Question about releasing agents and reuptake inhibitors.

[Hammilton]

It's not fun for many reasons. L-dopa gets plenty into the brain, and it's far and away from enjoyable.

 

[atrollappears]

thank you a lot for your extensive answer! it made a lot of thing clearer to me.

but one question did newly arise: how do the things you said about serotonergic pathways fit with the strong effects of 5HT2A agonists?

Well, the thing about 5-HT2A receptors is that they're "functionally selective," meaning that even if two different chemicals can bind to and activate a certain receptor, they still might have different effects. This happens because, depending on how the chemical fits into the receptor, different chemical signals might be triggered. It turns out that serotonin can only activate the 5-HT2A receptor in a way that causes inositol triphosphate (IP3) signaling, which does not produce psychedelic effects. (2,5-dimethoxyamphetamine [2,5-DMA or DOH] also only activates IP3 signaling, it's in PiKHAL if you're interested in what that looks like.) To produce psychedelic effects, the arachidonic acid (AA) signaling pathway must be activated. LSD happens to be completely selective for the AA pathway.

I have another related question. Why are norepinephrine releasing agents like ephedrine stimulating yet NRIs(Like strattera, not NDRIs like ritalin and bupropion) are sedating for most people? Main side effect of strattera is somnolence.

Activation of alpha-2 receptors causes decreased NE release. I'm not exactly sure why alpha-2 receptors remain activated even as NE release is decreased (maybe they're extrasynaptic?), but that's the reason.

 

[doppelgänger1]

It is my understanding that releasing agents are also reuptake inhibitors (esp. at lower doses, below the threshold needed to cause release) but not all reuptake inhibitors are releasers.

That's the way i had remembered it.
Do you know which effect dominates at doses of 5-20mg d-amphetamine (as it is prescribed for add)?

 

[ungelesene_bettlek]

Well, the thing about 5-HT2A receptors is that they're "functionally selective," meaning that even if two different chemicals can bind to and activate a certain receptor, they still might have different effects. This happens because, depending on how the chemical fits into the receptor, different chemical signals might be triggered. It turns out that serotonin can only activate the 5-HT2A receptor in a way that causes inositol triphosphate (IP3) signaling, which does not produce psychedelic effects. (2,5-dimethoxyamphetamine [2,5-DMA or DOH] also only activates IP3 signaling, it's in PiKHAL if you're interested in what that looks like.) To produce psychedelic effects, the arachidonic acid (AA) signaling pathway must be activated. LSD happens to be completely selective for the AA pathway.

very interesting, thank you a lot for pointing this out to me! now it also makes sense that there are 5HT2A agonists which do not cause psychedelia at all (read this several times, always puzzeled me).

can you perhaps recommend me good reading (and/or another thread, since this is pretty off-topic here now) about which other serotonin receptor types are also involved in the action of classical psychedelics?

regarding 2,5-DMA: I knew the PiKHAL entry, but up to now I always assumed that the 4-substitution was neccessary to cause 5HT2A-agonism, and that the action of 2,5-DME was solely due to monoamine release.

 

[ungelesene_bettlek]

SRIs cancel out SRAs because SRIs do not acutely raise synaptic serotonin levels to any significant extent. This is because 5-HT1A autoreceptors decrease serotonin release with any rise in concentration. That these receptors must be desensitized/downregulated before SRIs can increase synaptic serotonin levels is one of the reasons for the delayed onset of action of SSRIs.

I just thought about this amazingly simple explanation for the "therapeutic lap" of SSRIs agan, and another question arised: it is well-known that SSRIs can cause suicidal tendencies while the "lap"; generally, this is explained by saying that the motivation and energy get increased before the actiual antidepressant effect fully emerges; is there probabyl a good explanation for this in the 5HT1A-downregulation theory?

 

[DexyDevil]

In addition, I've heard people say bupropion (DARI) potentiates the effects of adderall (DA releaser).

Bupropion completely blocks the effect of Adderall for me.

 

[specialspack]

Well, the thing about 5-HT2A receptors is that they're "functionally selective," meaning that even if two different chemicals can bind to and activate a certain receptor, they still might have different effects. This happens because, depending on how the chemical fits into the receptor, different chemical signals might be triggered. It turns out that serotonin can only activate the 5-HT2A receptor in a way that causes inositol triphosphate (IP3) signaling, which does not produce psychedelic effects. (2,5-dimethoxyamphetamine [2,5-DMA or DOH] also only activates IP3 signaling, it's in PiKHAL if you're interested in what that looks like.) To produce psychedelic effects, the arachidonic acid (AA) signaling pathway must be activated. LSD happens to be completely selective for the AA pathway.

This isn't quite correct though. 5HT activates both the IP and AA pathways, with similar EC50s - 120 and 80 nM respectively, and it's IA is of course 100% for both. So serotonin is actually slightly better, if anything, at activating AA than IP.

LSD on the other hand is 10nM / 20% for the IP pathway and 20nM / 56% for AA. So comparing via EC50s, LSD is actually better at producing IP, although not if comparing IAs.

In Kurrasch-Orbaugh et al 2003 they conclude:

We tested both hallucinogenic and nonhallucinogenic compounds, because the possibility existed that preferential activation of PLA2 over PLC, or vice versa, might correlate with the biological activity of these agonists.

We did not, however, observe differential activation of either PLC or PLA2 by the two types of compounds, suggesting that psychotropic versus nonpsychotropic agonists, as a group, do not differ in their ability to activate selectively 5-HT2A receptor-mediated PLA2 or PLC signaling. Whether or not the generally greater potency of most ligands for activating the PLA2 pathway is relevant to the action of hallucinogenic drugs remains to be investigated. Taken together, these results are not compatible with the hypothesis that structurally similar compounds might stabilize a particular conformation of the receptor such that one 5-HT2A receptor-mediated PLC or PLA2 pathway might be differentially enhanced.

NB - the PLC pathway produces IP, the PLA2 pathway produces AA.

Unless there's newer data that says otherwise?


Kurrasch-Orbaugh, D. M., Watts, V. J., Barker, E. L., & Nichols, D. E. (2003). Serotonin 5-hydroxytryptamine 2A receptor-coupled phospholipase C and phospholipase A2 signaling pathways have different receptor reserves. The Journal of pharmacology and experimental therapeutics, 304(1), 229–37. doi:10.1124/jpet.102.042184

 

[ebola?]

This isn't quite correct though. 5HT activates both the IP and AA pathways, with similar EC50s - 120 and 80 nM respectively, and it's IA is of course 100% for both. So serotonin is actually slightly better, if anything, at activating AA than IP.

Thanks. This solves the mysteries of:
1. why there would be a second messengering pathway that's not affected by the endogenous ligand and
2. how mdma can prove psychedelic at higher doses.

ebola

 

[specialspack]

Thanks. This solves the mysteries of:
1. why there would be a second messengering pathway that's not affected by the endogenous ligand and
2. how mdma can prove psychedelic at higher doses.

ebola

You're suggesting that MDMA is psychedelic at high doses indirectly, via 5HT release? And that therefore large enough amounts of synaptic 5HT alone can produce psychedelic effects..?

I think it's more likely that psychedelics do have functional selectivity, we just haven't worked out which pathways yet.

Can you be specific about what subjective effects and what doses you deem are "psychedelic" for MDMA (broader than just the general description of "mind-manifesting" etc)..?

 

[ebola?]

You're suggesting that MDMA is psychedelic at high doses indirectly, via 5HT release? And that therefore large enough amounts of synaptic 5HT alone can produce psychedelic effects..?

Yes.

Can you be specific about what subjective effects and what doses you deem are "psychedelic" for MDMA (broader than just the general description of "mind-manifesting" etc)..?

Yes, mild geometric patterning (particularly with eyes closed) and mild visual trails.

ebola