16 replies to this topic

[the_apollo]

I've read alot about how one can increase the Dopamine receptor density or activity (D2 and D3 mainly), but almost nothing about the Dopamine D4 receptor,,
the thing is that's interesting to me is that the D4 receptor is said to be involved in higher cognitive processes, and that responsiveness to methylphenidate is dependant on D4 receptor density/function.

So what i have in mind to ask is; Is it possible to increase the D4 receptor density(?), not just activity like Dopamine agonists does, but increase the density of the D4 receptors that can be activated.

[Thorsten3]

I thought D1 was more significant than D4 for cognitive processes, although, I could be wrong. I think D4 is important too, but, D1 is like the on switch for glutamaterigc functioning in the prefontal cortex.

I've always been interested in what the effects of 'increased density' actually are, though? Just because you have more receptor sites, does that equal greater function? Will your brain have to upregulate in order to keep up with these extra sites? Or, will homeostasis go the other way, and the receptor sites diminish? (once the drug is taken away). Does 'increased density' actually mean anything? I mean, if I have increased density of 5HT1A, does that then mean I won't be depressed and I then become super social!?!?

I suppose smokers who go without their nicotine probably suffer from such a thing. You know when they crabby and irritable, and need their next fix? D2 downregualtion (or, even decreased density of receptors) probably plays a part in their 'yoyo mindstates'.

Edited by Thorsten2, 18 April 2013 - 09:28 PM.

[Dissolvedissolve]

Increased density is a form of upregulation, and in the context of neurotransmitters, the term "upregulate" almost always refers to an increase in receptor density Your brain is constantly changing receptor density in order to maintain homeostasis. Now of course there is the paradox that nicotine increases ACh receptor density, but that's a special case that isn't well understood as far as I know.

[the_apollo]

No one ?

There's a lot, a LOT of supplements that can increase D2 receptor density or/and activity, BDNF increase D3 receptor activity and of course - Sulbutiamine increase D1 receptor density through a compensatory mechanism, but is there absolutely no way to increase the D4 receptor Density?

[Thorsten3]

Increased density is a form of upregulation, and in the context of neurotransmitters, the term "upregulate" almost always refers to an increase in receptor density Your brain is constantly changing receptor density in order to maintain homeostasis. Now of course there is the paradox that nicotine increases ACh receptor density, but that's a special case that isn't well understood as far as I know.

Thanks dude!

Ahh; That would explain why St Johns Wort upregulates 5HT1A, whilst also, increasing the density of 5HT1A.

Edited by Thorsten2, 24 April 2013 - 12:02 PM.

[brainslugged]

From what I understand, not much really affects the density of D4 receptors at all. There is minimal change in them even with dopamine-increasing stimulants.

For D4, you would probably be better off with an agonist.
http://www.ncbi.nlm....pubmed/19932171
http://www.ncbi.nlm....pubmed/19020411

[the_apollo]

From what I understand, not much really affects the density of D4 receptors at all. There is minimal change in them even with dopamine-increasing stimulants.

For D4, you would probably be better off with an agonist.
http://www.ncbi.nlm....pubmed/19932171
http://www.ncbi.nlm....pubmed/19020411

Really? Damn.. Thought it would be do-able to increase the D4 receptor density, would be good since methylphenidate responsiveness seems to be related to the D4 receptor and such..
Well, the good thing then is that the receptor seems as resistant to downregulation as to upregulation.

Then i have a second related question; Dopamine agonist which have D4 receptor agonist properties, will they mediate the D4 receptor activity just as dopamine would or would it be any difference in responsiveness versus Dopamine itself, ?

[brainslugged]

Well, the upside is that the major theraputic effects don't build much tolerance.

There may be things that upregulate D4, but it will probably be more difficult to find since it is probably controlled by an external system. I would look into drugs that seem to improve concentration with no known direct dopamine or ne affects. I am talking about things like sigma agonism which we dont understand. Perhaps D4 receptors are regulated by sigma activation, no idea if that iseven semivalid but you get thepoint.

There will always be a differencebetween agonism, releasing agents, and reuptake inhibitors. Since D4 agonists aren't mainstream, we dont know how that will turn out. I dont know if D4 activity is highly conditional or if it is more constant.D2 is an example of something that would not be good to agonize, but I have no idea about D4. Maybe it causes focus when activated, or maybe its activation passively allows concentration. If it is the former, agonism may be bad.

[Redux]

'

Edited by Redux, 30 April 2013 - 05:27 AM.

[Redux]

Zinc in highly bioavailable form (Methioine) increases density, from own experience it feels almost like amphetamine-like compound.

Zinc regulates the dopamine transporter in a membrane potential and chloride dependent manner.

Pifl C, Wolf A, Rebernik P, Reither H, Berger ML.

Source

Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria. christian.pifl@meduniwien.ac.at

Abstract


The dopamine transporter (DAT), a membrane protein specifically expressed by dopaminergic neurons and mediating the action of psychostimulants and dopaminergic neurotoxins, is regulated by Zn(2+) which directly interacts with the protein. Herein, we report a host-cell-specific direction of the Zn(2+) effect on wild type DAT. Whereas low mumolar Zn(2+) decreased dopamine uptake by DAT expressing HEK293 cells, it stimulated uptake by DAT expressing SK-N-MC cells. Inhibition or stimulation was lost in a DAT construct without the binding site for Zn(2+). Also reverse transport was differentially affected by Zn(2+), dependent on whether the DAT was expressed in HEK293 or SK-N-MC cells. Pre-treatment of DAT expressing cells with phorbol-12-myristate-13-acetate, an activator of protein kinase C, attenuated the inhibitory effect of Zn(2+) on uptake in HEK293 cells and increased the stimulatory effect in SK-N-MC cells. Patch-clamp experiments under non-voltage-clamped conditions revealed a significantly higher membrane potential of HEK293 than SK-N-MC cells and a reduced membrane potential after phorbol ester treatment. Lowering chloride in the uptake buffer switched the stimulatory effect of Zn(2+) in SK-N-MC cells to an inhibitory, whereas high potassium depolarization of HEK293 cells switched the inhibitory effect of Zn(2+) to a stimulatory one. This study represents the first evidence that DAT regulation by Zn(2+) is profoundly modulated by the membrane potential and chloride.



CDP-Choline is another one that indiscriminately increases density among dopamine group, might be lucky to increase in really low doses (like my case).


Changes in brain striatum dopamine and acetylcholine receptors induced by chronic CDP-choline treatment of aging mice.


R. Giménez, J. Raïch, and J. Aguilar

Author information ► Copyright and License information ►


This article has been cited by other articles in PMC.



Abstract

1. Spiroperidol binding (dopamine D2 receptors) and quinuclidinyl benzilate binding (muscarinic receptors) in striata of 19-month old mice was analyzed for animals that had received chronic administration of cytidine 5'-diphosphocholine (CDP-choline) incorporated into the chow consumed (100 or 500 mg kg-1 added per day) for the 7 months before they were killed. 2. Treated animals displayed an increase in the dopamine receptor densities of 11% for those receiving 100 mg kg-1 and 18% for those receiving 500 mg kg-1 as compared to the control aged animals that had received no CDP-choline. Control animals showed, from 2 months to 19 months of life, a 28% decrease in the receptor density. No change in the affinity of the receptors for spiroperidol was found in the treated or untreated animals. 3. Muscarinic acetylcholine receptor densities were also partially recovered by the same treatment in aged animals that showed a 14% decrease of these receptors in this case. The muscarinic receptor density increased 6% for the animals that received 100 mg kg-1 and 17% for the animals that received 500 mg kg-1 without any change in the affinity of the receptor for quinuclidinyl benzilate. 4. Aged animals displayed a slight increase in brain membrane fluidity as indicated by a decrease in the polarization value of the non-polar fluorophore 1,6-diphenyl-1,3,5-hexatriene. Interestingly, in the treated animals a greater increase in membrane fluidity was determined and found to be very similar for the two doses.(ABSTRACT TRUNCATED AT 250 WORDS

http://www.ncbi.nlm....les/PMC1908237/

My last 2 cents: Look for a way to raise dopamine overwall

Edited by Redux, 30 April 2013 - 05:26 AM.

[Mr Serendipity]

CDP Choline increases D2 Density I think

[the_apollo]

Zinc in highly bioavailable form (Methioine) increases density, from own experience it feels almost like amphetamine-like compound.

Interesting,
do you have a souce for that claim regarding Zinc increasing Dopamine D4 receptor activity?

[Guardian4981]

I have been using manganese lately and feel it has some kind of benefit to dopamine.

[NeuroNootropic]

Zinc in highly bioavailable form (Methioine) increases density, from own experience it feels almost like amphetamine-like compound.

I've tried L-OptiZinc in the past and it did not stimulate me at all. I took it before bed. Would the same benefits still apply to an individual who is not deficient in zinc?

[the_apollo]

What i think is so wierd about that the D4-receptor density cannot be effected, is that the D1, D2, D3 and D5 receptor are all dynamic, their activity and density change due to Dopamine activity, and density can be changed by different methods/ and activity,, but Not the D4?
Is the whole Dopamine-system dynamic in function, but the D4-receptor is static?

[Multicultural Harmony]

WAY-100,635 interacts with D4.

http://www.ncbi.nlm....pubmed/16915381

Edited by Pitolisant, 30 December 2013 - 06:38 PM.

[Area-1255]

WAY-100,635 interacts with D4.

http://www.ncbi.nlm....pubmed/16915381

Yes, as an agonist, but it doesn't upregulate it.