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Trying to understand neurotransmitter receptor regulation


(Michael Hrenka) #1

Preface: This first post should be seen as work in progress. I’m not happy with the state it’s currently in. There are so many things like warnings, questions, observations, evidence (for and against), further conclusions, possible experiments that are still missing. Yet, it should be useful in its current form already, so you are indeed invited to comment on it. In the following I will take dopamine in place of any kind of neurotransmitter. Similar considerations should be true for other neurotransmitters like noradrenalin, serotonin, endorphins, acetylcholine, glutamate, GABA, and so on.

Neurotransmitter receptor regulation is an approach that might be useful for changing how your brain operates. Recently I’ve got the insight that a lot of problems might be connected to a lack of dopamine, especially in the brain. Therefore I’ve focused on how to increase those dopamine levels and have written down a supplement and drug combination that should work pretty well (11th post in the following thread):

Afterwards I started questioning whether it would actually be a good idea to flood the brain with dopamine. After all, that’s what makes certain drugs so addictive. It’s not like the supplement combination I’ve written down would have a significant addiction potential, but I feared that it might have some of the unwanted effects of addictive drugs. Do people’s lives get better by taking such drugs? Usually not, in many cases they have quite the opposite effect. But why? Sure, addictive drugs grant you a short term dopamine boost at the expense of a dopamine shortage afterwards, but what’s the problem about that? After all, you could just sit out the “low” phase.

And here’s the crux: If people actually did that consistently, then addictive drugs could be used quite effectively as nootropics for chemical self-regulation. They wouldn’t be very harmful if consumed in moderation. The real problem arises from the obvious fact that people like being “high” and dislike feeling “low”. And of course they know that the drug is what makes them “high”. So, the temptation to take that drug again to replicate the previous “high” is quite strong, especially during the “low” phase.

So, what happens when they take the drug again during the “low” phase? I’m not exactly sure, I’m not an expert in this field, and this is mostly based on snippets of knowledge plus reasonable speculation, but there are two interesting scenarios:

  1. The dopamine release on the second use of the drug is lower, because the brain has already used to its dopamine reserves and the concentration of dopamine precursors is low. Therefore, the effect on one’s mood would be lower, if one takes the same dosage as on the first use. Overall, the effect would be a smaller “high” and a prolonged and exacerbated “low” afterwards that would increase the temptation to repeat the use of the drug even stronger.
  2. Dopamine release is the same as during the first use of the drug. The “high” is just about as intense. In this case, the problem is that the brain is dealing with a prolonged phase of elevated dopamine levels. That would be awesome, if the brain didn’t have negative feedback mechanisms; but it does: As result of dramatically increased dopamine levels the brain readjusts by reducing the number of dopamine receptors or making them less sensitive to dopamine. So, you would need to get a higher concentration of dopamine to get the same stimulating effect. Additionally normal functioning of the brain is impaired persistently, because normal activities don’t trigger the usual “dopamine kick”, but a much weaker reaction.

How would both scenarios actually differ? In scenario 1 the brain would be pretty much normal again, after the “low” phase has been completed without taking an addictive drug during that time. Of course, there would probably be a permanent association of that drug with the “high”, so the probability of taking it again would be at least slightly higher. If taking the drug in certain situations as coping mechanism, that habit would need to be broken. But once that was completed, things would be almost as before.

In scenario 2 things become more difficult, because neurotransmitter receptor regulation seems to be a long-term effect. The “low” wouldn’t stop after the drug has been eliminated from your system and dopamine synthesis has become normal again. You would be stuck in a persistent “low” state for quite a while. And because that’s so unpleasant, the temptation to take the drug again to finally get out of that “low” state and at least feel “normal” again becomes even stronger than in scenario 1. It’s not hard to see that the danger of falling into a vicious circle of ever higher dosages and ever more neurotransmitter receptor down-regulation is pretty high in this scenario.

A solution that might work for both scenarios would be enduring the “low” phases as long as they last. Unfortunately it’s not clear whether that would be sufficient for scenario 2. If neurotransmitter receptor regulation only happens when the deviation from normal neurotransmitter densities is extreme, like when taking a high dosage on an addictive drug, then it should be expected that even experiencing the “low” caused by persistent neurotransmitter receptor down-regulation would not be enough to trigger neurotransmitter receptor up-regulation. In other words: You would be permanently screwed! Unless … you can probably guess it: Unless you cause an extremely low concentration of dopamine that’s even below the permanent “low” state, so that dopamine receptor up-regulation is triggered.

How could you do that? One possibility would be to abstain from all kinds of stimulating experiences and drugs, so that dopamine release becomes minimal. That should be very effective, but it’s a very hard, very unnatural, and totally counter-intuitive thing to do on a consistent basis. Doing this for short periods of time might be enough, though. That might explain why meditation is so effective! If you do it right, there shouldn’t be much stimulation (in the form of distracting or interesting thoughts!) during meditation.

Another approach would be to interfere with dopamine synthesis, or dopamine release chemically. I’m not sure whether there are suitable drugs for that already, but I guess there are, especially for addiction treatment.

A third option would be to do things that “burn up” dopamine quickly. I guess that’s the case for actions that require a lot of willpower / self-regulation. Doing hard things, and for a long time. Ideally you’d stop sleeping or having any fun for a few days! If you lose your will to live during that process, it should be especially effective (killing oneself in that phase is nearly impossible, because that would require way more motivation than is available during that time of dopamine-deprivation).

The overall theme for this kind of “therapy” is about the following: Do not fight strong feelings of boredom, anxiety, despair, meaninglessness, depression, agony, lack of motivation, or similar negative emotions, but seek, embrace, or at least ignore and endure them! They are pretty much necessary for healing!

Ok, that “therapy” might sound crazy, but it would be a plausible approach, if my hypothesis turns out to be correct. We have a natural tendency to fight negative emotions one way or another. Embracing or ignoring them is indeed very unnatural and counter-intuitive. But what I’ve found is that it’s one of the few approaches that actually seem to help me significantly and consistently. Fighting negative feelings seems to be dysfunctional for healing!

Finally, a little side-note: It seems likely that something like the mechanisms behind scenario 2 are responsible for the hedonic treadmill.


The natural tragedy – and how to deal with overwhelming stress