I agree that in general, downregulation is to be expected, but it doesn’t always happen (depending on the specific receptor, affinity for their presynaptic counterpart, or biased agonism).
E.g.
the psychedelic DMT doesn’t cause downregulation of the receptors it agonises (5-HT2A), because it doesn’t target β-arrestin2, which is what supposedly leads to downregulation of this receptor.
my optimism about non-agonist (and non-dopamine-releasing) compounds affecting dopamines comes partially from the supposedly non-withdrawal-causing drug bromantane (which seems to act on transcription of tyrosine hydroxylase)
In vitro, even some dopamine agonists (including dopamine itself!) cause upregulation (of D2 long—the postsynaptic version of D2)
The D1 receptor specifically seems to have less of a tendency to downregulate with biased agonists: (Some ligands from this series also displayed G protein bias and were found to produce less receptor desensitization with more sustained in vivo activity after repeat dosing, when compared to a typical unbiased agonist (Gray et al., 2018).)
SSRIs seem to have a delay in part due to desensitising the 5-HT1 presynaptic (inhibitory) receptors faster than the actual postsynaptic receptors, causing those to become continuously activated after about 3 weeks of use.
Some ligands, like the 5-HT2A antagonist Mirtazapine, seem to act oppositely to downregulation, causing reverse tolerance
In short, (as someone not super-informed in biology), I think that even those negative feedback loops can be hacked, or avoided. The brain naturally tries to keep in homeostasis, but when the mechanisms are targeted on a low level, the brain isn’t always equipped to counteract them.
Maybe the brain has learned to downregulate even on low levels of control, to prevent potential mind-controlling parasites, but those parasites would likely be dumber than we are, so it seems likely that there are still niches of control that the brain hasn’t learned to downregulate in.
I agree that in general, downregulation is to be expected, but it doesn’t always happen (depending on the specific receptor, affinity for their presynaptic counterpart, or biased agonism).
E.g.
the psychedelic DMT doesn’t cause downregulation of the receptors it agonises (5-HT2A), because it doesn’t target β-arrestin2, which is what supposedly leads to downregulation of this receptor.
my optimism about non-agonist (and non-dopamine-releasing) compounds affecting dopamines comes partially from the supposedly non-withdrawal-causing drug bromantane (which seems to act on transcription of tyrosine hydroxylase)
In vitro, even some dopamine agonists (including dopamine itself!) cause upregulation (of D2 long—the postsynaptic version of D2)
The D1 receptor specifically seems to have less of a tendency to downregulate with biased agonists: (Some ligands from this series also displayed G protein bias and were found to produce less receptor desensitization with more sustained in vivo activity after repeat dosing, when compared to a typical unbiased agonist (Gray et al., 2018).)
SSRIs seem to have a delay in part due to desensitising the 5-HT1 presynaptic (inhibitory) receptors faster than the actual postsynaptic receptors, causing those to become continuously activated after about 3 weeks of use.
Some ligands, like the 5-HT2A antagonist Mirtazapine, seem to act oppositely to downregulation, causing reverse tolerance
In short, (as someone not super-informed in biology), I think that even those negative feedback loops can be hacked, or avoided. The brain naturally tries to keep in homeostasis, but when the mechanisms are targeted on a low level, the brain isn’t always equipped to counteract them.
Maybe the brain has learned to downregulate even on low levels of control, to prevent potential mind-controlling parasites, but those parasites would likely be dumber than we are, so it seems likely that there are still niches of control that the brain hasn’t learned to downregulate in.