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Stimulants and psychedelics
Published in Ilana B. Crome, Richard Williams, Roger Bloor, Xenofon Sgouros, Substance Misuse and Young People, 2019
All amphetamines have been identified as potent full agonists of trace amine-associated receptor 1 (TAAR-1) (Miller, 2011), which is important in the regulation of brain monoamines. Notably, amphetamines bind to TAAR-1 but not monoamine auto-receptors (e.g., D2 short, presynaptic α2, and presynaptic 5-HT1A) (ibid.; Grandy et al., 2016). Amphetamines exert their action primarily in the reward and executive function pathways of the brain; their administration results in the release of newly synthesised norepinephrine and dopamine (Bidwell et al., 2011; Miller, 2011), due to inhibition of the monoamine transporter function. This is in contrast to other types of stimulants, such as methylphenidate and cocaine, which act through storage pools of catecholamines (Borowsky et al., 2001; Eiden and Weihe, 2011; Miller, 2011). In addition, high doses of amphetamines release 5-hydroxytryptamine and may affect serotonergic neurons (Miller, 2011).
Efficacy, safety, and tolerability of ulotaront (SEP-363856, a trace amine-associated receptor 1 agonist) for the treatment of schizophrenia and other mental disorders: a systematic review of preclinical and clinical trials
Published in Expert Opinion on Investigational Drugs, 2023
Gia Han Le, Emily S. Gillissie, Taeho Greg Rhee, Bing Cao, Yazen Alnefeesi, Ziji Guo, Joshua D. Di Vincenzo, Muhammad Youshay Jawad, Andrew M. March, Ranuk Ramachandra, Leanna M.W. Lui, Roger S. McIntyre
Substantial evidence has accumulated about the trace-amine associated receptor 1 (TAAR1), a novel therapeutic target for the treatment of schizophrenia [28]. TAAR1 is a G-protein coupled receptor that is especially abundant in limbic and monoaminergic areas. TAAR1 modulates and maintains the homeostasis of serotonergic, glutamatergic, and dopaminergic systems; therefore, it is involved in the regulation of attention, memory, fear, mood, and addiction [29]. Specifically, TAAR1 activation can stimulate the Gβγ-dependent inwardly rectifying potassium channel Kir3 to induce potassium efflux. Given potassium efflux through Kir3, it is proposed that TAAR1 agonists may reduce the positive symptoms of schizophrenia by decreasing dopaminergic neuronal firing in the ventral tegmental area (Figure 1) [30,31].
Trace amine associated receptor 1 (TAAR1) modulators: a patent review (2010-present)
Published in Expert Opinion on Therapeutic Patents, 2020
Michele Tonelli, Elena Cichero
TAAR1 is a G-protein-coupled receptor (Gαs) that responds to various endogenous molecules named trace amines (TAs). TAAR1 expression is found in various organs as the stomach, pancreas, intestines and the central nervous system. In the brain, TAAR1 was found in structures associated with dopamine (ventral tegmental area) and serotonin (dorsal raphe nuclei) regulation, thus suggesting that TAAR1 has a role in the classical monoamine neurotransmitters regulation [1]. TAAR1 has low affinity for classic monoamines, while is activated with nanomolar to micromolar affinity by some endogenous amines, particularly p-tyramine, β-phenylethylamine and tryptamine which are produced by the decarboxylation of aromatic amino acids (respectively, tyrosine, phenylalanine, and tryptophan) catalyzed by the enzyme aromatic amino acid decarboxylase (AADC) [2]. TAs include some of their derivatives, namely 2-hydroxy-p-tyramine (octopamine), N-methyl-2-hydroxy-p-tyramine (synephrine), and 3-methoxy-p-tyramine [3] and also 3-iodothyronamine (T1AM) which is probably derived from the metabolism of thyroid hormones and may represent a novel branch of these hormones signaling [4].
Trace amine-associated receptor 1: a multimodal therapeutic target for neuropsychiatric diseases
Published in Expert Opinion on Therapeutic Targets, 2018
Michael D. Schwartz, Juan J. Canales, Riccardo Zucchi, Stefano Espinoza, Ilya Sukhanov, Raul R. Gainetdinov
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 intracellular 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.