Monoamine releasing agent


A monoamine releasing agent, 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. The monoamine neurotransmitters include serotonin, norepinephrine, and dopamine; MRAs can induce the release of one or more of these neurotransmitters.
MRAs work by reversing the direction of the monoamine transporters, including the serotonin transporter, norepinephrine transporter, and/or dopamine transporter, causing them to promote efflux of non-vesicular cytoplasmic monoamine neurotransmitter rather than reuptake of synaptic monoamine neurotransmitter. Many, but not all MRAs, also reverse the direction of the vesicular monoamine transporter 2, thereby additionally resulting in efflux of vesicular monoamine neurotransmitter into the cytoplasm.
A variety of different classes of drugs induce their effects in the body and/or brain via the release of monoamine neurotransmitters. 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. Trace amines like phenethylamine and tryptamine, as well as the monoamine neurotransmitters themselves, are endogenous MRAs. It is thought that monoamine release by endogenous mediators may play some physiological regulatory role.
MRAs must be distinguished from monoamine reuptake inhibitors and monoaminergic activity enhancers, which similarly increase synaptic monoamine neurotransmitter levels and enhance monoaminergic signaling but work via distinct mechanisms.

Types and selectivity

MRAs can be classified by the monoamines they mainly release, although these drugs lie on a spectrum:
The differences in selectivity of MRAs 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.
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. Several selective SDRAs, including tryptamine, -α-ethyltryptamine, 5-chloro-αMT, and 5-fluoro-αET, are known. However, besides their serotonin release, many of these compounds additionally act as non-selective serotonin receptor agonists, including of the serotonin 5-HT2A receptor, and some of them are known to act as monoamine oxidase inhibitors.

Effects and uses

MRAs can produce varying effects depending on their selectivity for inducing the release of different monoamine neurotransmitters.
Selective SRAs such as chlorphentermine have been described as dysphoric and lethargic. Less selective SRAs that also stimulate the release of dopamine, such as methylenedioxymethamphetamine, are described as more pleasant, more reliably elevating mood and increasing energy and sociability. 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 because they can produce much larger increases in serotonin levels in comparison.
DRAs, usually non-selective for both norepinephrine and dopamine, have psychostimulant effects, causing an increase in energy, motivation, elevated mood, and euphoria. Other variables can significantly affect the subjective effects, such as infusion rate and psychological expectancy effects. They are used in the treatment of attention deficit hyperactivity disorder, 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. They may also be performance-enhancing, in contrast to reboxetine which is solely a norepinephrine reuptake inhibitor. 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.

Mechanism of action

Mechanisms of monoamine release by MRAs

MRAs induce the release of the monoamine neurotransmitters serotonin, norepinephrine, and/or dopamine from monoaminergic neurons in the brain and/or periphery. MRAs are substrates of the plasma membrane-associated monoamine transporters, including of the serotonin transporter, norepinephrine transporter, and/or dopamine transporter, and enter presynaptic monoaminergic neurons via these transporters. To a much lesser extent, sufficiently lipophilic MRAs may also passively diffuse into monoaminergic neurons. Once in the intracellular space of the neuron, MRAs reverse the direction of the MATs, as well as of the organic cation transporter 3, such that they mediate efflux of cytosolic monoamine neurotransmitters into the extracellular synaptic cleft rather than the usual reuptake. Many, though notably not all MRAs, additionally act at the vesicular monoamine transporter 2 on synaptic vesicles to enhance the pool of cytosolic monoamine neurotransmitters available for efflux. However, MRAs can still induce monoamine release without VMAT2, for instance by releasing newly synthesized cytosolic neurotransmitters. In addition to their induction of monoamine release, MRAs act less potently as monoamine reuptake inhibitors. This is due to substrate competition with monoamine neurotransmitters for the MATs and/or induction of MAT internalization and consequent inactivation. The monoamine neurotransmitters released by MRAs bind to and activate monoamine receptors on presynaptic and postsynaptic neurons to facilitate monoaminergic neurotransmission. As such, MRAs can be described as indirect monoamine receptor agonists.
The mechanisms by which MRAs induce MAT reverse transport and efflux are complex and incompletely understood. The process appears to depend on a number of intracellular changes, including sodium ion and calcium ion elevation, protein kinase C activation, and Ca2+/calmodulin-dependent protein kinase II alpha activation, among others. Activation of protein kinases including PKC, CaMKIIα, and others results in phosphorylation of the MATs causing them to mediate efflux instead of reuptake. Exactly how MRAs induce the preceding effects is unclear however. A more recent study suggests that intracellular Ca2+ elevation, PKC activation, and CaMKIIα might all be dispensable for MRA-induced monoamine release, but more research is needed.
The trace amine-associated receptor 1 is a receptor for trace amines like β-phenethylamine and tryptamine, as well as for monoamine neurotransmitters like dopamine and serotonin, and is a known target of many MRAs, such as amphetamine and methamphetamine. The TAAR1 is a largely intracellular receptor expressed both in presynaptic and postsynaptic monoaminergic neurons and appears to be extensively co-localized with MATs in the brain. Some in-vitro studies have found that TAAR1 agonism by MAT substrates like MRAs can produce PKC activation and thereby induce MAT reverse transport and monoamine efflux. As such, TAAR1 agonism, coupled with MAT substrate activity, could mediate or contribute to the monoamine release of MRAs. However, findings in this area are conflicting, with other studies unable to replicate the results. In addition, MRAs can still induce monoamine efflux in the absence of TAAR1 in vitro, well-known MRAs like amphetamine and methamphetamine exhibit only low-potency human TAAR1 agonism that is of uncertain general significance in humans, many other MRAs are inactive as TAAR1 agonists in humans, the monoamine release and behavioral effects of amphetamines are not only preserved but substantially augmented in TAAR1 knockout mice, and the monoamine release and behavioral effects of amphetamines are strongly reduced or abolished in mice with TAAR1 overexpression. Besides induction of monoamine release, TAAR1 agonism, as well as other mechanisms, may mediate MAT internalization. MAT internalization may limit the capacity of MRAs to induce MAT reverse transport and monoamine efflux. TAAR1 signaling also activates G protein-coupled inwardly rectifying potassium channels and thereby robustly inhibits the firing rates of brain monoaminergic neurons and suppresses exocytotic monoamine release. Due to the preceding mechanisms, potent TAAR1 agonism by MRAs that possess this action may actually auto-inhibit and constrain their monoaminergic effects.
Although induction of MAT reverse transport and consequent monoamine efflux is the leading theory of how MRAs act, an alternative and more recent theory has proposed that amphetamine, at therapeutic doses, may not actually act by inducing DAT reverse transport and dopamine efflux, but instead by augmenting exocytotic dopamine release and hence by enhancing phasic rather than tonic dopaminergic signaling. According to this model, DAT reverse transport may only be relevant at supratherapeutic doses and may be more associated with toxicity, for instance induction of psychosis. It is unclear how amphetamine might act to enhance exocytotic dopamine release, and more research is needed to evaluate this theory.
Aside from the mechanisms mediating the monoamine release of MRAs, other targets of some MRAs, such as the intracellular sigma σ1 receptor, have been found to inhibit MRA-induced monoamine efflux via interactions with the MATs. Conversely, activation of the sigma σ2 receptor has been found to potentiate amphetamine-induced dopamine efflux. The mechanism mediating this effect is unknown, but it has been postulated that it may be due to elevation of intracellular calcium and consequent downstream effects.