themodernsound asked: So while we're talking about bupropion; to my knowledge every Serotonin-Dopamine Reputake Inhibitor yet researched has been shelved as a potential anti-depressant because of abuse liability. Why, in your estimation, would this be any different than combining bupropion with an SSRI (discounting NRI activity of course but that would really only further highlight my curiosity/confusion)?

slatestarscratchpad:

It shouldn’t be. The serotonin should be irrelevant. The interesting question is why bupropion doesn’t have abuse potential.

(it sort of does - there are people who will abuse bupropion - but it’s not that common and you have to be desperate)

The answer is “nobody knows anything about any of this”. Sinemet is Literally Dopamine, and you can take it and recover from hypodopaminergic disorders, yet it’s not addictive. Pramipexole is a great dopamine agonist and it’s not addictive either.

My guess is this stuff has to do with where in the brain it increases dopamine, how quickly, how much, by what method, etc. But that’s all just a guess.

We totally know about this!  Some dopamine “reuptake inhibitors” bind to the dopamine transporter when it’s in the “open configuration” and others when it’s in the “closed configuration,” and the difference maps onto abuse potential: cocaine and methylphenidate are on one side (”binds to open DAT”), bupropion/hydroxybupropion and modafinil are on the other(”binds to closed DAT”), and there are some more esoteric/research-type chemicals on each side which also fit the pattern.  Here is a paper about it, and here’s another.

The latter paper speculates, at the end, that the DAT is just more frequently in the open configuration than the closed one (at least I think that’s what they’re saying).  So drugs that bind to open DATs get more chances to bind than those that bind to closed DATs, all else being equal.

Of course, all else isn’t ever equal, and this is presumably just one (important) contribution to the overall effect, along with the usual ones like binding affinity and rate of delivery to the brain.  Bupropion is particularly complicated because it is largely a prodrug to the metabolite hydroxybupropion when taken orally (you end up with way more hydroxybupropion than bupropion in plasma), and hydroxybupropion is a much weaker dopamine reuptake inhibitor than bupropion.  As @wirehead-wannabe mentioned, people do (ab)use bupropion recreationally by insufflating it (or injecting it), which bypasses first-pass metabolism, so you get more actual bupropion as opposed to hydroxybupropion in your brain (and of course it is delivered way faster).  It makes sense that this would be more reinforcing, although one would think the “binds to closed DAT” thing would still mean it isn’t all that reinforcing.  (Which seems likely to be true: if snorted bupropion produced a high anywhere near comparable to cocaine, you’d think it would get really widely abused and be made a controlled substance.)

(N.B. the first paper linked above is about modafinil, which is apparently a “binds to closed DAT” reuptake inhibitor, like bupropion.  From what I have read, e.g. this paper, it looks like that is probably all modafinil is; the fancy hypotheses about histamine and orexin don’t explain anything that dopamine reuptake inhibition wouldn’t.  So modafinil is probably a much “cleaner” example of what you get from “binds to closed DAT” inhibitors, without all the bupropion-specific weirdness discussed above.)

Anyway, I don’t know anything about SDRIs, but if the ones mentioned by the anon asker were the “binds to open DAT” kind of DRI, that would explain everything nicely.