Releasing agent
A releasing agent, or simply releaser, is a drug that induces the release of a neurotransmitter from the presynaptic neurone into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitter. Many drugs use neurotransmitter release to exert their psychological and physiological effects, namely the amphetamines and related compounds. Virtually all currently known releasing agents affect the monoamine neurotransmitters serotonin, noradrenaline, and/or dopamine, and as such, they are often referred to more formally as monoamine releasing agents (MRAs).
Mechanism of Action
Releasing agents cause the release of neurotransmitters by first entering the presynaptic neurone, primarily via membrane transporters. Some, such as amphetamine and methamphetamine, can also diffuse directly across the cell membrane. Next, they inhibit vesicular uptake of the neurotransmitter by interfering with a vesicular transporter, and thus inhibit the repackaging of the neurotransmitter from the pre-synaptic neurone into vesicles. Finally, releasing agents reverse the action of reuptake receptor, allowing the neurotransmitter to flow out from the pre-synaptic neurone into the nerve terminal or synapse. The result is increased neurotransmission. The postsynaptic effect is enhanced due to the interaction with reuptake receptors; one method by which the action of neurotransmitters is terminated is via reuptake into the presynaptic neuron, and disruption of this process causes further increases in extracellular neurotransmitter concentration.
Selectivity
Releasing agents act to varying extents on the monoamine neurotransmitters. Some will induce the release of all three monoamines, an example of this is MDMA. Others are more selective, methamphetamine is a potent releasing agent of dopamine and noradrenaline, but is a weak releaser of serotonin.
Neurotoxicity
Many releasing agents, notably many of those derived from amphetamine, have been found to be neurotoxic to serotonin and/or dopamine neurons via damage to axons and dendrites, enzymes, mitochondria, DNA, plasmalemmal and vesicular transporters, and the cell membrane, ultimately causing cell death as a result. The neurotoxicity of some of these drugs is believed to be caused by oxidative stress induced by the generation of reactive oxygen species or free radicals, highly reactive particles that rip apart proteins and induce chain reactions of destruction. The free radicals are thought to be generated as byproducts when either the base compound or one or more of its metabolites are broken down by the enzymes monoamine oxidase (MAO-B) and/or cyclooxygenase (COX). It is thought hyperthermia and concurrent serotonin-dopamine release may also play a major role in augmenting damage.