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TRANSCRIPT
Trace amine-associated receptor 1: a multimodal therapeutic target for
neuropsychiatric diseases.
Michael D. Schwartz1, Juan J. Canales2, Riccardo Zucchi3, Stefano Espinoza4, Ilya Sukhanov5, Raul R.
Gainetdinov6,7
1. Center for Neuroscience, SRI International, Menlo Park CA, USA
2. Division of Psychology, School of Medicine, College of Health and Medicine, University of Tasmania,
Private Bag 30, Hobart, TAS 7001, Australia
3. Fondazione Istituto Italiano di Tecnologia, Neuroscience and Brain Technologies Dept., Via Morego 30,
16163 Genoa, Italy
4. Department of Pathology, University of Pisa, Pisa, Italy
5. Institute of Pharmacology, Pavlov Medical University, St. Petersburg, Russia
6. Institute of Translational Biomedicine, St. Petersburg State University, 199034 St. Petersburg, Russia
7. Skolkovo Institute of Science and Technology, 143025 Moscow, Russia.
Disclaimer:
Support: IS is supported by the Russian Science Foundation Grant № 17-75-20177; RRG is supported
by the Russian Science Foundation Grant № 14-50-00069.
Word count:
Abstract: 198
Body text: 5964
Figures: 0
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.
1. Introduction
1.1. Trace amines and trace amine-associated receptor 1 (TAAR1)
The trace amines, endogenous amines closely related to the biogenic amine neurotransmitters (eg.
dopamine (DA), serotonin (5-hydroxytryptamine; 5-HT) and norepinephrine (NE)) have been known to exert
physiological and neurological effects since the early 20th 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 conventional 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-associated receptor 1 (TAAR1), is part of a large
and evolutionarily diverse family of TAARs with 6 functional members in humans [5]. Several TAARs act as
olfactory receptors [6]. In the mammalian brain, the finding that TAAR1 powerfully modulates monoaminergic
neurotransmission [7, 8, 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 dopaminergic ventral tegmental area (VTA)/substantia nigra and serotonergic dorsal raphe nucleus (DRN)
[1, 10, 11], and is therefore ideally positioned to regulate the activity of these neurotransmitter systems. Indeed,
transgenic mice lacking TAAR1 exhibit markedly elevated discharge rates of DA and 5-HT neurons [12],
suggesting that TAAR1 activation down-regulates monoaminergic neurotransmission. The strategic
neuroanatomical location of TAAR1 and its remarkable ability to regulate aminergic 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 biomolecules such as 3-iodothyronamine. While beyond the scope of this review, there
is also significant peripheral TAAR1 expression in pancreas, stomach and leukocytes, suggesting 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 vs other aminergic receptors, but the Ki’s for some other receptors – namely α2
adrenergic, 5-HT2 5-HTergic, µ and κ opioid, and I1 imidazoline receptors – are in the nanomolar range, 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, since 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 3,5,3’-triiodothyronine (T3) through the sequential action of deiodinases
and amino acid decarboxylases (possibly ornithine decarboxylase) [17], but the precise biosynthetic pathway
and the physiological site(s) of production 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, 19, 20, 21, 22, 23].
In 2004, T1AM was reported to be a powerful activator of TAAR1 [16]. Its EC50 for a biochemical
response (cAMP production) 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
physiological 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 fasting 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 movement (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 EC50 = 2.7 µM [29].
T1AM’s pro-learning and anti-amnestic effects may depend on histaminergic activity, since they were
dampened or abolished by histamine receptor antagonists and in transgenic mice lacking histidine
decarboxylase, the key enzyme regulating histamine biosynthesis [21, 22]. Modulation of adrenergic and
histaminergic activity could also underlie wake promotion since both neurotransmitters are robustly wake -
promoting [30, 31, 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 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 therapeutic 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 other TAARs (particularly TAAR5), α2A 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, histamine and
3-iodothyroacetic acid are involved in the accelerated response to the hot plate test, suggesting reduced pain
threshold [20, 22]. Further investigation with TAAR1 antagonists and/or KO mice are 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 derivatives [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 evaluation of T1AM
analogs is expected to clarify several features of T1AM/TAAR1 interactions and structure-activity relationships
[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, 41, 42], whereas decreased PEA
levels were associated with depression [43, 44, 45]. However, the lack of an identifiable endogenous receptor
and dearth of suitable investigative tools limited advancement 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, 8, 9] has renewed interest in this association. Brain DA is critically involved in the
etiology and pathogenesis of neuropsychiatric disorders including schizophrenia, Attention Deficit and
Hyperactivity Disorder (ADHD) and Parkinson’s disease; DA dysregulation is proposed to contribute 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, 49, 50] and selective pharmacological compounds[10,
11, 13, 14, 15], these advances have vastly enhanced understanding of TAAR1’s role in neuropsychiatric
disorders and its potential therapeutic applications.
3.2. TAAR1 and schizophrenia
3.2.1. Dopaminergic dysregulation and schizophrenia
The DA theory of schizophrenia asserts that increased dopaminergic tone or D2 receptor sensitivity
resulting in dysregulated DA signaling, underlies the development of schizophrenia, particularly its positive
symptoms (e.g. hallucinations, delusions and disordered thoughts and speech). This theory has a strict
predictive validity, since all known clinically effective antipsychotics are D2 receptor antagonists [51].
Hyperactivity induced by dopaminergic psychostimulants is considered a behavioral manifestation of increased
dopaminergic activity in the mesolimbic pathway [52], and potentiated 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 antipsychotics [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 behavioral 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 amphetamine, methamphetamine or MDMA compared to WTs [48, 50,
57, 58], as well as high doses of the selective D2/ D3 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 hyperlocomotion in WT mice [11, 14,
61] and Wistar rats [13] and enhanced olanzapine (atypical antipsychotic)-induced inhibition of locomotor
activity following cocaine [14]. Conversely, amphetamine-induced hyperactivity was strongly attenuated in
TAAR1-overexpressing (OE) mice, and ‘rescued’ by the selective partial agonist RO5073012 [61]. Together,
these findings indicate TAAR1 as a viable locus for treatment of positive psychotic symptoms, likely mediated
by modulation of dopaminergic signaling. Consistent with this hypothesis, TAAR1 agonism blocks
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 similarly 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 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 exaggerated 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, 67, 68]. Intriguingly, TAAR1 deletion
greatly attenuated climbing and other stereotypy behaviors induced by high doses of the mixed D1/D2 agonist
apomorphine [69], likely due to a direct agonistic action of apomorphine at TAAR1 [4]. Since apomorphine-
induced stereotypies are also used to screen for antipsychotics [70, 71, 72], these findings imply a need for care
when interpreting apomorphine-induced behaviors in rodents.
Whereas all clinically used antipsychotics augment haloperidol-induced catalepsy, partial TAAR1
agonists actually reduce this phenomenon [13, 14] and do not themselves induce catalepsy [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 demonstrate
schizophrenia-like phenotypes in animals because human schizophrenic patients exhibit an analogous deficit
[74]. By contrast, spatial working memory in the forced alternation 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 therefore warranted, particularly in key cognitive domains such as
attention and learning.
In general, the loss of TAAR1 induces elevated DA neurotransmission in the mesolimbic pathway in
mice. Specific TAAR1 agonists ameliorate pharmacologically- and genetically-induced hyperlocomotion
without the undesirable motor side effects characteristic of D2 receptor-blocking antipsychotics. Moreover,
TAAR1 agonists may be effective in treating cognitive 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 amphetamines 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
“antiparkinsonian” 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, 78,
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 (Leo
et al., 2018). 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 correlated with deficient prefrontal cortical
glutamatergic transmission [84]. Furthermore, RO5166017 and RO5203648 decreased premature responding in
a fixed interval conditioning schedule in WT mice [84]. RO5256390 and RO5263397 also increased the
number of reinforcers earned in a differential reinforcement of low response rates test in cynomolgus macaques
[13]. In a recent paper, 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 delay of reward test
in vehicle-treated rats [81].
3.5. TAAR1 and OCD
Although selective 5-HT reuptake inhibitors (SSRI) form the first line of drugs to treat OCD [85] a role
for DA function in OCD pathogenesis has been actively studied in recent years (for review see [86]).
Antipsychotics form a second line of OCD treatment since about 50% OCD patients are resistant to SSRI
therapy. RO5263397 reduced obsessive drinking in schedule-induced polydipsia, a popular preclinical model
of compulsive behavior [87]. Additionally, the full TAAR1 agonist RO5256390 blocked compulsive eating in
rats [88]. Thus, studies 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 demonstrated antidepressant action in the forced
swim test [13, 14, 88], a test which has high predictive validity for identification of new antidepressants [89].
This effect could be mediated via a TAAR1-dependent enhancement of serotonergic signaling since the
antidepressant effect was only seen with partial agonists, which increase 5-HT firing [11, 13, 14]. However,
several lines of evidence also support dopaminergic involvement in affective disorders (for review see [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 interventions, constitute irreplaceable initiatives to aid in recovery, there exists
considerable agreement among psychiatrists and health professionals specializing in addiction that novel
pharmacological approaches are needed to treat the disorder more effectively [91, 92]. 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 problematic 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 corresponding receptor targets,
play a critical role [93]. The DA substitution approach in stimulant addiction involves the use of a competing
Dopaminergic agonist to potentially suppress withdrawal and drug craving in abstinent individuals [94].
Although this is still an avenue under investigation, compounds 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 indirectly modulate DA
transmission through the ups and downs of the addiction cycle. Due to 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, especially addiction.
4.3. TAAR1 & stabilization of dysregulated DA signaling
The development of synthetic TAAR1 ligands have proven critical 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, 95, 96], their effects on DA neuron firing rate can be different. 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 constitutively 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 neurochemical 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 “normalizing” DA neuron cell
discharge, which is known to be dysregulated following chronic cocaine exposure [97, 98]. In agreement with
these physiological observations, and supporting 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 overexpression 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 medications. Motor sensitization, a
process that evolves following repeated psychomotor stimulant treatment and that involves plasticity changes in
the mesolimbic DA system, was attenuated by the partial TAAR1 agonists RO5203648 [99] and RO5263397
[100, 101]. 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 [99, 100]. Importantly, RO5203648 was able to block stimulant self-administration without
concomitant decreases in response rates for food self-administration, thus ruling out motor or motivational
deficits. Subsequent work demonstrated that both RO5203648 and the full TAAR1 agonist, RO5256390,
flattened the dose-response curve for cocaine self-administration, indicating that TAAR1 activation effectively
decreased the reinforcing effects of cocaine [102].
4.4. TAAR1 regulates reward mechanisms
In addition to perturbing motor behavior and promoting reinforcement 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
reinforcement, 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 [95, 96]. These data clearly indicate that TAAR1 activation reduces stimulant reward and the
motivation to seek and self-administer stimulant 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 prevented context-induced cocaine relapse in a
model of forced abstinence [95] and cue- and cocaine prime-induced reinstatement of cocaine and
methamphetamine seeking after extinction training [95, 96, 101]. 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 distribution is predominantly
intracellular [4, 103], stimulating both accumulation of cAMP, via Gαs-adenylyl cyclase activation which
promotes PKA and PKC phosphorylation [3, 4, 104], and a G protein-independent, β-arrestin2-dependent
pathway involving a DA D2 receptor-regulated protein kinase B (AKT)/glycogen synthase kinase (GSK-3)
[105]. 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 neurochemical actions that involves TAAR1. Upon
TAAR1 stimulation, such pathway recruits D2 autoreceptors functionally linked to TAAR1 and downstream
molecular targets converging on GSK-3, but not on PKA or PKC [7]. It is worth noting that GSK-3 has
been previously implicated in cocaine sensitization [106] and cocaine reward memory [107]. These results
open new avenues to further explore such complex molecular interactions, with a view to optimize TAAR1-
based drug development in the area of addiction treatment.
4.7. Summary
Although changes in DA transmission are undoubtedly important, it is now recognized that the spiral of
cycles of abstinence 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, have been linked
to impaired “top-down” control and impulsivity trait, which predict drug escalation and increased relapse to
drug abuse. Recent data showed that Taar1 KO mice exhibited impulsive behavior and dysregulated function in
the prefrontal 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 [108]. 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 suggests that TAAR1 is uniquely placed to exert a
decisive influence over key neurochemical processes and behaviors associated with drug effects and addiction.
Indeed, both neurochemical and behavioral observations demonstrate the ability 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 exact significant costs in terms of personal health consequences and economic
productivity [109, 110]. Sleep and circadian dysregulation are common comorbidities in neuropsychiatric and
neurodegenerative disorders [111] [112, 113] as well as addiction [114, 115]. This link is not surprising, since
the monoaminergic and glutamatergic neurotransmitter systems whose dysregulation underlies these diseases
also play fundamental roles in the regulation of sleep and wakefulness (for detailed reviews see [30, 31, 32,
116]). Investigations of TAAR1’s involvement 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 instrumented for EEG/EMG recording and compared to a common pool of WT littermates under
standard 12h light:dark (LD) cycles [117]. 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 transition 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, since both
knockout and overexpression is associated with elevated VTA DA and DRN 5-HT firing rates in vitro [11, 61],
and both DA [118, 119, 120] and 5-HT [121, 122] activity are positively correlated with wakefulness.
However, TAAR1 overexpression also elevates firing in LC noradrenergic neurons as well as VTA GABAergic
neurons [61], both of which are associated with wake promotion [123, 124], 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 [125], 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 dysregulation in KO
mice [11], although 5-HT suppresses gamma and theta activity [126, 127], rather than enhancing it as seen in
Taar1 KOs. Alternatively, dysregulated arousal states and EEG spectra could result from abnormal
glutamatergic regulation [84]. Enhancing glutamatergic transmission via group II metabotropic glutamate
receptors [128], particularly mGluR2 [129], as well as group I mGluR5 receptors [130, 131, 132] 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).
5.3. 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 [117]. Importantly, both RO5203648 and
RO5263397 promoted wakefulness without increasing locomotor activity, in contrast to the hyperactivity
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 [117]; in rats RO5263397
decreased NREM delta power. This pharmaco-EEG profile was entirely dependent on Taar1 expression, as
RO5263397 was entirely ineffectual when given to Taar1 KO mice, while wake promotion and REM
suppression was strongly potentiated in OE mice[117].
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, 133]. In rats, RO5256390 was totally ineffective at all
doses tested, whereas in WT mice RO5256390 suppressed REM sleep [133]. 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 [134, 135]. 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 [133].
5.3.3. Prospective mechanisms underlying TAAR1-mediated wake promotion
The wake-promoting effects of RO5203648 and RO5263397 could result from enhanced
monoaminergic signaling following partial TAAR1 agonism [14], especially since the full agonist RO5256390-
which suppresses monoaminergic signaling- failed to promote wakefulness [14, 133]. Similarly, the profound
REM-suppressing effect of TAAR1 partial agonism could be mediated via enhanced DA signaling [119, 136,
137] or via interactions with 5-HT1a and 5-HT1b receptors [11, 138, 139], both of which regulate REM sleep
[140, 141, 142]. 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 pharmacological tooklit.
5.4. TAAR1 agonism as a narcolepsy therapeutic
Narcolepsy is a sleep disorder characterized by hypersomnolence, sleep disruption, sleep paralysis and
cataplexy, a sudden loss of skeletal muscle tone during wakefulness. Narcolepsy arises from dysregulation of
the wake-promoting and –stabilizing hypocretin/orexin (Hcrt) neurons located in the lateral hypothalamus [143,
144, 145]. Current pharmacological treatments for narcolepsy, including stimulants such as amphetamines and
modafinil and the GABA agonist gamma-hydroxy butyrate (GHB), either offer limited therapeutic value (eg.
Modafinil treats the somnolence but does not improve cataplexy) or carry significant side effects (eg.
tolerance/abuse risk, sedation); thus novel therapeutics are needed [146]. 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 [147] 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 [148]. Both RO5263397 and RO5256390 reduced the number of cataplexy episodes and the
time spent in cataplexy [133], comparing favorably with the norepinephrine reuptake inhibitor desipramine, a
known anticataplectic [149]. Anticataplectic effects could be mediated via serotonergic modulation [150, 151]
and/or D2 signaling [59, 152]. 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 agonism may also be
useful in treating sleep disorders, as demonstrated by the narcolepsy studies.
6. Conclusions
TAAR1 is a promising locus for treatment of neurological, neuropsychiatric and behavioral conditions
that have historically proven difficult to address, including schizophrenia, addiction, and sleep disorders. In
fact, two pharmacological companies have already initiated late-stage clinical trials of TAAR1-based drugs in
schizophrenia patients (Berry et al., 2018). While the influence of TAAR1 on Dopaminergic systems is likely
critical to its efficacy, serotonergic and glutamatergic signaling likely also play prominent roles. Indeed, such
multimodal actions could underlie the utility of TAAR1 agonists in ameliorating side effects (motor
dysregulation, weight gain), abuse potential (especially for dopaminergic drugs), and limited therapeutic profile
(eg. positive vs. negative symptoms of schizophrenia; sleep disturbance vs. cataplexy in narcolepsy).
Similarly, the T1AM studies illustrate the importance of studying endogenous trace amines, which may reveal
new therapeutic applications [33] as well as roles for other TAARs [153].
7. Expert opinion
TAAR1 is a confirmed regulator of at least three major neurotransmitter systems that are intimately involved
with psychosis, motivation, affect, impulse control and cognition, as well as integrative physiological
functions like metabolism and sleep. Pharmacological targeting of TAAR1 shows great promise in a variety
of disease models, including but not limited to schizophrenia, addiction, depression, ADHD, Parkinson
disease and OCD. To date, much of the research has centered on Dopaminergic circuits and dysregulation,
yet TAAR1 manipulation impacts the serotonergic and glutamatergic systems in addition to DA. Thus,
further novel therapeutic applications are not only conceivable, but likely.
This area has benefited immensely from the recent development of transgenic animals and new,
highly selective small-molecule ligands. However, 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 work towards isolating the individual contributions of dopaminergic, serotonergic and
glutamatergic circuits to the behavioral/organismal effects seen to date. These will require novel tools and
applications, such as genetic approaches to target TAAR1-expressing neurons and selective human
antibodies. Such work is expected to 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.
8. 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 psychostimulant self-administration, reward mechanisms and relapse
potential.
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, depression,
ADHD, Parkinson disease and OCD.
References
1. Grandy DK. Trace amine-associated receptor 1—Family archetype or iconoclast? Pharmacology & Therapeutics. 2007 12//;116(3):355-390. doi: 10.1016/j.pharmthera.2007.06.007.
2. Berry MD, Gainetdinov RR, Hoener MC, et al. Pharmacology of human trace amine-associated receptors: Therapeutic opportunities and challenges. Pharmacol Ther. 2017 Jul 16. doi: 10.1016/j.pharmthera.2017.07.002. PubMed PMID: 28723415.* Comprehensive review of trace amines and TAAR1 pharmacology.
3. Borowsky B, Adham N, Jones KA, et al. Trace amines: identification of a family of mammalian G protein-coupled receptors. Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):8966-71. doi: 10.1073/pnas.151105198. PubMed PMID: 11459929; PubMed Central PMCID: PMCPMC55357* One of two papers that independently identified TAAR1.
4. Bunzow JR, Sonders MS, Arttamangkul S, et al. Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor. Mol Pharmacol. 2001 Dec;60(6):1181-8. PubMed PMID: 11723224.* The second of two papers that independently identified TAAR1.
5. Lindemann L, Hoener MC. A renaissance in trace amines inspired by a novel GPCR family. Trends Pharmacol Sci. 2005 May;26(5):274-81. doi: 10.1016/j.tips.2005.03.007. PubMed PMID: 15860375.
6. Liberles SD, Buck LB. A second class of chemosensory receptors in the olfactory epithelium. Nature. 2006 Aug 10;442(7103):645-50. doi: 10.1038/nature05066. PubMed PMID: 16878137.* Identification of TAAR family members as olfactory receptors.
7. Asif-Malik A, Hoener MC, Canales JJ. Interaction Between the Trace Amine-Associated Receptor 1 and the DA D2 Receptor Controls Cocaine's Neurochemical Actions. Sci Rep. 2017 Oct 24;7(1):13901. doi: 10.1038/s41598-017-14472-z. PubMed PMID: 29066851; PubMed Central PMCID: PMCPMC5655641.* Reveals TAAR1-dopaminergic interactions underlying addictive properties of cocaine.
8. Espinoza S, Salahpour A, Masri B, et al. Functional interaction between trace amine-associated receptor 1 and DA D2 receptor. Mol Pharmacol. 2011 Sep;80(3):416-25. doi: 10.1124/mol.111.073304. PubMed PMID: 21670104; PubMed Central PMCID: PMCPMC3164335.
9. Leo D, Mus L, Espinoza S, et al. Taar1-mediated modulation of presynaptic dopaminergic neurotransmission: role of D2 DA autoreceptors. Neuropharmacology. 2014 Jun;81:283-91. doi: 10.1016/j.neuropharm.2014.02.007. PubMed PMID: 24565640.
10. Bradaia A, Trube G, Stalder H, et al. The selective antagonist EPPTB reveals TAAR1-mediated regulatory mechanisms in dopaminergic neurons of the mesolimbic system. Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):20081-6. doi: 10.1073/pnas.0906522106. PubMed PMID: 19892733; PubMed Central PMCID: PMCPMC2785295.* Reveals inhibitory actions of TAAR1 on monoaminergic neurotransmission.
11. Revel FG, Moreau JL, Gainetdinov RR, et al. TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity. Proc Natl Acad Sci U S A. 2011 May 17;108(20):8485-90. doi: 10.1073/pnas.1103029108. PubMed PMID: 21525407; PubMed Central PMCID: PMCPMC3101002.* First report about in vivo effects of TAAR1 agonists.
12. Revel F, Bradaia A, Trube G, et al. Modulation of dopaminergic activity in the mesolimbic system by trace amine-associated receptor 1 (TAAR1) modification. European Neuropsychopharmacology. 2009;19:S273.
13. Revel FG, Moreau JL, Gainetdinov RR, et al. Trace amine-associated receptor 1 partial agonism reveals novel paradigm for neuropsychiatric therapeutics. Biol
Psychiatry. 2012 Dec 1;72(11):934-42. doi: 10.1016/j.biopsych.2012.05.014. PubMed PMID: 22705041.* This study demonstrates antipsychotic effects of TAAR1 agonists.
14. Revel FG, Moreau JL, Pouzet B, et al. A new perspective for schizophrenia: TAAR1 agonists reveal antipsychotic- and antidepressant-like activity, improve cognition and control body weight. Mol Psychiatry. 2013 May;18(5):543-56. doi: 10.1038/mp.2012.57. PubMed PMID: 22641180.* This study demonstrated preclinical efficacy of TAAR1 agonists in neuropsychiatric disease models, addiction, and modulating sleep-wake state.
15. Stalder H, Hoener MC, Norcross RD. Selective antagonists of mouse trace amine-associated receptor 1 (mTAAR1): discovery of EPPTB (RO5212773). Bioorg Med Chem Lett. 2011 Feb 15;21(4):1227-31. doi: 10.1016/j.bmcl.2010.12.075. PubMed PMID: 21237643.
16. Scanlan TS, Suchland KL, Hart ME, et al. 3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone. Nat Med. 2004 Jun;10(6):638-42. doi: 10.1038/nm1051. PubMed PMID: 15146179.* Identifies T1AM as an endogenous TAAR1 agonist.
17. Hoefig CS, Wuensch T, Rijntjes E, et al. Biosynthesis of 3-Iodothyronamine From T4 in Murine Intestinal Tissue. Endocrinology. 2015 Nov;156(11):4356-64. doi: 10.1210/en.2014-1499. PubMed PMID: 26348473.
18. Galli E, Marchini M, Saba A, et al. Detection of 3-iodothyronamine in human patients: a preliminary study. J Clin Endocrinol Metab. 2012 Jan;97(1):E69-74. doi: 10.1210/jc.2011-1115. PubMed PMID: 22031514.
19. Hoefig CS, Kohrle J, Brabant G, et al. Evidence for extrathyroidal formation of 3-iodothyronamine in humans as provided by a novel monoclonal antibody-based chemiluminescent serum immunoassay. J Clin Endocrinol Metab. 2011 Jun;96(6):1864-72. doi: 10.1210/jc.2010-2680. PubMed PMID: 21490071.
20. Laurino A, De Siena G, Saba A, et al. In the brain of mice, 3-iodothyronamine (T1AM) is converted into 3-iodothyroacetic acid (TA1) and it is included within the signaling network connecting thyroid hormone metabolites with histamine. Eur J Pharmacol. 2015 Aug 15;761:130-4. doi: 10.1016/j.ejphar.2015.04.038. PubMed PMID: 25941083.
21. Manni ME, De Siena G, Saba A, et al. Pharmacological effects of 3-iodothyronamine (T1AM) in mice include facilitation of memory acquisition and retention and reduction of pain threshold. Br J Pharmacol. 2013 Jan;168(2):354-62. doi: 10.1111/j.1476-5381.2012.02137.x. PubMed PMID: 22889145; PubMed Central PMCID: PMCPMC3572562.* First report of T1AM's procognitive effects.
22. Musilli C, De Siena G, Manni ME, et al. Histamine mediates behavioural and metabolic effects of 3-iodothyroacetic acid, an endogenous end product of thyroid hormone metabolism. Br J Pharmacol. 2014 Jul;171(14):3476-84. doi: 10.1111/bph.12697. PubMed PMID: 24641572; PubMed Central PMCID: PMCPMC4105934.
23. Saba A, Chiellini G, Frascarelli S, et al. Tissue distribution and cardiac metabolism of 3-iodothyronamine. Endocrinology. 2010 Oct;151(10):5063-73. doi: 10.1210/en.2010-0491. PubMed PMID: 20739399.
24. Coster M, Biebermann H, Schoneberg T, et al. Evolutionary Conservation of 3-Iodothyronamine as an Agonist at the Trace Amine-Associated Receptor 1. Eur Thyroid J. 2015 Sep;4(Suppl 1):9-20. doi: 10.1159/000430839. PubMed PMID: 26601069; PubMed Central PMCID: PMCPMC4640299.
25. Zucchi R, Accorroni A, Chiellini G. Update on 3-iodothyronamine and its neurological and metabolic actions. Front Physiol. 2014;5:402. doi: 10.3389/fphys.2014.00402. PubMed PMID: 25360120; PubMed Central PMCID: PMCPMC4199266.* Review of T1AM and its effects on CNS and peripheral physiology.
26. Dhillo WS, Bewick GA, White NE, et al. The thyroid hormone derivative 3-iodothyronamine increases food intake in rodents. Diabetes Obes Metab. 2009 Mar;11(3):251-60. doi: 10.1111/j.1463-1326.2008.00935.x. PubMed PMID: 18671794.
27. Manni ME, De Siena G, Saba A, et al. 3-Iodothyronamine: a modulator of the hypothalamus-pancreas-thyroid axes in mice. Br J Pharmacol. 2012 May;166(2):650-8. doi: 10.1111/j.1476-5381.2011.01823.x. PubMed PMID: 22225569; PubMed Central PMCID: PMCPMC3417495.
28. James TD, Moffett SX, Scanlan TS, et al. Effects of acute microinjections of the thyroid hormone derivative 3-iodothyronamine to the preoptic region of adult male rats on sleep, thermoregulation and motor activity. Horm Behav. 2013 Jun;64(1):81-8. doi: 10.1016/j.yhbeh.2013.05.004. PubMed PMID: 23702093; PubMed Central PMCID: PMCPMC4091812.
29. Gompf HS, Greenberg JH, Aston-Jones G, et al. 3-Monoiodothyronamine: the rationale for its action as an endogenous adrenergic-blocking neuromodulator. Brain Res. 2010 Sep 10;1351:130-40. doi: 10.1016/j.brainres.2010.06.067. PubMed PMID: 20615397; PubMed Central PMCID: PMCPMC2926234.
30. Brown RE, Basheer R, McKenna JT, et al. Control of sleep and wakefulness. Physiol Rev. 2012 Jul;92(3):1087-187. doi: 10.1152/physrev.00032.2011. PubMed PMID: 22811426; PubMed Central PMCID: PMCPMC3621793.
31. Jones BE. From waking to sleeping: neuronal and chemical substrates. Trends Pharmacol Sci. 2005 Nov;26(11):578-86. doi: 10.1016/j.tips.2005.09.009. PubMed PMID: 16183137.
32. Saper CB, Fuller PM, Pedersen NP, et al. Sleep state switching. Neuron. 2010 Dec 22;68(6):1023-42. doi: S0896-6273(10)00974-8 [pii] 10.1016/j.neuron.2010.11.032. PubMed PMID: 21172606; PubMed Central PMCID: PMC3026325. eng.
33. Accorroni A, Criscuolo C, Sabatini M, et al. 3-iodothyronamine and trace amine-associated receptor 1 are involved in the expression of long-term potentiation in mouse enthorhinal cortex. [abstract]. Eur Thyroid J. 2016;5(1):21-22.
34. Hoefig CS, Zucchi R, Kohrle J. Thyronamines and Derivatives: Physiological Relevance, Pharmacological Actions, and Future Research Directions. Thyroid. 2016 Dec;26(12):1656-1673. doi: 10.1089/thy.2016.0178. PubMed PMID: 27650974.* Comprehensive review of thyronamine biology.
35. Hart ME, Suchland KL, Miyakawa M, et al. Trace amine-associated receptor agonists: synthesis and evaluation of thyronamines and related analogues. J Med Chem. 2006 Feb 9;49(3):1101-12. doi: 10.1021/jm0505718. PubMed PMID: 16451074.
36. Tan ES, Miyakawa M, Bunzow JR, et al. Exploring the structure-activity relationship of the ethylamine portion of 3-iodothyronamine for rat and mouse trace amine-associated receptor 1. J Med Chem. 2007 Jun 14;50(12):2787-98. doi: 10.1021/jm0700417. PubMed PMID: 17497842.
37. Chiellini G, Nesi G, Digiacomo M, et al. Design, Synthesis, and Evaluation of Thyronamine Analogues as Novel Potent Mouse Trace Amine Associated Receptor
1 (mTAAR1) Agonists. J Med Chem. 2015 Jun 25;58(12):5096-107. doi: 10.1021/acs.jmedchem.5b00526. PubMed PMID: 26010728.
38. Chiellini G, Nesi G, Sestito S, et al. Hit-to-Lead Optimization of Mouse Trace Amine Associated Receptor 1 (mTAAR1) Agonists with a Diphenylmethane-Scaffold: Design, Synthesis, and Biological Study. J Med Chem. 2016 Nov 10;59(21):9825-9836. doi: 10.1021/acs.jmedchem.6b01092. PubMed PMID: 27731647.
39. Chiellini G, Bellusci L, Sabatini M, et al. Thyronamines and Analogues - The Route from Rediscovery to Translational Research on Thyronergic Amines. Mol Cell Endocrinol. 2017 Dec 15;458:149-155. doi: 10.1016/j.mce.2017.01.002. PubMed PMID: 28069535.
40. Boulton AA. Some aspects of basic psychopharmacology: the trace amines [Research Support, Non-U.S. Gov't]. Progress in neuro-psychopharmacology & biological psychiatry. 1982;6(4-6):563-70. PubMed PMID: 6298892; eng.
41. Davis BA. Biogenic amines and their metabolites in body fluids of normal, psychiatric and neurological subjects [Research Support, Non-U.S. Gov't Review]. Journal of chromatography. 1989 Apr 19;466:89-218. PubMed PMID: 2663901; eng.
42. Potkin SG, Karoum F, Chuang LW, et al. Phenylethylamine in paranoid chronic schizophrenia. Science. 1979 Oct 26;206(4417):470-1. PubMed PMID: 504988; eng.
43. Davis BA, Boulton AA. The trace amines and their acidic metabolites in depression--an overview [Research Support, Non-U.S. Gov't Review]. Progress in neuro-psychopharmacology & biological psychiatry. 1994 Jan;18(1):17-45. PubMed PMID: 8115671; eng.
44. Sandler M, Ruthven CR, Goodwin BL, et al. Decreased cerebrospinal fluid concentration of free phenylacetic acid in depressive illness [Comparative Study]. Clinica chimica acta; international journal of clinical chemistry. 1979 Apr 2;93(1):169-71. PubMed PMID: 436296; eng.
45. Szabo A, Billett E, Turner J. Phenylethylamine, a possible link to the antidepressant effects of exercise? [Clinical Trial]. British journal of sports medicine. 2001 Oct;35(5):342-3. PubMed PMID: 11579070; PubMed Central PMCID: PMC1724404. eng.
46. Beaulieu JM, Gainetdinov RR. The physiology, signaling, and pharmacology of DA receptors. Pharmacol Rev. 2011 Mar;63(1):182-217. doi: 10.1124/pr.110.002642. PubMed PMID: 21303898.* Comprehensive review of DA receptor signaling, including relation to mental illness.
47. Berry MD. Mammalian central nervous system trace amines. Pharmacologic amphetamines, physiologic neuromodulators. J Neurochem. 2004 Jul;90(2):257-71. doi: 10.1111/j.1471-4159.2004.02501.x. PubMed PMID: 15228583.
48. Di Cara B, Maggio R, Aloisi G, et al. Genetic deletion of trace amine 1 receptors reveals their role in auto-inhibiting the actions of ecstasy (MDMA). J Neurosci. 2011 Nov 23;31(47):16928-40. doi: 10.1523/JNEUROSCI.2502-11.2011. PubMed PMID: 22114263.
49. Lindemann L, Meyer CA, Jeanneau K, et al. Trace amine-associated receptor 1 modulates dopaminergic activity. J Pharmacol Exp Ther. 2008 Mar;324(3):948-56. doi: 10.1124/jpet.107.132647. PubMed PMID: 18083911.* Shows that TAAR1 deletion leads to dysregulated DA signaling and psychostimulant responses.
50. Wolinsky TD, Swanson CJ, Smith KE, et al. The Trace Amine 1 receptor knockout mouse: an animal model with relevance to schizophrenia. Genes Brain Behav. 2007 Oct;6(7):628-39. doi: 10.1111/j.1601-183X.2006.00292.x. PubMed PMID: 17212650.* Shows that TAAR1 deletion elicits schizophrenia-relevant phenotypes.
51. Seeman P. DA D2 receptors as treatment targets in schizophrenia. Clin Schizophr Relat Psychoses. 2010 Apr;4(1):56-73. doi: 10.3371/CSRP.4.1.5. PubMed PMID: 20643630.
52. Zetterstrom T, Sharp T, Marsden CA, et al. In vivo measurement of DA and its metabolites by intracerebral dialysis: changes after d-amphetamine. J Neurochem. 1983 Dec;41(6):1769-73. PubMed PMID: 6196446.
53. Zhuang X, Oosting RS, Jones SR, et al. Hyperactivity and impaired response habituation in hyperdopaminergic mice. Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1982-7. doi: 10.1073/pnas.98.4.1982. PubMed PMID: 11172062; PubMed Central PMCID: PMCPMC29368.
54. Groves PM, Rebec GV. Biochemistry and behavior: some central actions of amphetamine and antipsychotic drugs. Annu Rev Psychol. 1976;27:91-127. doi: 10.1146/annurev.ps.27.020176.000515. PubMed PMID: 773267.
55. Lipska BK, Weinberger DR. To model a psychiatric disorder in animals: schizophrenia as a reality test. Neuropsychopharmacology. 2000 Sep;23(3):223-39. doi: 10.1016/S0893-133X(00)00137-8. PubMed PMID: 10942847.
56. Panas HN, Lynch LJ, Vallender EJ, et al. Normal thermoregulatory responses to 3-iodothyronamine, trace amines and amphetamine-like psychostimulants in trace amine associated receptor 1 knockout mice. J Neurosci Res. 2010 Jul;88(9):1962-9. doi: 10.1002/jnr.22367. PubMed PMID: 20155805; PubMed Central PMCID: PMCPMC3587846.
57. Achat-Mendes C, Lynch LJ, Sullivan KA, et al. Augmentation of methamphetamine-induced behaviors in transgenic mice lacking the trace amine-associated receptor 1. Pharmacol Biochem Behav. 2012 Apr;101(2):201-7. doi: 10.1016/j.pbb.2011.10.025. PubMed PMID: 22079347; PubMed Central PMCID: PMCPMC3288391.
58. Sotnikova TD, Zorina OI, Ghisi V, et al. Trace amine associated receptor 1 and movement control. Parkinsonism Relat Disord. 2008;14 Suppl 2:S99-102. doi: 10.1016/j.parkreldis.2008.04.006. PubMed PMID: 18585080.
59. Espinoza S, Ghisi V, Emanuele M, et al. Postsynaptic D2 DA receptor supersensitivity in the striatum of mice lacking TAAR1. Neuropharmacology. 2015 Jun;93:308-13. doi: 10.1016/j.neuropharm.2015.02.010. PubMed PMID: 25721394.
60. Sukhanov I, Caffino L, Efimova EV, et al. Increased context-dependent conditioning to amphetamine in mice lacking TAAR1. Pharmacol Res. 2016 Jan;103:206-14. doi: 10.1016/j.phrs.2015.11.002. PubMed PMID: 26640076.
61. Revel FG, Meyer CA, Bradaia A, et al. Brain-specific overexpression of trace amine-associated receptor 1 alters monoaminergic neurotransmission and decreases sensitivity to amphetamine. Neuropsychopharmacology. 2012 Nov;37(12):2580-92. doi: 10.1038/npp.2012.109. PubMed PMID: 22763617; PubMed Central PMCID: PMCPMC3473323.
62. Leo D, Sukhanov I, Zoratto F, et al. Pronounced Hyperactivity, Cognitive Dysfunctions and Bdnf Dysregulation in DA Transporter Knockout Rats. J Neurosci. 2018 Jan 18. doi: 10.1523/JNEUROSCI.1931-17.2018. PubMed PMID: 29348190.
63. Danysz W, Essmann U, Bresink I, et al. Glutamate antagonists have different effects on spontaneous locomotor activity in rats. Pharmacol Biochem Behav. 1994 May;48(1):111-8. PubMed PMID: 8029281.
64. Ford LM, Norman AB, Sanberg PR. The topography of MK-801-induced locomotor patterns in rats. Physiol Behav. 1989 Oct;46(4):755-8. PubMed PMID: 2557649.
65. Gleason SD, Shannon HE. Blockade of phencyclidine-induced hyperlocomotion by olanzapine, clozapine and 5-HT receptor subtype selective antagonists in mice. Psychopharmacology (Berl). 1997 Jan;129(1):79-84. PubMed PMID: 9122367.
66. Harkness JH, Shi X, Janowsky A, et al. Trace Amine-Associated Receptor 1 Regulation of Methamphetamine Intake and Related Traits. Neuropsychopharmacology. 2015 Aug;40(9):2175-84. doi: 10.1038/npp.2015.61. PubMed PMID: 25740289; PubMed Central PMCID: PMCPMC4613607.
67. Jing L, Li JX. Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction. Eur J Pharmacol. 2015 Aug 15;761:345-52. doi: 10.1016/j.ejphar.2015.06.019. PubMed PMID: 26092759; PubMed Central PMCID: PMCPMC4532615.
68. Thorn DA, Zhang C, Zhang Y, et al. The trace amine associated receptor 1 agonist RO5263397 attenuates the induction of cocaine behavioral sensitization in rats. Neurosci Lett. 2014 Apr 30;566:67-71. doi: 10.1016/j.neulet.2014.02.024. PubMed PMID: 24561093; PubMed Central PMCID: PMCPMC3991844.
69. Sukhanov I, Espinoza S, Yakovlev DS, et al. TAAR1-dependent effects of apomorphine in mice. Int J Neuropsychopharmacol. 2014 Oct;17(10):1683-93. doi: 10.1017/S1461145714000509. PubMed PMID: 24925023.
70. Costall B, Naylor RJ, Nohria V. Climbing behaviour induced by apomorphine in mice: a potential model for the detection of neuroleptic activity. Eur J Pharmacol. 1978 Jul 1;50(1):39-50. PubMed PMID: 28233.
71. Protais P, Costentin J, Schwartz JC. Climbing behavior induced by apomorphine in mice: a simple test for the study of DA receptors in striatum. Psychopharmacology (Berl). 1976 Oct 20;50(1):1-6. PubMed PMID: 827755.
72. Puech AJ, Simon P, Boissier JR. Antagonism by sulpiride of three apomorphine-induced effects in rodents. Eur J Pharmacol. 1976 Apr;36(2):439-41. PubMed PMID: 945169.
73. Sharma T, Antonova L. Cognitive function in schizophrenia. Deficits, functional consequences, and future treatment. Psychiatr Clin North Am. 2003 Mar;26(1):25-40. PubMed PMID: 12683258.
74. Geyer MA, Krebs-Thomson K, Braff DL, et al. Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology (Berl). 2001 Jul;156(2-3):117-54. PubMed PMID: 11549216.
75. Alvarsson A, Zhang X, Stan TL, et al. Modulation by Trace Amine-Associated Receptor 1 of Experimental Parkinsonism, L-DOPA Responsivity, and Glutamatergic Neurotransmission. J Neurosci. 2015 Oct 14;35(41):14057-69. doi: 10.1523/JNEUROSCI.1312-15.2015. PubMed PMID: 26468205.
76. Sotnikova TD, Beaulieu JM, Barak LS, et al. DA-independent locomotor actions of amphetamines in a novel acute mouse model of Parkinson disease. PLoS Biol. 2005 Aug;3(8):e271. doi: 10.1371/journal.pbio.0030271. PubMed PMID: 16050778; PubMed Central PMCID: PMCPMC1181539.
77. Cheon KA, Ryu YH, Kim YK, et al. DA transporter density in the basal ganglia assessed with [123I]IPT SPET in children with attention deficit hyperactivity disorder. Eur J Nucl Med Mol Imaging. 2003 Feb;30(2):306-11. doi: 10.1007/s00259-002-1047-3. PubMed PMID: 12552351.
78. DiMaio S, Grizenko N, Joober R. DA genes and attention-deficit hyperactivity disorder: a review. J Psychiatry Neurosci. 2003 Jan;28(1):27-38. PubMed PMID: 12587848; PubMed Central PMCID: PMCPMC161723.
79. Dougherty DD, Bonab AA, Spencer TJ, et al. DA transporter density in patients with attention deficit hyperactivity disorder. Lancet. 1999 Dec 18-25;354(9196):2132-3. doi: 10.1016/S0140-6736(99)04030-1. PubMed PMID: 10609822.
80. Leo D, Gainetdinov RR. Transgenic mouse models for ADHD. Cell Tissue Res. 2013 Oct;354(1):259-71. doi: 10.1007/s00441-013-1639-1. PubMed PMID: 23681253; PubMed Central PMCID: PMCPMC3785710.
81. Gainetdinov RR, Mohn AR, Bohn LM, et al. Glutamatergic modulation of hyperactivity in mice lacking the DA transporter. Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11047-54. doi: 10.1073/pnas.191353298. PubMed PMID: 11572967; PubMed Central PMCID: PMCPMC58681.
82. Giros B, Jaber M, Jones SR, et al. Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the DA transporter. Nature. 1996 Feb 15;379(6566):606-12. doi: 10.1038/379606a0. PubMed PMID: 8628395.
83. Gainetdinov RR, Wetsel WC, Jones SR, et al. Role of 5-HT in the paradoxical calming effect of psychostimulants on hyperactivity. Science. 1999 Jan 15;283(5400):397-401. PubMed PMID: 9888856.
84. Espinoza S, Lignani G, Caffino L, et al. TAAR1 Modulates Cortical Glutamate NMDA Receptor Function. Neuropsychopharmacology. 2015 Aug;40(9):2217-27. doi: 10.1038/npp.2015.65. PubMed PMID: 25749299; PubMed Central PMCID: PMCPMC4613611.* Study showing TAAR1's role in controlling response of NMDA receptors.
85. Kellner M. Drug treatment of obsessive-compulsive disorder. Dialogues Clin Neurosci. 2010;12(2):187-97. PubMed PMID: 20623923; PubMed Central PMCID: PMCPMC3181958.
86. Koo MS, Kim EJ, Roh D, et al. Role of DA in the pathophysiology and treatment of obsessive-compulsive disorder. Expert Rev Neurother. 2010 Feb;10(2):275-90. doi: 10.1586/ern.09.148. PubMed PMID: 20136383.
87. Dolgorukova A, Dorotenko A, Mus L, et al. Activation of trace amine-associated receptor 1 reduces schedule-induced polydipsia in rats. European Neuropsychopharmacology. 2017 Oct;27:S673-S673. PubMed PMID: WOS:000413847701074; English.
88. Ferragud A, Howell AD, Moore CF, et al. The Trace Amine-Associated Receptor 1 Agonist RO5256390 Blocks Compulsive, Binge-like Eating in Rats. Neuropsychopharmacology. 2017 Jun;42(7):1458-1470. doi: 10.1038/npp.2016.233. PubMed PMID: 27711047; PubMed Central PMCID: PMCPMC5436108.
89. Can A, Dao DT, Arad M, et al. The mouse forced swim test. J Vis Exp. 2012 Jan 29(59):e3638. doi: 10.3791/3638. PubMed PMID: 22314943; PubMed Central PMCID: PMCPMC3353513.
90. Ashok AH, Marques TR, Jauhar S, et al. The DA hypothesis of bipolar affective disorder: the state of the art and implications for treatment. Mol Psychiatry. 2017 May;22(5):666-679. doi: 10.1038/mp.2017.16. PubMed PMID: 28289283; PubMed Central PMCID: PMCPMC5401767.
91. Kampman KM. What's new in the treatment of cocaine addiction? Curr Psychiatry Rep. 2010 Oct;12(5):441-7. doi: 10.1007/s11920-010-0143-5. PubMed PMID: 20697850.
92. Penberthy JK, Ait-Daoud N, Vaughan M, et al. Review of treatment for cocaine dependence. Curr Drug Abuse Rev. 2010 Mar;3(1):49-62. PubMed PMID: 20088819.
93. Lin Z, Canales JJ, Bjorgvinsson T, et al. Monoamine transporters: vulnerable and vital doorkeepers. Prog Mol Biol Transl Sci. 2011;98:1-46. doi: 10.1016/B978-0-12-385506-0.00001-6. PubMed PMID: 21199769; PubMed Central PMCID: PMCPMC3321928.
94. Velazquez-Sanchez C, Canales JJ. Atypical DA transporter inhibitors: candidates for the treatment of psychostimulant addiction. In: Emerging Targets for Drug
Addiction Treatment (Juan J Canales, ed), Nova Publishers, New York. 2012 Jul 1:pp. 103-150. doi: 10.1016/j.pnpbp.2013.01.016 S0278-5846(13)00018-3 [pii]. PubMed PMID: 23385166; eng.
95. Pei Y, Lee J, Leo D, et al. Activation of the trace amine-associated receptor 1 prevents relapse to cocaine seeking. Neuropsychopharmacology. 2014;39(10):2299-2308.
96. Pei Y, Asif-Malik A, Hoener M, et al. A partial trace amine-associated receptor 1 agonist exhibits properties consistent with a methamphetamine substitution treatment. Addict Biol. 2017 Sep;22(5):1246-1256. doi: 10.1111/adb.12410. PubMed PMID: 27193165.
97. Marinelli M, White FJ. Enhanced vulnerability to cocaine self-administration is associated with elevated impulse activity of midbrain DA neurons. J Neurosci. 2000 Dec 1;20(23):8876-85. PubMed PMID: 11102497.
98. McCutcheon JE, White FJ, Marinelli M. Individual differences in DA cell neuroadaptations following cocaine self-administration. Biol Psychiatry. 2009 Oct 15;66(8):801-3. doi: 10.1016/j.biopsych.2009.04.018. PubMed PMID: 19539267; PubMed Central PMCID: PMCPMC2767203.
99. Cotter R, Pei Y, Mus L, et al. The trace amine-associated receptor 1 modulates methamphetamine's neurochemical and behavioral effects. Frontiers in neuroscience. 2015;9.
100. Jing L, Zhang Y, Li J-X. Effects of the trace amine associated receptor 1 agonist RO5263397 on abuse-related behavioral indices of methamphetamine in rats. International Journal of Neuropsychopharmacology. 2014:pyu060.
101. Thorn DA, Jing L, Qiu Y, et al. Effects of the trace amine-associated receptor 1 agonist ro5263397 on abuse-related effects of cocaine in rats. Neuropsychopharmacology. 2014.
102. Pei Y, Mortas P, Hoener MC, et al. Selective activation of the trace amine-associated receptor 1 decreases cocaine's reinforcing efficacy and prevents cocaine-induced changes in brain reward thresholds. Progress in neuro-psychopharmacology & biological psychiatry. 2015 Dec 3;63:70-5. doi: 10.1016/j.pnpbp.2015.05.014. PubMed PMID: 26048337.
103. Xie Z, Miller GM. Trace amine-associated receptor 1 is a modulator of the DA transporter. J Pharmacol Exp Ther. 2007 Apr;321(1):128-36. doi: jpet.106.117382 [pii] 10.1124/jpet.106.117382. PubMed PMID: 17234899; eng.
104. Miller GM, Verrico CD, Jassen A, et al. Primate trace amine receptor 1 modulation by the DA transporter. Journal of Pharmacology and Experimental Therapeutics. 2005;313(3):983-994.
105. Harmeier A, Obermueller S, Meyer CA, et al. Trace amine-associated receptor 1 activation silences GSK3β signaling of TAAR1 and D2R heteromers. European Neuropsychopharmacology. 2015.
106. Xu CM, Wang J, Wu P, et al. Glycogen synthase kinase 3beta in the nucleus accumbens core mediates cocaine-induced behavioral sensitization. J Neurochem. 2009 Dec;111(6):1357-68. doi: 10.1111/j.1471-4159.2009.06414.x. PubMed PMID: 19799712.
107. Shi X, Miller JS, Harper LJ, et al. Reactivation of cocaine reward memory engages the Akt/GSK3/mTOR signaling pathway and can be disrupted by GSK3 inhibition. Psychopharmacology (Berl). 2014 Aug;231(16):3109-18. doi: 10.1007/s00213-014-3491-8. PubMed PMID: 24595501; PubMed Central PMCID: PMCPMC4110417.
108. Xue Z, Siemian JN, Johnson BN, et al. Methamphetamine-induced impulsivity during chronic methamphetamine treatment in rats: Effects of the TAAR 1 agonist
RO5263397. Neuropharmacology. 2018 Feb;129:36-46. doi: 10.1016/j.neuropharm.2017.11.012. PubMed PMID: 29128305.
109. Daley M, Morin CM, LeBlanc M, et al. The economic burden of insomnia: direct and indirect costs for individuals with insomnia syndrome, insomnia symptoms, and good sleepers. Sleep. 2009 Jan;32(1):55-64. PubMed PMID: 19189779; PubMed Central PMCID: PMCPMC2625324.
110. Hillman DR, Murphy AS, Pezzullo L. The economic cost of sleep disorders. Sleep. 2006 Mar;29(3):299-305. PubMed PMID: 16553015.
111. Wulff K, Dijk DJ, Middleton B, et al. Sleep and circadian rhythm disruption in schizophrenia. Br J Psychiatry. 2012 Apr;200(4):308-16. doi: 10.1192/bjp.bp.111.096321. PubMed PMID: 22194182; PubMed Central PMCID: PMCPMC3317037.
112. Happe S, Baier PC, Helmschmied K, et al. Association of daytime sleepiness with nigrostriatal dopaminergic degeneration in early Parkinson's disease. J Neurol. 2007 Aug;254(8):1037-43. doi: 10.1007/s00415-006-0483-6. PubMed PMID: 17351722.
113. Rye DB. Parkinson's disease and RLS: the dopaminergic bridge. Sleep Med. 2004 May;5(3):317-28. doi: 10.1016/j.sleep.2004.01.016. PubMed PMID: 15165542.
114. Brower KJ. Alcohol's effects on sleep in alcoholics. Alcohol Res Health. 2001;25(2):110-25. PubMed PMID: 11584550; PubMed Central PMCID: PMCPMC2778757.
115. Brower KJ, Perron BE. Sleep disturbance as a universal risk factor for relapse in addictions to psychoactive substances. Med Hypotheses. 2010 May;74(5):928-33. doi: 10.1016/j.mehy.2009.10.020. PubMed PMID: 19910125; PubMed Central PMCID: PMCPMC2850945.
116. Scammell TE, Arrigoni E, Lipton JO. Neural Circuitry of Wakefulness and Sleep. Neuron. 2017 Feb 22;93(4):747-765. doi: 10.1016/j.neuron.2017.01.014. PubMed PMID: 28231463; PubMed Central PMCID: PMCPMC5325713.
117. Schwartz MD, Black SW, Fisher SP, et al. Trace Amine-Associated Receptor 1 Regulates Wakefulness and EEG Spectral Composition. Neuropsychopharmacology. 2017 May;42(6):1305-1314. doi: 10.1038/npp.2016.216. PubMed PMID: 27658486; PubMed Central PMCID: PMCPMC5437878.* Shows that endogenous TAAR1 signaling regulates arousal state.
118. Wisor JP, Nishino S, Sora I, et al. Dopaminergic role in stimulant-induced wakefulness. J Neurosci. 2001 Mar 01;21(5):1787-94. PubMed PMID: 11222668.
119. Eban-Rothschild A, Rothschild G, Giardino WJ, et al. VTA dopaminergic neurons regulate ethologically relevant sleep-wake behaviors. Nat Neurosci. 2016 Oct;19(10):1356-66. doi: 10.1038/nn.4377. PubMed PMID: 27595385; PubMed Central PMCID: PMCPMC5519826.
120. Cho JR, Treweek JB, Robinson JE, et al. Dorsal Raphe DA Neurons Modulate Arousal and Promote Wakefulness by Salient Stimuli. Neuron. 2017 Jun 21;94(6):1205-1219 e8. doi: 10.1016/j.neuron.2017.05.020. PubMed PMID: 28602690.
121. McGinty DJ, Harper RM. Dorsal raphe neurons: depression of firing during sleep in cats. Brain Res. 1976 Jan 23;101(3):569-75. PubMed PMID: 1244990.
122. Morairty SR, Hedley L, Flores J, et al. Selective 5-HT2A and 5-HT6 receptor antagonists promote sleep in rats. Sleep. 2008 Jan;31(1):34-44. PubMed PMID: 18220076; PubMed Central PMCID: PMCPMC2225549.
123. Aston-Jones G, Bloom FE. Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle. J Neurosci. 1981 Aug;1(8):876-86. PubMed PMID: 7346592.
124. Brown RE, McKenna JT. Turning a Negative into a Positive: Ascending GABAergic Control of Cortical Activation and Arousal. Front Neurol. 2015;6:135. doi: 10.3389/fneur.2015.00135. PubMed PMID: 26124745; PubMed Central PMCID: PMCPMC4463930.
125. Ferris MJ, Espana RA, Locke JL, et al. DA transporters govern diurnal variation in extracellular DA tone. Proc Natl Acad Sci U S A. 2014 Jul 01;111(26):E2751-9. doi: 10.1073/pnas.1407935111. PubMed PMID: 24979798; PubMed Central PMCID: PMCPMC4084435.
126. Cape EG, Jones BE. Differential modulation of high-frequency gamma-electroencephalogram activity and sleep-wake state by noradrenaline and 5-HT microinjections into the region of cholinergic basalis neurons. J Neurosci. 1990;18(7):2653-66.
127. Vertes RP, Kocsis B. Brainstem-diencephalo-septohippocampal systems controlling the theta rhythm of the hippocampus. Neuroscience. 1997 Dec;81(4):893-926. PubMed PMID: 9330355.
128. Feinberg I, Schoepp DD, Hsieh KC, et al. The metabotropic glutamate (mGLU)2/3 receptor antagonist LY341495 [2S-2-amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-yl)propanoic acid] stimulates waking and fast electroencephalogram power and blocks the effects of the mGLU2/3 receptor agonist ly379268 [(-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate] in rats. J Pharmacol Exp Ther. 2005 Feb;312(2):826-33. doi: 10.1124/jpet.104.076547. PubMed PMID: 15383637.
129. Ahnaou A, de Boer P, Lavreysen H, et al. Translational neurophysiological markers for activity of the metabotropic glutamate receptor (mGluR2) modulator JNJ-40411813: Sleep EEG correlates in rodents and healthy men. Neuropharmacology. 2016 Apr;103:290-305. doi: 10.1016/j.neuropharm.2015.11.031. PubMed PMID: 26686390.
130. Gilmour G, Broad LM, Wafford KA, et al. In vitro characterisation of the novel positive allosteric modulators of the mGlu(5) receptor, LSN2463359 and LSN2814617, and their effects on sleep architecture and operant responding in the rat. Neuropharmacology. 2013 Jan;64:224-39. doi: 10.1016/j.neuropharm.2012.07.030. PubMed PMID: 22884720.
131. Ahnaou A, Langlois X, Steckler T, et al. Negative versus positive allosteric modulation of metabotropic glutamate receptors (mGluR5): indices for potential pro-cognitive drug properties based on EEG network oscillations and sleep-wake organization in rats. Psychopharmacology (Berl). 2015 Mar;232(6):1107-22. doi: 10.1007/s00213-014-3746-4. PubMed PMID: 25323624.
132. Lindemann L, Porter RH, Scharf SH, et al. Pharmacology of basimglurant (RO4917523, RG7090), a unique metabotropic glutamate receptor 5 negative allosteric modulator in clinical development for depression. J Pharmacol Exp Ther. 2015 Apr;353(1):213-33. doi: 10.1124/jpet.114.222463. PubMed PMID: 25665805.
133. Black SW, Schwartz MD, Chen TM, et al. Trace Amine-Associated Receptor 1 Agonists as Narcolepsy Therapeutics. Biol Psychiatry. 2017 Nov 1;82(9):623-633. doi: 10.1016/j.biopsych.2016.10.012. PubMed PMID: 27919403; PubMed Central PMCID: PMCPMC5395352.* Demonstrates eficacy of TAAR1 agonism in preclinical models of narcolepsy.
134. Borbely AA. A two process model of sleep regulation. Hum Neurobiol. 1982;1(3):195-204. PubMed PMID: 7185792.
135. Mistlberger RE. Circadian regulation of sleep in mammals: role of the suprachiasmatic nucleus. Brain Res Brain Res Rev. 2005 Nov;49(3):429-54. doi: 10.1016/j.brainresrev.2005.01.005. PubMed PMID: 16269313.
136. Lena I, Parrot S, Deschaux O, et al. Variations in extracellular levels of DA, noradrenaline, glutamate, and aspartate across the sleep--wake cycle in the medial prefrontal cortex and nucleus accumbens of freely moving rats. J Neurosci Res. 2005 Sep 15;81(6):891-9. doi: 10.1002/jnr.20602. PubMed PMID: 16041801.
137. Dahan L, Astier B, Vautrelle N, et al. Prominent burst firing of dopaminergic neurons in the ventral tegmental area during paradoxical sleep. Neuropsychopharmacology. 2007 Jun;32(6):1232-41. doi: 10.1038/sj.npp.1301251. PubMed PMID: 17151599.
138. Xie Z, Miller GM. Beta-phenylethylamine alters monoamine transporter function via trace amine-associated receptor 1: implication for modulatory roles of trace amines in brain. J Pharmacol Exp Ther. 2008 May;325(2):617-28. doi: 10.1124/jpet.107.134247. PubMed PMID: 18182557.
139. Xie Z, Westmoreland SV, Miller GM. Modulation of monoamine transporters by common biogenic amines via trace amine-associated receptor 1 and monoamine autoreceptors in human embryonic kidney 293 cells and brain synaptosomes. J Pharmacol Exp Ther. 2008 May;325(2):629-40. doi: 10.1124/jpet.107.135079. PubMed PMID: 18310473.
140. Boutrel B, Franc B, Hen R, et al. Key role of 5-HT1B receptors in the regulation of paradoxical sleep as evidenced in 5-HT1B knock-out mice. J Neurosci. 1999;19(8):3204-12.
141. Boutrel B, Monaca C, Hen R, et al. Involvement of 5-HT1A receptors in homeostatic and stress-induced adaptive regulations of paradoxical sleep: studies in 5-HT1A knock-out mice. J Neurosci. 2002 Jun 1;22(11):4686-92. doi: 20026427. PubMed PMID: 12040075.
142. Monti JM, Monti D, Jantos H, et al. Effects of selective activation of the 5-HT1B receptor with CP-94,253 on sleep and wakefulness in the rat. Neuropharmacology. 1995 Dec;34(12):1647-51. PubMed PMID: 8788962.
143. Chemelli RM, Willie JT, Sinton CM, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell. 1999 Aug 20;98(4):437-51. PubMed PMID: 10481909.
144. Thannickal TC, Moore RY, Nienhuis R, et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron. 2000 Sep;27(3):469-74. PubMed PMID: 11055430.
145. Nishino S, Ripley B, Overeem S, et al. Hypocretin (orexin) deficiency in human narcolepsy. Lancet. 2000 Jan 1;355(9197):39-40. doi: 10.1016/S0140-6736(99)05582-8.
146. Black SW, Yamanaka A, Kilduff TS. Challenges in the development of therapeutics for narcolepsy. Prog Neurobiol. 2017 May;152:89-113. doi: 10.1016/j.pneurobio.2015.12.002. PubMed PMID: 26721620; PubMed Central PMCID: PMCPMC5114175.
147. Hara J, Beuckmann CT, Nambu T, et al. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron. 2001 May;30(2):345-54. PubMed PMID: 11394998.
148. Tabuchi S, Tsunematsu T, Black SW, et al. Conditional ablation of orexin/hypocretin neurons: a new mouse model for the study of narcolepsy and orexin system function. J Neurosci. 2014 May 07;34(19):6495-509. doi: 10.1523/JNEUROSCI.0073-14.2014. PubMed PMID: 24806676; PubMed Central PMCID: PMCPMC4012309.
149. Burgess CR, Peever JH. A noradrenergic mechanism functions to couple motor behavior with arousal state. Curr Biol. 2013 Sep 23;23(18):1719-25. doi: 10.1016/j.cub.2013.07.014. PubMed PMID: 23993842.
150. Hasegawa E, Maejima T, Yoshida T, et al. 5-HT neurons in the dorsal raphe mediate the anticataplectic action of orexin neurons by reducing amygdala activity. Proc
Natl Acad Sci U S A. 2017 Apr 25;114(17):E3526-E3535. doi: 10.1073/pnas.1614552114. PubMed PMID: 28396432; PubMed Central PMCID: PMCPMC5410844.
151. Hasegawa E, Yanagisawa M, Sakurai T, et al. Orexin neurons suppress narcolepsy via 2 distinct efferent pathways. J Clin Invest. 2014 Feb;124(2):604-16. doi: 10.1172/JCI71017. PubMed PMID: 24382351; PubMed Central PMCID: PMCPMC3904620.
152. Burgess CR, Tse G, Gillis L, et al. Dopaminergic regulation of sleep and cataplexy in a murine model of narcolepsy. Sleep. 2010 Oct;33(10):1295-304. PubMed PMID: 21061851; PubMed Central PMCID: PMCPMC2941415.
153. Dinter J, Muhlhaus J, Wienchol CL, et al. Inverse agonistic action of 3-iodothyronamine at the human trace amine-associated receptor 5. PLoS One. 2015;10(2):e0117774. doi: 10.1371/journal.pone.0117774. PubMed PMID: 25706283; PubMed Central PMCID: PMCPMC4382497.