Monoamine releasing agent

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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[edit]

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

Mechanism of action[edit]

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).[1] 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).


Monoamine release agents can have a wide variety of effects depending upon their selectivity for monoamines. Selective serotonin release agents 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.[2][2][3] Less selective serotonergic agents that stimulate an efflux in dopamine, such as MDMA are described as more pleasant, increasing energy, sociability and elevating mood.[4] Dopamine release agents, usually selective for both norepinephrine and dopamine have psychostimulant effect, causing an increase in energy, and elevated mood.[5] Other variables can significantly affect the subjective effects, such as infusion rate(increasing positive effects of cocaine), and expectancy.[6][6] Selectively noradrenergic drugs are minimally psychoactive, but as demonstrated by ephedrine may be distinguished from placebo, and trends towards liking.[7] They may also be ergogenic,[8] in contrast to solely reuptake inhibitor reboxetine.[9][10]


Selecitivities of MRAs (Ki (nM)):[11][12][13][14][15][16]
Compound NE DA 5-HT
4-Fluoroamphetamine 28.0 51.5 939
4-Methylamphetamine 22.2 44.1 53.4
4-Methylmethcathinone 62.7 49.1 118.3
Aminorex 26.4 49.4 193
D-Amphetamine 7.07 24.8 1765
Benzylpiperazine 62 175 6050
Cathine 15.0 68.3 >10000
L-Cathinone 12.4 18.5 2366
Chlorphentermine >10000 2650 30.9
L-Ephedrine 43.1 236 >10000
D-Ephedrine 218 2104 >10000
Fenfluramine 739 >10000 79.3
Dexfenfluramine 302 >10000 51.7
Levfenfluramine >10000 >10000 147
D-Methamphetamine 12.3 24.5 736
L-Methamphetamine 28.5 416 4640
L-Methcathinone 13.1 14.8 1772
MDA 108 190 160
MDMA 110 278 72
Methylone 152.3 133 242.1
Naphthylisopropylamine 11.1 12.6 3.4
Norfenfluramine 168 1925 104
Phenmetrazine 50.4 131 7765
Phentermine 39.4 262 3511
Phenylpropanolamine 89.5 836.6 >10000
L-Pseudoephedrine 224 1988 >10000
Tyramine 40.6 119 2775

MRAs act to varying extents on serotonin, norepinephrine, and dopamine. Some induce the release of all three neurotransmitters to a similar degree, like 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 dopamine, respectively) and MBDB is a fairly balanced SNRA but a weak releaser of dopamine (~6- and 10-fold lower for dopamine than 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.[17] Several selective SDRAs are known however, though these compounds also act as non-selective serotonin receptor agonists.[18]

See also[edit]


  1. ^ 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): 164–76. PMC 3005101Freely accessible. PMID 21073468. doi:10.1111/j.1471-4159.2010.07109.x. 
  2. ^ a b Brust JC (2004). Neurological Aspects of Substance Abuse. Butterworth-Heinemann. pp. 117–. ISBN 978-0-7506-7313-6. 
  3. ^ United States. Congress. Senate. Select Committee on Small Business. Subcommittee on Monopoly and Anticompetitive Activities (1976). 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. pp. 2–. 
  4. ^ 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. ISSN 1099-1077. doi:10.1002/(SICI)1099-1077(199709/10)12:53.0.CO;2-V. 
  5. ^ 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): 177–92. PMC 3624068Freely accessible. PMID 23271193. doi:10.1007/s00213-012-2954-z. 
  6. ^ a b Nelson RA, Boyd SJ, Ziegelstein RC, Herning R, Cadet JL, Henningfield JE, Schuster CR, Contoreggi C, Gorelick DA (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. PMID 16144747. doi:10.1016/j.drugalcdep.2005.08.004. 
  7. ^ Berlin I, Warot D, Aymard G, Acquaviva E, Legrand M, Labarthe B, Peyron I, Diquet B, Lechat P (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): 447–55. PMID 11699608. 
  8. ^ Powers ME (October 2001). "Ephedra and its application to sport performance: another concern for the athletic trainer?". Journal of Athletic Training. 36 (4): 420–4. PMC 155439Freely accessible. PMID 16558668. 
  9. ^ 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. PMID 17004850. doi:10.2165/00007256-200636100-00006. 
  10. ^ 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): 229–46. PMID 20199121. doi:10.2165/11533670-000000000-00000. 
  11. ^ Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse. 39 (1): 32–41. PMID 11071707. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. 
  12. ^ Rothman RB, Baumann MH (2006). "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry. 6 (17): 1845–59. PMID 17017961. doi:10.2174/156802606778249766. 
  13. ^ Rothman RB, Vu N, Partilla JS, Roth BL, Hufeisen SJ, Compton-Toth BA, Birkes J, Young R, Glennon RA (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): 138–45. PMID 12954796. doi:10.1124/jpet.103.053975. 
  14. ^ Rothman RB, Blough BE, Woolverton WL, Anderson KG, Negus SS, Mello NK, Roth BL, Baumann MH (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): 1361–9. PMID 15761112. doi:10.1124/jpet.104.082503. 
  15. ^ 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): 848–54. PMID 15677348. doi:10.1124/jpet.104.080101. 
  16. ^ Roth, BL; Driscol, J (12 January 2011). "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 8 November 2013. 
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