Amphetamines, new psychoactive drugs and the monoamine transporter cycle

Abstract

In monoaminergic neurons, the vesicular transporters and the plasma membrane transporters operate in a relay. Amphetamine and its congeners target this relay to elicit their actions: most amphetamines are substrates, which pervert the relay to elicit efflux of monoamines into the synaptic cleft. However, some amphetamines act as transporter inhibitors. Both compound classes elicit profound psychostimulant effects, which render them liable to recreational abuse. Currently, a surge of new psychoactive substances occurs on a global scale. Chemists bypass drug bans by ingenuous structural variations, resulting in a rich pharmacology. A credible transport model must account for their distinct mode of action and link this to subtle differences in activity and undesired, potentially deleterious effects.

Amphetamine Action at the Cocaine- and Antidepressant-Sensitive Serotonin Transporter Is Modulated by αCaMKII

“…At the concentrations used, CaMKII inhibitors did not blunt inward transport of substrate through SERT regardless of whether ␣CaMKII was present or absent. More importantly, these observations and related findings with DAT (Steinkellner et al, 2012 stress the apparent asymmetry of substrate uptake by and efflux through monoamine transporters (Sitte and Freissmuth, 2015). A comparable asymmetry in uptake and efflux has also been found for the interaction of SERT and DAT with phosphoinositides: depletion of phosphatidylinositol-4,5-bisphosphate impaired amphetamine-induced efflux through SERT and DAT, but had no effect on substrate uptake (Buchmayer et al, 2013;Hamilton et al, 2014).…”

“…For example, D-amphetamine ("speed") has higher affinities for DAT and NET compared with SERT, whereas fenfluramine or 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") show a higher affinity for SERT (Green et al, 2003). Similarly, the mechanism of action of amphetamines is complex (Sitte and Freissmuth, 2015): amphetamines are recognized as substrates of both plasma membrane transporters and VMATs (Schuldiner et al, 1993). Accordingly, they accumulate within the synaptic vesicles, where they dissipate the proton gradient; therefore, 5-HT increases within the cytosol.…”

Structure-Activity Relationships of Substituted Cathinones, with Transporter Binding, Uptake, and Release

“…Drug substrates for the transporters have several functions, competing with extracellular neurotransmitter for reuptake into the presynaptic neuron and inducing release of intracellular neurotransmitter. There are several theories for the molecular mechanism of substrate-induced release, including forward and reverse transport by the same protein, referred to as the "facilitated exchange diffusion model," and forward and reverse transport mediated by different proteins within an oligomeric complex (reviewed by Sitte and Freissmuth, 2015). Another theory is the channel model, whereby substrates are depolarizing and excitatory, causing neurotransmitter release by vesicle fusion (reviewed by De Felice et al, 2014).…”

Big Lessons from Tiny Flies:<em> Drosophila Melanogaster </em>as a Model to Explore Dysfunction of Dopaminergic and Serotonergic Neurotransmitter Systems

“…Accordingly, Drosophila can be used to study the action of addictive drugs. Amphetamine and its congeners switch monoamine transporters from a forward transport mode to a substrate exchange mode [37]. This is contingent on transporter phosphorylationby CaMkinase II [41,42] .…”

“…Monoamine transporters have a rich pharmacology comprising atypical inhibitors and partial substrates, i.e. compounds, which trap the transporters at different stages of their conformational cycle [37]. Partial substrates of monoamine transporters can also act as pharmacochaperones but their effectiveness may be limited by their high affinity [65].…”