Why do some 5HT2A antagonists block psychedelics, but others don't?

[jaiho]

TCAs appear to potentiate psychedelics, and all of them are potent 5HT2A antagonists.
It's thought that anti psychotics & some other meds like, Trazodone, can cancel a trip, via 5HT2A antagonism.

Why do TCAs not cancel a trip, but anti psychotics do?

 

[aced126]

The TCAs in general seem to have affinities in the range of 100nM for 5HT2a (amitriptyline being the strongest binding, at 5.6nM). LSD and a lot of other tryptamines have very high 2a affinity and will simply be able to displace the TCA from the receptor. Antipsychotics on the other hand bind with much lower affinity than TCAs to 2a, meaning psychedelics are less able to displace them and bind themselves, activating their respective signalling pathway.

 

[serotonin2A]

The TCAs in general seem to have affinities in the range of 100nM for 5HT2a (amitriptyline being the strongest binding, at 5.6nM). LSD and a lot of other tryptamines have very high 2a affinity and will simply be able to displace the TCA from the receptor. Antipsychotics on the other hand bind with much lower affinity than TCAs to 2a, meaning psychedelics are less able to displace them and bind themselves, activating their respective signalling pathway.

I've seen posts like this a lot, but they misinterpret why displacement occurs. Just because a ligand has high affinity doesn't mean it will be particularly good at displacing other ligands -- just as ligands with micromolar affinities are not necessarily bad at displacing other ligands. In other words, say you have two ligands for a single receptor: ligand A (Ki = 1 nM) and ligand B (Ki = 1000 nM). There is no inherent reason why ligand A would be a better antagonist than ligand B as long as both ligands are present at high enough concentrations to interact with the receptor.

What actually matters is the association rate of the displacing ligand. If two drugs are competing for the same population of receptors, and one can associate at a faster rate, then it is gradually going to displace the other ligand. Since the on rate is part of what determines the Kd, there is a tendancy for ligands with fast association kinetics to also have high affinity, but that isn't universally true.

The issues with TCAs is that they potentiate psychedelics after chronic use due to desensitization of serotonin autoreceptors. So TCAs may produce some blockade, but that effect is apparently offset by other effects of TCAs.

 

[aced126]

How would autoreceptor desensitisation potentiate psychedelic effect?

 

[Cotcha Yankinov]

^I'm curious as well...

 

[serotonin2A]

^ Sorry if that is confusing, I was referring to 5-HT1A and 5-HT1B/1D receptors, which are often classified as serotonin autoreceptors. I guess technically some of the effects might be mediated by heteroreceptors or postsynaptic receptors too, but...

There is pretty good preclinical evidence that the 5-HT1A and 5-HT1B/1D activation produced by LSD and tryptamine hallucinogens tends to inhibit their 5-HT2A-mediated effects. Strassman tested whether this occurs with DMT in humans:

https://www.ncbi.nlm.nih.gov/pubmed/8788488

So TCA-induced desensitization of 5-HT1A and 5-HT1B/1D receptors would tend to enhance the psychedelic effects of LSD and tryptamine hallucinogens.

 

[Cotcha Yankinov]

Interesting..

Don't 5-HT1A receptors at the axon-hillock inhibit the spread of lateral excitation, therefore you would expect a greater spatial extent of activation with 5-HT2A activation after 5-HT1A blockade, and 5-HT1A activation could also oppose that lateral spread?

I forget where I have heard this, but I remember hearing something about psychedelic activation of 5-HT2A on apical dendrites enhancing the ability of pyramidal cells in the PFC to send out collaterals to the adjacent cortical columns.. Am I remembering wrong?

 

[serotonin2A]

Interesting..

Don't 5-HT1A receptors at the axon-hillock inhibit the spread of lateral excitation, therefore you would expect a greater spatial extent of activation with 5-HT2A activation after 5-HT1A blockade, and 5-HT1A activation could also oppose that lateral spread?

5-HT1A receptors at the axon-hillock of cortical pyramidal neurons inhibit action potential generation, which would inhibit activation of downstream neurons (potentially including neighboring pyramidal neurons). But the effect of 5-HT1A blockade wouldn't be limited to influencing the spread of excitation laterally across cortex.

I forget where I have heard this, but I remember hearing something about psychedelic activation of 5-HT2A on apical dendrites enhancing the ability of pyramidal cells in the PFC to send out collaterals to the adjacent cortical columns.. Am I remembering wrong?

Axons have collaterals, not dendrites. You are right about 5-HT2A receptors being on apical dendrites, but I'm not sure exactly what you are specifically thinking of in terms of the effects on other cortical neurons.