Neuroscience Psychedelics Slip Past Cell Membranes When Treating Depression

[Mr. Krinkle]

The antidepressant properties of hallucinogenic drugs may stem from their ability to bind to intracellular serotonin receptors, a study suggests.​

Besides inducing “trips,” psychedelics such as LSD—administered in parallel to psychological support—have been shown to have beneficial effects in cases of depression, anxiety, and addiction. Although these clinical observations tend to be weakened by the absence of adequate placebo-controlled conditions, several research groups are joining efforts to understand how these drugs can sometimes surpass common antidepressants in efficacy and speed.

Psychedelics Slip Past Cell Membranes When Treating Depression

The antidepressant properties of hallucinogenic drugs may stem from their ability to bind to intracellular serotonin receptors, a study suggests.

www.the-scientist.com

 

[Skorpio]

I liked that paper a lot when it dropped.

Pretty simple concept (intracellular serotonin receptors mediate the neuroplasticity of psychadelics), which gets tested pretty elegantly (expressing serotonin transporters to bring the serotonin into the cells with these intracellular serotonin receptors to visualize dendrite growth).

I would be interested to see if the hypothesis that DMT is an endogenous ligand for these intracellular serotonin receptors holds up and what the flux of DMT concentration in relevant parts of the brain reaches.


This below paper suggests the basal level of DMT in a rat brain is about 1 micromolar, increasing during a heart attack. Now just to see how that correlates to a good DMT trip in terms of plasma levels.

Biosynthesis and Extracellular Concentrations of N,N-dimethyltryptamine (DMT) in Mammalian Brain - Scientific Reports

N,N-dimethyltryptamine (DMT), a psychedelic compound identified endogenously in mammals, is biosynthesized by aromatic-L-amino acid decarboxylase (AADC) and indolethylamine-N-methyltransferase (INMT). Whether DMT is biosynthesized in the mammalian brain is unknown. We investigated brain...

www.nature.com

 

[ecstacylover]

This below paper suggests the basal level of DMT in a rat brain is about 1 micromolar, increasing during a heart attack.

David and Charles Nichols actually wrote a response to that paper, where they stated that even if DMT is present at concentrations half that of 5-HT (which is present at a mean extracellular concentration of about 2nM), the much higher affinity of 5-HT would render the 5-HT2A receptor's occupation by DMT negligible.

 

[Skorpio]

David and Charles Nichols actually wrote a response to that paper, where they stated that even if DMT is present at concentrations half that of 5-HT (which is present at a mean extracellular concentration of about 2nM), the much higher affinity of 5-HT would render the 5-HT2A receptor's occupation by DMT negligible.

The rebuttal by Nichols and Nichols doesn't account for the recent hypothesis raised by Vargas et al, in that Science paper.

Extracellular DMT may have no chance of outcompeting serotonin, but there would be no competition at the intracellular receptors.

I am not yet ready to throw my hat in and say that this is the end all be all mechanism by which psychadelics differ from serotonin at the 2A receptor, but it is definately interesting.

I wonder if there are any big differences in the 2nd messenger coupling of the intracellular vs extracellular receptors (ie G-protein identity / the degree of beta arrestin involvement).

 

[ecstacylover]

Extracellular DMT may have no chance of outcompeting serotonin, but there would be no competition at the intracellular receptors.

Ah yeah, good point. Although DMT's 2A affinity is quite low, so I'd be surprised if endogenous DMT has much of an effect there.

I wonder if there are any big differences in the 2nd messenger coupling of the intracellular vs extracellular receptors (ie G-protein identity / the degree of beta arrestin involvement).

Maybe a Golgi-enriched fraction could be isolated to see, at the very least, if affinity differences exist between intracellular and extracellular receptors.

 

[Skorpio]

Maybe a Golgi-enriched fraction could be isolated to see, at the very least, if affinity differences exist between intracellular and extracellular receptors.

Yeah a sucrose gradient should be pretty good at separating membrane vesicles from different organelles.

I bet this question would be served well by proximity labeling (such as a bioID derived fusion protein) and then running the isolated, labeled, proteins/RNAs on mass spec/rtpcr.

That would tell you what is within 10 nm of each population, if there are different protein isoforms at each location, and if there is alternative splicing occurring (I'd probably put the rtpcr on the back burner unless I knew about weird isoforms).

 

[Mr. Krinkle]

 

[ecstacylover]

Yeah a sucrose gradient should be pretty good at separating membrane vesicles from different organelles.

That method is so confusing, like my intuition is that the different sucrose layers should mix much more rapidly.

I bet this question would be served well by proximity labeling (such as a bioID derived fusion protein) and then running the isolated, labeled, proteins/RNAs on mass spec/rtpcr.

That would tell you what is within 10 nm of each population, if there are different protein isoforms at each location, and if there is alternative splicing occurring (I'd probably put the rtpcr on the back burner unless I knew about weird isoforms).

That makes sense. I think BRET and FRET suggests that 5-HT2A and mGluR2 form heterodimers, I'm assuming nobody has used proximity labeling to answer this? Seems like you could additionally see if they interacted differentially depending on the subcellular compartment. Would be interesting to see the results for G proteins and arrestins as well like you said.

Another thing is that receptor orientation is preserved when going from the ER to the Golgi to the plasma membrane. So the expectation is that intracellular 5-HT2AR would signal within the Golgi, which would be more isolated from modulating ion channels expressed in the plasma membrane.

 

[Snafu in the Void]

"Slips past membranes"?

More like slips some molly in my drink and turns on a happy thoughts disco ball