Monoamine releasing agent

"Releasing agent" redirects here. For mold release agents, see Release agent.
Amphetamine, the prototypical monoamine releasing agent, which induces the release of dopamine and norepinephrine.[1]

A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of one or more monoamine neurotransmitters from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitters and hence enhanced signaling by those neurotransmitters.[2][3][4][1][5] The monoamine neurotransmitters include serotonin, norepinephrine, and dopamine; monoamine releasing agents can induce the release of one or more of these neurotransmitters.[2][3][4][1][5]

Monoamine releasing agents work by reversing the direction of the monoamine transporters (MATs), including the serotonin transporter (SERT), norepinephrine transporter (NET), and/or dopamine transporter (DAT), causing them to promote efflux of non-vesicular cytoplasmic monoamine neurotransmitter rather than reuptake of synaptic monoamine neurotransmitter.[5][6][1][7] Many, but not all monoamine releasing agents, also reverse the direction of the vesicular monoamine transporter 2 (VMAT2), thereby additionally resulting in efflux of vesicular monoamine neurotransmitter into the cytoplasm.[5]

A variety of different classes of drugs induce their effects in the body and/or brain via the release of monoamine neurotransmitters.[2][3] These include psychostimulants and appetite suppressants acting as dopamine and norepinephrine releasers like amphetamine, methamphetamine, and phentermine; sympathomimetic agents acting as norepinephrine releasers like ephedrine and pseudoephedrine; non-stimulant appetite suppressants acting as serotonin releasers like fenfluramine and chlorphentermine; and entactogens acting as releasers of serotonin and/or other monoamines like MDMA.[2][3] Trace amines like phenethylamine and tryptamine, as well as the monoamine neurotransmitters themselves, are endogenous monoamine releasing agents.[2][3][4] It is thought that monoamine release by endogenous mediators may play some physiological regulatory role.[4]

MRAs must be distinguished from monoamine reuptake inhibitors (MRIs) and monoaminergic activity enhancers (MAEs), which similarly increase synaptic monoamine neurotransmitter levels and enhance monoaminergic signaling but work via distinct mechanisms.[5][1][8][9]

  1. ^ a b c d e 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.
  2. ^ a b c d e 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.
  3. ^ a b c d e 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.
  4. ^ a b c d Blough B (July 2008). "Dopamine-releasing agents". Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. pp. 305–320. ISBN 978-0-470-11790-3. Archived from the original on 4 November 2024. TABLE 11-2 Comparison of the DAT- and NET-Releasing Activity of a Series of Amphetamines [...]
  5. ^ a b c d e 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).
  6. ^ Cite error: The named reference SchmittRothmanReith2013 was invoked but never defined (see the help page).
  7. ^ Cite error: The named reference HealGosdenSmith2014 was invoked but never defined (see the help page).
  8. ^ Cite error: The named reference ShimazuMiklya2004 was invoked but never defined (see the help page).
  9. ^ Cite error: The named reference Knoll2003 was invoked but never defined (see the help page).