عامل إطلاق مونوامين
مراجع

1 2 3 4 5  Vaughan، Roxanne A.؛ Henry، L. Keith؛ Foster، James D.؛ Brown، Christopher R. (2024). "Post-translational mechanisms in psychostimulant-induced neurotransmitter efflux". Advances in Pharmacology. Elsevier. ج. 99. ص. 1–33. DOI:10.1016/bs.apha.2023.10.003. ISBN:978-0-443-21933-7. ISSN:1054-3589. PMID:38467478. اطلع عليه بتاريخ 2025-01-19. The characteristics and mechanisms of efflux are complex and incompletely understood, and have been summarized in many comprehensive reviews including (Reith & Gnegy, 2020; Robertson, Matthies, & Galli, 2009; Sitte & Freissmuth, 2015). [...] Early studies implicating protein phosphorylation in AMPH-evoked DA efflux were performed by Giambalvo, who demonstrated that DAT-mediated uptake of AMPH impacted the activity and subcellular localization of protein kinase C (PKC) with characteristics that correlated with DA efflux (Giambalvo, 1992), and Gnegy and colleagues, whose many studies reinforced the relationship between efflux, kinases, and ionic conditions including PKC, PKCβ, Ca2+, and Ca1+-calmodulin regulated protein kinase (CaMK) (Gnegy et al., 2004; Johnson, Guptaroy, Lund, Shamban, & Gnegy, 2005; Kantor, Hewlett, & Gnegy, 1999). [...] With respect to DAT most studies have focused on PKC, CaMK, and mitogen activated protein kinases (MAPKs), but many other signaling and kinase pathways have been implicated in efflux mechanisms for all of the MATs (Bermingham & Blakely, 2016; Vaughan & Foster, 2013). [...] DAT phosphorylation stimulated by AMPH or METH also occurs on this domain and is blocked by PKC inhibitors (Cervinski et al., 2005; Karam et al., 2017), indicating the capacity of the drugs to involve the PKC pathway. How this occurs is not known, but could potentially follow from drug perturbation of local ion/Ca2+ concentrations that impact PTM enzymes, or alternatively could occur by substrate-driven induction of transporter conformations in which phosphorylation sites become more or less available to enzyme action. [...] There are many other Ser and Thr residues on DAT intracellular loops and domains that may serve as phosphorylation sites, and in vitro studies have demon- strated phosphorylation of N— and C—terminal peptide sequences by many kinases in addition to PKC, ERK, and CaMK that have been implicated in regulation and efflux including protein kinase A (PKA), protein kinase G (PKG), casein kinase 2 (CK2), p38 kinase, JNK2, Cdk5, and Akt1 (Gorentla I et al., 2009; Vaughan & Foster, 2013). [...] The regulatory, efflux, and post-translational characteristics of NET and SERT show many similarities to DAT that indicate conservation of mechanism, but also some distinct properties that reflect requirements of specific neuronal populations. [...] With respect to efflux there are many similarities between SERT, NET, and DAT that indicate conservation of mechanisms.
1 2 3  Schmitt KC، Reith ME (فبراير 2010). "Regulation of the dopamine transporter: aspects relevant to psychostimulant drugs of abuse". Ann N Y Acad Sci. ج. 1187: 316–340. DOI:10.1111/j.1749-6632.2009.05148.x. PMID:20201860. مؤرشف من الأصل في 2024-12-21. اطلع عليه بتاريخ 2025-01-19. However, another significant question remains: how might amphetaminergic substrates activate PKC in the first place? PKC activity is regulated by Ca2+ and diacylglycerol, a phospholipid metabolite generated in concert with inositol triphosphate by the enzyme phospholipase C (PLC), which is also Ca2+ dependent. [...] Usually, PLC is activated by agonist binding at GPCRs coupled to the Gq/11- type α-subunit; however, compounds, such as amphetamine and methamphetamine, lack significant affinity for GPCRs other than the trace amine-associated receptor 1 (TAAR1), a Gs-coupled receptor.74 [...] Interestingly, inhibition of the Na+/Ca2+ antiporter with amiloride also blocked amphetamine-induced PKC activation, suggesting that the ionic effects of DAT substrate translocation can directly influence activation of intracellular signaling cascades. When substrates are transported across the plasma membrane via the DAT, sodium ions are cotransported, and this increase in intracellular sodium concentration may cause Na+/Ca2+ antiporters at mitochondrial and endoplasmic reticulum membranes to operate in reverse, favoring a net flux of Ca2+ into the cytosolic compartment. [...]
↑  Bermingham DP، Blakely RD (أكتوبر 2016). "Kinase-dependent Regulation of Monoamine Neurotransmitter Transporters". Pharmacol Rev. ج. 68 ع. 4: 888–953. DOI:10.1124/pr.115.012260. PMC:5050440. PMID:27591044. مؤرشف من الأصل في 2025-01-20. اطلع عليه بتاريخ 2025-01-19.
↑  Støier JF، Konomi-Pilkati A، Apuschkin M، Herborg F، Gether U (أغسطس 2023). "Amphetamine-induced reverse transport of dopamine does not require cytosolic Ca2". J Biol Chem. ج. 299 ع. 8: 105063. DOI:10.1016/j.jbc.2023.105063. PMC:10448275. PMID:37468107. مؤرشف من الأصل في 2024-07-31. اطلع عليه بتاريخ 2025-01-19. [...] AMPH is a substrate of DAT and causes nonexocytotic efflux of DA by reversing the direction of transport via DAT through a yet not fully understood mechanism (4–7). To improve our insights into AMPH-induced efflux with a focus on the unsettled role of Ca2+, we establish here a novel approach enabling simultaneous assessment of DA efflux and intracellular signaling pathways by live fluorescent imaging of cultured DA midbrain neurons. [...] our data provide strong evidence that AMPH-induced DA efflux via DAT in DArgic neurons does not require Ca2+ but primarily relies on the concerted action of AMPH on VMAT2 and DAT. [...] [...] Summarized, we employ a live imaging approach enabling parallel monitoring of DA efflux and activation of intracellular signaling pathways in cultured DArgic neurons. Our data reveal in the neurons profound AMPH-induced DA efflux that strikingly neither requires Ca2+ signaling nor activation of the kinases PKC and CaMKIIα. However, the efflux depends on both the activity of VMAT2 and DAT, substantiating the unequivocal concerted importance of both transporters for the pharmacological action of AMPH on DArgic neurons. [...]
1 2  Miller GM (مارس 2012). "Avenues for the development of therapeutics that target trace amine associated receptor 1 (TAAR1)". J Med Chem. ج. 55 ع. 5: 1809–1814. DOI:10.1021/jm201437t. PMC:3618978. PMID:22214431. مؤرشف من الأصل في 2023-12-07. اطلع عليه بتاريخ 2025-01-19. Although a detailed and rigorous description of the regional distribution of TAAR1 protein and mRNA expression has yet to be accomplished, it is established that TAAR1 protein and mRNA are expressed in monoaminergic brain regions.3,16,26 In our laboratory, we exploited our prowess with assessing changes in kinetic activity of the dopamine transporter (DAT), norepinephrine transporter (NET) and serotonin transporter (SERT) to assess TAAR1 functionality. Because many of the identified ligands that activate TAAR1 are also substrates at the monoamine transporters and TAAR1 localization in transfected cells was shown to remain largely intracellular,4 we had reasoned early on that monoamine transporters could serve as conduits for TAAR1 agonists to enter cells, thereby providing access of the agonist to an intracellular pool of TAAR1 receptors. We speculated that if this were the case there could be a special relationship between TAAR1 and monoamine transporters because they share some of the same ligands. Indeed, we observed substantially enhanced CRE-luciferase signaling in transfected cells that co-expressed both TAAR1 and a monoamine transporter (DAT, NET or SERT).9,16 Because monoamine transporter kinetic regulation and internalization is a consequence of upregulated cellular phosphorylation cascades,27,28,29 we reasoned that the enhanced TAAR1 signaling could in turn trigger changes in the kinetic activity of the monoamine transporters under conditions of co-localization. This too was born out in a series of studies from our laboratory which demonstrated that TAAR1 activation drives the PKA and PKC cellular signaling cascades that result in inhibition of monoamine uptake and transporter reversal (efflux) in DAT/TAAR1, NET/TAAR1 and SERT/TAAR1 co-transfected cells in vitro, as well as in mouse and primate striatal (DAT, SERT) and thalamic (NET) synaptosomes ex vivo.22,23,24,25,30 TAAR1 specificity for mediation of the observed kinetic effects on the monoamine transporters was further confirmed in these studies by demonstrating the absence of noncompetitive effects of the trace amine beta-phenylethylamine (β-PEA),23 the common biogenic amines,24 and methamphetamine25 on uptake inhibition and substrate-induced monoamine efflux in synaptosomes generated from TAAR1 knockout mice. Accordingly, specific drugs that target TAAR1 will likely result in alterations in monoamine kinetic function and brain monoamine levels via this mechanism.
1 2 3 4 5 6  Miller GM (يناير 2011). "The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity". Journal of Neurochemistry. ج. 116 ع. 2: 164–176. DOI:10.1111/j.1471-4159.2010.07109.x. PMC:3005101. PMID:21073468. مؤرشف من الأصل في 2024-10-09. اطلع عليه بتاريخ 2025-01-19. In a later study, Xie and Miller (2009a) resolved this issue by demonstrating that methamphetamine could induce [3 H]dopamine efflux in DAT cells or in TAAR1 knockout mouse striatal synaptosomes when the cells or synaptosomes were loaded with high concentrations of [ 3 H]dopamine (1 μM or higher), indicating that the direct effect of methamphetamine on the dopamine transporter to cause [3 H]dopamine efflux is dependent on the pre-loading concentration of [3 H]dopamine. But the efflux caused by methamphetamine under these conditions in DAT cells was not associated with either the PKA or the PKC phosphorylation pathways whereas it was blocked by methylphenidate. Further studies showed that TAAR1-mediated effects of methamphetamine on [3 H]dopamine efflux occurred at both lower and higher (1 μM) loading concentrations of [ 3 H]dopamine in TAAR1-DAT cells or in wild type mouse striatal synaptosomes, which could be blocked not only by methylphenidate but also by the PKC inhibitor Ro32-0432 (Xie and Miller 2009a). At the higher loading concentration, there was a greater amount of efflux observed in the presence of TAAR1 (in TAAR1-DAT cells or wild-type mouse striatal synaptosomes) than in its absence (in DAT cells or TAAR1 knockout mouse striatal synaptosomes), and it was only this relative greater amount of efflux that was sensitive to PKC inhibition. Accordingly, the TAAR1-mediated effects of methamphetamine on [3 H]dopamine efflux are dependent on PKC phosphorylation, whereas an observed TAAR1-independent, PKC-independent efflux occurs when cells or synaptosomes are loaded with high concentrations of [ 3 H]dopamine. [...] In a different mouse line, Lindemann et al. (2008) reported that TAAR1 knockout mice show an increased locomotive response to d-amphetamine after a single application of either 1 or 2.5 mg/kg. The increased locomotion correlated with a two- to threefold increase in extracellular dopamine, norepinephrine and serotonin levels in the TAAR1 knockout mice as compared with wild-type mice. [...] In further studies, electrophysiological analysis of dopaminergic neurons in the ventral tegmental area of TAAR1 knockout and wild-type mice revealed that the spontaneous firing rate of dopaminergic neurons was 8.6-fold higher in the TAAR1 knockout mice, and that activation of TAAR1 by 10 μM p-tyramine decreased the firing rate of dopaminergic neurons in wild type mice but not in TAAR1 knockout mice (Lindemann et al. 2008).
1 2  Grandy DK، Miller GM، Li JX (فبراير 2016). ""TAARgeting Addiction"--The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference". Drug Alcohol Depend. ج. 159: 9–16. DOI:10.1016/j.drugalcdep.2015.11.014. PMC:4724540. PMID:26644139. مؤرشف من الأصل في 2025-01-20. اطلع عليه بتاريخ 2025-01-19.
1 2 3  Jing L، Li JX (أغسطس 2015). "Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction". Eur J Pharmacol. ج. 761: 345–352. DOI:10.1016/j.ejphar.2015.06.019. PMC:4532615. PMID:26092759. مؤرشف من الأصل في 2025-01-18. اطلع عليه بتاريخ 2025-01-19. In both wild-type and Taar 1-/- mice, amphetamine produced a robust increase in striatal release of DA, norepinephrine (NE), and serotonin (5-HT), but this effect was significantly greater in Taar 1-/- mice than in wild type mice (Lindemann et al., 2008; Wolinsky et al., 2007). These findings support the notion that TAAR 1 functionally operates as a negative modulator of monoaminergic neurotransmission. [...] amphetamine had no effect on the release of DA and NA in the NAc of Taar 1 Tg mice, which partially explains the finding that amphetamine-induced a weaker locomotor hyperactivity in Taar 1 Tg mice as compared to their wild type counterparts. [...] There are evidence that TAAR 1 can modulate DAT function in in vitro cell culture experiments. Xie et al reported that β-phenethylamine (β-PEA) inhibited uptake and induced efflux of monoamines in thalamic synaptosomes of rhesus monkeys and wild-type mice, but not in synaptosomes of Taar 1-/- mice. Furthermore, the effect of β-PEA on efflux was blocked by transporter inhibitors in either the transfected cells or wild-type mouse synaptosomes (Xie and Miller, 2008). They also found that methamphetamine inhibited DA uptake, enhanced dopamine efflux, and induced DAT internalization by acting as a TAAR 1 agonist (Xie and Miller, 2009). However, more recent studies show inconsistent results. Leo et al. found that the DA clearance was not changed in Taar 1-/- mice as compared to their wild type counterparts (Leo et al., 2014), suggesting that the DAT function remained intact. In addition, no significant changes of dopamine uptake were observed in slices from Taar 1-/- mice, suggesting that the effect of TAAR 1 activation on DA-related function is independent of DAT (Leo et al., 2014). These apparent discrepancies may be attributable to the assays and tissues used in the studies. Xie et al. used mouse and monkey cellular synaptosome preparations with tissues from putamen and thalamus (Xie and Miller, 2008) while Leo et al. used fast scan cyclic voltammetry to measure DA uptake in mouse striatal slices (Leo et al., 2014). [...] Taar 1-/- mice displayed a behavioral phenotype of supersensitivity to amphetamine and cocaine, as evidenced by drug-induced increases in both locomotor activity and rearing as compared with wild-type littermates (Lindemann et al., 2008; Wolinsky et al., 2007). In contrast, Taar Tg mice responded to amphetamine in an opposite manner and showed a reduced and delayed response to amphetamine as compared with wild-type mice, indicating that Taar Tg mice are hyposensitive to amphetamine (Revel et al., 2012a). Methamphetamine also produced similar behavioral outcome in Taar 1-/- mice (Achat-Mendes et al., 2012).
↑  Miner، Nicholas (2019). The Modulatory Role of TAAR1 in Neurotoxicity of Substituted Amphetamines (Thesis). unav. ص. 33–34. DOI:10.6083/qf85nb81p. مؤرشف من الأصل في 2020-02-29. اطلع عليه بتاريخ 2025-01-19. A significant body of in vitro research has investigated TAAR1 modulation of DAT, primarily by the Miller laboratory. [...] Functionality of DAT is also modulated by TAAR1 as application of DA inhibited [3H]DA uptake and induced [3H]DA release in TAAR1/DAT cells compared to cells only expressing DAT (Xie and Miller, 2007; Xie et al., 2008b). [...] However, it has been argued the conduction of this research in vitro diminishes its validity. Administration of β-PEA or the TAAR1 agonist RO5166017 diminishes hyperlocomotion in DAT-KO mice, indicating activation of TAAR1 functions independently of DAT (Sotnikova et al., 2004; Revel et al., 2011). This theory is bolstered by FSCV experiments. Evoked DA release and uptake, measured by Tau and half-life, are the same between genotypes. DA overflow is greater in the NAc of Taar1-KO than -WT mice, attributed to increased basal DA levels, but DA uptake is still the same between genotypes (Leo et al., 2014). Similarly, the partial TAAR1 agonist RO5203648 diminishes cocaine-induced DA overflow in the NAc without altering DA uptake, also indicating a DAT-independent mechanism (Pei et al., 2014). Further research is needed to better elucidate the interaction between TAAR1 and DAT.
1 2  Halff EF، Rutigliano G، Garcia-Hidalgo A، Howes OD (يناير 2023). "Trace amine-associated receptor 1 (TAAR1) agonism as a new treatment strategy for schizophrenia and related disorders". Trends Neurosci. ج. 46 ع. 1: 60–74. DOI:10.1016/j.tins.2022.10.010. PMID:36369028. مؤرشف من الأصل في 2025-01-20. اطلع عليه بتاريخ 2025-01-19. A study using the TAAR1-specific antagonist EPPTB showed that presynaptic blockade of TAAR1 reversed its ability to inhibit the firing rate of VTA dopaminergic neurons, which it normally brings about by activating inwardly rectifying potassium channels [45,48]. An increase in firing rates upon blocking TAAR1 with EPPTB suggests that TAAR1 is either constitutively active or under constant tonic activation from endogenous agonists. [...] A presynaptic interaction between TAAR1 and DAT function has also been suggested because some groups found evidence in cell culture that TAAR1 agonists inhibit DAT function via TAAR1 and D2AR [49,50,65]. Others find, however, that the effects of TAAR1 agonists and antagonist are unaltered in Dat−/− knockout mice, and that dopamine reuptake is unaffected by application of TAAR1 (ant)agonists or in TAAR1-KO animals [46,47]. One hypothesis that could unite the apparently conflicting findings is that TAs exert an inhibitory effect directly on DAT; indeed, PEA administration induces transient hyperlocomotion in mice, similar to the behaviour observed in Dat−/− animals [30]. More recent work suggests that TAAR1 activation mediates internalisation of DAT through regulating RhoA activity [53].
↑  Miner NB، Phillips TJ، Janowsky A (أكتوبر 2019). "The Role of Biogenic Amine Transporters in Trace Amine-Associated Receptor 1 Regulation of Methamphetamine-Induced Neurotoxicity". J Pharmacol Exp Ther. ج. 371 ع. 1: 36–44. DOI:10.1124/jpet.119.258970. PMC:6750185. PMID:31320495. مؤرشف من الأصل في 2025-01-20. اطلع عليه بتاريخ 2025-01-19. Previous research on TAAR1 modulation of DAT function has produced equivocal findings. In vitro, MA inhibits [3H]DA uptake, and [3H]DA release is increased in striatal tissue from Taar1 WT compared with KO mice (Xie and Miller, 2009). Similar findings were described in cells cotransfected with TAAR1 and DAT, compared with cells transfected only with DAT, in which MA-induced [3H]DA uptake inhibition and release were increased (Xie and Miller, 2007, 2009). However, these findings indicate MA-induced impairment of DAT function is increased when TAAR1 is activated, as opposed to in vivo treatment with AMPH or MDMA, by which striatal extracellular DA levels are increased when TAAR1 is not activated (Wolinsky et al., 2007; Lindemann et al., 2008; Di Cara et al., 2011). We were unable to replicate the results of Xie and Miller (2009) under similar in vitro conditions (Fig. 3). There was no difference in IC50 values for [3H]DA uptake inhibition by MA between synaptosomes from Taar1 WT and KO mice. [...] our results do not support an earlier hypothesis that TAAR1 modulates DAT (Xie and Miller, 2007, 2009; Xie et al., 2008b), as there was no evidence of an interaction under conditions described above. Recent reports support our findings that the DAT is unaffected by TAAR1. Coadministration of MA and the TAAR1 partial agonist RO523648 did not alter [3H]DA uptake and release in striatal synaptosomes in rats (Cotter et al., 2015). Fast-scan cyclic voltammetry showed no difference in DA clearance, as mediated by DAT, in striatal tissue from Taar1 WT compared with KO mice (Leo et al., 2014). [...] Given the lack of interaction, DAT is an improbable mediator of TAAR1 regulation of MA-induced neurotoxicity. [...] activation of TAAR1 did not modulate in vitro MA-impairment of DAT function or DAT expression. As TAAR1 activation did not alter the function or expression of DAT in whole synaptosomes or VMAT2 located on membrane-associated vesicles, these results indicate TAAR1 does not interact with these transporters on the plasma membrane but does affect intracellular VMAT2 function.
↑  Leo D، Mus L، Espinoza S، Hoener MC، Sotnikova TD، Gainetdinov RR (يونيو 2014). "Taar1-mediated modulation of presynaptic dopaminergic neurotransmission: role of D2 dopamine autoreceptors". Neuropharmacology. ج. 81: 283–291. DOI:10.1016/j.neuropharm.2014.02.007. PMID:24565640. مؤرشف من الأصل في 2025-01-18. اطلع عليه بتاريخ 2025-01-19. Importantly, we have documented that neither Tau nor the half-life of released DA are changed in slices from TAAR1-KO animals, indicating that TAAR1-KO mice exhibit unaltered DA uptake ability and thereby normal dopamine transporter (DAT) functionality. It is believed that Tau and the half-life of released DA are reliable measures for detecting changes in DA uptake because they are strongly correlated with changes in the Km of DAT mediated DA uptake (Yorgason et al., 2011). Thus, these neurochemical in vivo studies, as well as previous demonstrations of the functional activity of TAAR1 ligands in mice lacking the DAT (Sotnikova et al., 2004; Revel et al., 2012a), provide little support for the postulated role of TAAR1 in modulating DAT activity that is based mostly on in vitro cell culture experiments (Miller et al., 2005; Xie et al., 2008; Miller, 2011). [...] Notably, neither [the TAAR1 agonist (RO5166017) nor the TAAR1 antagonist (EPPTB)] changed the kinetics of DA uptake as evidenced by the Tau and DA half-life estimations, indicating that DAT-mediated function is not altered by the action of the drugs on TAAR1.
1 2  Di Cara B، Maggio R، Aloisi G، Rivet JM، Lundius EG، Yoshitake T، Svenningsson P، Brocco M، Gobert A، De Groote L، Cistarelli L، Veiga S، De Montrion C، Rodriguez M، Galizzi JP، Lockhart BP، Cogé F، Boutin JA، Vayer P، Verdouw PM، Groenink L، Millan MJ (نوفمبر 2011). "Genetic deletion of trace amine 1 receptors reveals their role in auto-inhibiting the actions of ecstasy (MDMA)". J Neurosci. ج. 31 ع. 47: 16928–16940. DOI:10.1523/JNEUROSCI.2502-11.2011. PMC:6623861. PMID:22114263. اطلع عليه بتاريخ 2025-01-19.
1 2 3  Lewin AH، Miller GM، Gilmour B (ديسمبر 2011). "Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class". Bioorganic & Medicinal Chemistry. ج. 19 ع. 23: 7044–7048. DOI:10.1016/j.bmc.2011.10.007. PMC:3236098. PMID:22037049. مؤرشف من الأصل في 2024-08-20. اطلع عليه بتاريخ 2025-01-19. While our data suggest a role for TAAR1 in eliciting amphetamine-like stimulant effects, it must be borne in mind that the observed in vivo effects are likely to result from interaction with both TAAR1 and monoamine transporters. Thus it has been shown that the selective TAAR1 agonist RO5166017 fully prevented psychostimulant-induced and persistent hyperdopaminergia-related hyperactivity in mice.42 This effect was found to be DAT-independent, since suppression of hyperactivity was observed in DAT-KO mice.42 The collected information leads us to conclude that TAAR1 is a stereoselective binding site for amphetamine and that TAAR1 activation by amphetamine and its congeners may contribute to the stimulant properties of this class of compounds. [...] it has been shown that β-PEA and methamphetamine effects in cells expressing TAAR-DAT significantly exceed those observed in cells expressing DAT only. Consistent with this conclusion is the higher potency of (S)-[amphetamine] in rat synaptosomes relative to cloned human DAT cells (EC50 60 nM vs 240 nM).
1 2 3  Jîtcă G، Ősz BE، Tero-Vescan A، Vari CE (مارس 2021). "Psychoactive Drugs-From Chemical Structure to Oxidative Stress Related to Dopaminergic Neurotransmission. A Review". Antioxidants (Basel). ج. 10 ع. 3: 381. DOI:10.3390/antiox10030381. PMC:8000782. PMID:33806320. مؤرشف من الأصل في 2024-08-14. اطلع عليه بتاريخ 2025-01-19. The DAT vs SERT ratios of synthetic cathinones are presented in Table 1. [...] Table 1. In vitro dopamine and serotonin uptake transporter inhibition (IC50 values) and release data (EC50 values). [...] The DAT vs SERT ratios of amphetamine derivatives and cocaine are presented in Table 2. [...] Table 2. In vitro dopamine and serotonin uptake transporter inhibition (IC50 values) and release data (EC50 values). [...] * in vitro studies for neurotransmitter reuptake inhibition and release using HEK293 (Human Embryonic Kidney 293) cell line expressing DAT and SERT (IC50 and EC50 values are expressed in μM). [(Note: HEK293 cells lack TAAR1 expression: "HEK-293 cells do not express TAAR1 (Reese et al., 2007; Xie and Miller, 2007)" (Small et al., 2023 [doi:10.1124/jpet.122.001573]).)]
1 2 3  Gainetdinov RR، Hoener MC، Berry MD (يوليو 2018). "Trace Amines and Their Receptors". Pharmacol Rev. ج. 70 ع. 3: 549–620. DOI:10.1124/pr.117.015305. PMID:29941461. مؤرشف من الأصل في 2025-01-21. اطلع عليه بتاريخ 2025-01-19.
1 2 3  Simmler LD، Buchy D، Chaboz S، Hoener MC، Liechti ME (أبريل 2016). "In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1". J Pharmacol Exp Ther. ج. 357 ع. 1: 134–144. DOI:10.1124/jpet.115.229765. PMID:26791601. مؤرشف من الأصل في 2025-01-07. اطلع عليه بتاريخ 2025-01-19.
↑  Grandy DK (ديسمبر 2007). "Trace amine-associated receptor 1-Family archetype or iconoclast?". Pharmacol Ther. ج. 116 ع. 3: 355–390. DOI:10.1016/j.pharmthera.2007.06.007. PMC:2767338. PMID:17888514. مؤرشف من الأصل في 2024-12-15. اطلع عليه بتاريخ 2025-01-19. [AMPH and METH] promote DA release from synaptic storage vesicles into the cytoplasm (Partilla et al., 2006) and then into the extracellular space via DAT with an EC50 of 25 nM and a Ki uptake in rat synaptosomes of 34 nM (Rothman et al., 2001). These are drug concentrations approximately 20-30 fold lower than the EC50 values Reese et al. (2007) calculated for eliciting an in vitro functional response from rTAAR1 (0.8 μM). However, experienced METH users can typically consume gram quantities of drug per day (Kramer et al., 1967) and achieve peak blood concentrations of 100 μM (Derlet et al., 1989; Baselt, 2002; Peters et al., 2003). [...] The extracellular free concentration of METH surrounding relevant human dopaminergic synapses in the brain presumably is the relevant pharmacodynamic parameter, at least in part, underlying the desirable effects of the drug. Although this value is not known with certainty for humans METH serum levels typically represent one tenth of what is found in rat brain (Riviere et al., 2000). Consequently, when considered together with the human forensic evidence the in vitro results of Reese et al. (2007) are consistent with the interpretation that in vivo the human TAAR1 is likely to be a mediator of at least some of METH's effects.