I love the idea of this. It basically describes everything there is to amphetamine. It's also very well-written and formatted. But there were some mistakes, mostly about the pharmacology of amphetamine.
Usually tolerance occurs to some extent through the downregulation of receptors, and usually also through a reduction of the release of neurotransmitter. Amphetamine tolerance does cause a downregulation of dopamine receptors like other drugs and it also involves a reduction of the release of dopamine (and to some extent, with NE and a little 5-HT). But the mechanism is slightly different.
Amphetamine is a substrate of dopamine transporter (DAT), which is the protein on the presynaptic cell that transports (reuptakes) dopamine from the synapse to inside the cell. As a substrate, it is also a competitive inhibitor. DAT confuses amphetamine for DA and reuptakes it, unlike most reuptake inhibitors (cocaine, prozac, wellbutrin, etc) which are purely inhibitors but not substrates. Inside the cell, it somehow actually reverses DAT so that it actually transports dopamine out of the cell, into the synapse, increasing synaptic transmission of dopaminergic cells. It also reverses vesicular monamine transporters (VMAT2) on the vesicle surfaces that normally transport dopamine into vesicles from the cell cytoplasm. This increases the dopamine inside the cell and DAT is reversed, so there is a HUGE increase in dopamine in the synapse and a huge increase in dopaminergic signaling. Methamphetamine does all of these but causes a much greater serotonin increase and also releases glutamate.
On the very short term, tolerance is developed to a large degree from depletion of vesicles, but also to a fair extent from downregulation of receptors and possibly downregulation of DAT. But downregulation occurs quickly and continues to happen as a binge continues or through daily use.
Furthermore, amphetamine ITSELF isn’t directly neurotoxic. It doesn’t act on pro-apoptopic receptors and it doesn’t directly do anything to harm a cell. What it does is increase release of toxic neurotransmitters and inhibit their breakdown, both by inhibition of MAO and by always pumping out of the cell where there is no MAO. Too much of any of the monoamines is usually neurotoxic and dopamine itself is a neurotoxin, being easily oxidized into its quinone, which is a free radical. Free radicals basically destroy molecules or bind to them covalently. This damages cells and can cause them to kill themselves (any cell that gets signals that it isn’t needed or harmful will try to kill itself). But “the amphetamine molecule itself” will not cause neural damage. Only indirectly via other agents.
Anyways, sorry to write so much that’s so in depth and esoteric, but I study this stuff for a living. Again, Spunky, I really liked the idea of and execution of your post and I don’t want to seem like I’m putting you down or anything for errors in pharmacology.
Sorry for the long post!
-Jaguraguguru
