Fig 1 DAT: cocaine vs amphetamine hover or focus a part · space: pause extracellular dopamine: baseline
presynaptic terminal synaptic vesicle (holds dopamine) VMAT2 synaptic cleft (schematic gap) postsynaptic cell plasma membrane dopamine transporter (DAT) dopamine receptors OH OH NH₂ dopamine O O O O N H H cocaine NH₂ amphetamine Mechanism of action only. Schematic cutaway of one dopamine terminal, not to scale; particle numbers and speeds are illustrative, not measured. Shapes in the legend mark dopamine, cocaine and amphetamine.
Drug state
NONE COCAINE AMPHETAMINE
Pause motion
arrows at DAT: in = reuptake, cross = blocked, out = efflux
Hover or focus a labelled part for a one-line explanation.
What the figure shows, and how sure we are
Educational mechanism-of-action explainer only. It is not medical advice, and it says nothing about risk, use, dose, route or effects of any substance, or about any person. It shows no numbers beyond the one cited below.
DAT is the main route that clears released dopamine, and the target of both drugs. In mice lacking DAT, dopamine persists at least 100 times longer in the extracellular space, and cocaine and amphetamine have no effect on locomotor activity or dopamine release and uptake (Giros et al., Nature 1996 , mouse). DAT competes with diffusion: it mostly sets the reach and lifetime of dopamine beyond a release site, and many receptors are extrasynaptic (Cragg & Rice, Trends Neurosci 2004 , review and model).Cocaine blocks reuptake. Blockade of dopamine reuptake is one way addictive drugs raise synaptic dopamine (Sulzer, Neuron 2011 , review). Crystal structures of Drosophila DAT show cocaine and analogues bound at the central site, while substrates (dopamine, amphetamines) bind the same site in a different conformation (Wang, Penmatsa & Gouaux, Nature 2015 ; Drosophila protein, not human).Amphetamine: substrate, vesicle disruption, efflux. Two primary mechanisms: redistribution of catecholamines from vesicles to the cytosol, and reverse transport through plasma-membrane carriers; uptake inhibition and other effects are additional (Sulzer et al., Prog Neurobiol 2005 , review). Amphetamine binds DAT and is transported in, which raises intracellular Na+ availability and enhances reverse transport of dopamine; cocaine blocked the amphetamine-induced DAT currents in these cells (Khoshbouei et al., J Biol Chem 2003 , HEK-293 cells expressing human DAT). DAT is needed for amphetamine’s releasing action but not for its vesicle-depleting action, and stimulated vesicular release disappears after amphetamine (Jones et al., J Neurosci 1998 , mouse striatal slices). DAT and VMAT2 are two principal targets of amphetamine (Fleckenstein et al., Annu Rev Pharmacol Toxicol 2007 , review). TAAR1, a receptor activated by amphetamine-related drugs, modulates DAT uptake and efflux in cell assays (Xie & Miller, J Pharmacol Exp Ther 2007 , HEK-293 cells, rhesus TAAR1); it is named here but not drawn.Structures. Skeletal formulas are flat redrawings of the PubChem 2D depictions, with the heavy-atom and hydrogen counts checked against the PubChem molecular formulas: dopamine CID 681 (C8H11NO2), cocaine CID 446220 (C17H21NO4), amphetamine CID 3007 (C9H13N, no stereochemistry given).
What was simplified. One terminal and one cleft stand for a dopamine synapse; sizes, the cleft width, numbers of vesicles, DAT and receptors, and every particle speed and rate are illustrative. Many dopamine neurons release dopamine from non-synaptic sites, which the cut ignores. Amphetamine’s weak-base and other actions, synthesis and metabolism, autoreceptors and downstream signalling are omitted. Vesicles are drawn with fewer dopamine dots and reduced exocytosis after amphetamine to stand for depleted storage; the figure gives no amounts. Cocaine is shown at DAT only. DAT work above mixes mouse, fly and cultured-cell systems; the schematic is not a claim about any one species. The Giros and Jones records were checked at abstract level (Europe PMC); full texts were not read.