Thank you for the detailed answer. I had a question regarding mirtazapine, an atypical antidepressant which is useful to treat insomnia because of its extremely high affinity to H1 receptors (Ki = 0.14nM). Essentially at lower doses mirtazapine binds exclusively to H1 instead of adrenergic and serotonin receptors. Would mirtazapine treatment upregulate/sensitise H1 over time, reducing its effectiveness as a sedative and potentially increasing the risk of allergies?

I’m also curious about the molecular mechanisms by which tolerance to antihistamines develops. IIRC antagonists and inverse agonists inhibit the receptor, except the latter bind at the agonist site and induce an opposite response instead of blocking it. Would inverse H1 agonists hence be more likely to sensitise H1 as the body tries to return to baseline? How does the neuron achieve this? By increasing the amount of H1 or by decoupling G proteins from the receptor?