T1AM) is an endogenous compound
whose chemical structure is related to thyroid hormones
[16]. The differences consist in the absence of the carboxyl
group and of all iodine atoms except one. It is thought to be
synthesized from 3,5,3ʹ-triiodothyronine (T3) through the
sequential action of deiodinases and amino acid decarboxy-
lases (possibly ornithine decarboxylase) [17], but the precise
biosynthetic pathway and the physiological site(s) of produc-
tion are still unclear. T1AM has been identified in rodent and
human blood, and in most rodent organs including the brain,
where its average endogenous level is on the order of a few
pmoles per g [16,18–23].
In 2004, T1AM was reported to be a powerful activator of
TAAR1 [16]. Its EC
50
for a biochemical response (cAMP produc-
tion) in human neoplastic cell lines expressing rat or mouse
TAAR1 averaged 14 nM and 112 nM, respectively, and so it
was lower than observed for endogenous trace amines,
namely tyramine and β-phenylethylamine. With human
TAAR1, the affinity for T1AM was in the micromolar range,
but it was still higher than observed for tyramine and β-
phenylethylamine [24]. So, T1AM qualifies as a bone fide phy-
siological TAAR1 agonist.
2.2. Neurophysiological effects of T1AM
T1AM modulates several integrative functions, particularly
feeding behavior, sleep, and cognition (reviewed by [25]). In
fed animals, i.c.v. T1AM administration increased food intake at
dosages as low as 1.2 nmol/Kg, and a similar effect was
observed after arcuate nucleus injection [26]. However, in fast-
ing animals, the response was biphasic: dosages in the low
nanomolar range were anorexic, while higher dosages
(51 nmol/Kg) had the opposite effect [27]. T1AM injection
(3 µg) in the preoptic region enhanced locomotor activity and
increased wakefulness while decreasing non-rapid eye move-
ment (NREM) sleep time [28]. i.c.v. T1AM injection (1.32 –4 µg/
Kg) elicited prolearning and antiamnestic effects in the passive
avoidance paradigm as well as increased curiosity in the novel
object recognition task [21].
2.3. Mechanisms of action
2.3.1. Neuromodulatory actions of T1AM
The basic cellular processes targeted by T1AM remain to be
determined but are proposed to be neuromodulatory in nature.
Manni et al. [21] reported that active dosages of T1AM increased
average brain T1AM concentration by about 30-fold, consistent
with a physiological role of endogenous T1AM. T1AM applied
locally in rat locus coeruleus modulated the activity of adrenergic
neurons with EC
50
= 2.7 µM [29]. T1AM’s pro-learning and anti-
amnestic effects may depend on histaminergic activity because
they were dampened or abolished by histamine receptor
antagonists and in transgenic mice lacking histidine decarbox-
ylase, the key enzyme regulating histamine biosynthesis [21,22].
Modulation of adrenergic and histaminergic activity could also
underlie wake promotion because both neurotransmitters are
robustly wake promoting [30–32].
2.3.2. T1AM and TAAR1
Preliminary evidence for a TAAR1-mediated effect has been
recently reported by electrophysiological recordings performed
in rat entorhinal cortex. In this model, T1AM rescued long-term
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, depres-
sion, ADHD, Parkinson’s disease, and OCD.
This box summarizes key points contained in the article.
514 M. D. SCHWARTZ ET AL.

potentiation in the presence of toxic concentrations of beta
amyloid, and the effect was abolished by the TAAR1 antagonist
EPPTB [33]. This exciting observation suggests additional ther-
apeutic utility for TAAR1 agonists because of the putative role
of beta amyloid in Alzheimer’s disease and other forms of
cognitive impairment.
However, it is presently unclear whether all the actions
produced by T1AM are mediated by TAAR1. Other potential
targets include 5HT1b receptors [Braunig 2018 [34] Front Ph],
other TAARs (particularly TAAR5), α
2A
adrenergic receptors,
transient receptor potential channels (particularly TRPM8),
and monoamine transporters [25,34]. The presence of multiple
physiological targets is not unusual for a chemical messenger,
but it casts doubts on a TAAR1-specific mechanism for T1AM.
Conversely, some effects observed after T1AM administration
could actually be mediated by 3-iodothyroacetic acid, the
product of T1AM oxidative deamination. For example, hista-
mine and 3-iodothyroacetic acid are involved in the acceler-
ated response to the hot plate test, suggesting reduced pain
threshold [20,22]. Further investigation with TAAR1 antago-
nists and/or KO mice is necessary to resolve this crucial issue.
2.4. Synthetic T1AM analogs
To address these questions, synthetic T1AM analogs have
been developed by modifying the thyronamine scaffold. The
first two series of analogs consisted of phenyltyramine deriva-
tives [35,36], while more recently halogen-free biaryl-methane
thyronamine analogs (the so-called ‘SG compounds’) have
been synthesized [37,38]. Some of these compounds were
equipotent or even more potent than T1AM, as measured by
cAMP induction. They also reproduced the in vivo effects of
T1AM on glucose homeostasis and cognitive function in
mouse. However, their selectivity has not yet been specifically
evaluated, so the same questions raised for T1AM regarding
interaction with different targets apply here. Systematic eva-
luation of T1AM analogs is expected to clarify several features
of T1AM/TAAR1 interactions and structure-activity relation-
ships [39] and provides a valuable background for further
research in the TAAR1 pharmacology.
3. TAAR1 in neuropsychiatric disorders
3.1. Trace amines, DA, and neuropsychiatric disease
Trace amine dysregulation has long been associated with several
psychiatric and neurological diseases. For example, elevated PEA
content has been documented in schizophrenia [40–42],
whereas decreased PEA levels were associated with depression
[43–45]. However, the lack of an identifiable endogenous recep-
tor and dearth of suitable investigative tools limited advance-
ment on this front for some time [2]. The identification of TAAR1
[3,4] and subsequent demonstration that TAAR1 modulates DA
and 5-HT neurotransmission [7–9] has renewed interest in this
association. Brain DA is critically involved in the etiology and
pathogenesis of neuropsychiatric disorders including schizo-
phrenia, Attention Deficit and Hyperactivity Disorder (ADHD),
and Parkinson’s disease; DA dysregulation is proposed to con-
tribute to Obsessive-Compulsive and Related Disorders (OCD),
bipolar disorder, major depression, and dyskinesias [46]. Most of
these conditions have been previously linked to dysregulated
endogenous trace amines [1,47]. With the development of
TAAR1-specific mutant mice [48–50] and selective pharmacolo-
gical compounds [10,11,13–15], these advances have vastly
enhanced understanding of TAAR1’s role in neuropsychiatric
disorders and their potential therapeutic applications.
3.2. TAAR1 and schizophrenia
3.2.1. Dopaminergic dysregulation and schizophrenia
The DA theory of schizophrenia asserts that increased dopa-
minergic tone or D
2
receptor sensitivity resulting in dysregu-
lated DA signaling underlies the development of
schizophrenia, particularly its positive symptoms (e.g. halluci-
nations, delusions, and disordered thoughts and speech). This
theory has a strict predictive validity because all known clini-
cally effective antipsychotics are D
2
receptor antagonists [51].
Hyperactivity induced by dopaminergic psychostimulants is
considered a behavioral manifestation of increased dopami-
nergic activity in the mesolimbic pathway [52], and poten-
tiated psychostimulant-induced activity is used as an animal
correlate of positive symptoms [53]. Accordingly, the ability of
a drug to antagonize this hyperactivity has been used for
decades as a preclinical screening tool to identify novel anti-
psychotics [54,55].
3.2.2. TAAR1 and dopaminergic tone
Taar1 KO mice do not differ in size, weight, and temperature
from wild type (WT) littermates and perform normally in beha-
vioral tests including motor coordination, visual acuity, grip
test, nociception, and locomotor activity in the open field
[49,50,56]. However, these mice exhibit increased locomotor
responses to dopaminergic psychostimulants such as amphe-
tamine, methamphetamine, or MDMA compared to WTs
[48,50,57,58] as well as high doses of the selective D
2
/D
3
agonist
quinpirole [59]. Taar1 KO mice were also more sensitive to
locomotor sensitization induced by repeated amphetamine
and methamphetamine administration [57,60]. TAAR1 agonists
prevented cocaine- and amphetamine-induced hyperlocomo-
tion in WT mice [11,14,61] and Wistar rats [13] and enhanced
olanzapine (atypical antipsychotic)-induced inhibition of loco-
motor activity following cocaine [14]. Conversely, ampheta-
mine-induced hyperactivity was strongly attenuated in
TAAR1-overexpressing (OE) mice and ‘rescued’by the selective
partial agonist RO5073012 [61]. Together, these findings indi-
cate TAAR1 as a viable locus for treatment of positive psychotic
symptoms, likely mediated by modulation of dopaminergic
signaling. Consistent with this hypothesis, TAAR1 agonists
block hyperlocomotion in hyperdopaminergic DA transporter
knockout (DAT) KO mice and rats [11,13,62].
3.2.3. TAAR1 and NMDA hypofunction
N-methyl-D-aspartate (NMDA) receptor antagonists also
increase motor activation [63,64], and this hyperactivity is simi-
larly reversed by antipsychotics [65]. As with dopaminergic
psychostimulants, TAAR1 agonists reversed hyperlocomotion
induced by the NMDA antagonists L-687,414 and phencyclidine
[11,14]. The partial TAAR1 agonist RO5203648 also blocked
EXPERT OPINION ON THERAPEUTIC TARGETS 515

hyperlocomotion in NMDA receptor-deficient mice [13].
However, L-687,414-induced hyperactivity was not further
potentiated in Taar1 KO mice [11], in contrast to the exagger-
ated response to dopaminergic stimulants in these animals.
Future studies should examine the respective contributions of
dopaminergic versus glutamatergic pathways to the expression
of hyperactivity vis a vis TAAR1.
3.2.4. Caveats and questions
Some variability is reported in the direct locomotor effects of
TAAR1 agonists themselves. Some studies reported that
TAAR1 agonists decreased locomotor activity in intact animals
[13,14], while others did not find any effects of these drugs
when administered alone [61,66–68]. Intriguingly, TAAR1 dele-
tion greatly attenuated climbing and other stereotypy beha-
viors induced by high doses of the mixed D
1
/D
2
agonist
apomorphine [69], likely due to a direct agonistic action of
apomorphine at TAAR1 [4]. Because apomorphine-induced
stereotypies are also used to screen for antipsychotics [70–
72], these findings imply a need for care when interpreting
apomorphine-induced behaviors in rodents.
Whereas all clinically used antipsychotics augment haloper-
idol-induced catalepsy, partial TAAR1 agonists actually reduce
this phenomenon [13,14] and do not themselves induce cata-
lepsy [14]. Intriguingly, the catalepsy induced by haloperidol
was significantly reduced in Taar1 KO mice [8].
3.2.5. Cognitive symptoms of schizophrenia
Memory, attention, and other cognitive deficits form another
important aspect of the symptomatology of schizophrenia
[73]. Taar1 KO mice showed impairment in prepulse inhibition
of the acoustic startle response [50], indicating a sensorimotor
gating deficit. This abnormality is commonly used to demon-
strate schizophrenia-like phenotypes in animals because
human schizophrenic patients exhibit an analogous deficit
[74]. By contrast, spatial working memory in the forced alter-
nation test was intact in Taar1 KO mice [50]. The TAAR1
agonists RO5256390, RO5203648, and RO5263397 increased
accuracy in the object retrieval task in cynomolgus macaques
[13,14], and RO5256390 (1.0 and 3.0 mg/kg) fully reversed
executive function deficits induced by repeated PCP treatment
(5.0 mg/kg) in the attention set shift task in rats [14]. Further
assessment of procognitive effects of TAAR1 agonists is there-
fore warranted, particularly in key cognitive domains such as
attention and learning.
In general, the loss of TAAR1 induces elevated DA neuro-
transmission in the mesolimbic pathway in mice. Specific
TAAR1 agonists ameliorate pharmacologically and genetically
induced hyperlocomotion without the undesirable motor side
effects characteristic of D
2
receptor-blocking antipsychotics.
Moreover, TAAR1 agonists may be effective in treating cogni-
tive deficits associated with schizophrenia.
3.3. TAAR1 and Parkinson’s disease
Loss of nigrostriatal dopaminergic neurotransmission is the
key point in pathogenesis of Parkinson’s disease. L-DOPA,
the chemical precursor of DA, is the first and the most widely
used treatment of Parkinson’s disease. Taar1-KO mice in which
dopaminergic neurons were unilaterally lesioned with the
neurotoxin 6-OHDA had increased sensitivity to L-DOPA-
induced rotational behavior and dyskinesia compared to WT
littermates [75]. Thus, it would be important to determine
whether partial TAAR1 agonists ameliorate L-DOPA-associated
side-effects such as dyskinesia. Intriguingly, Sotnikova and
colleagues observed ‘antiparkinsonian’effects of ampheta-
mines and MDMA in DA-depleted DAT KO mice [76], but the
same effect persisted in double knockout mice lacking both
DAT and TAAR1, indicating that this potential ‘antiparkinso-
nian’action of amphetamines is TAAR1-independent [58].
3.4. TAAR1 and ADHD
Evidence increasingly suggests that DAT dysfunction is
involved in the pathogenesis of ADHD [77–79]; indeed, DAT
KO mice are a known genetic animal model of ADHD [80]. In a
novel environment, these mice exhibit profound hyperactivity
[81,82]. TAAR1 agonists blocked hyperlocomotion in these
mice [11], mimicking the calming effect of amphetamine and
methylphenidate [83], the drugs clinically used to treat ADHD
patients. Similar effects of the partial TAAR1 agonist
RO5203648 were observed in DAT KO rats [62]. Conversely,
double DAT/Taar1 KO mice demonstrated further increased
hyperactivity over DAT KO mice [13], providing additional
support for TAAR1’s role in dopaminergic control.
ADHD patients are also characterized by increased
impulsivity. A recent study has shown that lack of TAAR1
led to perseverative and impulsive behaviors that corre-
lated with deficient prefrontal cortical glutamatergic trans-
mission [84]. Furthermore, RO5166017 and RO5203648
decreased premature responding in a fixed interval condi-
tioningscheduleinWTmice[84]. RO5256390 and
RO5263397 also increased the number of reinforcers
earned in a differential reinforcement of low response
rates test in cynomolgus macaques [13]. RO5263397
reduced hyperimpulsivity (5CSRTT) in methamphetamine-
treated rats but did not affect the number of premature
responses in 5CSRTT and choice of large reward in the
delay discounting task in vehicle-treated rats [85].
Similarly, RO5203648 failed to change impulsive behavior
in DAT-null and WT rats in the Intolerance-to-Delay Task
[86]. Thus, some studies to date have supported a role for
TAAR1 in impulsive and compulsive behavior, while others
have not; future studies should try to tease apart the
contributions of dopaminergic versus glutamatergic sys-
tems to these behaviors, as TAAR1’sinfluencecouldbe
more ‘weighted’toward one or the other.
3.5. TAAR1 and OCD
Although selective 5-HT reuptake inhibitors (SSRI) form the
first line of drugs to treat OCD [87], a role for DA function in
OCD pathogenesis has been actively studied in recent years
(for review, see [88]). Antipsychotics form a second line of OCD
treatment because about 50% OCD patients are resistant to
SSRI therapy. RO5263397 reduced obsessive drinking in sche-
dule-induced polydipsia, a popular preclinical model of com-
pulsive behavior [89]. Additionally, the full TAAR1 agonist
516 M. D. SCHWARTZ ET AL.

RO5256390 blocked compulsive eating in rats [90]. Thus, stu-
dies on TAAR1’s involvement in animal models of compulsivity
and OCD, while promising, require further exploration.
3.6. TAAR1 and affective disorders
RO5263397 and RO5203648, but not RO5256390, demon-
strated antidepressant action in the forced swim test in rats
[13,14,90], a test that has high predictive validity for identifica-
tion of new antidepressants [91]. Similarly, RO5203648 showed
anxiolytic effects in the stress-induced hyperthermia test in
mice [13,14,90]. These effects could be mediated via TAAR1-
dependent enhancement of serotonergic signaling because
the antidepressant effect was only seen with partial agonists,
which increase 5-HT firing [11,13,14]. However, several lines of
evidence support dysregulated DA receptor and/or transpor-
ter homeostasis in affective disorders [92]. Consistent with this
hypothesis, RO5263397, RO5203648, and RO5256390 were
effective in another test reflective of antidepressant action in
Cynomolgus monkeys, the differential reinforcement of low-
rate behavior paradigm [13,14,90]. Further studies aimed at
the neurochemical basis for the antidepressive effects of
TAAR1 agonism are therefore warranted.
4. TAAR1 and addiction therapeutics
4.1. Therapeutic challenges in psychostimulant
addiction
Drug addiction is a multifaceted neuropsychiatric disorder
with widespread medical and societal implications.
Improving the treatment, support, and rehabilitation of those
affected by drug addiction continues to be an important
research agenda. Although behavioral and cognitive therapy,
combined with psychosocial support and community inter-
ventions, constitute irreplaceable initiatives to aid in recovery,
considerable agreement exists among psychiatrists and health
professionals specializing in addiction that novel pharmacolo-
gical approaches are needed to treat the disorder more effec-
tively [93,94]. Chiefly, new medications are required to better
manage withdrawal symptoms and craving in the early days
and weeks after drug discontinuation. Such medications could
facilitate compliance and engagement in behavioral therapy,
multiplying the beneficial effects of non-pharmacological
approaches. In this context, addiction to stimulant drugs,
such as cocaine and methamphetamine, is particularly proble-
matic due to the lack of effective treatment options.
4.2. The biogenic amines and addiction
Research into the neurobiological mechanisms that contribute
to drug addiction suggests that the classical biogenic amines,
including DA, norepinephrine and 5-HT, and their correspond-
ing receptor targets, play a critical role [95]. The DA substitu-
tion approach in stimulant addiction involves the use of a
competing dopaminergic agonist to potentially suppress with-
drawal and drug craving in abstinent individuals [96].
Although this is still an avenue under investigation, com-
pounds that act directly at the DA transporter (e.g. slow-acting
transporter blockers), or at DA receptors, are themselves more
likely to have abuse potential and long-term side effects. This
liability justifies the search for new receptor targets to indir-
ectly modulate DA transmission through the ups and downs
of the addiction cycle. Because of its unique association with
ascending dopaminergic projections and key associated limbic
circuits, TAAR1 has emerged as one of the most promising
targets for the treatment of neuropsychiatric disorders, espe-
cially addiction.
4.3. TAAR1 and stabilization of dysregulated DA
signaling
The development of synthetic TAAR1 ligands has proven cri-
tical in elucidating its physiological and behavioral functions.
While both full and partial TAAR1 agonists decrease stimulant-
induced DA overflow in the nucleus accumbens (NAcb)
[7,97,98], their effects on DA neuron firing rate can be differ-
ent. In patch clamp preparations, the full agonist RO5256390
attenuated neuronal firing in the VTA [11], whereas the partial
agonist RO5263397 augmented the firing frequency as did the
antagonist EPPTB [10]. This suggests that TAAR1 is constitu-
tively active and/or tonically activated by endogenous ligands
at the level of midbrain such that partial agonism results in
antagonistic-like effects. Consequently, the use of a partial
agonist may be more advantageous in situations where neu-
rochemical imbalance (e.g. induced by drug exposure) leads to
insufficient or excessive TAAR1 stimulation, providing a means
to ‘stabilize’TAAR1 activity. In addition, through induction of
pacemaker activation, partial agonism may contribute to ‘nor-
malizing’DA neuron cell discharge, which is known to be
dysregulated following chronic cocaine exposure [99,100]. In
agreement with these physiological observations, and sup-
porting the notion that TAAR1 activation may indeed dampen
DA transmission under certain conditions, Taar1 KO mice
exhibited increased sensitivity to amphetamine and increased
striatal DA release [49], whereas brain-specific TAAR1 over-
expression reduced the psychomotor stimulant effects of
amphetamine [61].
The development of TAAR1-selective agonists has since
allowed the accumulation of compelling evidence in support
of TAAR1 as a candidate for the design of addiction medica-
tions. Motor sensitization, a process that evolves following
repeated psychomotor stimulant treatment and that involves
plasticity changes in the mesolimbic DA system, was attenu-
ated by the partial TAAR1 agonists RO5203648 [101] and
RO5263397 [102,103]. Self-administration models are the
gold standard in addiction research, allowing the study of a
variety of behavioral processes. TAAR1 activation with the
partial agonist, RO5203648, dose-dependently decreased
cocaine self-administration [13], with similar reductions
being observed in methamphetamine self-administration
[101,102]. Importantly, RO5203648 was able to block stimu-
lant self-administration without concomitant decreases in
response rates for food self-administration, thus ruling out
motor or motivational deficits. Subsequent work demon-
strated that both RO5203648 and the full TAAR1 agonist,
RO5256390, flattened the dose-response curve for cocaine
EXPERT OPINION ON THERAPEUTIC TARGETS 517

self-administration, indicating that TAAR1 activation effec-
tively decreased the reinforcing effects of cocaine [104].
4.4. TAAR1 regulates reward mechanisms
In addition to perturbing motor behavior and promoting rein-
forcement learning, stimulants are known to increase brain
reward and recruit motivational mechanisms to instigate
their procurement. TAAR1 activation regulates reward and
motivational processes induced by stimulant drugs. Using an
intracranial self-stimulation paradigm, Pei et al. (2015) showed
that both RO5263397 and RO5256390 lowered cocaine self-
stimulation thresholds, thus suggesting reduced cocaine
reward. Moreover, in a progressive ratio schedule of reinforce-
ment, RO5203648 dose-dependently shifted both cocaine’s
and methamphetamine’s response rate curve rightward and
delayed the time to reach break point while elevating the
break point for food self-administration [97,98]. These data
clearly indicate that TAAR1 activation reduces stimulant
reward and the motivation to seek and self-administer stimu-
lant drugs.
4.5. Preventing drug relapse
There is a myriad of catalysts that can trigger drug relapse, one of
the most insidious problems associated with drug addiction.
Models of relapse have been employed in the laboratory to
investigate the potential of TAAR1 agonists to regulate relapse
to drug-seeking behavior. Data have been similarly convincing in
that both RO5203648 and RO5263397 dose-dependently pre-
vented context-induced cocaine relapse in a model of forced
abstinence [97] and cue- and cocaine prime-induced reinstate-
ment of cocaine and methamphetamine seeking after extinction
training [97,98,103]. Recent local microinfusion studies suggest
that TAAR1 acts in the VTA, prelimbic cortex and especially NAc
to attenuate drug-seeking and reinstatement-related behaviors
[105,106]. These observations support the notion that TAAR1
agonists may be useful in relapse prevention and management
of rehabilitation processes in addiction.
4.6. TAAR1 and the molecular mechanisms of addiction
The molecular mechanisms and signaling pathways through
which TAAR1 exerts such remarkable effects on stimulant-
induced behaviors are still poorly understood. TAAR1 distribu-
tion is predominantly intracellular [4,107], stimulating both
accumulation of cAMP, via Gα
s
-adenylyl cyclase activation
that promotes PKA and PKC phosphorylation [3,4,108], and a
G protein-independent, β-arrestin2-dependent pathway invol-
ving a DA D
2
receptor-regulated protein kinase B (AKT)/glyco-
gen synthase kinase (GSK-3) [109]. To uncover the
mechanisms through which TAAR1 prevents cocaine effects
on DA transmission, Asif-Malik et al. (2017) recently conducted
in vitro fast-scan cyclic voltammetry experiments, elegantly
demonstrating a new pathway to control cocaine’s neuro-
chemical actions that involves TAAR1 (Figure 1). Upon TAAR1
stimulation, such pathway recruits D
2
autoreceptors function-
ally linked to TAAR1 and downstream molecular targets con-
verging on GSK-3, but not on PKA or PKC [7]. It is worth noting
that GSK-3 has been previously implicated in cocaine sensiti-
zation [110] and cocaine reward memory [111]. These results
open new avenues to further explore such complex molecular
interactions, with a view to optimize TAAR1-based drug devel-
opment in the area of addiction treatment.
4.7. Summary
Although changes in DA transmission are undoubtedly impor-
tant, it is now recognized that the spiral of cycles of absti-
nence and relapse that characterizes stimulant addiction is
associated with widespread metabolic changes in the brain
and alterations in the way that different brain regions connect,
communicate, and function. These connectivity problems,
especially loss of prefrontal-to-striatal functional connectivity,
Figure 1. Intracellular mechanisms though which TAAR1 controls cocaine-induced neurochemical effects on dopamine (DA) transmission. Cocaine blocks the DAT and as
a result increases DA transmission at the synapse (1). The DA D
2
receptor and TAAR1 can form heterodimeric complex that signals through alternative intracellular
messenger systems. This complex potentiates DA D
2
receptor-mediated pre-synaptic DA autoinhibition. TAAR1 is sensitive to shifts in DA concentrations and
promotes DA homeostasis and therefore acts as an intracellular sentinel (2). The DA D
2
receptor agonist, sumanirole, causes a similar inhibition of cocaine-induced
changes in DA uptake (3) whereas the DA D
2
receptor antagonist, L-741,626, enhances cocaine-induced effects on DA clearance (4). DA D
2
receptor activation
activates the GSK-3 β-arrestin2-dependent pathway (5) but activation of the TAAR1/DA D
2
receptor complex inhibits GSK-3 through the same pathway (6). Inhibition
of GSK-3 with the inhibitor, SB631736, activates AKT, which is bound to the D
2
/DAT complex, thereby enhancing DA reuptake (7). Adapted from [7].
518 M. D. SCHWARTZ ET AL.

have been linked to impaired ‘top-down’control and impul-
sivity trait, which predict drug escalation and increased relapse
to drug abuse. Recent data showed that Taar1 KO mice exhib-
ited impulsive behavior and dysregulated function in the pre-
frontal cortex, whereas pharmacological activation of TAAR1
with selective agonists reduced premature impulsive
responses [84]. In agreement with these findings, RO5263397
attenuated methamphetamine-induced impulsive behavior
[85]. This evidence suggests that TAAR1 also exerts control
over addiction-related circuits and behaviors that extend
beyond the DA system and its associated functions.
In conclusion, the evidence reviewed in this section sug-
gests that TAAR1 is uniquely placed to exert a decisive influ-
ence over key neurochemical processes and behaviors
associated with drug effects and addiction. Indeed, both neu-
rochemical and behavioral observations demonstrate the abil-
ity of TAAR1 to regulate not only the effects of cocaine and
methamphetamine on DA transmission but also a wide range
of behavioral, motivational, and cognitive processes that are
affected by chronic drug exposure. As noted, the effects of
TAAR1 activation on drug self-administration, drug reward,
and relapse are particularly striking. Taken together, these
findings support the candidacy of TAAR1 as one of the most
promising therapeutic targets in addiction.
5. TAAR1 and wakefulness
5.1. TAAR1, the monoamines, and sleep-wake regulation
Sleep disturbances exert significant costs in terms of personal
health consequences and economic productivity [112,113].
Sleep and circadian dysregulation are common comorbidities
in neuropsychiatric and neurodegenerative disorders [114–
116] as well as addiction [117,118]. This link is not surprising
because the monoaminergic and glutamatergic systems
whose dysregulation underlies these diseases also play funda-
mental roles in regulating sleep and wakefulness (for detailed
reviews see [30–32,119]). Investigations of TAAR1’s involve-
ment in arousal state control suggest an important role in
regulating basal sleep and wakefulness as well as potential
therapeutic value for the sleep disorder narcolepsy.
5.2. TAAR1 mutants and sleep
5.2.1. Basal sleep-wake regulation in TAAR1 mutants
To determine the role of endogenous TAAR1 in regulating
sleep and wakefulness, Taar1 KO and OE mice were instru-
mented for EEG/EMG recording and compared to a common
pool of WT littermates under standard 12h light:dark (LD)
cycles [120]. Circadian organization of locomotor activity,
core body temperature, sleep and waking was normal in
both mutant strains, with wakefulness concentrated in the
dark phase. Total wake time was increased in OE mice relative
to WTs over 24h and was associated with an increased number
of wake bouts; by contrast, KO mice exhibited decreased
wakefulness and increased NREM sleep at the lights-on transi-
tion compared to OEs and WTs. Compensatory recovery sleep
following a 6h sleep deprivation was normal in both mutants,
indicating that homeostatic sleep regulation was unaffected
by TAAR1 mutation. Thus, constitutive TAAR1 overexpression
and deletion elicit a mild but significant increase and decrease
in basal wakefulness, respectively. These opposing effects are
somewhat surprising because both knockout and overexpres-
sion are associated with elevated VTA DA and DRN 5-HT firing
rates in vitro [11,61], and both DA [121–123] and 5-HT
[124,125] activities are positively correlated with wakefulness.
However, TAAR1 overexpression also elevates firing in LC
noradrenergic neurons and VTA GABAergic neurons [61],
both of which are associated with wake promotion [126,127],
which may explain the enhanced wakefulness seen in OE, but
not KO mice. Conditional deletion/expression of TAAR1 in vivo
would be of considerable help in identifying how TAAR1
influences basal arousal states.
By contrast, TAAR1 deletion was associated with impulsivity
and increased nocturnal nose-poke activity in a goal-directed
task [84], suggesting a greater perturbation of rest-activity
cycles than seen in the sleep EEG studies. Such a phenotype
could arise from an interaction between the normal diurnal
cycling of extracellular DA, which peaks at lights-off [128], and
dysregulated DA signaling in Taar1 KO mice [9]. This hypothesis
could explain both the temporal bias of the phenotype and its
emergence in a reward-associated context (compared to a
more neutral homecage environment) but has yet to be tested.
5.2.2. EEG spectral abnormalities
TAAR1 mutation elicited marked alterations in EEG spectral
composition; specifically, theta (4–8 Hz) and gamma (> 30Hz)
band activity was elevated in KO compared to OE mice in both
sleep and wakefulness, with WT mice intermediate between
them. Such a phenotype could arise from serotonergic dysre-
gulation in KO mice [11], although 5-HT suppresses gamma
and theta activity [129,130], rather than enhancing it as seen
in Taar1 KOs. Alternatively, dysregulated arousal states and
EEG spectra could result from abnormal glutamatergic regula-
tion [84]. Enhancing glutamatergic transmission via group II
metabotropic glutamate receptors [131], particularly mGluR2
[132], as well as group I mGluR5 receptors [133–135] promotes
waking and high-frequency EEG activity (i.e. gamma power),
while inhibition tends to potentiate NREM sleep and EEG slow
wave activity (i.e. delta power, 0.5–4Hz).
5.2.3. TAAR1 deletion and stimulant efficacy
TAAR1 deletion is associated with exaggerated neurochemical
and locomotor responses to amphetamines and their deriva-
tives [49,50]. By contrast, wake-promoting responses to the
psychostimulants modafinil and caffeine were largely normal
in TAAR1 KO mice [136], while locomotor upregulation
induced by both drugs was attenuated in KO mice, as was
drug-induced upregulation of EEG gamma activity. These
results suggest that TAAR1 may have a more central influence
on locomotor and spectral components of psychostimulant
actions than on wake promotion itself, even in the case of
dopaminergic psychostimulants (modafinil acts primarily by
inhibiting DAT [121]).
EXPERT OPINION ON THERAPEUTIC TARGETS 519

5.3. TAAR1 agonism and wake promotion
5.3.1. TAAR1 partial agonism
The partial agonists RO5203648 and RO5263397 increased
total time awake while suppressing non-REM and REM sleep
for up to 3h in WT rats [13,14] and mice [120]. Importantly,
both RO5203648 and RO5263397 promoted wakefulness with-
out increasing locomotor activity, in contrast to the hyperac-
tivity frequently produced by psychostimulants. In mice,
RO5263397 decreased mid- to high-range frequencies in the
waking and NREM EEG spectra, representing the alpha, beta,
and gamma bands [120]; in rats RO5263397 decreased NREM
delta power. This pharmaco-EEG profile was entirely depen-
dent on TAAR1 expression, as RO5263397 was entirely ineffec-
tual when given to Taar1 KO mice, while wake promotion and
REM suppression was strongly potentiated in OE mice [120].
5.3.2. TAAR1 full agonism
The full agonist RO5256390 failed to increase wakefulness in
WT rats and mice when administered in the mid-dark and mid-
light phase, respectively [14,137]. In rats, RO5256390 was
totally ineffective at all doses tested, whereas in WT mice
RO5256390 suppressed REM sleep [137]. This unexpected
result was hypothesized to reflect species differences in the
intrinsic activity of RO5256390, increasing the likelihood of
some partial agonist-like effects in mice compared to rats.
Timing of drug administration may also have played a part;
RO5256390 was tested in rats during the dark phase, when
REM sleep is normally reduced compared to the light phase
[138,139]. On the other hand, RO5256390 elicited a similar EEG
spectral profile as RO5263397 in mice (i.e. decreased power in
the theta, alpha and beta bands; M. Schwartz, unpublished
observations). As with RO5263397, all observed effects on
sleep and waking following RO5256390 were abolished in
Taar1 KO mice, indicating a TAAR1-mediated effect [137].
5.3.3. Prospective mechanisms underlying TAAR1-
mediated wake promotion
The wake-promoting effects of RO5203648 and RO5263397
could result from enhanced monoaminergic signaling follow-
ing partial TAAR1 agonism [14], especially since the full ago-
nist RO5256390 –which suppresses monoaminergic signaling
–failed to promote wakefulness [14,137]. Similarly, the pro-
found REM-suppressing effect of TAAR1 partial agonism could
be mediated via enhanced DA signaling [122,140,141] or via
interactions with 5-HT1a and 5-HT1b receptors [11,142,143],
both of which regulate REM sleep [144–146]. Thus, the
enhancement of wakefulness would appear to depend heavily
on the ‘antagonist-like’actions of the partial agonists. On the
other hand, the similarity in EEG power spectral profiles
induced by the full and partial agonists suggests a common
mechanism relying on the agonist-induced activation of
TAAR1. While still speculative, this striking combination of
TAAR1 activation and inhibition is rarely seen within the
same assay. To help isolate the contributions of these possible
mechanisms, a specific TAAR1 antagonist suitable for in vivo
studies would be a welcome addition to the existing pharma-
cological toolkit.
5.4. TAAR1 agonism as a narcolepsy therapeutic
Narcolepsy is a sleep disorder characterized by hypersomno-
lence, sleep disruption, sleep paralysis, and cataplexy, a sud-
den loss of skeletal muscle tone during wakefulness.
Narcolepsy arises from dysregulation of the wake-promoting
and wake–stabilizing hypocretin/orexin (Hcrt) neurons located
in the lateral hypothalamus [147–149]. Current pharmacologi-
cal treatments for narcolepsy, including stimulants such as
amphetamines and modafinil and the GABA agonist gamma-
hydroxy butyrate (GHB), either offer limited therapeutic value
(e.g. Modafinil treats the somnolence but does not improve
cataplexy) or carry significant side effects (e.g. tolerance/abuse
risk, sedation); thus novel therapeutics are needed [150]. To
test efficacy of TAAR1 as a therapeutic target for narcolepsy,
RO5263397 and RO5256390 were given to two different
mouse narcolepsy models, the orexin-ataxin3 mouse [151]in
which Hcrt neurons degenerate shortly after birth, and the
orexin/tTA- diphtheria toxin A fragment (DTA) mouse, in which
Hcrt degeneration is conditionally regulated via doxycycline
access [152]. Both RO5263397 and RO5256390 reduced the
number of cataplexy episodes and the time spent in cataplexy
[137], comparing favorably with the norepinephrine reuptake
inhibitor desipramine, a known anticataplectic [153].
Anticataplectic effects could be mediated via serotonergic
modulation [154,155] and/or D2 signaling [59,156]. At the
highest dose, RO5256390 increased wakefulness in DTA but
not ataxin mice, with no further effects on NREM or REM sleep.
RO5263397 suppressed REM sleep in ataxin but not DTA mice,
without altering wake or NREM sleep. As in WT mice and rats,
neither drug elicited hyperlocomotion.
5.5. Summary
In contrast to the similarity of full and partial agonism on
neurobehavioral assays and studies of addiction, the sleep
studies to date highlight the complexity of TAAR1 signaling.
For example, the full and partial agonists exhibit divergent
actions on wakefulness, but similar impact on EEG spectral
profiles and anticataplectic efficacy. These divergent effects
likely reflect the multimodal nature of TAAR1’s actions in vivo
and highlight the complexity of manipulating endogenous
TAAR1 signaling, particularly with partial agonists that exhibit
both agonist- and antagonist-like properties. Nevertheless, the
studies to date suggest a potentially key role for TAAR1 in
regulating arousal state and cortical activation. TAAR1 agon-
ism may also be useful in treating sleep disorders, as demon-
strated by the narcolepsy studies.
6. Conclusions
TAAR1 is a promising locus for treatment of neurological,
neuropsychiatric, and behavioral conditions that have histori-
cally proven difficult to address, including schizophrenia,
addiction, and sleep disorders (Table 1). In fact, two pharma-
cological companies have already initiated late-stage clinical
trials of TAAR1-based drugs in schizophrenia patients [2].
While the influence of TAAR1 on dopaminergic systems is
likely critical to its efficacy, serotonergic and glutamatergic
520 M. D. SCHWARTZ ET AL.

signaling likely also play prominent roles. Indeed, such multi-
modal actions could underlie the utility of TAAR1 agonists in
ameliorating side effects (motor dysregulation, weight gain),
abuse potential (especially for dopaminergic drugs), and lim-
ited therapeutic profile (e.g. positive vs. negative symptoms of
schizophrenia; sleep disturbance vs. cataplexy in narcolepsy).
Similarly, the T1AM studies illustrate the importance of study-
ing endogenous trace amines, which may reveal new thera-
peutic applications [33] as well as roles for other TAARs [157].
7. Expert opinion
TAAR1 is a confirmed regulator of monoaminergic and glu-
tamatergic neurotransmitter systems intimately involved with
psychosis, motivation, affect, impulse control, and cognition.
Research on TAAR1’s mechanisms of action to date has
revealed a critical role in regulating dopaminergic tone via
multiple intracellular pathways. In particular, TAAR1 power-
fully regulates mesocorticolimbic dopamine circuits underly-
ing motivation and reward, and TAAR1-based interventions
are effective in curbing addictive responses. Pharmacological
targeting of TAAR1 shows great promise in a variety of
neuropsychiatric diseases, including but not limited to schi-
zophrenia, addiction, depression, ADHD, Parkinson disease,
and OCD. Indeed, TAAR1-based small molecules have already
entered clinical trials for treatment of depression and schizo-
phrenia. The addiction field in particular appears promising
for development of TAAR1 as a therapeutic target, on the
basis of TAAR1’s involvement in regulating behaviors asso-
ciated with abuse of psychostimulants, ethanol [158], and
nicotine [105,161].
While TAAR1 also regulates serotonergic and glutamatergic
signaling, the downstream impact of these actions is less clear
at present and therefore represents a key knowledge gap.
Major questions include improved understanding of the intra-
cellular signaling pathways underlying TAAR1’s actions in 5HT
and glutamate neurons; whether TAAR1 similarly regulates
‘homeostasis’of 5HT and glutamate signaling as it appears
to do for DA circuits, and whether such processes generalize
across multiple neurotransmitter systems, as well as within
them. Thus, in the coming years, TAAR1 is expected to play
a central role in elucidating the neurochemical bases of affect,
cognition, and their disturbances in mental illness. Further
novel therapeutic applications are not only conceivable, but
likely.
A second major growth area for future exploration lies in
integrative physiological functions like metabolism and sleep.
A full TAAR1 agonist was shown to decrease weight gain, food
intake, and glucose dysregulation [159], while T1AM exhibits
both thermoregulatory and food intake-related effects. TAAR1
as well as other TAARs are expressed in the periphery; while
not a focus of this article, the roles of peripheral TAARs and
trace amine signaling in regulating physiological functions like
metabolism should be evaluated alongside the CNS-related
effects.
Similarly, the actions of TAAR1 partial agonism on sleep
and wakefulness, EEG spectra and cataplectic symptoms likely
involve a combination of dopaminergic, serotonergic, and
glutamatergic effects. This presents an opportunity to explore
TAAR1’s actions on a more mechanistic level, particularly in
aspects of neural function known to be dysregulated in neu-
ropsychiatric illness, such as EEG gamma band activity in
schizophrenia. Sleep disturbance is a common comorbidity
for mental illness [160]. By directly acting on monoamine
and glutamate transmission, TAAR1 may therefore provide
an entry point for understanding the neural basis for these
commonalities. Novel TAAR1-directed therapeutics thus have
the potential to ameliorate both primary neurosychiatric
symptoms along with debilitating comorbidities such as
sleep disruption.
Our understanding of TAAR1’s actions in CNS has benefited
immensely from the recent development of transgenic ani-
mals and especially from new, highly selective small-molecule
ligands such as the Roche full and partial agonists. However, a
lack of selective brain-permeable TAAR1 antagonists with
good in vivo pharmacokinetic properties has hampered devel-
opment of preclinical animal models. The partial and full
TAAR1 agonists developed by Roche show a combination of
similar effects (e.g. antipsychotic actions) and divergent
actions (e.g. wake promotion); while the divergent effects are
typically hypothesized to be mediated by the ‘antagonist-like’
profile of the partial agonists, a bona fide TAAR1 antagonist
suitable for in vivo study would be most helpful in parsing out
these mechanisms. Future development of such compounds
will certainly broaden the repertoire of pathological conditions
that could be managed by targeting TAAR1.
A significant gap remains between what is known of the
cellular and molecular actions of TAAR1 and the behavioral
outputs resulting from those actions. Future efforts should
therefore work toward isolating the individual contributions
of dopaminergic, serotonergic, and glutamatergic circuits to
the behavioral/organismal effects seen to date as described
Table 1. Potential therapeutic applications for TAAR1, based on preclinical/
proof-of-concept studies.
Clinical
indication Assay Species Source
Schizophrenia Stimulant-induced Hyperactivity Mouse, rat 13, 14
Object retrieval task NHP 13, 14
Attentional set shift Rat 14
Prepulse inhibition Mouse 50
Depression Forced swim test Rat 13, 14, 90
Anxiety Stress-induced hyperthermia Mouse 13, 14, 90
ADHD Spontaneous hyperactivity Mouse, rat 11, 13, 62
Impulsivity Mouse 84
Reinforcement of low-rate
behavior
NHP 13
OCD Schedule-induced polydipsia Rat 89
Compulsive eating Rat 90
Addiction Locomotor sensitization Rat 101–103
Self-administration (cocaine) Rat 13, 97, 104
Self-administration
(methamphetamine)
Rat 98, 101–102
Reinstatement/relapse (cocaine,
methamphetamine)
Rat 97, 98, 103,
106
Nicotine addiction Rat 105
Ethanol sensitivity, consumption Mouse 160
Metabolism Food intake Mouse 25–26, 158
Weight gain Rat, mouse 13, 158
Glucose regulation mouse 27, 158
Narcolepsy Wake promotion Mouse, rat 13, 14, 28,
120
Cataplexy reduction mouse 137
EXPERT OPINION ON THERAPEUTIC TARGETS 521

above. These will require novel tools and applications, espe-
cially genetic approaches to isolate, identify, and interrogate
TAAR1-expressing neurons and development of selective
human and animal TAAR1 antibodies. Such work will clarify
how TAAR1 regulates neuronal ‘tone’and thereby modulates
how the brain experiences, and responds to, environmental
stimuli in intact and pathological conditions. Finally, clinical
studies evaluating the efficacy of TAAR1 agonists in psychiatric
patients are in progress; the results of these studies will
powerfully shape the direction of future research in this field.
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.
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 relation-
ships to disclose
ORCID
Michael D. Schwartz http://orcid.org/0000-0002-3472-8900
Raul R. Gainetdinov http://orcid.org/0000-0003-2951-6038
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