5 replies to this topic

[Lufega]

This may already be known but a new study claims that the dopaminergic effect of caffeine is mediated via increasing D2/D3 receptor availability, rather than dopamine production.  If caffeine increased dopamine synthesis directly, it would actually downregulate these receptors.

 

 

 

Caffeine increases striatal dopamine D2/D3 receptor availability in the human brain.

Abstract

Caffeine, the most widely consumed psychoactive substance in the world, is used to promote wakefulness and enhance alertness. Like other wake-promoting drugs (stimulants and modafinil), caffeine enhances dopamine (DA) signaling in the brain, which it does predominantly by antagonizing adenosine A2A receptors (A2AR). However, it is unclear if caffeine, at the doses consumed by humans, increases DA release or whether it modulates the functions of postsynaptic DA receptors through its interaction with adenosine receptors, which modulate them. We used positron emission tomography and [(11)C]raclopride (DA D2/D3 receptor radioligand sensitive to endogenous DA) to assess if caffeine increased DA release in striatum in 20 healthy controls. Caffeine (300 mg p.o.) significantly increased the availability of D2/D3 receptors in putamen and ventral striatum, but not in caudate, when compared with placebo. In addition,caffeine-induced increases in D2/D3 receptor availability in the ventral striatum were associated withcaffeine-induced increases in alertness. Our findings indicate that in the human brain, caffeine, at doses typically consumed, increases the availability of DA D2/D3 receptors, which indicates that caffeine does not increase DA in the striatum for this would have decreased D2/D3 receptor availability. Instead, we interpret our findings to reflect an increase in D2/D3 receptor levels in striatum with caffeine (or changes in affinity). The association between increases in D2/D3 receptor availability in ventral striatum and alertness suggests that caffeine might enhance arousal, in part, by upregulating D2/D3 receptors.

 

I was looking for a way to upregulate the receptors to work around a Taq1a mutation and increase motivation.  In addition, borrowing from a post on ergo-log, it seems that ornithine can potentiate and prolong the effect of caffeine on dopamine activity.

 

Ornithine-strengthens-mental-effects-of-caffeine

 

Mechanism

The researchers refer to a couple of ideas they found in the literature as to why the ornithine-caffeine combo is so effective. One is that caffeine inhibits the enzyme arginase.

Arginase breaks down L-arginine. If arginase isn't working so well, the amount of L-arginine increases. Ornithine is a precursor of arginine, and therefore also causes a rise in arginine levels. More arginine means that the body synthesises more nitrogen monoxide (NO), and NO in turn can boost the concentration of the brain's mood enhancing neurotransmitter dopamine. And caffeine boosts the activity of dopamine too.

 

 

Can this be used as a possible nootropic/motivation enhancing stack?  I haven't seen anyone talk about this yet.

 

[Junk Master]

I'm a long time coffee drinker and used to experiment with taking ornithine.  I never really noticed any synergistic effects, but it might be worth a try again.

 

Nice find.

[noot_in_the_sky]

Thank you Lufega, it's a very interesting study.   Although, I wounder its long term effects, especially with heavy coffee drinkers.

Edited by noot_in_the_sky, 14 July 2015 - 03:20 PM.

[noot_in_the_sky]

Take a look at Theacrine as well compound that is an adenosine antagonist & is well tolerated.

 

 

http://www.ncbi.nlm....pubmed/22579816

 

 

 

Locomotor activation by theacrine, a purine alkaloid structurally similar to caffeine: involvement of adenosine and dopamine receptors.

Feduccia AA¹, Wang Y, Simms JA, Yi HY, Li R, Bjeldanes L, Ye C, Bartlett SE.

Abstract

Purine compounds, such as caffeine, have many health-promoting properties and have proven to be beneficial in treating a number of different conditions. Theacrine, a purine alkaloid structurally similar to caffeine and abundantly present in Camellia kucha, has recently become of interest as a potential therapeutic compound. In the present study, theacrine was tested using a rodent behavioral model to investigate the effects of the drug on locomotor activity. Long Evans rats were injected with theacrine (24 or 48 mg/kg, i.p.) and activity levels were measured. Results showed that the highest dose of theacrine (48 mg/kg, i.p.) significantly increased locomotor activity compared to control animals and activity remained elevated throughout the duration of the session. To test for the involvement of adenosine receptors underlying theacrine's motor-activating properties, rats were administered a cocktail of the adenosine A₁ agonist, N⁶-cyclopentyladenosine (CPA; 0.1 mg/kg, i.p.) and A(2A) receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS-21680; 0.2 mg/kg, i.p.). Pre-treatment with theacrine significantly attenuated the motor depression induced by the adenosine receptor agonists, indicating that theacrine is likely acting as an adenosine receptor antagonist. Next, we examined the role of DA D₁ and D₂ receptor antagonism on theacrine-induced hyperlocomotion. Both antagonists, D₁R SCH23390 (0.1 or 0.05 mg/kg, i.p.) and D₂R eticlopride (0.1 mg/kg, i.p.), significantly reduced theacrine-stimulated activity indicating that this behavioral response, at least in part, is mediated by DA receptors. In order to investigate the brain region where theacrine may be acting, the drug (10 or 20 μg) was infused bilaterally into nucleus accumbens (NAc). Theacrine enhanced activity levels in a dose-dependent manner, implicating a role of the NAc in modulating theacrine's effects on locomotion. In addition, theacrine did not induce locomotor sensitization or tolerance after chronic exposure. Taken together, these findings demonstrate that theacrine significantly enhances activity; an effect which is mediated by both the adenosinergic and dopaminergic systems.

 

 

http://www.ncbi.nlm....pubmed/23678853

 

 

Theacrine, a purine alkaloid obtained from Camellia assamica var. kucha, attenuates restraint stress-provoked liver damage in mice.

Li WX¹, Li YF, Zhai YJ, Chen WM, Kurihara H, He RR.

Abstract

Theacrine (1,3,7,9-tetramethyluric acid), a purine alkaloid, has proven to be beneficial in maintaining several brain functions and is being studied for potential medicinal uses in recent years. In this study, we isolated theacrine from Camellia assamica var. kucha and investigated its protective effects on liver damage induced by restraint stress in mice. Results showed that 18 h of restraint stress could induce liver damage, with an obvious increase in levels of plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST). This finding was further confirmed by hepatic pathological examination, which showed inflammatory cell infiltration and focal necrosis of hepatocytes. However, oral administration of theacrine (10, 20, 30 mg/kg for 7 consecutive days) was found to decrease plasma ALT and AST levels, reduce hepatic mRNA levels of inflammatory mediators (IL-1β, TNF-α, IL-6, and IFN-γ), and reverse the histologic damages in stressed mice. Simultaneously, theacrine also significantly decreased the content of malondialdehyde and increased oxygen radical absorbance capacity (ORAC) level in the plasma and liver of stressed mice. These results suggested that the protective effects of theacrine on stress-induced liver damage might be correlated with its antioxidative activity. The antioxidative capacity of theacrine was further evaluated by in vitro ORAC and cellular antioxidant activity assay. The results suggested that the antioxidative capacity of theacrine was not due to the direct action on free radical clearance. Moreover, the elevated activities and gene expressions of superoxide dismutase, catalase, and glutathione peroxidase, as well as the reduced activity of xanthine oxidase by theacrine treatment in stressed mice suggested that the antioxidative activity might be due to the strengthening of the antioxidant system in vivo. On the basis of the above results, theacrine is possibly a good candidate for protecting against or treating lifestyle diseases and might contribute to the study of natural products. 

 

 

http://www.ncbi.nlm....pubmed/20227468

 

 

Theacrine, a purine alkaloid with anti-inflammatory and analgesic activities.

Wang Y¹, Yang X, Zheng X, Li J, Ye C, Song X.

Abstract

The anti-inflammatory and analgesic effects of theacrine (1, 3, 7, 9-tetramethyluric acid), a purine alkaloid which is abundantly present in Camellia kucha, were investigated. Xylene-induced ear edema, acetic acid-induced vascular permeability and lambda-carrageenan-induced paw edema were used to investigate anti-inflammatory activity, and acetic acid-induced writhing and hot-plate tests were used to determine analgesic effect. Oral administration of theacrine (8-32 mg/kg) induced dose-related anti-inflammatory and analgesic effects. On the other hand, oral caffeine administration (8-32 mg/kg) did not show an inhibitory effect on the inhibition of inflammatory response or cause analgesia. Additionally, the result of the acute toxicity test showed that the LD(50) of theacrine was 810.6 mg/kg (769.5-858.0mg/kg). The data obtained suggest theacrine possessed analgesic and anti-inflammatory activities.

 

[Duchykins]

That study was published in a journal that is owned by Nature.  Nice find, OP.   

   

 

http://www.ncbi.nlm....les/PMC4462609/

 

Subjects

This study included 20 healthy male controls (38±8 years of age, body mass index 26±3; years of education 14±2) recruited through advertisements in local newspapers. Exclusion criteria included consumption of more than two caffeine beverages per day, current or past psychiatric disease as per DSM IV including any substance use disorder (smokers were excluded); past or present history of neurological, cardiovascular or endocrinological disease; history of head trauma with loss of consciousness greater than 30 min; and current medical illness. Seventeen of the participants reported that they did not drink coffee (or caffeinated beverages), one reported one cup a day and two reported two cups a day. Written informed consent was obtained from all the subjects and the studies were reviewed and approved by the Institutional Review Board at Stony Brook University Medical Center.

 

Discussion

Here we show that caffeine increases D2/D3R availability in striatum (evidenced as increases in BPND in dorsal putamen and VS) in a group of healthy controls with low levels of daily caffeine intake. These findings are consistent with findings from a prior PET [11C]raclopride study done in a small group of subjects (eight habitual coffee drinkers) that also reported increases in D2/D3R availability in striatum with caffeine (200 mg).24 The findings from these two studies thus suggest that caffeine at doses typically consumed by humans might enhance DA signaling by increasing D2/D3R levels or their affinity rather than by increasing DA release in the striatum.

Here we interpret our results of increases in BPND (in BPND availability) with caffeine to suggest that they reflect increases in D2/D3R levels rather than reflecting decreases in endogenous DA, which is the way that typically increases in BPND are interpreted (reduced competition from DA to bind to D2/D3R). The reasons for this interpretation follow. First, it is recognized that alerting drugs (amphetamine, methylphenidate and modafinil) increase DA release in the striatum.3, 25, 36 Second, clinical studies have shown that the DA increases in striatum induced by stimulant drugs are associated with increases in alertness.5 Finally, preclinical studies have shown that the increases in striatal DA induced by stimulants and modafinil is necessary for their wake-promoting actions.6 Thus, if caffeine had reduced DA in the striatum, this would have resulted in an increase in tiredness and sleepiness instead of the increases in alertness observed after caffeine administration. Our interpretation that the increases in striatal D2/D3R availability in VS with caffeine reflect an increase in D2/D3R levels is also consistent with our findings that downregulation of D2/D3R in VS after sleep deprivation is associated with reduced alertness.5

Striato-pallidal neurons adjust their excitability by changing D2R levels in the membrane.37 Thus, D2R downregulate with DA stimulation38 and upregulate with reduced DA signaling.39, 40 DA stimulation of D2R triggers their internalization,38 which can then be recycled or degraded.38, 41 Internalization of D2R is regulated by A2AR,42 agonists facilitate its internalization through the binding of β-arrestin 2 to A2AR-D2R receptor heteromers43 whereas A2AR antagonists interfere with D2R internalization in striatal neurons.44Thus, caffeine might interfere with a tonic A2AR-dependent internalization of D2R mediated by endogenous adenosine, which could contribute to its psychostimulant effects.14, 19, 45, 46 Indeed, our findings along with those previously reported showing that caffeine increased D2R availability in striatum,24 support this interpretation. As caffeine modulates DA signaling, in part, by its antagonism of A2AR,47 caffeine-induced D2R increases in striatum would be consistent with caffeine's antagonism of A2A-mediated D2R internalization. Indeed, A2A receptor knockout mice show increased D2R levels in striatum;48 though we cannot necessarily equate the chronic state of a knockout with the effects from acute caffeine exposure.

However, regardless of the mechanism responsible for the increases in striatal D2/D3R availability, our results indicate that in humans, caffeine at the doses typically consumed, does not increase DA in the striatum. This is consistent with findings from microdialysis studies in rodent showing that caffeine (0.25–5 mg kg−1 intravenously or 1.5 to 30 mg kg−1 intraperitoneally) did not increase DA in the nucleus accumbens,22, 23 though a study reported increases with a large (10 mg kg−1 intraperitoneally) but not a lower caffeine dose (3 mg kg−1 intraperitoneally).21 Thus, on the basis of the current and prior findings24and the preclinical results, caffeine at doses that are relevant to human consumption does not appear to increase DA in the nucleus accumbens. As the ability of drugs of abuse to increase DA is necessary for their rewarding effects and for the neuroadaptations associated with the addiction phenotype,49 this could explain why caffeine does not produce the compulsive administration and the loss of control that characterizes addiction.50

Caffeine-induced increases in D2/D3R in VS were associated with increases in alertness. This association between alertness and D2/D3R replicates our previous findings with sleep deprivation but in the opposite direction, in which we showed that the decreases in D2/D3R availability in VS with sleep deprivation were associated with reductions in alertness.5 In the prior PET study, caffeine-induced increases in striatal D2/D3R availability were associated with reduced tiredness.24 Thus this provides evidence that enhanced signaling through D2/D3R in striatal regions might enhance alertness or decrease tiredness, whereas reduced signaling might decrease alertness or increase fatigue.

 

Study limitations

Traditionally, increases in D2/D3R availability with [11C]raclopride, as observed here, have been interpreted to reflect decreases in DA release. Instead, our model leads us to interpret them as increases in D2/D3R levels and/or increases in affinity. However, our model cannot rule out the potential confound that more than one factor could be affecting the binding of [11C]raclopride. In this respect, preclinical experiments that use more selective compounds should be performed to investigate whether caffeine's effects on [11C]raclopride binding reflect changes in the expression or in the affinity of D2/D3R and whether these effects reflect caffeine's antagonism at A2AR. Also because [11C]raclopride binds to both D2R and D3R,51 we cannot distinguish whether caffeine-induced increases in striatal BPND reflects only increases in D2R or also in D3R. However, in putamen where the relative density of D3R is much lower than that of D2R,52 the effects of caffeine are likely to reflect D2R. Another potential confound in our study is that caffeine significantly reduces cerebral blood flow,53 which could interfere with the BPND measures as cerebral blood flow effects differ between cerebellum and striatum.54 However, because caffeine decreases cerebral blood flow in striatum to a greater extent than in cerebellum,54 this would lead to decreases in striatal BPND, whereas we showed the opposite; that is increases in striatal BPND with caffeine, indicating that our findings are not due to caffeine-induced changes in cerebral blood flow. Though the raclopride PET method cannot distinguish between presynaptic and postsynaptic D2/D3R, the fact that caffeine is an antagonist at A2A receptors, which are expressed in medium spiny neurons expressing D2R but not in DA neurons lead us to presume that the effects are postsynaptic. Another confound in our studies is the order effect as placebo was always given 2 h before caffeine. However, studies that have evaluated test–retest reproducibility for raclopride binding (including ours)55, 56 have reported no significant differences between measures even when the repeated measures were performed on the same day57 as per the current study, indicating that the order effect is unlikely to account for our findings. We are unable to assess if the participants were able to determine if they received caffeine or placebo as we did not query them at the end of the study. Finally, we did not collect blood samples for epinephrine and norepinephrine, which are increased by caffeine.58 Thus, we cannot rule out the contribution of caffeine's effects in the autonomic system on the behavioral effects of caffeine. Nonetheless, the significant association between increases in D2R availability in VS and alertness indicates that caffeine's effects on D2R signaling contribute to its alerting effects.

 

 

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*going out for coffee*

[Lufega]

I gave it a go around the time I posted this.  I tried 500 mg ornithing with 200 mg caffeine and all It did was make me sleepy.  I tried again with citrulline instead but I can't speak of any additive effect.  Caffeine alone worked fine.

 

I probably used too much ornithine.  Maybe lower doses would have worked best?  It is an interesting find if you can get it to work.  Then again, nothing works on me, so there's that.