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Cited by 166Neurotransmitter Receptor Influence on BehaviorNeuroscience and Neuropharmacology ResearchReceptor Mechanisms and Signaling

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

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Rutigliano, Grazia, Accorroni, Alice, Zucchi, Riccardo·2018·Frontiers in Pharmacology
DOI 10.3389/fphar.2017.00987PMC PMC5767590
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Abstract

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

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  • TAAR1 activation leads to intracellular cAMP signalling that results in PKA and PKC phosphorylation and activation.

    “TAAR1 activation leads to intracellular cAMP signalling that results in PKA and PKC phosphorylation and activation [178–180].”

    From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [180]

    The Receptor Pharmacology section (page unavailable) reports that TAAR1 agonists activate intracellular pathways leading to cAMP production. The paper does not say that this results in phosphorylation and activation of PKA and PKC; its Conclusion also cautions that TAAR1 can signal through other pathways. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Rutigliano, G., Accorroni, A., & Zucchi, R.
Affiliations
  • Scuola Superiore Sant'Anna (IT)
  • University of Pisa (IT)
Corresponding author
Zucchi, Riccardo
ORCID
Venue
Frontiers in Pharmacology
Publisher
Frontiers Media SA
Published
2018-01-10
Volume
8
Pages
987-987
ISSN
1663-9812 (ISSN-L)
DOI
10.3389/fphar.2017.00987
PMC
PMC5767590
OpenAlex
W2783313812
Cited by
166
References
2
Citations by year
2026: 16 · 2025: 22 · 2024: 21 · 2023: 23 · 2022: 22 · 2021: 20 · 2020: 20 · 2019: 17 · 2018: 4
FWCI
1.98
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Pharmacology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords
TAAR1, trace amine-associated receptors, 3-iodothyronamine, trace amines, neuromodulation, tyramine, phenylethylamine, monoaminergic neurotransmission, anxiety, working memory, ethanol addiction, amphetamine response, schizophrenia susceptibility, bipolar disorder, single nucleotide polymorphisms

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