[username135]

Youd have to figure out how to continuously produce dopamine and serotonin, or replicate their effects from the perspective of pleasure. Pretty tall order since they have multiple purposes inside you. Trillion dollar idea though.

[gosub100]

I was more suggesting that if the receptors could be targeted (I have no idea how, just spit-balling) by another agent, then tolerance would perhaps not occur. The addict/user would still need the original drug.

[SturgeonsLaw]

Receptor downregulation plays a key role in maintaining homeostasis within normal brain function, so attempting to intefere with that process is playing a dangerous game, however it is in theory possible, since the effects of receptor activation are separate from the downregulation process, though they are linked.

When a neuron's receptors get strongly activated, that neuron can withdraw receptors from its surface into the interior of the cell (a process call internalisation), and from there either digest the receptors (downregulation) or move the receptors back to the surface of the cell where they resume their typical function (resensitisation). Those processes are potential targets for a tolerance-mitigating drug.

The tricky part is that they are very fundamental processes across all neurons and it would be very hard to target, say, dopaminergic receptors in the nucleus accumbens to ventral tegmental area (the "reward circuit") without also affecting neurons across the entire brain.

The best cure for tolerance is taking a break :) easier said than done, I know.