• N&PD Moderators: Skorpio | thegreenhand

  • Neuroscience & Pharmacology Discussion Welcome Guest
    Posting Rules Bluelight Rules
    Recent Journal Articles Chemistry Mega-Thread
    FREE Chemistry Databases! Self-Education Guide

Neuroscience Psychedelics promote plasticity by directly binding to BDNF receptor TrkB.

This thread contains discussion about a Neuroscience-related topic
I wonder how this will pan out with regard to the whole Bryan Roth & proteges camp who placed their bets on biased 5ht2a agonism causing both psychadelic and antidepressant effects?

pubmed.ncbi.nlm.nih.gov

Structure-based discovery of nonhallucinogenic psychedelic analogs - PubMed

Drugs that target the human serotonin 2A receptor (5-HT<sub>2A</sub>R) are used to treat neuropsychiatric diseases; however, many have hallucinogenic effects, hampering their use. Here, we present structures of 5-HT<sub>2A</sub>R complexed with the psychedelic drugs psilocin (the active...
pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov

Or that paper showing psychadelics bind intracellular pools of 5HT2A receptors, and serotonin can be made to promote neurogenesis if specific transporters are genetically added to cells.

pubmed.ncbi.nlm.nih.gov

Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors - PubMed

Decreased dendritic spine density in the cortex is a hallmark of several neuropsychiatric diseases, and the ability to promote cortical neuron growth has been hypothesized to underlie the rapid and sustained therapeutic effects of psychedelics. Activation of 5-hydroxytryptamine (serotonin) 2A...
pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov

Honestly I like the direct BDNF binding angle as it gives a wider breadth for non-psychadelic antidepressants such as ketamine/5-hydroxynorketamine, and scopolamine. I wish those compounds as well as other atypical ADs were tried in the BDNF nature paper.

I wonder which one will pan out. I would like this recent one to pan out (and I love seeing people use FRAP, great technique), but it will be interesting to see if other teams follow it up, and how these two seemingly opposing theories are consolidated.
 
Well it does make sense that the psychedelic and AD effects are separate, since past research has found neurogenesis with low doses.

My own personal experience seems to tell a similar story, the antidepressant effects don’t depend on how hard I trip. And if anything tripping too hard can have the opposite effect..

-GC
 
Skorpio said:
Or that paper showing psychadelics bind intracellular pools of 5HT2A receptors, and serotonin can be made to promote neurogenesis if specific transporters are genetically added to cells.
Click to expand...
I've been out of the loop for awhile, but some of the Vargas results (e.g. lipophilicity correlates with psychoplastogenicity, membrane permeability is required for psychedelic-induced neuroplasticity) don't seem incompatible with the Moliner paper. Perhaps this allosteric TRKB site can only be accessed via an intracellular path?

What is weird is that Vargas showed that ketanserin blocks both DMT and psilocin-mediated spinogenesis, while Moliner found that that M100907 has no effect on LSD-mediated spinogenesis. Moliner suggests that off-target effects of ketanserin (it has high affinity for alpha-1 receptors and moderate affinity for alpha-2 receptors, among others) and not its 5-HT2A antagonism might account for its plasticity-inhibiting effects.

I wonder if a downstream consequence of this TRKB PAM activity is Gas redistribution away from lipid rafts and increased cAMP levels, which is something observed in vitro with both ketamine, HNK, and fluoxetine, all of which share a common upstream mechanism (TRKB PAM). Postmortem brain samples of depressed patients show increased Gas localization to lipid rafts, while PET studies of depressed patients reveal global decreases in cAMP signaling which rebounds to control levels following antidepressant treatment (the Gas redistribution increases its functional coupling with adenylyl cyclase, which in turn increases cAMP levels). There's also potential for a positive feedback loop, as cAMP-PKA-CREB axis increases BDNF transcription (and chronic fluoxetine increases BDNF mRNA).

I'd love to see some data on whether psychedelics can produce a similar redistribution of Gas (perhaps this is how DOM and 25CN-NBOH increase cAMP levels in vitro), because I imaginee that ketanserin's off-target effects could interfere somewhere upstream of that. Btw, Lisuride was found to not increase cAMP, yet it does seem to be acting as a TRKB PAM. Very confusing..

Personally, in the case of ketamine, I think this TRKB PAM action probably isn't very relevant. It has even lower TRKB affinity than its metabolite HNK, yet HNK plasma levels are negatively associated with antidepressant response to ketamine. Ketamine has a completely separate mechanism (inhibition of spontaneous NMDAr transmission) which has been studied in great detail, and that seems to be the main driver of its antidepressant activity.
 
ecstacylover said:
I've been out of the loop for awhile, but some of the Vargas results (e.g. lipophilicity correlates with psychoplastogenicity, membrane permeability is required for psychedelic-induced neuroplasticity) don't seem incompatible with the Moliner paper. Perhaps this allosteric TRKB site can only be accessed via an intracellular path?

What is weird is that Vargas showed that ketanserin blocks both DMT and psilocin-mediated spinogenesis, while Moliner found that that M100907 has no effect on LSD-mediated spinogenesis. Moliner suggests that off-target effects of ketanserin (it has high affinity for alpha-1 receptors and moderate affinity for alpha-2 receptors, among others) and not its 5-HT2A antagonism might account for its plasticity-inhibiting effects.

I wonder if a downstream consequence of this TRKB PAM activity is Gas redistribution away from lipid rafts and increased cAMP levels, which is something observed in vitro with both ketamine, HNK, and fluoxetine, all of which share a common upstream mechanism (TRKB PAM). Postmortem brain samples of depressed patients show increased Gas localization to lipid rafts, while PET studies of depressed patients reveal global decreases in cAMP signaling which rebounds to control levels following antidepressant treatment (the Gas redistribution increases its functional coupling with adenylyl cyclase, which in turn increases cAMP levels). There's also potential for a positive feedback loop, as cAMP-PKA-CREB axis increases BDNF transcription (and chronic fluoxetine increases BDNF mRNA).

I'd love to see some data on whether psychedelics can produce a similar redistribution of Gas (perhaps this is how DOM and 25CN-NBOH increase cAMP levels in vitro), because I imaginee that ketanserin's off-target effects could interfere somewhere upstream of that. Btw, Lisuride was found to not increase cAMP, yet it does seem to be acting as a TRKB PAM. Very confusing..

Personally, in the case of ketamine, I think this TRKB PAM action probably isn't very relevant. It has even lower TRKB affinity than its metabolite HNK, yet HNK plasma levels are negatively associated with antidepressant response to ketamine. Ketamine has a completely separate mechanism (inhibition of spontaneous NMDAr transmission) which has been studied in great detail, and that seems to be the main driver of its antidepressant activity.
Click to expand...
I always thought the Gs/Gq thing was falling out of favor, compared to the beta arrestin/Gq balance determining what makes a serotonin 2a agonist psychadelic (like the results from the Cao 2022 paper from my first reply). I do worry about generalizing the effects of cAMP, as PKA is differentially scaffolded to different signaling cascades both within a cell and in different cell/tissue types. This paper demonstrates differences in cytoplasmic and internalized adenylal cyclase sources producing different cardiac effects, while this paper demonstrates reservoirs of cyclic AMP formed through liquid liquid phase condensates which restricts what cAMP substrates get activated. Furthermore, I don't see a tonne of recent lipid raft papers about g protein signaling, which strikes me as a bit odd, considering all of the advances in super resolution imaging and the development of microscopy based biosensors allowing for dissection of these pathways.

The PKA anchoring protein AKAP79 for example binds both PKA and the phosphatase PP2B at postsynaptic membranes and facilitates long term depression via gluR1a phosphorylation and turnover. I am much more familiar with this side of cAMP signaling than G protein localization, unfortunately.

Furthermore this new paper: Psychedelics reopen the social reward learning critical period, demonstrates that beta arrestin 2 knockout mice are insensitive to social antidepressant effects of LSD and MDMA but not ketamine or ibogaine. They use ketanserin to assess the serotonin 2a receptors, which doesn't address the concerns about its dirtiness regarding adrenergic receptors unfortunately. This result to me implies that there are events upstream to bdnf activation by psychadelics.

This is such an exciting time for psychadelic research. In the past say 5 years there has been a real surge in labs producing good data on psychadelics. I bet it won't be extremely long for some of these conclusions to be tested within the same model system, so that they can be directly compared rather than having to hope the different paradigms used produce similar outcomes.
 
Skorpio said:
This is such an exciting time for psychadelic research. In the past say 5 years there has been a real surge in labs producing good data on psychadelics. I bet it won't be extremely long for some of these conclusions to be tested within the same model system, so that they can be directly compared rather than having to hope the different paradigms used produce similar outcomes.
Click to expand...
Very exciting but hard to keep up!
 
ecstacylover said:
I've been out of the loop for awhile, but some of the Vargas results (e.g. lipophilicity correlates with psychoplastogenicity, membrane permeability is required for psychedelic-induced neuroplasticity) don't seem incompatible with the Moliner paper. Perhaps this allosteric TRKB site can only be accessed via an intracellular path?

What is weird is that Vargas showed that ketanserin blocks both DMT and psilocin-mediated spinogenesis, while Moliner found that that M100907 has no effect on LSD-mediated spinogenesis. Moliner suggests that off-target effects of ketanserin (it has high affinity for alpha-1 receptors and moderate affinity for alpha-2 receptors, among others) and not its 5-HT2A antagonism might account for its plasticity-inhibiting effects.

I wonder if a downstream consequence of this TRKB PAM activity is Gas redistribution away from lipid rafts and increased cAMP levels, which is something observed in vitro with both ketamine, HNK, and fluoxetine, all of which share a common upstream mechanism (TRKB PAM). Postmortem brain samples of depressed patients show increased Gas localization to lipid rafts, while PET studies of depressed patients reveal global decreases in cAMP signaling which rebounds to control levels following antidepressant treatment (the Gas redistribution increases its functional coupling with adenylyl cyclase, which in turn increases cAMP levels). There's also potential for a positive feedback loop, as cAMP-PKA-CREB axis increases BDNF transcription (and chronic fluoxetine increases BDNF mRNA).

I'd love to see some data on whether psychedelics can produce a similar redistribution of Gas (perhaps this is how DOM and 25CN-NBOH increase cAMP levels in vitro), because I imaginee that ketanserin's off-target effects could interfere somewhere upstream of that. Btw, Lisuride was found to not increase cAMP, yet it does seem to be acting as a TRKB PAM. Very confusing..

Personally, in the case of ketamine, I think this TRKB PAM action probably isn't very relevant. It has even lower TRKB affinity than its metabolite HNK, yet HNK plasma levels are negatively associated with antidepressant response to ketamine. Ketamine has a completely separate mechanism (inhibition of spontaneous NMDAr transmission) which has been studied in great detail, and that seems to be the main driver of its antidepressant activity.
Click to expand...

I can’t hold a candle to the knowledge you just put forth but LSD is definitely a “dirtier” psychedelic in that it hits on alot of different receptor sites. We see neurogenesis happening with low doses of amphetamine/methamphetamine I wonder if LSD can promote neurogenesis via its D2 agonism?

-GC
 
G_Chem said:
I can’t hold a candle to the knowledge you just put forth but LSD is definitely a “dirtier” psychedelic in that it hits on alot of different receptor sites. We see neurogenesis happening with low doses of amphetamine/methamphetamine I wonder if LSD can promote neurogenesis via its D2 agonism?

-GC
Click to expand...
Does (meth)amphetamine promote neurogenesis or neurite outgrowth? Because neurogenesis would only apply to neural stem cells (very few of these in the brain, although they are important in the hippocampus). AFAIK psychedelics generally don't promote neurogenesis, aside from DMT (via a sigma-1R pathway IIRC). Most of what they do is promote dendrite and dendritic spine formation. But that's an interesting suggestion about D2, would be very interesting to see if D2 antagonism could inhibit LSD-mediated plasticity.
 
ecstacylover said:
Does (meth)amphetamine promote neurogenesis or neurite outgrowth? Because neurogenesis would only apply to neural stem cells (very few of these in the brain, although they are important in the hippocampus). AFAIK psychedelics generally don't promote neurogenesis, aside from DMT (via a sigma-1R pathway IIRC). Most of what they do is promote dendrite and dendritic spine formation. But that's an interesting suggestion about D2, would be very interesting to see if D2 antagonism could inhibit LSD-mediated plasticity.
Click to expand...

Good question that is very much outside my pay grade 😉 but I just learned a thing or two so thank you for that.

So psilocybin/Psilocin doesn’t hit on sigma-1r? I’m surprised given the similarities to DMT.

-GC
 
G_Chem said:
So psilocybin/Psilocin doesn’t hit on sigma-1r? I’m surprised given the similarities to DMT.
Click to expand...
Looks like the 4 sub is no good for sigma-1r affinity according to this paper, but 5-MeO-DMT also appears to share this action with DMT according to a couple papers.
 
Last edited:
You must log in or register to reply here.
Top