Downregulation mean unique parts of high gone or just twice the amount?

[terlem]

Let's say your receptors are downregulated to 50%. Are there any unique parts of your high shut off? Or do you get the exact same high as a new user just with twice the amount? The second seems likely but too good to be true. (Or the third and by far most unlikely, being the same high as a new user but can only go upto half the amount.)

I don't know if a receptor is all equal or the parts that get shut off are slightly different than the ones that remain, which is why i ask. Speaking of cannabinoid receptors, marijuana tolerance. Appreciate the help.

 

[sekio]

Downregulation implies you have fewer active G-protien receptors availiable to bind a ligand. Hence the total amount of electrical activity produced by a cell upon exposure to the ligand is reduced.

With drugs that produce their effect at one primary receptor, downregulation simply means the drug will lose efficacy and you will need more (usually exponentially more) to produce the same effect. If you have a multifaceted drug that acts at multiple targets then it is possible some of the effects will downregulate faster than others. (For instance, a combination stimulant/psychedelic may lose efficacy as a psychedelic but not a stimulant after repeated use)

Downregulation as far as I know is not linear and cannot be easily measured/quantitated. Receptors almost never downregulate to the point where a drug has no effect whatsoever. But at the same time, it's not always as simple as "taking twice as much", because drugs can be less selective in their effects at high doses.

there is also a deeper factor to consider - high level situational tolerance where your psyche becomes habituated to the effects of drugs and you simply "feel" less of the effects because you are used to them. Basically, novel drugs will almost always produce a stronger effect than drugs that are used regularly.

 

[cannibalsnail]

I too have wondered about this. For example taking highers doses of psychedelics: 2A is downregulated, but is 2C or 3? These are "negative" and would increase unwanted side effects.

What about Ketamine/MXE? They are D2 agonists. D2 does not downregulate like NMDA. So over time the increased doses will lead to more and more D2 activation, increasing psychotic/manic side effects.

 

[AlphaMethylPhenyl]

I've heard of MXE being a d2 agonist but not Ketamine

 

[sekio]

At normally achievable concentrations neither K or MXE are particularly effective D2 agonists.

D2 does not downregulate like NMDA

I'm pretty sure all GPCRs will downregulate to some extent with high enough levels of stimulation. And NMDA antagonism in the case of e.g. MK-801 will most definitely induce psychotic behaviour in some.

 

[cannibalsnail]

I'm not 100% sure on this but I think D2 type receptors either don't downregulate or do very slowly. ADD medications are effective for long periods of time without any significant tolerance to the therapeutic effects (mediated by D4) and the same is true of RLS medications such as Pramipexole which are mixed D2 type agonists.

Then again the binding efficacy of Ketamine D2 is unknown to me so it was merely speculation. Frequent use of MXE/K does seem to bring out extreme psychotic symptoms and I haven't seen an explanation for the mechanism (I'm sure one exists).

 

[terlem]

Okay so if all receptors were surely downregulated to 50%, double the dosage would produce the exact same effect as a brand new marijuana user? Correct? (Bolded as this is the main Q and pretty sure understand the rest : )

Downregulation implies you have fewer active G-protien receptors availiable to bind a ligand. Hence the total amount of electrical activity produced by a cell upon exposure to the ligand is reduced.

With drugs that produce their effect at one primary receptor, downregulation simply means the drug will lose efficacy and you will need more (usually exponentially more) to produce the same effect. If you have a multifaceted drug that acts at multiple targets then it is possible some of the effects will downregulate faster than others. (For instance, a combination stimulant/psychedelic may lose efficacy as a psychedelic but not a stimulant after repeated use)

Downregulation as far as I know is not linear and cannot be easily measured/quantitated. Receptors almost never downregulate to the point where a drug has no effect whatsoever. But at the same time, it's not always as simple as "taking twice as much", because drugs can be less selective in their effects at high doses.

there is also a deeper factor to consider - high level situational tolerance where your psyche becomes habituated to the effects of drugs and you simply "feel" less of the effects because you are used to them. Basically, novel drugs will almost always produce a stronger effect than drugs that are used regularly.

Underline 1. Targets meaning receptors i believe, not different targets on one. This is due to certain receptors downregulating faster than others like how the hippocampus lowers faster than the striatum and therefore the the effects given by each region would decrease by said amount. No change in effects in a single receptor with a higher dose exactly accounting for the downregulation. Correct?

Underline 2. Hmm, even if all receptors were surely at 50%?

 

[endotropic]

Okay so if all receptors were surely at 50%, double the dosage would produce the exact same effect as a brand new marijuana user? Correct?

No, not necessarily. Lets say that the first time someone smokes pot they smoke enough that 100% of their CB1 receptors are bound by THC. That person continues smoking pot for a long period to the point CB1 receptors are at 50%, now no matter how much they increase their dose they won't reach the same level of activation that they had originally.

This is assuming that 100% of the receptors are necessary for a maximum effect. Let's say in system A only 50% of the receptors need to be activated to produce a maximum effect, and in system B 100% of the receptors need to be activated for the maximum effect. Obviously system A is going to be a lot less prone to desensitization, as 50% of its receptors can be lost before the maximum effect is diminished. Another way of saying this is system A has a high "receptor reserve".

This is also assuming that cannabinoid receptors desensitize appreciably at all. It's likely that they do, but I wouldn't just assume that without any evidence.

 

[sekio]

The way I think of receptor desensitization, is like so

say a naive user has a population of 1000 receptors.
these receptors will each produce depolarisations of approximately, say, 5 uW/s when fully activated with THC. (the depolarisation might be stronger with a stronger agonist, say CP-55940)
this means there is a sum total of 5000 uW/s of depolarisation when THC is at its maximal effective concentration. a more typically achievable value may be (for example) 2500 uW/s.

in order to produce the same 2500 uW/s in a similarly sized set of neurons that has 50% of CB1 internalised, depending on the curve of ([drug])/(depolarisation energy), one may need 2x or even more of the concentration of THC to achieve a similar effect. But a level of 5000 uW/s is unachievable with THC in a population of downregulated neurons unless you use a super-agonist.

 

[MeDieViL]

As an anecdote, with most stimulants tolerance leads me to needing a higher dose while with desoxy the effects just completely disappeared, even if id try 60mg a few times a day i wouldnt feel more awake or anything or fall asleep more slowly) i just got completely immume while other stims still work.

After stopping desoxy i need a combo of mpa and ethyl and in very high doses to feel them, they barely broke trough while they did work, just felt tired still, while i kept using them over the days they got stronger and stronger and now work normally like i wasnt tolerant to them (or the level of tolerance i would have after using them for as many days i used them).

Interesting as they should pretty much all activate the same receptors, desoxy probably acts on other receptors wich regulate the sensivity of da receptors (kinda like how cannabinoids upregulate 5HT2A).