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5-HT(2A) Receptor Help (self.neuroscience)
submitted 11y ago by followmesoccer
I'm trying to learn about serotonin receptors and I have some questions that I can't seem to find the answers for. I was hoping that Reddit would be able to help me out. My three biggest questions are:
1) Why do 5-HT(2A) agonist AND antagonists (such as mianserin) both induce receptor desensitization and down-regulation?
2) Why does cocaine induce supersensitivity of 5-HT(2A) receptors?
3) Why does 5-HT(2A) agonists (such as LSD, psilocin and mescaline) cause pleasurable effects (aside from the effects of the other monoamines), while antagonists can be used for depression? I know you can't make sweeping generalizations such as "activation of 5-HT(2A) receptors corresponds to happiness in terms of mood; while inactivation corresponds to a reduction of happiness in terms of mood", but is there a general rule of thumb for serotonin?
1) Why do 5-HT(2A) agonist AND antagonists (such as mianserin) both induce receptor desensitization and down-regulation?
2) Why does cocaine induce supersensitivity of 5-HT(2A) receptors?
3) Why does 5-HT(2A) agonists (such as LSD, psilocin and mescaline) cause pleasurable effects (aside from the effects of the other monoamines), while antagonists can be used for depression? I know you can't make sweeping generalizations such as "activation of 5-HT(2A) receptors corresponds to happiness in terms of mood; while inactivation corresponds to a reduction of happiness in terms of mood", but is there a general rule of thumb for serotonin?
[deleted] 5 points
1) In order to keep homeostasis. I don't know enough about 5-HT antagonists to answer more to that, but I'm sure it has to do with *how* the antagonist reduces 5-HT activity.
2) This paper claims that it is due to a higher density of a high-affinity state of 5-HT2A g-proteins which occurs during withdrawal.
>Although, the mechanisms by which cocaine withdrawal mediates 5-HT2A receptor supersensitivity in PVN are not completely understood, our present and published data indicates that they could involve: (1) increased density of 5-HT2A receptors in a “high-affinity” state at least at 24 h of withdrawal; and (2) increased levels of membrane-associated Gαq and Gα11 proteins at 48 h of withdrawal.
3) Well, most of the agonist and antagonists don't selectively target 5-HT2A receptors, those are simply the ones associated with psychedelic effects of psychedelic drugs. Serotonin agonists are also used (and used more commonly) than antagonists to treat depression, such as SSRIs...however as any psychedelic user can tell you, these drugs can make you experience both emotional highs and lows, so mood doesn't necessary have a linear response to serotonergic activity. Many of the pleasurable effects of the psychedelics are associated with their simultaneous stimulation of dopaminergic transmission along with the other neurochemical changes induced by said drugs (increase in NE, etc.). I'm not a clinician, so I can't tell you a 'rule of thumb' as far as treatment goes. I am sure someone more focused on psychopharmacology (my research lies in the auditory system) can provide more detailed answers.
Uh thanks for the downvotes? If I'm wrong at all, please feel free to step in and correct me.
2) This paper claims that it is due to a higher density of a high-affinity state of 5-HT2A g-proteins which occurs during withdrawal.
>Although, the mechanisms by which cocaine withdrawal mediates 5-HT2A receptor supersensitivity in PVN are not completely understood, our present and published data indicates that they could involve: (1) increased density of 5-HT2A receptors in a “high-affinity” state at least at 24 h of withdrawal; and (2) increased levels of membrane-associated Gαq and Gα11 proteins at 48 h of withdrawal.
3) Well, most of the agonist and antagonists don't selectively target 5-HT2A receptors, those are simply the ones associated with psychedelic effects of psychedelic drugs. Serotonin agonists are also used (and used more commonly) than antagonists to treat depression, such as SSRIs...however as any psychedelic user can tell you, these drugs can make you experience both emotional highs and lows, so mood doesn't necessary have a linear response to serotonergic activity. Many of the pleasurable effects of the psychedelics are associated with their simultaneous stimulation of dopaminergic transmission along with the other neurochemical changes induced by said drugs (increase in NE, etc.). I'm not a clinician, so I can't tell you a 'rule of thumb' as far as treatment goes. I am sure someone more focused on psychopharmacology (my research lies in the auditory system) can provide more detailed answers.
Uh thanks for the downvotes? If I'm wrong at all, please feel free to step in and correct me.
quaternion 2 points
I don't know why you were downvoted, but I would also like whomever did that to explain, in case they have knowledge that supersedes ours in some way.
I agree that 5HT2A cannot be equated with happy moods etc, but it is also worth noting that 25i-NBOMe has very uplifting subjective effects and yet is one of the most selective 5HT2A agonists available. In all likelihood there will simply not be a straightforward mapping between neurotransmitters - or even particular receptor subtypes - and subjective states of experience. There is an intervening *computational* mechanism that we have to understand first; for example, while it is popular to say that dopamine is "the pleasure neurochemical" this is a grossly misleading overgeneralization, whereas the (much more computational) "reward prediction error" role does a much better job of explaining the linkage between dopaminergic agonism/antagonism and cognition/behavior.
Similar computational hypotheses about serotonin have only recently been proposed. As far as I know, actually, there is only a single horse in the race right now: the punishment prediction error hypothesis (e.g., of Daw Dayan & colleagues; pdf link: http://bit.ly/zyOJwB).
Of course, it's probably wrong. But it's the only compelling and somewhat unifying hypothesis I've seen yet.
I agree that 5HT2A cannot be equated with happy moods etc, but it is also worth noting that 25i-NBOMe has very uplifting subjective effects and yet is one of the most selective 5HT2A agonists available. In all likelihood there will simply not be a straightforward mapping between neurotransmitters - or even particular receptor subtypes - and subjective states of experience. There is an intervening *computational* mechanism that we have to understand first; for example, while it is popular to say that dopamine is "the pleasure neurochemical" this is a grossly misleading overgeneralization, whereas the (much more computational) "reward prediction error" role does a much better job of explaining the linkage between dopaminergic agonism/antagonism and cognition/behavior.
Similar computational hypotheses about serotonin have only recently been proposed. As far as I know, actually, there is only a single horse in the race right now: the punishment prediction error hypothesis (e.g., of Daw Dayan & colleagues; pdf link: http://bit.ly/zyOJwB).
Of course, it's probably wrong. But it's the only compelling and somewhat unifying hypothesis I've seen yet.
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