It depends what drug you're talking about. For dopaminergic stuff like amphetamines, think of it as depleting your dopamine and then there's so much free dopamine that it gets turned into something that kills the dopamine receptor. For stuff like opiates, you can think of it as the activated receptors getting brought into the cell to do stuff which results in less opiate receptors total. .I think it tends to be more toxicity/downstream consequences more than an indirect detector. Instead what's getting you high (the dopamine activating the dopamine receptor) is the same thing resulting in downregulation or toxicity. Maybe NMDA receptor antagonists can help along with a few other novel things but you can't beat tolerance.
