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Exploiting the brain's homeostasis mechanism

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ProducedRaw

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With typical recreational drugs we agonise the receptors in question, enjoy the effects and then suffer while our brains try to make sense of it all and return to balance. What if the problem was approached from the opposite side where antagonists are used in order to force the brain to sling-shot the neurochemical balance into euphoria after the antagonist is out of the body? It appears to completely bypass the problem of tolerance and we already know that this works with, for example, low dose Naloxone and mu-opioid receptors. Why not do the same for dopamine or serotonin? The biggest issue I see with this approach is that antagonising feel-good receptors will probably cause significant discomfort and dysphoria but perhaps this could be overcome by inducing anaesthesia and/or unconsciousness while the antagonist is still present in the body. In other words, dose up on a dopamine antagonist and something which causes unconsciousness before going to sleep and wake up feeling like you're on speed. Does this approach have any merit? Has anyone tried it?

On a related note, is homeostasis governed by a particular part of the brain or is it a distributed mechanism?
 
flaming said:
Could you provide a source for this? I would be interested to read it.

D2 upregulation following dopamine antagonist antipsychotic use is a well documented phenomenon... and it's also well documented to cause acute tardive dyskinesia.
http://www.springerlink.com/content/th1yrjuwmckl7829/
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http://www.lowdosenaltrexone.org/

The brief blockade of opioid receptors between 2 a.m. and 4 a.m. that is caused by taking LDN at bedtime each night is believed to produce a prolonged up-regulation of vital elements of the immune system by causing an increase in endorphin and enkephalin production. Normal volunteers who have taken LDN in this fashion have been found to have much higher levels of beta-endorphins circulating in their blood in the following days. Animal research by I. Zagon, PhD, and his colleagues has shown a marked increase in metenkephalin levels as well.
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Regarding side effects like tardive dyskinesia from dopamine overload, I'm becoming increasingly convinced that the ratio of neurotransmitters is the most important part of the equation. So if raising dopamine levels, I imagine that side effects like the previously mentioned could be avoided by concurrently up-regulating the receptors which the relevant inhibitory neurotransmitter targets (in this case, probably GABA).

While we're on the subject, I wonder if this is, in fact, the mechanism behind meditation. You "stop your mind" (antagonise the good stuff), then feel great on the rebound. I wonder if sleep is a similar process too.
 
ProducedRaw said:
Regarding side effects like tardive dyskinesia from dopamine overload, I'm becoming increasingly convinced that the ratio of neurotransmitters is the most important part of the equation. So if raising dopamine levels, I imagine that side effects like the previously mentioned could be avoided by concurrently up-regulating the receptors which the relevant inhibitory neurotransmitter targets (in this case, probably GABA).
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Since GABA upregulation is often quite difficult to establish, would you also support the notion that these side effects could be avoided by simply using a GABA agonist rather than relying on the upregulation rebound from a GABA antagonist?

While we're on the subject, I wonder if this is, in fact, the mechanism behind meditation. You "stop your mind" (antagonise the good stuff), then feel great on the rebound. I wonder if sleep is a similar process too.
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I sincerely doubt it, although my opinion here is as baseless as yours.
 
flaming said:
Since GABA upregulation is often quite difficult to establish, would you also support the notion that these side effects could be avoided by simply using a GABA agonist rather than relying on the upregulation rebound from a GABA antagonist?

I sincerely doubt it, although my opinion here is as baseless as yours.
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Sure, but that would bring with it all of the problems associated with ever increasing tolerance, which is the part I'm interested in evading. Maybe a periodic dosing schedule could be used for the antagonist to prevent too much up-regulation from occurring. For people who happen to have an existing deficiency, perhaps balancing out the excitation wouldn't be necessary in the first place (e.g. treating a dopamine deficiency in a recovering addict).
 
I can vouch for the fact what withdrawals from a 5-HT2a and D2 antagonist (olanzapine) is extremely uncomfortable and has no recreational value what so ever. According to your hypothesis it seems that it should cause a pleasant psychedelic experience, but this is definitely not the case, although there were some traces of quasi-psychedelic mindfuck and visual effects.
 
This is a great post. I would say that down-regulation is caused by phosphorylation either directly or indirectly and up-regulation is caused by phosphatase which would be the opposite. So the actual mechanism of the effects of activating a receptor causes the tolerance.

You have to be more specific when you say dopamine because D2-like are generally dysphoric and D1-like are generally euphoric. So perhaps a D1-like antagonist would bring about pleasant effects as tolerance as long as you were numb while it went on but this would effect many other parts of your body then your emotions so that would have to be tested.

Try and used non-biased more scientific sourcing next time. I have never heard of a mechanism that will promote the actual production of neurotransmitters/neuropeptides other than adequate precursor supply but if you have a source for that I would be interested.
 
First, you would have to restimulate the receptors when you are awake to get "more" out of having upregulated a receptor system. Taking olanzapine as an example, those upregulated D2 receptors wouldn't provide you any benefit unless you are able to stimulate them in a manner that is stronger or different from what your body normally elicits. A better hypothetical example would be the 5HT2A receptor, where we know serotonin is not going to provoke the psychedelic response, thus you would never take a 5HT2A antagonist and wake up into psychedelia.

You would have to take something like LSD, which would activate the psychedelic G protein response from those 5HT2A receptors. However I question if this would even be beneficial because GPCRs function to amplify much greater numbers of intracellular signals per single receptor that is activated. So you can wonder if there is even much of a point in having say 5X the number of 5HT2A receptors per neuron around when a single one is enough to elicit plenty of intracellular response.

Second, a potential problem could exist in the whole body distribution of receptors that you upregulate. Specifically what receptor and sub-type populations would be upregulated, and where? I just bring this up because you wouldn't want to inadvertently upregulate heart serotonin receptors and then blast them with an agonist.

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I think a better strategy to make psychedelics stronger would be to find a way to increase the time that the G protein signal stays active inside the cell, however this could certainly have inherent drawbacks or difficulties as well.

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Regarding homeostasis, I don't think you can isolate this concept to any single part of anatomy. All biological systems (cells) want to be at homeostasis all the time. Of course, our actions as people constantly disrupt their attempt to do this, but homeostasis itself is a by-product of the thermodynamic properties of biological components (proteins, DNA, RNA etc) as manifested by their enclosure inside a membrane.
 
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