72 replies to this topic

[rwac]

Changes in brain striatum dopamine and acetylcholine receptors induced by chronic CDP-choline treatment of aging mice.R. Giménez, J. Raïch, and J. AguilarDepartment of Biochemistry, Faculty of Pharmacy, University of Barcelona, Spain.
Abstract1. 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.

5 It is concluded that chronic administration of CDP-choline to aged animals promoted a partial
recovery of the striatum dopamine and acetylcholine receptor function normally reduced with aging,
which might be explicable in terms of mechanisms involving fluidity of the brain neuronal membrane.

Keywords: Muscarinic receptor; dopamine D2 receptor; aging; striatum; choline donor; CDP-choline (cytidine
5'-diphosphocholine); membrane fluidity

http://www.ncbi.nlm....?tool=pmcentrez

Attached Files

•  brjpharm00231_0009.pdf   828.83KB   56 downloads

[matthias7]

Good article. Thanks. Big fan of citicoline. FunkyO pointed out iHerb was a cheap source.

[Lufega]

100 to 500 mg/kg? Hmmm.. I weigh 80 kg so I would have to consume 8 grams citicoline per day? Imagine that 250 mg gives me reflux, something I've never had before. Lol

I wonder if high dose lecithin will do the same???

Also, if this increases D2R density, then why does choline use decrease dopamine for some people?

Edited by Lufega, 29 November 2009 - 03:02 AM.

[Saber]

I periodically megadose CDP-choline and/or alphaGPC to manage anticholinergic tolerance and downregulate acetylcholine receptors.
This is very strange because increasing acetylcholine receptors density should increase the tolerance even more.
Maybe it has been placebo all along but I would like to know how much it affects the peripheral acetylcholine receptors.

Edited by Saber, 29 November 2009 - 03:26 AM.

[rwac]

100 to 500 mg/kg? Hmmm.. I weigh 80 kg so I would have to consume 8 grams citicoline per day? Imagine that 250 mg gives me reflux, something I've never had before. Lol

I wonder if high dose lecithin will do the same???

Also, if this increases D2R density, then why does choline use decrease dopamine for some people?

There's a conversion factor of 12.3 for conversion of mice to human dosage I believe.
So equivalent dosage would be 8000/12.3=650mg.
Getting closer there.

I would imagine that increased dopamine receptor density can lead to reduced dopamine.
Similar to brain-fog caused by the racetams.

[rwac]

Seems like CDP-Choline is much under-appreciated.

CDP-choline: pharmacological and clinical review.

Secades JJ, Frontera G.

F.I.S.A. Medical Department, Barcelona.

Cytidine 5'-diphosphocholine, CDP-choline or citicoline, is an essential intermediate in the biosynthetic pathway of the structural phospholipids of cell membranes, especially in that of phosphatidylcholine. Upon oral or parenteral administration, CDP-choline releases its two principle components, cytidine and choline. When administered orally, it is absorbed almost completely, and its bioavailability is approximately the same as when administered intravenously. Once absorbed, the cytidine and choline disperse widely throughout the organism, cross the blood-brain barrier and reach the central nervous system (CNS), where they are incorporated into the phospholipid fraction of the membrane and microsomes. CDP-choline activates the biosynthesis of structural phospholipids in the neuronal membranes, increases cerebral metabolism and acts on the levels of various neurotransmitters. Thus, it has been experimentally proven that CDP-choline increases noradrenaline and dopamine levels in the CNS. Due to these pharmacological activities, CDP-choline has a neuroprotective effect in situations of hypoxia and ischemia, as well as improved learning and memory performance in animal models of brain aging. Furthermore, it has been demonstrated that CDP-choline restores the activity of mitochondrial ATPase and of membranal Na+/K+ ATPase, inhibits the activation of phospholipase A2 and accelerates the reabsorption of cerebral edema in various experimental models. CDP-choline is a safe drug, as toxicological tests have shown; it has no serious effects on the cholinergic system and it is perfectly tolerated. These pharmacological characteristics, combined with CDP-choline's mechanisms of action, suggest that this drug may be suitable for the treatment of cerebral vascular disease, head trauma of varying severity and cognitive disorders of diverse etiology. In studies carried out on the treatment of patients with head trauma, CDP-choline accelerated the recovery from post-traumatic coma and the recuperation of walking ability, achieved a better final functional result and reduced the hospital stay of these patients, in addition to improving the cognitive and memory disturbances which are observed after a head trauma of lesser severity and which constitute the disorder known as postconcussion syndrome. In the treatment of patients with acute cerebral vascular disease of the ischemic type, CDP-choline accelerated the recovery of consciousness and motor deficit, attaining a better final result and facilitating the rehabilitation of these patients. The other important use for CDP-choline is in the treatment of senile cognitive impairment, which is secondary to degenerative diseases (e.g., Alzheimer's disease) and to chronic cerebral vascular disease. In patients with chronic cerebral ischemia, CDP-choline improves scores on cognitive evaluation scales, while in patients with senile dementia of the Alzheimer's type, it slows the disease's evolution. Beneficial neuroendocrine, neuroimmunomodulatory and neurophysiological effects have been described. CDP-choline has also been shown to be effective as co-therapy for Parkinson's disease. No serious side effects have been found in any of the groups of patients treated with CDP-choline, which demonstrates the safety of the treatment.

http://www.ncbi.nlm..../pubmed/8709678

Edited by rwac, 29 November 2009 - 07:18 AM.

[rwac]

Efficacy and safety of oral CDP-choline. Drug surveillance study in 2817 cases.

Lozano Fernández R.

A drug surveillance study has been carried out with oral cytidine diphosphate choline (CDP-choline, citicoline, Somazina) in 2817 patients of all ages, predominating those between 60 and 80 years old. They were suffering from several neurological processes, mainly the vasculocerebral insufficiency and senile involution. Treatment was carried out for between 15 days and 2 months, the mean dose being 6 ml/d. The efficacy of the treatment was determined on the basis of the disappearance, improvement or worsening of clinical manifestations, most frequently shown by patients. The most benefited clinical manifestations by the treatment were: dizziness disappearing in 48.4% of the cases, and improving in 25.2%, cephalea disappearing in 46.5% and improving in 26.7%, insomnia with 38.6% and 24.9%, respectively; depression with 36.9% and 24.1% and memory shortage with 21.2% and 44.7% respectively. The best results were obtained in chronic cerebrovascular insufficiency, the improvements obtained in dizziness, cephalea, insomnia, fatigue and speech troubles being the most important. The safety of the drug was excellent since side effects were observed only in 5.01% of the patients. Among these effects, the most frequently seen were digestive troubles, observed in 3.6% of the cases.

http://www.ncbi.nlm..../pubmed/6684470

[rwac]

Lots of articles on CDP-choline

http://brainmeta.com...showtopic=14296

[meursault]

Receptor density increase doesn't necessarily mean "upgrade" or "enhancement." Don't overlook the fact that a lot of these studies were performed on the elderly, those who have experienced head trauma, degenerative diseases, etc... not saying that it isn't helpful for those populations, but it doesn't seem like young and healthy populations will benefit in terms of increased intelligence. Just a warning for those college students out there ready to dish out $40 on something that might just be worth the cash...

Edited by czukles, 30 November 2009 - 03:17 AM.

[k10]

I prefer Alpha GPC. I believe similar research has been done on Alpha GPC as well from what I remember.

[Lufega]

100 to 500 mg/kg? Hmmm.. I weigh 80 kg so I would have to consume 8 grams citicoline per day? Imagine that 250 mg gives me reflux, something I've never had before. Lol

I wonder if high dose lecithin will do the same???

Also, if this increases D2R density, then why does choline use decrease dopamine for some people?

There's a conversion factor of 12.3 for conversion of mice to human dosage I believe.
So equivalent dosage would be 8000/12.3=650mg.
Getting closer there.

I would imagine that increased dopamine receptor density can lead to reduced dopamine.
Similar to brain-fog caused by the racetams.

Increased receptor density means upregulation. This means your body/brain will be MORE sensitive to even small increases in a neurotransmitter. This is a good thing. Rwac, thanks for all the studies. It seems that CDP-choline helps my condition indirectly. I will try a 750 mg dose per day.

Edited by Lufega, 30 November 2009 - 06:17 AM.

[Pike]

I periodically megadose CDP-choline and/or alphaGPC to manage anticholinergic tolerance and downregulate acetylcholine receptors.
This is very strange because increasing acetylcholine receptors density should increase the tolerance even more.
Maybe it has been placebo all along but I would like to know how much it affects the peripheral acetylcholine receptors.

that is a rather interesting idea! megadosing an ACh precursor in pursuit of downregulating the receptors.... i can actually think of how this could be useful. you've just inspired me to do some experimenting!

[Saber]

I periodically megadose CDP-choline and/or alphaGPC to manage anticholinergic tolerance and downregulate acetylcholine receptors.
This is very strange because increasing acetylcholine receptors density should increase the tolerance even more.
Maybe it has been placebo all along but I would like to know how much it affects the peripheral acetylcholine receptors.

that is a rather interesting idea! megadosing an ACh precursor in pursuit of downregulating the receptors.... i can actually think of how this could be useful. you've just inspired me to do some experimenting!

It's easy to fall for placebo when performing self-experimentation, but it certainly worked for me.
3 months off anticholinergic and the tolerance barely decrease, but 2 weeks megadosing of cdp choline halve the tolerance.
It makes logical sense that the receptors should decrease in density when you have all these excess acetylcholine floating around, but increase density would make the body more susceptible to the side effects of excess acetylcholine.

Of course, it's a linear model and the body is much more complex than that. There's always a surprise.

[Pike]

I periodically megadose CDP-choline and/or alphaGPC to manage anticholinergic tolerance and downregulate acetylcholine receptors.
This is very strange because increasing acetylcholine receptors density should increase the tolerance even more.
Maybe it has been placebo all along but I would like to know how much it affects the peripheral acetylcholine receptors.

that is a rather interesting idea! megadosing an ACh precursor in pursuit of downregulating the receptors.... i can actually think of how this could be useful. you've just inspired me to do some experimenting!

It's easy to fall for placebo when performing self-experimentation, but it certainly worked for me.
3 months off anticholinergic and the tolerance barely decrease, but 2 weeks megadosing of cdp choline halve the tolerance.
It makes logical sense that the receptors should decrease in density when you have all these excess acetylcholine floating around, but increase density would make the body more susceptible to the side effects of excess acetylcholine.

Of course, it's a linear model and the body is much more complex than that. There's always a surprise.

well i must say that your technique is a refreshingly creative idea! i'll try running an ACH-downregulating mini-cycle after my finals. CDP-Choline would certainly make the perfect candidate for this experiment; with it's dual blood-peaks and whatnot. in fact, this might just give me a use for those AChE-inhibitors i have lying around.

what did your downregulation regimen look like? i'm thinking 4 doses of 250mg a day, with each administration 4 hours apart from each other (for the 16 hours that i'm awake). i'll have to make sure to wear my retainer in case my HGH-levels start to have a party.

[PerfectSeek]

CDP Choline is the ONLY source of choline that has had a positive effect for me. Alpha GPC and lecithin had no effect.

I think is it underrated.

Edited by PerfectSeek, 20 December 2009 - 07:42 PM.

[nito]

i finished a bottle of CDP from iherb. It's hard to say what it has done as it's not noticiable to me at least. I don't know how some can feel it working,

[Steve_86]

I wonder if these effects also occur with Centrophenoxine and Alpha GPC.

[chrono]

I wonder if these effects also occur with Centrophenoxine and Alpha GPC.

It appears that they occur with Alpha GPC:

Farmaco Sci. 1986 Apr;41(4):325-34.
Changes in the interaction between CNS cholinergic and dopaminergic neurons induced by L-alpha-glycerylphosphorylcholine, a cholinomimetic drug.
Trabucchi M, Govoni S, Battaini F.

The present study investigates the cholinomimetic properties of the drug L-alpha-glycerylphosphorylcholine (alpha-GPC) at CNS level. Experiments using tritium labelled alpha-GPC indicate that the drug reaches the brain after i.p. and per os administration. In order to study the cholinomimetic properties of this drug an indirect functional index of cholinergic activation was used. In fact cholinergic agonists induce an activation of striatal dopaminergic output. alpha-GPC both i.p. and per os administered increased striatal dihydroxyphenylacetic acid (DOPAC) content. In addition, the in vitro K+ stimulated dopamine release was increased in rats treated in vivo with alpha-GPC. Since alpha-GPC has a weak displacing activity in QNB binding, the in vivo cholinergic activity might be due to the fact that this drug may increase the availability of choline for acetylcholine synthesis leading to increased acetylcholine production. This activity may be useful in those situations such as aging in which cholinergic activity is deficient.

When starting GPC recently, I didn't give it really any time by itself. Has anyone been able to notice anything like a dopaminergic response to GPC or CDP?

Edited by chrono, 18 February 2010 - 11:39 PM.

[curiouskid23]

why wouldn't you want more ACh receptors? If you had less, wouldn't that mean that you would need more choline supplementation to get the same effect?

[sam7777]

I definitely notice increased frontal cortex spatial/reasoning increase, ergo dopamine, with citicoline. It really goes well with Phenylalanine and N-acetyl-Tyrosine. Increased dopamine for sensitized dopamine receptors. More dopamine overall.

[Cephalon]

Hi Chrono,

I get a dopaminergic response from CDP Choline, but not from Alpha GPC.
I used several drugs that work through dopamine like Ritalin and Amphetamine and CDP Choline feels like (a very) dilluted dopaminerigc.
Though I do not get this effect everytime, and the effects seem to level of with time.
Shouldn't it get stronger over time, while density progresses?

I think it perfectly combines with Oxiracetam. They share some properties and work in a similar direction: focus, clarity, sharpness, stimulation

[chrono]

@cephalon: interesting! Re-reading this thread, I may give CDP a try sometime. Alpha GPC has some negative effects for me, unless my choline and carbohydrate intake is very low.

Unfortunately, the finding of increased receptor density is probably not quite as awesome as it first sounds. There are two gross types of dopamine receptors: presynaptic and postsynaptic. The postsynaptic ones are those which 'receive' dopamine signaling, and produce the effects most of us would be looking for. Presynaptic (autoreceptors) monitor and control the amount of dopamine released into the synapse. If more dopamine than usual gets released, the presynaptic receptors sense this, and adjust the release amount downward in response.

There are 5 types of dopamine receptors, and autoreceptors are almost entirely D2 type. The study cited in the first post based its measurements entirely on D2 type receptors (though the other types may have been increased, as well). What this means is that CDP probably also increases the kind of receptors which downregulate dopamine release, so that even though the receiving receptors are increased in number, there could be less dopamine released to make them work. It's really tough to say how balanced the different sides of this equation are, but in theory, the net effect could end up being 0 after a while. The effect is probably a lot more pronounced in the elderly, where this would be restoring a decreased number of postsynaptic receptors.

Edited by chrono, 12 November 2011 - 09:48 PM.

[protoject]

Since I've been on citicoline my libido has gone back up to "youthful levels" . I'm not that old but I'd say they've gone back up to the levels they were at in highschool.. almost.

[MrHappy]

Most of the effects we are seeing here regarding dendrite and receptor density is because cdp-choline breaks down into uridine in humans. Add DHA/EPA to see a more efficient process. Like wise, read the uridine thread to learn why folate and B12 is important to prevent genotoxicity with uridine / cdp-choline.

[Cephalon]

The human body is just fascinating, it almost always gets back into balance no matter what we put into it.
More receptor, less release, less receptors, more release ...
That makes it so hard to find drugs that improve motivation longterm.

CDP also significantly improved my libido, and I did read about this several times. Maybe due to the action on HPA hormones.

Thanks Mr. Happy for the tip on DHA/EPA. I do not have much knowledge about EFA though they are a very important factor in diet.
Do you think it would be enough to supplement with flax oil instead to see the benefits you mentioned?

@ Chrono: do you have cardiovascular/ peristalsis side effects?

I had very bad peripheral ACh related side effects, mixing Alpha GPC with Donepezil.
I also notice mild side effects from aprox. 500mg Choline Bitartrate.
Just CDP-Choline seems to have a more central effect.

[chrono]

Most of the effects we are seeing here regarding dendrite and receptor density is because cdp-choline breaks down into uridine in humans.

It seems so. This study is somewhat contradictory, though the age and lack of choline cosupplementation means it's not a direct conflict. I guess we could flip a coin as to whether studies of the young or old are more applicable to those of us in the middle.

Chronic uridine treatment reduces the level of [3H]spiperone-labelled dopamine receptors and enhances their turnover rate in striatum of young rats: relationship to dopamine-dependent behaviours.
Farabegoli C, Merlo Pich E, Cimino M, Agnati LF, Fuxe K.

The effect was studied of chronic uridine treatment on the recovery of striatal D-2 dopamine (DA) receptors after their irreversible blockade by N-ethoxycarbonyl-2-ethoxy-I,2-dihydroquinoline (EEDQ) in young (40 days old) and adult (14 months old) male rats using [3H]spiperone as radioligand. Chronic uridine treatment (15 mg kg-1 day-1, i.p., 14 days) causes a reduction of [3H]spiperone binding sites in striatum of young rats. This treatment also produces an increase in the rate of recovery of striatal [3H]spiperone-labelled DA receptors in young, but not in adult rats. Catalepsy and exploratory locomotor activity, two behaviours associated with blockade versus activation of DA receptors, were evaluated in the same rats. The behavioural recovery from the EEDQ-induced syndrome is more rapid in the young rats treated with uridine than in the saline-treated group. The behavioural recovery in old rats was not affected by chronic uridine treatment. Thus, in young rats the pyrimidine nucleoside uridine may modulate the steady state and the turnover rate of striatal D-2 DA receptors.

PMID: 2906500

@ Chrono: do you have cardiovascular/ peristalsis side effects?

Nope, I get weird mood and cognitive effects from GPC. Pretty unpleasant. I'm glad to hear CDP can be different.

Edited by chrono, 13 November 2011 - 04:12 AM.

[Propoxy]

From what I've read CDP-choline increases dopamine receptor densitites, making more. My question is would this make a mental illness effected by dopamine worse or better? example OCD, Schizophrenia, Bipolar, psychosis.

[sam7777]

With citicoline- it is over exciting. Problematic to the illness prone. Take piracetam with it, take some N-acetyl-l-Tyrosine in smaller doses, and some antioxidants, omega 3, and possibly taurine/magnesium. Be careful with the caffeine. Read more around. CDP is discussed a lot.

[MrHappy]

Thanks Mr. Happy for the tip on DHA/EPA. I do not have much knowledge about EFA though they are a very important factor in diet.
Do you think it would be enough to supplement with flax oil instead to see the benefits you mentioned?

Yes. I use flaxseed oil myself. ALA breaks down to EPA & DHA. You just end up taking like 10 times as much flaxseed oil..

[Cephalon]

@Mr.Happy: Thanks I will try it with a flax oil supplement, though I won't be able to use 10times the amount than fishoil I would be left eating a carrot not to exceed my kcals, while having met 5% of my nutrition goals. We will see how much is necessary. I guess 1-2grams won't hurt.