N&PD Moderators: Skorpio | thegreenhand
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?
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.
That's the way i had remembered it.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.
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).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 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?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.
In addition, I've heard people say bupropion (DARI) potentiates the effects of adderall (DA releaser).
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.
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.
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
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..?
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)..?