monoamine releasers vs. opioid agonists

[hussness]

>>But is the comparison to the mean value really the useful definition? I don't think so. I think a better definition for the "right" adenosine level is simply that level which is most useful for you. So by that definition, you have an overabundance of adenosine.

Similarly, I think the "right" serotonin levels for someone with depression are those which make one able to cope with the depression best.>>

A couple points:
1. What is optimal for me? I, for one, would live a more fun and productive life if I felt like I were high on amphetamines and opiates all the time. I don't think that this alone means that I am deficient in monoamines and endorphins.
2. It is equally plausible that anti-depressants treat symptoms of depression through serotonergic action when the original problem that gives rise to depression in the first place is caused by something else. People generally tolerate the cranial biopsies that would be necessary to measure their serotonin pretty poorly.

ebola

My opinion is that the measurement of the levels of a certain neurotransmitter in an individual at a given time (assuming non-invasive technology existed to do this, which it currently doesn't) in comparison to population statistics will probably not provide useful information. A comparison to the mean will only tell you something useful medically if the mean is something that can be considered "good", in a primitive sense, for lack of a better term.
I think understanding the physiochemical principles that underlie receptor regulation will provide a much more robust understanding of psychiatric conditions. The way I see it, the advantage in considering the problem from this perspective mainly lies in the fact that it is not in any way entrenched in unstated philosophical and/or religious notions. Science, by nature, can't ascribe a purpose to something, it can only describe what happens.
I'll be the first to admit that this is all very lofty and theoretical, but its my take on the subject. I think many useful inferences can be obtained from psychology, but at the heart of it this field is completely subjective.

 

[rnd.id.]

Its not simply that your 5HT2a and 5HT2c receptors are being activated, but rather how they are being activated. Psilocybin modulates post-synaptic neurons in a very unusual (at least compared to serotonin) way.

You are right; I assume you are referring to the recent study about this (just read it, it's interesting). But as far as I can tell, they didn't test whether 5-HT itself activates the receptor like psychedelics or like lisuride? (The fact that we aren't usually tripping without drugs could be explained by the idea that there simply isn't enough 5-HT under normal conditions?)

 

[5-HT2]

(The fact that we aren't usually tripping without drugs could be explained by the idea that there simply isn't enough 5-HT under normal conditions?)

That might be a decent oversimplified explanation for the psychoactive effects of MDMA, but for hallucinogens, something a little more complicated is probably going on. Serotonergic hallucinogens decrease serotonin neuron firing in rats through their actions on 5-HT1A autoreceptors. Thus, the psychoactive effects of psychedelics may be a result of their simultaneous inhibition of serotonin release and selective activation of certain serotonin receptor subtypes. In this scenario, only the serotonin receptor subtypes for which psychedelics have high affinity are activated, and the other subtypes, which would normally be getting some level of stimulation from endogenous serotonin, do not even reach basal or tonic levels of activation.

 

[mad_scientist]

That might be a decent oversimplified explanation for the psychoactive effects of MDMA, but for hallucinogens, something a little more complicated is probably going on. Serotonergic hallucinogens decrease serotonin neuron firing in rats through their actions on 5-HT1A autoreceptors. Thus, the psychoactive effects of psychedelics may be a result of their simultaneous inhibition of serotonin release and selective activation of certain serotonin receptor subtypes. In this scenario, only the serotonin receptor subtypes for which psychedelics have high affinity are activated, and the other subtypes, which would normally be getting some level of stimulation from endogenous serotonin, do not even reach basal or tonic levels of activation.

But in that case taking serotonergic hallucinogens alongside MDMA should make the hallucinogen not work properly, whereas actually the combination makes the hallucinogen work better if anything....

Maybe hallucinogens are just stimulating the 5HT2A and 5HT2C receptors in a different way to the endogenous agonist, activating the signalling pathways inside the cell in a different pattern or something?

 

[fastandbulbous]

It'd be nice to have something that could inhibit the breakdown of the opioid peptides, though. Perhaps it'd make for an antidepressant if the effects are mild.

Thiorphan is an enkephalinase inhibitor if I remember correctly (not sure if I've spelled it correctly) - it's role is analogous to MAO for the monoamine neurotransmitters

Google it as there's a shitload of articles aboput it, but here's a link to a basic overview of what it is http://www.websters-online-dictionary.org/Th/Thiorphan.html

 

[rnd.id.]

I'm too inebriated right now for a real answer, but:

@5-HT2: They tried it in 5-HT1-knockout mice, didn't chance anything IIRC.

@mad_scientist: Yes, exactly. Take a look at the paper I linked (they have the full text), it explains a lot. But I still wonder whether serotonin itself can activate the "psychedelic signaling pathway"