Is there a way to prevent adenosine A1 receptor upregulation. As everyone knows, caffeine causes an upregulation and sensitization for the neural and peripheral adenosine a1 receptors. I'm wondering if there's any supplement that could possibly halt or slow down this process? I know Curcumin is an a1 agonist, so maybe that would be of use? Any thoughts would be appreciated.

Thanks

https://doi.org/10.3390/nu13114082

https://pubmed.ncbi.nlm.nih.gov/34836344

Abstract

It has been previously demonstrated that KEKS food containing exogenous ketogenic supplement ketone salt (KS) and ketone ester (KE) decreased the lipopolysaccharide (LPS)-generated increase in SWD (spike-wave discharge) number in Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats, likely through ketosis. KEKS-supplemented food-generated ketosis may increase adenosine levels, and may thus modulate both neuroinflammatory processes and epileptic activity through adenosine receptors (such as A1Rs and A2ARs). To determine whether these adenosine receptors are able to modify the KEKS food-generated alleviating effect on LPS-evoked increases in SWD number, an antagonist of A1R DPCPX (1,3-dipropyl-8-cyclopentylxanthine, 0.2 mg/kg) with LPS (50 µg/kg) and an antagonist of A2AR SCH58261 (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine, 0.5 mg/kg) with LPS were co-injected intraperitoneally (i.p.) on the ninth day of KEKS food administration, and their influence not only on the SWD number, but also on blood glucose, R-beta-hydroxybutyrate (R-βHB) levels, and body weight were measured. We showed that inhibition of A1Rs abolished the alleviating effect of KEKS food on LPS-generated increases in the SWD number, whereas blocking A2ARs did not significantly modify the KEKS food-generated beneficial effect. Our results suggest that the neuromodulatory benefits of KEKS-supplemented food on absence epileptic activity are mediated primarily through A1R, not A2AR.

------------------------------------------ Info ------------------------------------------

Open Access: True

Authors: Brigitta Brunner - Csilla Ari - Dominic P. D’Agostino - Zsolt Kovács -

Additional links:

https://www.mdpi.com/2072-6643/13/11/4082/pdf

From what I understand about caffeine, it attaches itself to adenosine receptors because it’s chemically pretty similar to it. Adenosine, the chemical that tells your brain that you’re tired and need sleep, gets blocked out of the receptors, and you don’t feel tired. If adenosine has already reached and attached to the receptors, then caffeine won’t work as effectively.

However, if you started drinking caffeine before you ever got tired at all, and kept drinking enough to prevent any adenosine from leaking through, could you stay awake and alert indefinitely?

Obviously not gonna try this, as prolonged sleep deprivation can cause all sorts of health issues, and excessive caffeine intake can as well, but would this actually work?

here's a case scenario:

Lets say that i'm not a regular caffeine user. i've just woken up about 2 hours ago and i'm fully awake. I decide out of the blue to have a half a cup of coffee, even though i don't feel like i need it. as a result i feel more energized and focused.

since caffeine doesn't actually "give" you energy, but replaces adenosine in receptors so you don't feel as tired, i would imagine that the only reason caffeine would give a non caffeine dependent person energy in the morning time would be because their sleep quality is not optimal. even though it's hard to imagine the best of sleepers to not feel energized from a cup of coffee, i wonder about this.

is there something else about caffeine that produces the psychoactive effects of focus and energy?

Full disclosure: I found nothing on this online, which makes me think it's probably a stupid nonsensical idea.

It seems like the main concern with nootropics is the maintenance of a sustained positive effect: even if you find something that works for you, you typically hit tolerance issues sooner or later. So we (or at least, I) end up looking for new substances that could provide the desired boost, or resort to cycling.

One of the strongest nootropics out there is caffeine, which works, in part, by blocking adenosine receptors. The tolerance, at least to the wakefulness/stimulant effects, seems to be a result of additional adenosine receptors our brains develop in response to routine caffeine administration (note: based on a quick lit review, this may not be the only pathway, but it at least seems worth experimenting with).

So this leads to my naive, uninformed question: what if we developed an intervention that targets adenosine receptor count/growth, downregulating it? Could we then enjoy caffeine without worrying as much about tolerance, maintaining its powerful effect? Has something like this been explored/considered?

Adenosine prevents release of Dopamine, Acetylcholine and Noradrenaline. If I quit dopaminergic substances at the same time as increasing Adenosine, this should theoretically cause a deficit in Dopamine, which in turn should cause an upregulation of Dopamine receptors. Do you guys think this will work out?

Also, do you have any supplement recommendations for me to add during my break? Thanks a bunch!

At present, the novel Covid-19 pneumonia is prevalent, affecting millions of people. Here, we summarized the pharmacological basis of adenosine, adenosine receptors, adenosine agonist cordycepin (3'- deoxyadenosine), and Cordyceps product in the brain protection and amelioration of pneumonia to provide useful information to cope with the global pandemic of novel coronavirus (COVID-19).

Adenosine, a mediator of innate immunity, is abundantly secreted by the injured lung tissues during inflammation. Through the activation of adenosine receptors A1, A2A, A2B and A3, adenosine plays an important role in protecting against acute lung injury and brain injury.

Cordycepin (3'-deoxyadenosine) is an activator of adenosine receptors. It can enhance human immunity, promote anti-inflammatory processes, inhibit RNA virus reproduction, protect against brain, lung, liver, heart, and kidney damage, and ameliorate lungfibrosis in clinical and animal models.

Cordyceps and cordycepin products could be used as a potential medicinal adenosine receptor agonist that can play a beneficial role in the amelioration of Covid-19 pneumonia and protection of brain .

Full text :

- https://fortunepublish.com/articles/10.26502.jbb.2642-91280035.pdf

I was curious about this. If adenosine is already in its receptors, can it block caffeine from binding?