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Monoamine releasing agent

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"Releasing agent" redirects here. For mold release agents, see Release agent.
Amphetamine, the prototypical monoamine releasing agent, which acts on norepinephrine and dopamine.

A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of a monoamine neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitter. Many drugs induce their effects in the body and/or brain via the release of monoamine neurotransmitters, e.g., trace amines, many substituted amphetamines, and related compounds.

Types of MRAs

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MRAs can be classified by the monoamines they mainly release, although these drugs lie on a spectrum.

MRAs must be distinguished from monoamine reuptake inhibitors and monoaminergic activity enhancers, which work via distinct mechanisms.

Endogenous MRAs

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A number of endogenous compounds are known to act as MRAs.[1][2][3][4] These include the monoamine neurotransmitters dopamine (an NDRA),[1] norepinephrine (an NDRA),[1] and serotonin (an SRA) themselves,[1] as well as the trace amines phenethylamine (an NDRA),[4][5][6][7] tryptamine (an SDRA or imbalanced SNDRA),[2][3] and tyramine (an NDRA).[1] Synthetic MRAs are substantially based on structural modification of these endogenous compounds, most prominently including the substituted phenethylamines and substituted tryptamines.[1][8][9][2][10][11][12]

Mechanism of action

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Main article: Amphetamine § Pharmacodynamics

MRAs cause the release of monoamine neurotransmitters by various complex mechanism of actions. They may enter the presynaptic neuron primarily via plasma membrane transporters, such as the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT). Some, such as exogenous phenethylamine, amphetamine, and methamphetamine, can also diffuse directly across the cell membrane to varying degrees. Once inside the presynaptic neuron, they may inhibit the reuptake of monoamine neurotransmitters through vesicular monoamine transporter 2 (VMAT2) and release the neurotransmitters stores of synaptic vesicles into the cytoplasm by inducing reverse transport at VMAT2. MRAs can also bind to the intracellular receptor TAAR1 as agonists, which triggers a phosphorylation cascade via protein kinases that results in the phosphorylation of monoamine transporters located at the plasma membrane (i.e., the dopamine transporter, norepinephrine transporter, and serotonin transporter); upon phosphorylation, these transporters transport monoamines in reverse (i.e., they move monoamines from the neuronal cytoplasm into the synaptic cleft).[13] The combined effects of MRAs at VMAT2 and TAAR1 result in the release of neurotransmitters out of synaptic vesicles and the cell cytoplasm into the synaptic cleft where they bind to their associated presynaptic autoreceptors and postsynaptic receptors. Certain MRAs interact with other presynaptic intracellular receptors which promote monoamine neurotransmission as well (e.g., methamphetamine is also an agonist at σ1 receptor).

In spite of findings that TAAR1 activation by amphetamines can reverse the monoamine transporters and mediate monoamine release however,[13][14][15][16] major literature reviews on monoamine releasing agents by experts like Richard B. Rothman and David J. Heal state that the nature of monoamine transport reversal is not well understood and/or do not mention TAAR1 activation.[17][18][19][20] Moreover, amphetamines continue to produce psychostimulant-like effects and induction of dopamine and norepinephrine release in TAAR1 knockout mice.[13][21][22][23][24] In fact, TAAR1 knockout mice are supersensitive to the effects of amphetamines and TAAR1 activation appears to inhibit the striatal dopaminergic effects of psychostimulants.[13][22][21][23][24] Additionally, many substrate-type MRAs that do not bind to and/or activate the (human) TAAR1 are known, including most cathinones, ephedrine, 4-methylamphetamine, and 4-methylaminorex derivatives, among others.[25][26][27][28]

Dopamine reuptake inhibitors (DRIs) have been grouped into two types, typical or conventional DRIs like cocaine, WIN-35428 (β-CFT), and methylphenidate that produce potent psychostimulant, euphoric, and reinforcing effects, and atypical DRIs like vanoxerine (GBR-12909), modafinil, benztropine, and bupropion, which do not produce such effects or have greatly reduced such effects.[20][18][4][29] It has been proposed that typical DRIs may not actually be acting primarily as DRIs but rather as dopamine releasing agents (DRAs) via mechanisms distinct from conventional substrate-type DRAs like amphetamines.[20] A variety of different pieces of evidence support this hypothesis and help to explain otherwise confusing findings.[20] Under this model, typical cocaine-like DRIs have been referred to with the new label of dopamine transporter (DAT) "inverse agonists" to distinguish them from conventional substrate-type DRAs.[20] An alternative theory is that typical DRIs and atypical DRIs stabilize the DAT in different conformations, with typical DRIs resulting in an outward-facing open conformation that results in differing pharmacological effects from those of atypical DRIs.[18][4][29][30]

Some MRAs, like the amphetamines amphetamine and methamphetamine, as well as trace amines like phenethylamine, tryptamine, and tyramine, are additionally monoaminergic activity enhancers (MAEs).[31][32][5] That is, they induce the action potential-mediated release of monoamine neurotransmitters (in contrast to MRAs, which induced uncontrolled monoamine release independent of neuronal firing).[31][32][5] They are usually active as MAEs at much lower concentrations than those at which they induce monoamine release.[31][32][5] The MAE actions of MAEs may be mediated by TAAR1 agonism, which has likewise been implicated in monoamine-releasing actions.[33][34] MAEs without concomitant potent monoamine-releasing actions, like selegiline (L-deprenyl), phenylpropylaminopentane (PPAP), and benzofuranylpropylaminopentane (BPAP), have been developed.[31][32]

Effects and uses

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MRAs can have a wide variety of effects depending upon their selectivity for inducing release of different monoamine neurotransmitters.

Selective SRAs such as fenfluramine and related compounds are described as dysphoric and lethargic in lower doses, and in higher doses some hallucinogenic effects have been reported.[35][36] Less selective SRAs that also stimulate the release of dopamine, such as methylenedioxymethamphetamine (MDMA), are described as more pleasant, elevating mood and increasing energy and sociability.[37] SRAs have been used as appetite suppressants and as entactogens. They have also been proposed for use as more effective antidepressants and anxiolytics than selective serotonin reuptake inhibitors (SSRIs) owing to the fact that they can produce much larger increases in serotonin levels in comparison.[38]

DRAs, usually non-selective for both norepinephrine and dopamine, have psychostimulant effects, causing an increase in energy, motivation, elevated mood, and euphoria.[39] Other variables can significantly affect the subjective effects, such as infusion rate (increasing positive effects of DRAs) and psychological expectancy effects.[40] They are used in the treatment of attention deficit hyperactivity disorder (ADHD), as appetite suppressants, wakefulness-promoting agents, to improve motivation, and are drugs of recreational use and misuse.

Selective NRAs are minimally psychoactive, but as demonstrated by ephedrine, may be distinguished from placebo, and may trends towards liking.[41] They may also be performance-enhancing,[42] in contrast to reboxetine which is solely a norepinephrine reuptake inhibitor.[43][44] In addition to their central effects, NRAs produce peripheral sympathomimetic effects like increased heart rate, blood pressure, and force of heart contractions. They are used as nasal decongestants and bronchodilators, but have also seen use as wakefulness-promoting agents, appetite suppressants, and antihypotensive agents. They have additionally seen use as performance-enhancing drugs, for instance in sports.

Selectivity

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MRAs act to varying extents on serotonin, norepinephrine, and dopamine. Some induce the release of all three neurotransmitters to a similar degree, like methylenedioxymethamphetamine (MDMA), while others are more selective. As examples, amphetamine and methamphetamine are NDRAs but only very weak releasers of serotonin (~60- and 30-fold less than of dopamine, respectively) and MBDB is a fairly balanced SNRA but a weak releaser of dopamine (~6- and 10-fold lower of dopamine than of norepinephrine or serotonin, respectively). Even more selective include agents like fenfluramine, a selective SRA, and ephedrine, a selective NRA. The differences in selectivity of these agents is the result of different affinities as substrates for the monoamine transporters, and thus differing ability to gain access into monoaminergic neurons and induce monoamine neurotransmitter release via the TAAR1 and VMAT2 proteins.

As of present, no selective DRAs are known. This is because it has proven extremely difficult to separate DAT affinity from NET affinity and retain releasing efficacy at the same time.[45] Several selective SDRAs, including tryptamine, (+)-α-ethyltryptamine (αET), 5-chloro-αMT, and 5-fluoro-αET, are known.[3][46] However, besides their serotonin release, these compounds additionally act as non-selective serotonin receptor agonists, including of the serotonin 5-HT2A receptor (with accompanying hallucinogenic effects), and some of them are known to act as monoamine oxidase inhibitors.[3][46]

Neurotoxicity

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Some MRAs have been found to act as monoaminergic neurotoxins and hence to produce long-lasting damage to monoaminergic neurons.[47][48] Examples include dopaminergic neurotoxicity with amphetamine and methamphetamine and serotonergic neurotoxicity with methylenedioxymethamphetamine (MDMA).[47][48] Amphetamine may produce significant dopaminergic neurotoxicity even at therapeutic doses.[49][50][51][52][53][54] However, clinical doses of amphetamine producing neurotoxicity is controversial and disputed.[55][49][51] In contrast to amphetamines, monoamine reuptake inhibitors like methylphenidate lack apparent neurotoxic effects.[49]

Analogues of MDMA with retained MRA activity but reduced or no serotonergic neurotoxicity, like 5,6-methylenedioxy-2-aminoindane (MDAI) and 5-iodo-2-aminoindane (5-IAI), have been developed.[56][57] Certain drugs have been found to block the neurotoxicity of MRAs in animals.[48] For instance, the selective MAO-B inhibitor selegiline has been found to prevent the serotonergic neurotoxicity of MDMA in rodents.[48]

Activity profiles

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See also: Monoamine reuptake inhibitor § Binding profiles
Activity profiles of MRAs (EC50, nM)[8][9]
Compound 5-HTTooltip Serotonin NETooltip Norepinephrine DATooltip Dopamine Type Class Ref
2C-E >100000 >100000 >100000 IA Phenethylamine [58]
2C-I >100000 >100000 >100000 IA Phenethylamine [58]
3-Chloromethcathinone ND ND 46.8 ND Cathinone [4]
3-Fluoroamphetamine 1937 16.1 24.2 NDRA Amphetamine [59]
3-Methylamphetamine 218 18.3 33.3 NDRA Amphetamine [59]
4-Fluoroamphetamine 730–939 28.0–37 51.5–200 NDRA Amphetamine [59][58]
cis-4-Methylaminorex 53.2 4.8 1.7 NDRA Aminorex [60]
4-Methylamphetamine 53.4 22.2 44.1 SNDRA Amphetamine [59]
4-Methylphenethylamine ND ND 271 ND Phenethylamine [4]
4-Methylthiomethamphetamine 21 ND ND ND Amphetamine [61]
4,4'-Dimethylaminorex ND ND ND SNDRA Aminorex ND
  ''cis''-4,4'-Dimethylaminorex 17.7–18.5 11.8–26.9 8.6–10.9 SNDRA Aminorex [60][62]
  ''trans''-4,4'-Dimethylaminorex 59.9 31.6 24.4 SNDRA Aminorex [62]
5-(2-Aminopropyl)indole 28–104.8 13.3–79 12.9–173 SNDRA Amphetamine [46][63]
  (''R'')-5-(2-Aminopropyl)indole 177 81 1062 SNRA Amphetamine [46]
  (''S'')-5-(2-Aminopropyl)indole ND ND ND SNDRA Amphetamine ND
5-Chloro-αMT 16 3434 54 SDRA Tryptamine [3][46]
5-Fluoro-αET 36.6 5334 150 SDRA Tryptamine [3]
5-Fluoro-αMT 19 126 32 SNDRA Tryptamine [46]
5-MeO-αMT 460 8900 1500 SNDRA Tryptamine [58]
5-MeO-DMT >100000 >100000 >100000 IA Tryptamine [58]
6-(2-Aminopropyl)indole 19.9 25.6 164.0 SNDRA Amphetamine [63]
α-Ethyltryptamine 23.2 640 232 SDRA Tryptamine [3]
α-Methyltryptamine 21.7–68 79–112 78.6–180 SNDRA Tryptamine [58][3]
Amfepramone (diethylpropion) >10000 >10000 >10000 PD Cathinone [64]
Aminorex 193–414 15.1–26.4 9.1–49.4 SNDRA Aminorex [1][60]
Amphetamine ND ND ND NDRA Amphetamine ND
  D-Amphetamine 698–1765 6.6–7.2 5.8–24.8 NDRA Amphetamine [1][65]
  L-Amphetamine ND ND ND NRA Amphetamine ND
β-Ketophenethylamine ND ND 208 ND Phenethylamine [4]
BDB 180 540 2,300 NDRA Amphetamine [58]
Benzylpiperazine ≥6050 62–68 175–600 NDRA Arylpiperazine [58][66][9]
Bufotenin 30.5 >10000 >10000 SRA Tryptamine [2]
Butylamphetamine ND ND IA ND Amphetamine [4]
Cathinone ND ND ND NDRA Cathinone ND
  D-Cathinone ND ND ND NRA Cathinone ND
  L-Cathinone 2366 12.4 18.5 NDRA Cathinone [67]
Chlorphentermine 30.9 >10000 2650 SRA Amphetamine [1]
DMPP 26 56 1207 SNRA Arylpiperazine [61]
DMT 114 4166 >10000 SRA Tryptamine [2]
Dopamine >10000 66.2 86.9 NDRA Phenethylamine [1]
DPT >100000 >100000 >100000 IA Tryptamine [58][2]
Ephedrine (racephedrine) ND ND ND NDRA Cathinol ND
  D-Ephedrine (ephedrine) >10000 43.1–72.4 236–1350 NDRA Cathinol [1]
  L-Ephedrine >10000 218 2104 NRA Cathinol [1][67]
Epinephrine ND ND ND NDRA Phenethylamine ND
Ethcathinone 2118 99.3 >1000 NRA Cathinone [64]
Ethylamphetamine ND ND 296 ND Amphetamine [4]
Fenfluramine 79.3–108 739 >10000 SRA Amphetamine [1][68][69]
  D-Fenfluramine 51.7 302 >10000 SNRA Amphetamine [1][68]
  L-Fenfluramine 147 >10000 >10000 SRA Amphetamine [68][70]
MBDB 540 3300 >100000 SNRA Amphetamine [58]
mCPP 28–38.1 ≥1400 63000 SRA Arylpiperazine [58][70][71]
MDA 160 108 190 SNDRA Amphetamine [69]
  (''R'')-MDA 310 290 900 SNDRA Amphetamine [69]
  (''S'')-MDA 100 50 98 SNDRA Amphetamine [69]
MDEA 47 2608 622 SNDRA Amphetamine [61]
  (''R'')-MDEA 52 651 507 SNDRA Amphetamine [61]
  (''S'')-MDEA 465 RI RI SRA Amphetamine [61]
MDMA 49.6–72 54.1–110 51.2–278 SNDRA Amphetamine [1][72][63][69]
  (''R'')-MDMA 340 560 3700 SNDRA Amphetamine [69]
  (''S'')-MDMA 74 136 142 SNDRA Amphetamine [69]
MDMAR ND ND ND SNDRA Aminorex ND
  ''cis''-MDMAR 43.9 14.8 10.2 SNDRA Aminorex [62]
  ''trans''-MDMAR 73.4 38.9 36.2 SNDRA Aminorex [62]
Mephedrone 118.3–122 58–62.7 49.1–51 SNDRA Cathinone [72][65]
Methamnetamine 13 34 10 SNDRA Amphetamine [61]
Methamphetamine ND ND ND NDRA Amphetamine ND
  D-Methamphetamine 736–1291.7 12.3–13.8 8.5–24.5 NDRA Amphetamine [1][72]
  L-Methamphetamine 4640 28.5 416 NRA Amphetamine [1]
Methcathinone ND ND ND NDRA Cathinone ND
  D-Methcathinone ND ND ND NRA Cathinone ND
  L-Methcathinone 1772 13.1 14.8 NDRA Cathinone [67]
Methylone 234–242.1 140–152.3 117–133.0 SNDRA Cathinone [72][65]
Naphthylisopropylamine 3.4 11.1 12.6 SNDRA Amphetamine [73]
Norephedrine (phenylpropanolamine) ND ND ND NDRA Cathinol ND
  D-Norephedrine >10000 42.1 302 NDRA Cathinol [67]
  L-Norephedrine >10000 137 1371 NRA Cathinol [67]
Norepinephrine >10000 164 869 NDRA Phenethylamine [1]
Norfenfluramine 104 168–170 1900–1925 SNRA Amphetamine [68][69]
Norpropylhexedrine ND ND ND NDRA Cyclohexethylamine ND
Norpseudoephedrine ND ND ND NDRA Cathinol ND
  D-Norpseudoephedrine (cathine) >10000 15.0 68.3 NDRA Cathinol [67]
  L-Norpseudoephedrine >10000 30.1 294 NDRA Cathinol [67]
oMPP 175 39.1 296–542 SNDRA Arylpiperazine [74][4]
PAL-738 23 65 58 SNDRA Phenylmorpholine [61]
Phendimetrazine >100000 >10000 >10000 PD Phenylmorpholine [75]
Phenethylamine ND ND 39.5 NDRA Phenethylamine [4]
Phenmetrazine 7765 50.4 131 NDRA Phenylmorpholine [75]
Phentermine 3511 39.4 262 NDRA Amphetamine [1]
Phenylalaninol ND ND ND ND Amphetamine ND
  D-Phenylalaninol >10000 106 1355 NRA Amphetamine [74]
  L-Phenylalaninol ND ND ND ND Amphetamine ND
Phenylisobutylamine ND ND 225 ND Amphetamine [4]
pMPP 3200 1500 11000 SNRA Arylpiperazine [58]
pNPP 43 >10000 >10000 SRA Arylpiperazine [61]
Propylamphetamine ND ND RI (1013) ND Amphetamine [4]
Propylhexedrine ND ND ND NDRA Cyclohexethylamine ND
Pseudoephedrine (racemic pseudoephedrine) ND ND ND NDRA Cathinol ND
  D-Pseudoephedrine >10000 4092 9125 NDRA Cathinol [67]
  L-Pseudoephedrine (pseudoephedrine) >10000 224 1988 NRA Cathinol [67]
Pseudophenmetrazine >10000 514 RI NRA Phenylmorpholine [75]
Psilocin 561 >10000 >10000 SRA Tryptamine [61][2]
Serotonin 44.4 >10000 >10000 SRA Tryptamine [1]
TFMCPP 33 >10000 >10000 SRA Arylpiperazine [61]
TFMPP 121 ND >10000 SRA Arylpiperazine [66]
Trimethoxyamphetamine 16000 >100000 >100000 IA Amphetamine [58]
Tryptamine 32.6 716 164 SDRA Tryptamine [2][3]
Tyramine 2775 40.6 119 NDRA Phenethylamine [1]
Notes: The smaller the value, the more strongly the substance releases the neurotransmitter.

See also

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References

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  1. ^ a b c d e f g h i j k l m n o p q r s t u Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, et al. (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse. 39 (1): 32–41. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID 11071707. S2CID 15573624.
  2. ^ a b c d e f g h Blough BE, Landavazo A, Decker AM, Partilla JS, Baumann MH, Rothman RB (October 2014). "Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes". Psychopharmacology. 231 (21): 4135–4144. doi:10.1007/s00213-014-3557-7. PMC 4194234. PMID 24800892.
  3. ^ a b c d e f g h i Blough BE, Landavazo A, Partilla JS, Decker AM, Page KM, Baumann MH, et al. (October 2014). "Alpha-ethyltryptamines as dual dopamine-serotonin releasers". Bioorganic & Medicinal Chemistry Letters. 24 (19): 4754–4758. doi:10.1016/j.bmcl.2014.07.062. PMC 4211607. PMID 25193229.
  4. ^ a b c d e f g h i j k l m Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, et al. (February 2015). "Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter". Drug and Alcohol Dependence. 147: 1–19. doi:10.1016/j.drugalcdep.2014.12.005. PMC 4297708. PMID 25548026.
  5. ^ a b c d Knoll J, Miklya I, Knoll B, Markó R, Rácz D (1996). "Phenylethylamine and tyramine are mixed-acting sympathomimetic amines in the brain". Life Sciences. 58 (23): 2101–2114. doi:10.1016/0024-3205(96)00204-4. PMID 8649195.
  6. ^ Nakamura M, Ishii A, Nakahara D (May 1998). "Characterization of beta-phenylethylamine-induced monoamine release in rat nucleus accumbens: a microdialysis study". European Journal of Pharmacology. 349 (2–3): 163–169. doi:10.1016/s0014-2999(98)00191-5. PMID 9671094.
  7. ^ Zsilla G, Hegyi DE, Baranyi M, Vizi ES (October 2018). "3,4-Methylenedioxymethamphetamine, mephedrone, and β-phenylethylamine release dopamine from the cytoplasm by means of transporters and keep the concentration high and constant by blocking reuptake". European Journal of Pharmacology. 837: 72–80. doi:10.1016/j.ejphar.2018.08.037. PMID 30172789.
  8. ^ a b Rothman RB, Baumann MH (October 2003). "Monoamine transporters and psychostimulant drugs". European Journal of Pharmacology. 479 (1–3): 23–40. doi:10.1016/j.ejphar.2003.08.054. PMID 14612135.
  9. ^ a b c Rothman RB, Baumann MH (2006). "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry. 6 (17): 1845–1859. doi:10.2174/156802606778249766. PMID 17017961.
  10. ^ Shulgin AT, Shulgin A (1991). Pihkal: A Chemical Love Story. Biography/science. Transform Press. ISBN 978-0-9630096-0-9. Retrieved 18 August 2024.
  11. ^ Shulgin AT, Shulgin A (1997). Tihkal: The Continuation. Transform Press. ISBN 978-0-9630096-9-2. Retrieved 18 August 2024.
  12. ^ Shulgin A, Manning T, Daley PF (2011). The Shulgin Index: Psychedelic Phenethylamines and Related Compounds. Vol. 1. Transform Press. ISBN 978-0-9630096-3-0. Retrieved 2024-08-18.
  13. ^ a b c d Miller GM (January 2011). "The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity". Journal of Neurochemistry. 116 (2): 164–176. doi:10.1111/j.1471-4159.2010.07109.x. PMC 3005101. PMID 21073468.
  14. ^ Wu R, Liu J, Li JX (2022). "Trace amine-associated receptor 1 and drug abuse". Behavioral Pharmacology of Drug Abuse: Current Status. Adv Pharmacol. Vol. 93. pp. 373–401. doi:10.1016/bs.apha.2021.10.005. ISBN 978-0-323-91526-7. PMC 9826737. PMID 35341572. It is reported that methamphetamine (METH) interacts with TAAR1 and subsequently inhibits DA uptake, enhance DA efflux and induces DAT internalization, and these effects are dependent on TAAR1 (Xie & Miller, 2009). For example, METH-induced inhibition of DA uptake was observed in TAAR1 and DAT cotransfected cells and WT mouse and monkey striatal synaptosomes but not in DAT-only transfected cells or in striatal synaptosomes of TAAR1-KO mice (Xie & Miller, 2009). TAAR1 activation was enhanced by co-expression of monoamine transporters and this effect could be blocked by monoamine transporter antagonists (Xie & Miller, 2007; Xie et al., 2007). Furthermore, DA activation of TAAR1 induced C-FOS-luciferase expression only in the presence of DAT (Xie et al., 2007).
  15. ^ Xie Z, Miller GM (July 2009). "A receptor mechanism for methamphetamine action in dopamine transporter regulation in brain". The Journal of Pharmacology and Experimental Therapeutics. 330 (1): 316–325. doi:10.1124/jpet.109.153775. PMC 2700171. PMID 19364908.
  16. ^ Lewin AH, Miller GM, Gilmour B (December 2011). "Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class". Bioorganic & Medicinal Chemistry. 19 (23): 7044–7048. doi:10.1016/j.bmc.2011.10.007. PMC 3236098. PMID 22037049. 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.
  17. ^ Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, et al. (February 2015). "Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter". Drug and Alcohol Dependence. 147: 1–19. doi:10.1016/j.drugalcdep.2014.12.005. PMC 4297708. PMID 25548026. Converging lines of evidence have solidified the notion that DA releasers are substrates of the transporter and once translocated, they reverse the normal direction of transporter flux to evoke release of endogenous neurotransmitters. The nature of this reversal is not well understood, but the entire process is primarily transporter-dependent and requires elevated intracellular sodium concentrations, phosphorylation of DAT, and possible involvement of transporter oligomers (Khoshbouei et al., 2003, 2004; Sitte and Freissmuth, 2010).
  18. ^ a b c Schmitt KC, Rothman RB, Reith ME (July 2013). "Nonclassical pharmacology of the dopamine transporter: atypical inhibitors, allosteric modulators, and partial substrates". The Journal of Pharmacology and Experimental Therapeutics. 346 (1): 2–10. doi:10.1124/jpet.111.191056. PMC 3684841. PMID 23568856.
  19. ^ Heal DJ, Smith SL, Gosden J, Nutt DJ (June 2013). "Amphetamine, past and present--a pharmacological and clinical perspective". Journal of Psychopharmacology. 27 (6): 479–496. doi:10.1177/0269881113482532. PMC 3666194. PMID 23539642.
  20. ^ a b c d e Heal DJ, Gosden J, Smith SL (December 2014). "Dopamine reuptake transporter (DAT) "inverse agonism"--a novel hypothesis to explain the enigmatic pharmacology of cocaine". Neuropharmacology. 87: 19–40. doi:10.1016/j.neuropharm.2014.06.012. PMID 24953830.
  21. ^ a b Espinoza S, Gainetdinov RR (2014). "Neuronal Functions and Emerging Pharmacology of TAAR1". Taste and Smell. Topics in Medicinal Chemistry. Vol. 23. Cham: Springer International Publishing. pp. 175–194. doi:10.1007/7355_2014_78. ISBN 978-3-319-48925-4.
  22. ^ a b Liu J, Wu R, Li JX (March 2020). "TAAR1 and Psychostimulant Addiction". Cellular and Molecular Neurobiology. 40 (2): 229–238. doi:10.1007/s10571-020-00792-8. PMC 7845786. PMID 31974906.
  23. ^ a b Lindemann L, Meyer CA, Jeanneau K, Bradaia A, Ozmen L, Bluethmann H, et al. (March 2008). "Trace amine-associated receptor 1 modulates dopaminergic activity". The Journal of Pharmacology and Experimental Therapeutics. 324 (3): 948–956. doi:10.1124/jpet.107.132647. PMID 18083911.
  24. ^ a b Achat-Mendes C, Lynch LJ, Sullivan KA, Vallender EJ, Miller GM (April 2012). "Augmentation of methamphetamine-induced behaviors in transgenic mice lacking the trace amine-associated receptor 1". Pharmacology, Biochemistry, and Behavior. 101 (2): 201–207. doi:10.1016/j.pbb.2011.10.025. PMC 3288391. PMID 22079347.
  25. ^ Kuropka P, Zawadzki M, Szpot P (May 2023). "A narrative review of the neuropharmacology of synthetic cathinones-Popular alternatives to classical drugs of abuse". Hum Psychopharmacol. 38 (3): e2866. doi:10.1002/hup.2866. PMID 36866677. Another feature that distinguishes [substituted cathinones (SCs)] from amphetamines is their negligible interaction with the trace amine associated receptor 1 (TAAR1). Activation of this receptor reduces the activity of dopaminergic neurones, thereby reducing psychostimulatory effects and addictive potential (Miller, 2011; Simmler et al., 2016). Amphetamines are potent agonists of this receptor, making them likely to self‐inhibit their stimulating effects. In contrast, SCs show negligible activity towards TAAR1 (Kolaczynska et al., 2021; Rickli et al., 2015; Simmler et al., 2014, 2016). [...] The lack of self‐regulation by TAAR1 may partly explain the higher addictive potential of SCs compared to amphetamines (Miller, 2011; Simmler et al., 2013).
  26. ^ Simmler LD, Liechti ME (2018). "Pharmacology of MDMA- and Amphetamine-Like New Psychoactive Substances". Handb Exp Pharmacol. 252: 143–164. doi:10.1007/164_2018_113. PMID 29633178. The activation of human TAAR1 might diminish the effects of psychostimulation and intoxication arising from 7-APB effects on monoamine transporters (see 4.1.3. for more details). Affinity to mouse and rat TAAR1 has been shown for many psychostimulants, but species differences are common (Simmler et al. 2016). For example, [5-(2-aminopropyl)indole (5-IT)] and [4-methylamphetamine (4-MA)] bind and activate TAAR1 in the nanomolar range, but do not activate human TAAR1.
  27. ^ Simmler LD, Buchy D, Chaboz S, Hoener MC, Liechti ME (April 2016). "In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1". J Pharmacol Exp Ther. 357 (1): 134–144. doi:10.1124/jpet.115.229765. PMID 26791601.
  28. ^ Rickli A, Kolaczynska K, Hoener MC, Liechti ME (May 2019). "Pharmacological characterization of the aminorex analogs 4-MAR, 4,4'-DMAR, and 3,4-DMAR". Neurotoxicology. 72: 95–100. Bibcode:2019NeuTx..72...95R. doi:10.1016/j.neuro.2019.02.011. PMID 30776375.
  29. ^ a b Schmitt KC, Reith ME (2011). "The atypical stimulant and nootropic modafinil interacts with the dopamine transporter in a different manner than classical cocaine-like inhibitors". PLOS ONE. 6 (10): e25790. Bibcode:2011PLoSO...625790S. doi:10.1371/journal.pone.0025790. PMC 3197159. PMID 22043293.
  30. ^ Tanda G, Hersey M, Hempel B, Xi ZX, Newman AH (February 2021). "Modafinil and its structural analogs as atypical dopamine uptake inhibitors and potential medications for psychostimulant use disorder". Current Opinion in Pharmacology. 56: 13–21. doi:10.1016/j.coph.2020.07.007. PMC 8247144. PMID 32927246.
  31. ^ a b c d Shimazu S, Miklya I (May 2004). "Pharmacological studies with endogenous enhancer substances: beta-phenylethylamine, tryptamine, and their synthetic derivatives". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 28 (3): 421–427. doi:10.1016/j.pnpbp.2003.11.016. PMID 15093948. S2CID 37564231.
  32. ^ a b c d Knoll J (August 2003). "Enhancer regulation/endogenous and synthetic enhancer compounds: a neurochemical concept of the innate and acquired drives". Neurochemical Research. 28 (8): 1275–1297. doi:10.1023/a:1024224311289. PMID 12834268.
  33. ^ Harsing LG, Knoll J, Miklya I (August 2022). "Enhancer Regulation of Dopaminergic Neurochemical Transmission in the Striatum". International Journal of Molecular Sciences. 23 (15): 8543. doi:10.3390/ijms23158543. PMC 9369307. PMID 35955676.
  34. ^ Harsing LG, Timar J, Miklya I (August 2023). "Striking Neurochemical and Behavioral Differences in the Mode of Action of Selegiline and Rasagiline". International Journal of Molecular Sciences. 24 (17): 13334. doi:10.3390/ijms241713334. PMC 10487936. PMID 37686140.
  35. ^ Brust JC (2004). Neurological Aspects of Substance Abuse. Butterworth-Heinemann. pp. 117–. ISBN 978-0-7506-7313-6.
  36. ^ Competitive problems in the drug industry: hearings before Subcommittee on Monopoly and Anticompetitive Activities of the Select Committee on Small Business, United States Senate, Ninetieth Congress, first session. U.S. Government Printing Office. 1976. pp. 2–.
  37. ^ Parrott AC, Stuart M (1 September 1997). "Ecstasy (MDMA), amphetamine, and LSD: comparative mood profiles in recreational polydrug users". Human Psychopharmacology: Clinical and Experimental. 12 (5): 501–504. CiteSeerX 10.1.1.515.2896. doi:10.1002/(sici)1099-1077(199709/10)12:5<501::aid-hup913>3.3.co;2-m. ISSN 1099-1077.
  38. ^ Scorza C, Silveira R, Nichols DE, Reyes-Parada M (July 1999). "Effects of 5-HT-releasing agents on the extracellullar hippocampal 5-HT of rats. Implications for the development of novel antidepressants with a short onset of action". Neuropharmacology. 38 (7): 1055–1061. doi:10.1016/s0028-3908(99)00023-4. PMID 10428424.
  39. ^ Morean ME, de Wit H, King AC, Sofuoglu M, Rueger SY, O'Malley SS (May 2013). "The drug effects questionnaire: psychometric support across three drug types". Psychopharmacology. 227 (1): 177–192. doi:10.1007/s00213-012-2954-z. PMC 3624068. PMID 23271193.
  40. ^ Nelson RA, Boyd SJ, Ziegelstein RC, Herning R, Cadet JL, Henningfield JE, et al. (March 2006). "Effect of rate of administration on subjective and physiological effects of intravenous cocaine in humans". Drug and Alcohol Dependence. 82 (1): 19–24. doi:10.1016/j.drugalcdep.2005.08.004. PMID 16144747.
  41. ^ Berlin I, Warot D, Aymard G, Acquaviva E, Legrand M, Labarthe B, et al. (September 2001). "Pharmacodynamics and pharmacokinetics of single nasal (5 mg and 10 mg) and oral (50 mg) doses of ephedrine in healthy subjects". European Journal of Clinical Pharmacology. 57 (6–7): 447–455. doi:10.1007/s002280100317. PMID 11699608. S2CID 12410591.
  42. ^ Powers ME (October 2001). "Ephedra and its application to sport performance: another concern for the athletic trainer?". Journal of Athletic Training. 36 (4): 420–424. PMC 155439. PMID 16558668.
  43. ^ Meeusen R, Watson P, Hasegawa H, Roelands B, Piacentini MF (1 January 2006). "Central fatigue: the serotonin hypothesis and beyond". Sports Medicine. 36 (10): 881–909. doi:10.2165/00007256-200636100-00006. PMID 17004850. S2CID 5178189.
  44. ^ Roelands B, Meeusen R (March 2010). "Alterations in central fatigue by pharmacological manipulations of neurotransmitters in normal and high ambient temperature". Sports Medicine. 40 (3): 229–246. doi:10.2165/11533670-000000000-00000. PMID 20199121. S2CID 25717280.
  45. ^ Rothman RB, Blough BE, Baumann MH (January 2007). "Dual dopamine/serotonin releasers as potential medications for stimulant and alcohol addictions". The AAPS Journal. 9 (1): E1-10. doi:10.1208/aapsj0901001. PMC 2751297. PMID 17408232.
  46. ^ a b c d e f Banks ML, Bauer CT, Blough BE, Rothman RB, Partilla JS, Baumann MH, et al. (June 2014). "Abuse-related effects of dual dopamine/serotonin releasers with varying potency to release norepinephrine in male rats and rhesus monkeys". Experimental and Clinical Psychopharmacology. 22 (3): 274–284. doi:10.1037/a0036595. PMC 4067459. PMID 24796848.
  47. ^ a b Kostrzewa RM (2022). "Survey of Selective Monoaminergic Neurotoxins Targeting Dopaminergic, Noradrenergic, and Serotoninergic Neurons". Handbook of Neurotoxicity. Cham: Springer International Publishing. pp. 159–198. doi:10.1007/978-3-031-15080-7_53. ISBN 978-3-031-15079-1.
  48. ^ a b c d Moratalla R, Khairnar A, Simola N, Granado N, García-Montes JR, Porceddu PF, et al. (August 2017). "Amphetamine-related drugs neurotoxicity in humans and in experimental animals: Main mechanisms". Prog Neurobiol. 155: 149–170. doi:10.1016/j.pneurobio.2015.09.011. hdl:10261/156486. PMID 26455459.
  49. ^ a b c Baumeister AA (2021). "Is Attention-Deficit/Hyperactivity Disorder a Risk Syndrome for Parkinson's Disease?" (PDF). Harv Rev Psychiatry. 29 (2): 142–158. doi:10.1097/HRP.0000000000000283. PMID 33560690. It has been suggested that the association between PD and ADHD may be explained, in part, by toxic effects of these drugs on DA neurons.241 [...] An important question is whether amphetamines, as they are used clinically to treat ADHD, are toxic to DA neurons. In most of the animal and human studies cited above, stimulant exposure levels are high relative to clinical doses, and dosing regimens (as stimulants) rarely mimic the manner in which these drugs are used clinically. The study by Ricaurte and colleagues248 is an exception. In that study, baboons orally self-administered a racemic (3:1 d/l) amphetamine mixture twice daily in increasing doses ranging from 2.5 to 20 mg/day for four weeks. Plasma amphetamine concentrations, measured at one-week intervals, were comparable to those observed in children taking amphetamine for ADHD. Two to four weeks after cessation of amphetamine treatment, multiple markers of striatal DA function were decreased, including DA and DAT. In another group of animals (squirrel monkeys), d/l amphetamine blood concentration was titrated to clinically comparable levels for four weeks by administering varying doses of amphetamine by orogastric gavage. These animals also had decreased markers of striatal DA function assessed two weeks after cessation of amphetamine.
  50. ^ Asser A, Taba P (2015). "Psychostimulants and movement disorders". Front Neurol. 6: 75. doi:10.3389/fneur.2015.00075. PMC 4403511. PMID 25941511. Amphetamine treatment similar to that used for ADHD has been demonstrated to produce brain dopaminergic neurotoxicity in primates, causing the damage of dopaminergic nerve endings in the striatum that may also occur in other disorders with long-term amphetamine treatment (57).
  51. ^ a b Advokat C (July 2007). "Update on amphetamine neurotoxicity and its relevance to the treatment of ADHD". J Atten Disord. 11 (1): 8–16. doi:10.1177/1087054706295605. PMID 17606768.
  52. ^ Berman SM, Kuczenski R, McCracken JT, London ED (February 2009). "Potential adverse effects of amphetamine treatment on brain and behavior: a review". Mol Psychiatry. 14 (2): 123–142. doi:10.1038/mp.2008.90. PMC 2670101. PMID 18698321. Though the paradigm used by Ricaurte et al. 53 arguably still incorporates amphetamine exposure at a level above much clinical use,14,55 it raises important unanswered questions. Is there a threshold of amphetamine exposure above which persistent changes in the dopamine system are induced? [...]
  53. ^ Ricaurte GA, Mechan AO, Yuan J, Hatzidimitriou G, Xie T, Mayne AH, et al. (October 2005). "Amphetamine treatment similar to that used in the treatment of adult attention-deficit/hyperactivity disorder damages dopaminergic nerve endings in the striatum of adult nonhuman primates". J Pharmacol Exp Ther. 315 (1): 91–98. doi:10.1124/jpet.105.087916. PMID 16014752.
  54. ^ Courtney KE, Ray LA (2016). "Clinical neuroscience of amphetamine-type stimulants: From basic science to treatment development". Prog Brain Res. 223: 295–310. doi:10.1016/bs.pbr.2015.07.010. PMID 26806782. Repeated exposure to moderate to high levels of methamphetamine has been related to neurotoxic effects on the dopaminergic and serotonergic systems, leading to potentially irreversible loss of nerve terminals and/or neuron cell bodies (Cho and Melega, 2002). Preclinical evidence suggests that d-amphetamine, even when administered at commonly prescribed therapeutic doses, also results in toxicity to brain dopaminergic axon terminals (Ricaurte et al., 2005).
  55. ^ Gerlach M, Grünblatt E, Lange KW (June 2013). "Is the treatment with psychostimulants in children and adolescents with attention deficit hyperactivity disorder harmful for the dopaminergic system?". Atten Defic Hyperact Disord. 5 (2): 71–81. doi:10.1007/s12402-013-0105-y. PMID 23605387.
  56. ^ Oeri HE (May 2021). "Beyond ecstasy: Alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy". J Psychopharmacol. 35 (5): 512–536. doi:10.1177/0269881120920420. PMC 8155739. PMID 32909493.
  57. ^ Pinterova N, Horsley RR, Palenicek T (2017). "Synthetic Aminoindanes: A Summary of Existing Knowledge". Front Psychiatry. 8: 236. doi:10.3389/fpsyt.2017.00236. PMC 5698283. PMID 29204127.
  58. ^ a b c d e f g h i j k l m Nagai F, Nonaka R, Satoh Hisashi Kamimura K (March 2007). "The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain". European Journal of Pharmacology. 559 (2–3): 132–137. doi:10.1016/j.ejphar.2006.11.075. PMID 17223101.
  59. ^ a b c d Wee S, Anderson KG, Baumann MH, Rothman RB, Blough BE, Woolverton WL (May 2005). "Relationship between the serotonergic activity and reinforcing effects of a series of amphetamine analogs". The Journal of Pharmacology and Experimental Therapeutics. 313 (2): 848–854. doi:10.1124/jpet.104.080101. PMID 15677348. S2CID 12135483.
  60. ^ a b c Brandt SD, Baumann MH, Partilla JS, Kavanagh PV, Power JD, Talbot B, et al. (2014). "Characterization of a novel and potentially lethal designer drug (±)-cis-para-methyl-4-methylaminorex (4,4'-DMAR, or 'Serotoni')". Drug Testing and Analysis. 6 (7–8): 684–695. doi:10.1002/dta.1668. PMC 4128571. PMID 24841869.
  61. ^ a b c d e f g h i j Rothman RB, Partilla JS, Baumann MH, Lightfoot-Siordia C, Blough BE (April 2012). "Studies of the biogenic amine transporters. 14. Identification of low-efficacy "partial" substrates for the biogenic amine transporters". The Journal of Pharmacology and Experimental Therapeutics. 341 (1): 251–262. doi:10.1124/jpet.111.188946. PMC 3364510. PMID 22271821.
  62. ^ a b c d McLaughlin G, Morris N, Kavanagh PV, Power JD, Twamley B, O'Brien J, et al. (July 2015). "Synthesis, characterization, and monoamine transporter activity of the new psychoactive substance 3',4'-methylenedioxy-4-methylaminorex (MDMAR)". Drug Testing and Analysis. 7 (7): 555–564. doi:10.1002/dta.1732. PMC 5331736. PMID 25331619.
  63. ^ a b c Marusich JA, Antonazzo KR, Blough BE, Brandt SD, Kavanagh PV, Partilla JS, et al. (February 2016). "The new psychoactive substances 5-(2-aminopropyl)indole (5-IT) and 6-(2-aminopropyl)indole (6-IT) interact with monoamine transporters in brain tissue". Neuropharmacology. 101: 68–75. doi:10.1016/j.neuropharm.2015.09.004. PMC 4681602. PMID 26362361.
  64. ^ a b Yu H, Rothman RB, Dersch CM, Partilla JS, Rice KC (December 2000). "Uptake and release effects of diethylpropion and its metabolites with biogenic amine transporters". Bioorganic & Medicinal Chemistry. 8 (12): 2689–2692. doi:10.1016/s0968-0896(00)00210-8. PMID 11131159.
  65. ^ a b c Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, et al. (March 2013). "Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products". Neuropsychopharmacology. 38 (4): 552–562. doi:10.1038/npp.2012.204. PMC 3572453. PMID 23072836.
  66. ^ a b Baumann MH, Clark RD, Budzynski AG, Partilla JS, Blough BE, Rothman RB (March 2005). "N-substituted piperazines abused by humans mimic the molecular mechanism of 3,4-methylenedioxymethamphetamine (MDMA, or 'Ecstasy')". Neuropsychopharmacology. 30 (3): 550–560. doi:10.1038/sj.npp.1300585. PMID 15496938.
  67. ^ a b c d e f g h i Rothman RB, Vu N, Partilla JS, Roth BL, Hufeisen SJ, Compton-Toth BA, et al. (October 2003). "In vitro characterization of ephedrine-related stereoisomers at biogenic amine transporters and the receptorome reveals selective actions as norepinephrine transporter substrates". The Journal of Pharmacology and Experimental Therapeutics. 307 (1): 138–145. doi:10.1124/jpet.103.053975. PMID 12954796. S2CID 19015584.
  68. ^ a b c d Rothman RB, Clark RD, Partilla JS, Baumann MH (June 2003). "(+)-Fenfluramine and its major metabolite, (+)-norfenfluramine, are potent substrates for norepinephrine transporters". The Journal of Pharmacology and Experimental Therapeutics. 305 (3): 1191–1199. doi:10.1124/jpet.103.049684. PMID 12649307. S2CID 21164342.
  69. ^ a b c d e f g h Setola V, Hufeisen SJ, Grande-Allen KJ, Vesely I, Glennon RA, Blough B, et al. (June 2003). "3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro". Molecular Pharmacology. 63 (6): 1223–1229. doi:10.1124/mol.63.6.1223. PMID 12761331. S2CID 839426.
  70. ^ a b Rothman RB, Baumann MH (July 2002). "Therapeutic and adverse actions of serotonin transporter substrates". Pharmacology & Therapeutics. 95 (1): 73–88. doi:10.1016/s0163-7258(02)00234-6. PMID 12163129.
  71. ^ Rothman RB, Baumann MH (April 2002). "Serotonin releasing agents. Neurochemical, therapeutic and adverse effects". Pharmacology, Biochemistry, and Behavior. 71 (4): 825–836. doi:10.1016/s0091-3057(01)00669-4. PMID 11888573. S2CID 24296122.
  72. ^ a b c d Baumann MH, Ayestas MA, Partilla JS, Sink JR, Shulgin AT, Daley PF, et al. (April 2012). "The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue". Neuropsychopharmacology. 37 (5): 1192–1203. doi:10.1038/npp.2011.304. PMC 3306880. PMID 22169943.
  73. ^ Rothman RB, Blough BE, Woolverton WL, Anderson KG, Negus SS, Mello NK, et al. (June 2005). "Development of a rationally designed, low abuse potential, biogenic amine releaser that suppresses cocaine self-administration". The Journal of Pharmacology and Experimental Therapeutics. 313 (3): 1361–1369. doi:10.1124/jpet.104.082503. PMID 15761112. S2CID 19802702.
  74. ^ a b Kohut SJ, Jacobs DS, Rothman RB, Partilla JS, Bergman J, Blough BE (December 2017). "Cocaine-like discriminative stimulus effects of "norepinephrine-preferring" monoamine releasers: time course and interaction studies in rhesus monkeys". Psychopharmacology. 234 (23–24): 3455–3465. doi:10.1007/s00213-017-4731-5. PMC 5747253. PMID 28889212.
  75. ^ a b c Rothman RB, Katsnelson M, Vu N, Partilla JS, Dersch CM, Blough BE, et al. (June 2002). "Interaction of the anorectic medication, phendimetrazine, and its metabolites with monoamine transporters in rat brain". European Journal of Pharmacology. 447 (1): 51–57. doi:10.1016/s0014-2999(02)01830-7. PMID 12106802.

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