Some of these effects of arginine and NOS inhibitors in animal models of depression are likely to be occurring in parts of the brain other than the striatum, such as in the locus ceruleus, etc. This is a really complicated area, and the effects of arginine in animal models are mainly acute or short-term effects and would not be expected to be the same in the context of chronic stress or depression or in other situations. And the same compound or physiological process that is beneficial to one person may be detrimental to another, and that's the reason it's always necessary for people to discuss these things with one's doctor. But I think there's enough research on arginine and agmatine and nitrergic transmission to get a general picture of the dose-response relationships and some of the predominant pharmacological effects that would be expected to occur in humans (under various conditions).
The general idea is that, under conditions that are not producing acute or chronic activation of the stress response pathways in the brain (i.e. increases in the firing rates of noradrenergic neurons in the locus ceruleus, etc.), exogenous arginine at "low doses" will, in my opinion, exert its short term effects by producing NO-dependent inhibition of the glutamatergically-mediated release of noradrenaline or dopamine or both and simultaneously decrease the firing rates of noradrenergic neurons. More specifically, I think the NO-mediated decrease in calcium influx in response to NMDA receptor activation will be the type of effect that will, at lower doses of arginine, predominate over the excitatory effects of NO. Some of the effects of the acute administration of "low" dosages of arginine may also be mediated by agmatine, which is produced in the brain in large amounts in response to arginine supplementation in animals and probably also would be, in my opinion, in humans. At higher dosages, I think arginine would tend to produce enhancements in glutamatergic transmission, mediated by both increases in nNOS-derived NO and increases in agmatine levels (agmatine may release glutamate and thereby produce excitatory effects at higher dosages [Halaris and Pleitz, 2007: (http://www.ncbi.nlm.nih.gov/pubmed/17927294)]), that could well be counterproductive to the treatment of depression or chronic stress. Researchers have found that the dosages of intraperitoneal (i.p.) L-arginine, in mice, that produce "antidepressant-like" effects in animal models of depression scale to acute, single human dosages, for a 70-kg human (http://hardcorephysiologyfun.blogspot.com/2008/12/equations-for-animal-food-intake-and.html), of 3022-6045 mg (Da Silva et al., 2000), 6045-12090 mg (Inan et al., 2004), or 1209 mg (Ergun and Ergun, 2007). Inan et al. (2004) found that low dosages of i.p. arginine (dosages that scale to i.p. dosages of 302 or 1209 mg for a 70-kg human) produced "depressant" effects and blocked the antidepressant effects of potassium channel blockers or nNOS inhibitors, but Ergun and Ergun (2007) found that only low but not high doses of arginine were consistent with "antidepressant-like" effects. It's possible to make sense of these discrepancies, to some extent, but one can't look at data from those models in excessively-rigid terms.
The NMDA antagonistic effects of arginine-derived nitric oxide (and, more indirectly, of arginine-derived agmatine) would, in my opinion, have relevance to the augmentation of conventional antidepressants or to restoring the effectiveness of some psychopharmacological strategies, but there are a lot of details that are really complicated to get into. It's fairly clear, from the literature, that nitric oxide normally produces "tonic" (meaning under baseline conditions, in conditions other than animal models of chronic stress or depression, in which the firing rates of locus ceruleus neurons are going to be increased) excitatory influence on both noradrenaline release, by noradrenergic neurons in the locus ceruleus, and on dopamine release in the striatum. For example, arginine can increase dopamine release in the striatum by enhancing nNOS-derived NO [Liang and Kaufman, 1998: (http://www.ncbi.nlm.nih.gov/pubmed/9685635)] and can also increase the firing rates of noradrenergic neurons in the locus ceruleus, evidently by nNOS-independent glutamatergic effects (this might be due to agmatine) [Torrecilla et al., 2007: (http://www.ncbi.nlm.nih.gov/pubmed/17473915)]. Liang and Kaufman cite four other articles [Hirsch et al., 1993: (http://www.ncbi.nlm.nih.gov/pubmed/15335838); Lonart et al., 1992: (http://www.ncbi.nlm.nih.gov/pubmed/1425999); Strasser et al., 1994: (http://www.ncbi.nlm.nih.gov/pubmed/7533554) Zhu and Luo, 1992: (http://www.ncbi.nlm.nih.gov/pubmed/1494918)] showing the same nitrergically-mediated dopamine release in response to L-arginine, and I'm sure there are other articles showing that. That's probably partly a glutamatergic effect that's mediated by the nitric oxide-induced activation of glutamate release or inhibition of chloride influx in response to GABA-A-receptor activation, etc. But under conditions of chronic increases in the firing rates of noradrenergic neurons or pathological increases in glutamatergic transmission, more agmatine is formed from arginine and may help to limit the firing rates of noradrenergic neurons and thereby produce an "anti-stress" effect (this stress-induced increase in agmatine formation has been shown in animal experiments, in which acute stress roughly triples the tissue agmatine contents in multiple parts of the brain). In the striatum, NMDA receptor antagonism, such as by nitric oxide, can actually sensitize striatal neurons to D1 dopamine receptor activation via dopaminergic inputs from the ventral tegmental area. This can produce beneficial effects on working memory, to a point, but can then, at higher degrees of NMDA receptor antagonism, impair working memory by causing a breakdown of the organized, burst firing patterns of glutamatergic pyramidal neurons in the prefrontal cortex (in association with working memory impairment). So basal dopaminergic activity and noradrenergic activities appear to be dependent on an adequate level of NO-mediated glutamatergic activity, but the stress-induced activation of noradrenergic neurons, among other effects, could, in my opinion, narrow or even "abolish" the supposed therapeutic dosage range for something like arginine, in this context.
Incidentally, the acute oral dosages that would produce comparable effects in the brain (comparable to the i.p. dosages) would be expected to be higher than the i.p. dosages, and the increases in plasma arginine [Bode-Boger et al., 1998: (http://www.ncbi.nlm.nih.gov/pubmed/9833603)(http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1873701&blobtype=pdf)], following daily supplementation, can take 4-8 weeks to reach a steady state in humans [Campbell et al., 2006: (http://www.ncbi.nlm.nih.gov/pubmed/16928472)]. Bode-Boger et al. (1998) found that the absolute bioavailability of oral arginine in humans, in relation to i.v. arginine, was ~68 percent, and the ratio of the AUC(i.v.)/AUC(oral) was ~1.542 for dosages of 6 grams of arginine (by i.v. and oral routes). I think the ratio of the Cmax(i.v.)/Cmax(oral) (= 2.652 for arginine at dosages of 6 grams, given by i.v. and oral routes) is likely to be a more important determinant of the effects of arginine on the brain than the ratio of the AUC values, because the concentration of agmatine in the CSF (and, by extension, in the CNS intraparenchymal interstitial fluid) increases and decreases rapidly. This suggests to me that the rate of entry of arginine into the brain may importantly determine the metabolic fate of arginine. More specifically, the arginine-induced production of agmatine in the brain would be expected to be higher in response to arginine taken in the fasted state, meaning before breakfast in the morning, than in response to arginine taken between meals. The amounts of agmatine formed in the brain from exogenous arginine appear to be quite significant in primates and mice [Piletz et al., 2003: (http://www.ncbi.nlm.nih.gov/pubmed/15028571)], and I'll include my analysis of that type of data, together with my estimate of the short-term extracellular and intracellular concentrations of agmatine in response to scaled doses of arginine, in another posting. Suffice it to say that a single dose of intraperitoneally-administered arginine in a monkey (this scales to a human dose of 6176 mg arginine, given intraperitoneally) produced a peak level of 2200 nM (2.2 uM) agmatine in the CSF (up from baseline values of 46.9-181 nM). The Kd values for the binding of agmatine to I1 and I2 imidazoline receptors (IRs), producing competitive inhibition, are 700 nM (0.7 uM) and 1000 nM (1 uM), and the Kd for the binding of agmatine to alpha2-adrenoreceptors (alpha2-ARs), as an agonist, is ~4000 nM (4 uM). Clonidine produces activation of both I1-IRs and alpha2-ARs, and agmatine, to a meaningful extent, essentially produces clonidine-like effects. But the point is that the more robust activation of I1-IRs by agmatine, at extracellular agmatine levels less than the range of the 4 uM Kd value for strong alpha2-AR activation by agmatine, could reasonably be expected to augment the effect of low-level alpha2-AR activation by the arginine-induced increases in agmatine. I haven't seen much compelling evidence that meaningful antagonism of NMDA receptors occurs at extracellular concentrations of agmatine that occur under normal or therapeutic circumstances, in response to either arginine or agmatine administration. The Ki value is really high for NMDA receptor antagonism by agmatine, and the authors of one article, showing evidence of NMDA receptor antagonism in response to intrathecal agmatine (or i.c.v.--I can't remember right now and don't want to look it up), found that the effect only lasted between 10 and 30 minutes. The extracellular concentration was very high. One key point, though, is that i.v. arginine increased the CSF agmatine to a peak level that was 22 times as high as the increase in plasma agmatine. Thus, these articles that measure plasma agmatine in response to arginine are not going to be detecting the agmatine formed en masse in the CSF. I think arginine-induced agmatine participates in the arginine-induced growth hormone release, also. Additionally, I think the agmatine levels would accumulate over time intracellularly. It's rapidly transported into neurons by a polyamine transporter that transports spermine and putrescine (and presumably spermidine), and the results of the article by Piletz et al. (2003) (cited above) suggest that most of the tissue agmatine levels, at three hours post-i.p. injection, will be intracellular and not extracellular. I can't extrapolate the intracellular concentration that accompanied the large peak in CSF agmatine that occurred in the primates, but, under steady-state conditions, it's pretty clear that about 95.6 percent of a measurement of the tissue agmatine levels, in ng/g wet weight, is intracellular (with the rest being extracellular). I'll put the simple calculations up on another posting. (You can estimate this if you know, roughly, both the steady-state CSF concentration and the tissue concentration, in ng/g ww.) Finally, in the longer term, there's evidence to suggest that the inhibitory effects of arginine-derived agmatine on nNOS activity may become more significant and produce meaningful effects, by glutamatergic or other mechanisms, on noradrenergic or dopaminergic transmission. The Ki value for irreversible (noncompetitive) inhibition of nNOS by agmatine (as agmatine aldehyde) is 29 uM (Piletz et al., 2003, cited above) (the Ki value for competitive inhibition by agmatine is much higher), and the supposed accumulation of stored, intracellular agmatine could conceivably produce some gradual inhibition of nNOS activity over time. That could produce NMDA receptor antagonism, by reducing nNOS-derived NO, but the direct antagonism of NMDA receptors by agmatine seems to be an effect that, in my opinion, is unlikely to become meaningful.In any case, this is too complicated a topic to discuss all at once. Arginine has also been shown to augment creatine formation in the brain in humans, in two articles, and in animals, and low-dose creatine (3-5 grams/d) was shown to be beneficial, in a small study, in augmenting conventional antidepressant medications in people with treatment-resistant depression [Roitman et al., 2007: (http://www.ncbi.nlm.nih.gov/pubmed/17988366)]. I think arginine would be safer for that effect [discussed here: (http://hardcorephysiologyfun.blogspot.com/2009/02/glutamate-glutamine-cycle-de-novo.html)], but one approach could be to use extremely small doses of creatine, such as 1-2 grams/d. Supposedly, diets high in red meat provide 1-2 grams of creatine/d, but I think some of those estimates of dietary creatine overestimate the amounts that people would be getting. It's interesting that Roitman et al. (2007) found that a couple of the people lost the mood-elevating effect from creatine as they increased the dosage from 3 to 5 grams per day. When they went back to the 3 g/d dosage, they benefited from it again. I think that's plausible, that there would be a dose-response relationship across very small dosage increments. The main problem, in my opinion, is not with the short-term effects of creatine but with the fact that the long-term effects can be very complicated and can become counterproductive, even in the extreme, in my opinion. The therapeutic window for creatine dosing, for psychiatric or cognitive effects [Roitman et al. (2007) cite research showing cognitive enhancement from something like 5 grams/d of creatine in normal people, and there's a vast amount of research on its effects on the brain], is probably very narrow, and the therapeutic dosages could be, in my opinion, as low as 1-3 grams/d. Also, there's the issue of the conversion of ornithine or agmatine, both derived from arginine, into putrescine and the other polyamines, and putrescine has been shown to produce antidepressant effects in animal models. The antidepressant effects that S-adenosylmethionine (SAM-e) has been shown to exert in animal models may partly be due to the SAM-e-induced elevations in the levels of putrescine and other polyamines in the brain, but, in my opinion, the effects of SAM-e have more to do with increases in the adenosine nucleotide pools in neurons and astrocytes and could be mimicked by exogenous adenosine (and guanosine). Decarboxylated SAM-e is a cofactor for spermine synthase, which converts spermidine into spermine, and spermidine synthase, an enzyme that converts putrescine into spermidine. Putrescine can be formed by the catabolism of agmatine by agmatinase or by the pyridoxal 5'-phosphate (PLP)-dependent enzyme ornithine decarboxylase. The authors of one article I discussed [Geng et al., 1995: (http://hardcorephysiologyfun.blogspot.com/2009/01/mechanisms-of-neuroprotection-by.html)] found evidence that the neuroprotective effects of vitamin B6 (pyridoxine), in cultured cells, were partially mediated by the PLP-dependent increase in ornithine decarboxylase activity (via the formation of putrescine and the other polyamines, which then can either antagonize or produce positive allosteric activation of NMDA receptors), given that ifenprodil partially blocked the PLP-mediated neuroprotection. The same modulation of NMDA receptor activation could account for the effects of changes in polyamine levels on cognitive functioning or psychiatric conditions, but research on polyamines seems to be rather chaotic and confusing for just about everyone who writes about it.
Arginine could be expected to increase both agmatine and ornithine and to increase putrescine formation from either agmatine or ornithine, whereas ornithine may not increase agmatine nearly as much and would tend to inhibit creatine formation by arginine:glycine amidinotransferase (AGAT) (the first enzyme in creatine biosynthesis that is expressed throughout the brain). There's also the issue of peroxynitrite formation by the reaction of excessive NO with superoxide or by the uncoupling of nNOS by asymmetric N(guanidino),N(guanidino)-dimethylarginine (ADMA) or N(omega)-monomethylarginine (endogenously-produced inhibitors of NOS enzymes), etc., and maintaining a high-normal CSF uric acid level, with low-dose purines, could, in my opinion, help to limit peroxynitrite formation and downregulate iNOS expression. I can't link to 100 articles in one posting, though.
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