Cholinergic Mechanisms of ALCAR
nootropics choline piracetam cognitive enhancement ALCAR
This research project grew out of a desire to explain an effect I observed in myself: ALCAR fulfilled a very definite requirement for choline supplementation in piracetam usage. Taking even small amounts of ALCAR with alpha GPC resulted in a tension headache (sign of ACh overload), while much larger doses of either did not. This suggested to me that ALCAR had some kind of synergistic (i.e. multiplicative) effect somewhere in the acetylcholine pathway.
This is very much a work in progress; research of this kind generates a torrential cascade of references, and leads into general areas of inquiry in the pursuit of adequate explanation. But enough people have been asking about these mechanisms that I felt it would be helpful to publish a document with the most relevant details, if not a complete explanation. There are several more mechanisms by which ALCAR impacts the acetylcholine system, which are mentioned briefly at the end of the review. These will be fleshed out and referenced as I have time to read more papers, and adjustments will be made to existing explanations as I receive more full texts.
Feel free to post comments here, though I've created a forum thread to announce updates, discuss the research, and collect experience accounts of those who have tried the ALCAR + piracetam combination.
Piracetam and Choline
There is some confusion about the cholinergic potential of ALCAR, that results from the terminology we use on the board. We say that piracetam requires a "choline source," when what we more precisely mean is that we need to increase production and release of acetylcholine (ACh) to compensate for the hippocampal ACh depletion that piracetam causes [1-2].
The most common way to achieve this is by exogenous supplementation of choline, or a precursor which is converted into (or already is) one of the forms of choline useful in the brain . Exogenous choline protects against artificial ACh depletion  (like piracetam), and increases the rate of resynthesis [3, 42, 49-50]. Improved choline supply may also provide a "backup" pool which may be mobilized for synthesis later [4-5, 43]; and increases the magnitude of ACh production in response to neural  or chemical [6-7, 42] stimulation.
But there are some drawbacks to this route. A certain elevated concentration of extracellular brain choline is required to effect an increase in ACh ; this is one of the reasons why many studies show no increase of ACh in response to exogenous choline [49-54]. An increase in plasma choline results in a net Ch increase in the brain , though by a lesser factor . Most of this is rapidly taken up into cells or phosphorylated, and the surplus removed to the CSF [45, 47]—resulting in a small level of sustained extracellular choline [45-46]. In the absence of neural or chemical stimulation, increasing the amount of choline in the brain will only provide a very small and short-lived spike in basal ACh release in the hippocampus and cortex [6, 25]. The fact that added choline does not result in increased basal ACh shows that there are many systems of regulation—activity dependence, phosphorylation, plasma-brain-CSF exchange, choline uptake transporters, and recycling system—which make choline supplementation alone an inefficient and possibly ineffective means. This is where ALCAR comes in.
The Acetyl Moieity
This incredibly helpful graphic illustrates the course of the acetyl moieity (group) that ends up in acetyl-choline :
The first enzyme (on the left) is Carnitine Acetyltransferase (CarAT), which transfers the acetyl group from ALCAR to acetyl-Coenzyme A (acetyl-CoA). Then the enzyme Choline Acetyltransferase (ChAT) transfers the acetyl group to choline to yield ACh. (This process has been demonstrated in slices of rat brains [8, 11, 23], and proposed by several others who could not construct the proper experimental system to demonstrate all of the effects [22-23]).
So, how might increasing availability of the acetyl moeity help us? The answer is in the equilibria of the coupled enzyme reaction above. The CarAT reaction has equilibrium near unity [9-10]; this means that it will utilize about half of any added substrates (ALCAR) to synthesize new products (acetyl-CoA). However, the equilibrium of the ChAT reaction is greatly in favor of the products (Keq of 12.3  or 13.3 ); the vast majority of an added substrate will be converted into ACh. In other words, provided that CoA and choline are available, ALCAR should have a dose-dependent impact on amount of acetylcholine produced. (see Acetylcholine Release, below)
(It is worth noting that CarAT is able to acetylate choline directly , but with a very low affinity. It is speculated that it plays virtually no role in brain ACh biosynthesis . However, it has been shown to account for up to half of ACh production in some muscular models [56-59], so a possible role in the brain cannot be discounted.)
Other enzymes and substrates are also responsible for the synthesis of acetyl-CoA, and are responsible for a greater amount than is contributed by ALCAR [11, 18-21]. The substrate which makes the largest contribution to the acetyl-CoA pool is pyruvate [12-13] (a metabolite of glucose), which is converted to acetyl-CoA by pyruvate dehydrogenase (PDC) in the mitochondrial matrix  (though PDC may exist extra-mitochondrially ). Glucose is slightly less preferred as a source, presumably because it must first be converted to pyruvate. Citrate and acetate play a role, though much less than pyruvate or glucose. ALCAR is preferred about 66% as much as glucose in this rat brain model :
An important point is that ALCAR does not compete with glucose  or pyruvate  in relative contribution to final ACh production. This means that, even in abnormally high concentrations, ALCAR and other acetyl-CoA substrates still maintain an individual dose-response relationship. This is because the enzymes CarAT and ChAT have a very large amount of excess capacity at the physiological concentrations of their respective substrates, and so are far from saturation [8, 15].
The CarAT reaction has an equilibrium constant near unity [9-10], but is also reversible ; this reversibility means that ALCAR may be produced if acetyl-CoA and L-carnitine are in excess (in a certain area). Some of these other substrates (esp. pyruvate) are converted to acetyl-CoA inside the mitochondrial matrix . CarAT itself is a membrane-bound enzyme, probably active at both inner and outer mitochondrial membrane sites [30-32]. One hypothesis is that, since carnitine is able to "shuttle" acetyl groups through the membrane [16-17, 30-35], ALCAR is used to transfer the acetyl groups from mitochondrial pyruvate-derived acetyl-CoA to the cellular cytoplasm, where it can be utilized by ChAT [8, 15]. (CoA and acetyl-CoA are able to pass the mitochondrial membrane directly in the presence of Ca2+ ions, but the required ion concentration is higher than has been demonstrated as possible in intact nerve cells [15, 37-40]). Thus, in addition to providing the acetyl moieity directly, ALCAR/carnitine may also serve as a carrier molecule to bring acetyl-CoA from other substrates, into the cytoplasm.
ALCAR also increases the utilization of glucose in the brain [22, 60], probably by stimulating non-oxidative pyruvate dehydrogenase activity [66, 68], which effectively increases the amount of ACh synthesized from glucose/pyruvate . Utilization increases to varying extents in different regions, and increases more in the aged (who generally suffer from decreased glucose utilization) [62-63].
ALCAR is also able to increase the utilization of alternative energy sources like ketone bodies and lipid substrates [67, 69]; evidence also suggests that more ALCAR is taken up into the brain when levels of glucose are low .
It's also interesting that glucose and exogenous choline combine synergistically to increase ACh release , in a model of awake mice, when neither alone had much of an effect. While it isn't necessarily healthy to increase glucose intake, ALCAR's enhancement of glucose utilization (theoretically resulting in the same thing: more acetyl-CoA) may result in something of the same synergy.
In the above reactions, CoA is recycled continuously. It is tempting to attempt to increase the quantitiy of this substrate as well, to drive the CarAT reaction forward from another direction. A potential drawback exists, in that CoA is a potent inhibitor of the forward action of the ChAT enzyme [8, 36]. An elegant feature of the CarAT-ChAT enzyme loop is that, in synthesizing acetyl-CoA, levels of this inhibitory product are decreased, allowing an increase in ChAT activity.
It is unknown whether supplementation of pantothenic acid (B5) or pantethine, precursors of CoA, will increase acetyl-CoA more than they interfere with ChAT. Only one paper exists which demonstrates an increase in ACh due to B5 supplementation , but it may only be applicable to correcting ACh deficiency due to B5 deficit (see discussion here). From the anecdotal reports of pantethine use, it sounds like ACh is being increased, if anything. Clearly, more experimentation is required. However, I suggest that moderate doses should be used, as increasing the pool of unacetylated CoA will have a negative impact on ACh production :
Transport of choline into nerve terminals, where it is converted into acetylcholine by the aforementioned process, is carried out by high- and low-affinity choline transporters (CHT); high-affinity choline uptake (HACU) is responsible for most of this process under normal circumstances. ALCAR has been shown to increase the uptake of choline, though the mechanism is not fully understood; as the release of ACh from the terminal results in an influx of new choline, this alone is no doubt implicated to some degree.
Many studies demonstrate that ALCAR increases activity of this enzyme; indeed, this is the most obvious cholinergic mechanism mentioned in the relevant abstracts. However, this enzyme functions at the convergence of many cholinergic processes, making it difficult to ascertain the exact mechanisms responsible.
As ChAT is the enzyme necessary for synthesis of acetylcholine, any process increasing ACh production and release should concomitantly increase its activity. However, this doesn't rule out the possibility of a direct action on the enzyme. Nerve growth factor (NGF) has such a stimulatory effect on ChAT activity. To complicate this further, ALCAR interacts with NGF in several ways (see below), which may also increase its effect on ChAT in several ways. However, there is evidence to show that ALCAR increases ChAT activity in the absence of NGF, and that increased NGF levels do not necessarily elevate the enzyme activity.
ALCAR demonstrates the greatest efficacy in ameliorating age-related deficits in ChAT activity.
ALCAR has been shown to increase hippocampal levels of NGF. ALCAR also modulates the action of NGF by increasing the expression of its low-affinity receptor, p75-NGFR, and perhaps by acetylating some of NGF's amino acids. This has the effect of potentiating its action, by which much lower amounts produce the same neurotrophic effect. This effect feeds back into stimulation of ChAT, and greater ACh production.
ALCAR most effectively induces NGF activity in aged animals, who suffer a decrease in NGF activity in parallel with a cholinergic deficit.
ALCAR arginyl amide produces a direct neurotrophic effect on neurite outgrowth and cellular morphology. However, only two studies have been conducted, both by the manufacturer Sigma Tau, and it is unknown whether this putative effect translate to an in vivo efficacy.
ALCAR has a very slight direct agonistic effect on ACh receptors, but it is orders of magnitude smaller than that of the neurotransmitter; there is almost no chance that it plays any practical role.
Or, "the proof is in the pudding." An actual and significant increase in ACh levels has been shown in several studies, which demonstrates that these mechanisms actually do exert an influence.
Other neurological mechanisms
Dopamine: ALCAR ameliorates age-related decline in D2 receptor density, and induces release of vesicular dopamine in the corpus striatum of rats.
NMDA: Reduces age-related decrease in receptors, but increases receptor density by decreasing amounts in adult and young rats.
GABA: Increased the density of GABA-benzodiazepine (but not GABA-A) receptors in aged rats.
Calcium channel: Ameliorated age-related decrease in L-type voltage-gated Ca2+ channel receptors in the hippocampal membrane.
Glucocorticoid: Prevented age-related decrease in number of binding sites.
Neuroprotection: ALCAR inhibits increases in lipid hydroperoxidation, increases expression of NF-κB and mGlu2/3, inhibits ceramide generation, enhances histone acetylation, attenuates apoptosis, and protects against the neurotoxic effects of NMDA (in large doses), MPPP(+), NGF/BDNF/serum deprivation, and ischemia.
Anxiety: One study in rats showed that acute (i.e. single) doses of ALCAR were anxiogenic; this study also showed that in chronic administration, 10 and 100mg/kg had no effect on anxiety, while 50mg/kg was anxiolytic . This is suggestive of a bell-shaped response curve, which is consistent with dose-reponse curve of other effects in the Ames studies.
Ultrastructure: One abstract mentions that ALCAR induced a decrease in axosomatic synapses in young rats, in contrast to ameliorated decreases in axosomatic synapses and giant synapsis vesicles in aged rats . Without the full text, and knowledge of the dosage, ROA, and age of the "young" animals, it is difficult to predict whether this is cause for concern in human; though most studies use "young" as an age category quite separate from "adult."
Due to poor planning on my part, I didn't store the medline URLs in my reference list. I will work on linking these, but in the meantime, typing the title into google scholar is probably the easiest way to retrieve the abstract (clicking All Versions will call up the pubmed link).
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Update ChAT, NGF