Okay, after some research, I've concluded this:
amphetamine neurotoxicity seems to be mediated in a form that's fundamentally *different* from glutamate neurotoxicity. So what this means is that I really don't think that piracetam is going to substantially increase the neurotoxicity from Adderall.
most of amphetamine's neurotoxicity comes from the increase of dopamine in the presynaptic axon. Since amphetamine also inhibits VMAT-2, the released dopamine doesn't even go back into its synaptic vesicles. Much of this dopamine will be "forced" out of the cell, since the phosphorylated dopamine transporter protein will move them from the presynaptic axon into the extracellular space. BUT - some of this dopamine will stay in - and this dopamine is going to be destroyed by MAO and COMT - the byproducts of both MAO and COMT are both neurotoxic (you could reduce some of this by taking a MAO-A selective inhibitor like deprenyl, and the additional dopamine is probably going to end up in extracellular space, although more of it will also get destroyed through COMT or oxidized in the presynaptic axon). Also, dopamine is unstable and is easily oxidized, which contributes to further neurotoxicity in the presynaptic axon (which can destroy the axon, although it may not destroy the rest of the cell). This brings up an interesting question though - is it better for the dopamine to be destroyed outside of the cell than inside it? The reuptake inhibition is going to prevent most(?) of it from going back into the cell, so a lot of it will end up destroyed outside the cell. But is it really destroyed when it's outside the cell, or does it mostly stay there until reuptake inhibition subsides?
So anyways, the increase in extracellular dopamine levels is going to increase activity of the postsynaptic dopamine receptor. Now, there are D1 receptors and D2-like receptors. D1 receptors are stimulatory, so they increase adenylyl cyclase levels, and then they increase expression of the cAMP pathway. D2 receptors are inhibitory, so they have the exact opposite effect. Now, my intuition is that D2 receptors are more important because they're the receptors that are implicated for ADHD. But then this would seem weird because I wouldn't expect D2 receptors to inhibit cAMP pathway activity (the cAMP pathway is important for memory formation and long-term potentiation, since it will upregulate AMPA and NMDA receptors => such receptor upregulation does not necessarily contribute to neurotoxicity since it simply makes it "easier" for an action potential to happen => but then, do the receptors close up during an action potential? And what happens to the calcium ions?). Now, what does this have to do with calcium ions? Well, the cAMP pathway increases the expression of CaM kinases, so that binds some calcium ions for a while. But then what happens to the extra calcium ions after the CaM interaction is done with?
Now, there is some research that indicates that amphetamines increase glutamate release (glutamate being the chemical that binds with the AMPA receptor, increasing the influx of calcium into the postsynaptic cell). That is independent from the main effect of amphetamine though. I don't think that the effect is large at all, and there are other ways of increasing glutamate to higher levels. Now, piracetam is going to enhance activity at the AMPA receptors, which will probably cause more calcium to enter the cell. Now, calcium ions are quite neurotoxic in themselves, and if left untouched, can make the mitochondrial membranes more permeable, causing oxidation and ultimate destruction of the mitochondria and the entire cell (why this doesn't make piracetam neurotoxic in itself - I'd like someone to answer). But that is completely different from the amphetamine neurotoxicity I mentioned above.
Edited by InquilineKea, 12 January 2011 - 09:29 AM.
