Brain chemical studies of subjective mood differences influencing drug effects.

[Nagelfar]

For example, as anyone who is experienced with stimulants has likely noticed, the stimulant high is one thing, but if sexually excited / interested a whole other plateau of subjective high is reached. Which attention / focus can re-direct and offset, etc. Any studies observing the brain under these circumstances while test subjects are under the influence?

Is there a mediating neurotransmitter, an area of the brain that is flooded with a particular neurotransmitter, a glutamate channel, etc. that has been associated with this subjective change in effect not peculiar to the drug being administered by itself, and could that effect theoretically be articulated directly by an exogenous chemical itself?

 

[sekio]

Set and setting applies to all drugs, not just psychedelics. I don't think there's any one "euphoria chemical" that does it.

That said, engaging in activities that cause dopamine release - with concurrent tratment with a DRI drug - causes a much greater impact than dopamine release alone. Maybe that's what's going on.

 

[Nagelfar]

There are times that re-dosing, regardless of time after initial dose or amount re-dosed, that doesn't do what a change of mindset or environment will do. This however, has to be a chemical interaction endogenously that synergizes in some manner for there to be a further subjective change at all (for the sake of the postulate of this thread anyhow). Is it a specific area of the brain that the released monoamines are more readily channeled/redirected to? Some study has had to have at least attempted to observe this.

 

[3rd_I_blind]

...and they called in nucleus accumbens.

 

[Nagelfar]

Yes but isn't it related to the amount of cAMP throughout the mesolimbic system, mediated by dopamine in the nucleus accumbens? or is this 'chicken or the egg' reasoning?

 

[3rd_I_blind]

Search for 'nucleus accumbens + placebo effect' or 'nucleus accumbens + sexual arousal'.
I'm not sure what your background is, but you mentioning cAMP might indicate this is a bit too deep for your background knowledge (no effence).
Unfortunately, it's a bit beyond my knowledge to explain it without investing at least two hours of reading, so I'm afraid I'll have to pass.

 

[Nagelfar]

I'm not sure what your background is, but you mentioning cAMP might indicate this is a bit too deep for your background knowledge (no effence).

Why does my mentioning cAMP here affirm that as a consequent? The big four reinforcers aren't reinforcing if cAMP is blocked from its biological overshoot, is that not correct?

 

[3rd_I_blind]

Well, for starters, cAMP is an intracellular second messenger molecule. So there is not really an 'amount' of cAMP in the mesolimbic pathway, at least not in the sense that the cumulative concentration of cAMP in all neurons of the mesolimbic pathways indicates anything. Secondly, cAMP is a second messenger that is not exclusive to dopamine receptor activation. There's probably over 50 different processes that influence adenylyl cyclase, phosphodiesterase and other enzymes shaping the formation and degradation of cAMP. Thirdly, there are five different sybtypes of the dopamine receptor. Of these subtypes, the D1 and D5 receptor stimulate adenylyl cyclase, while the D2, D3 and D4 subtype inhibit adenylyl cyclase. Not all these receptors play a role in the subjective effect of stimulants, but nevertheless this shows that the actual concentration of cAMP in the mesolimbic pathway says virtually nothing about what will happen after a redose.

The bottom line in my deduction regarding your background was that it can more or less be considered common knowledge (among people with an education in this field) that cAMP is a second messenger for dozens of processes. It would be more or less the same as arguing that ketamine's effects are dependent on intracellular Ca2+ concentration. Again, no offense.

 

[Nagelfar]

You assumed a lot of my meaning, as for dopamine receptors, I meant all reinforcing drugs from nicotine/anti-cholinergic to GABAergics as per my mention of the big four reinforcers, etc. Anyhow, I had it on good authority that if you block cAMP overshoot, you block the reinforcing effects of all above mentioned drug types.

 

[3rd_I_blind]

You are right that I made some big assumptions and - perhaps - they were wrong. Perhaps, you could also aid the discussion by making a more elaborate contribution by, for instance, providing an article or an example of what it is exactly you want to address.

Anyway, the reinforcing effect of any drug is almost exclusively linked to dopamine release/potentiation/proliferation at some stage.

You are correct that inhibiting cAMP overshoot diminishes reinforcement/dependency. This, however, has absolutely nothing to do with any endogeneous mechanism relating to the subjective experiencing of a redose/change in setting. As I said before: You should look into the role of the nucleus accumbens in the placebo effect and sexual arousal, this probably explains what you are looking for.

 

[Nagelfar]

Really I was just interested in, if NAc is the culprit, what triggers NAc's placebo effect chemically (I don't mean the subjective qualia), or the cascade of chemicals/dopamine that are induced. I apologise I don't have much else to contribute if I don't know much more.

 

[negrogesic]

Generally speaking, there is no real single 'culprit' involved (such as a monoamine/neurotrans, site/region or complex). And to be frank, our understanding of the brain as a whole is in its relative infancy.

Subjective perceptions of drugs of abuse cannot be directly correlated with animal studies of reward/self-admin/tolerance because while enormously useful, laboratory animals have yet clearly express the nature of their "high".

 

[3rd_I_blind]

Really I was just interested in, if NAc is the culprit, what triggers NAc's placebo effect chemically (I don't mean the subjective qualia), or the cascade of chemicals/dopamine that are induced. I apologise I don't have much else to contribute if I don't know much more.

Well, this might be a bit oversimplified and a bit frustrating for you (who is probably looking for an insightful answer), but the truth is that the nucleus accumbens itself triggers the nucleus accumbens reaction which results in a placebo effect. Think of it like this: You are feeling very good, and suddenly you realize it 'MAN! Today I'm feeling fucking great!!'. And the mere realization that you are feeling so good, causes you to feel even better. That's a bit what happens with the dopaminergic system; self-reinforcing pathways. It's probably no surprise the nucleus accumbens also plays a role in repetitive motor behavior, just as much as it does in repetitive psychological behavior.

When dealing with the brain, the answer to a question is often ten new questions instead of one answer. Better luck next time, LOL.

EDIT: The above is not entirely true, but I think it is a good enough approximation of reality without the need of incorporating ten new brain areas in the explanation.