Increasing dopamine, or any compound that acts on the same receptors causes downregulation through different ways:
- downregulation of production (which you probably could reverse with a d2 antagonist), but also
- downregulation of receptors (meaning decrease in number of dopamine receptors)
- increase in dopamine turnover through increase in DAT, which moves dopamine back into the vesticle (which dri's block),
- and increased metabolism of dopamine through MAO and comt.
interfering with all of those paths is a bad idea, of course, because the brain needs to have selfregulatory
mechanisms to guard itself from neurotoxicity. Dopamine, as well as its metabolites can be neurotoxic, especially intracellular.
I would argue that those areas in the brain that are underactive in ADHD will not downregulate through increased dopamine, while the other areas will, which ultimately would lead to a homeostasis with equal brain activity in all parts of the brain.
Tolerance may in amphetamines also develop through catecholamine depletion. If there are not enough catecholamines in the brain, amphetamines can't release enough.
Tolerance, however, may not only come from the dopaminergic pathways. Maybe decreased serotonin levels play a role in tolerance. Meaning high dopamine levels likely lower serotonin levels, which when too low not only has problems on it's own, but also could decrease the effects of the dopaminergic system itself.
Then there is the possibilty of chronic tolerance through neurotoxicity: the more dopaminergic neurons get destroyed, the less dopamine can be produced, and ultimately, amphetamines stop working.
So to get tolerance with amphetamines under control, I would:
- decrease neurotoxicity
- test if increasing serotonin does improve symptoms
- test if supplying (very small amounts of) catecholamine precursors helps. (very small because in combination with amphetamines it can be very unpredictable, especially at first)
- Maybe take drug holidays
In context to your original post (lol, I drifted away too much) I would say that increasing dopamine through blocking d2 will not work because of the other regulatory measures, and an increase in receptor density should do the same thing.
You could, in theory, end up stopping catecholamine production alltogether, but supplement with l-dopa so there still are catecholamines in the system, but this would only work if you could stop receptor density decrease as a last adaptation. But this most likely would be a bad idea.
Maybe it works for the opioid system because it has less ways to adapt, maybe because opioids are less neurotoxic then dopamine and it's metabolites. I don't know that, though.
