Study -"The Adenosine Hypothesis of Schizophrenia-opportunities for pharmacotherapy"

[Cotcha Yankinov]

Study -"The Adenosine Hypothesis of Schizophrenia-opportunities for pharmacotherapy"

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3119785/

Very interesting study, goes over adenosine for those not familiar (Incredibly important neuromodulator) and provides a path for integration of the hyper-dopamine and hypo-glutamate theories because of adenosine's heterodimers and involvement with most brain cells. The regulation of adenosine is strange (that it is not stored in vesicles) and is known to change with astrogliosis/proliferation of astrocytes and the resulting adenosine kinase changes. Excuse the text itself, its an early copy of the study

----------Highlights:

• Adenosine is a homeostatic bioenergetic network modulator.
• Adenosine affects brain dopamine and glutamate activities.
• Adenosine dysfunction can cause select endophenotypes of schizophrenia.
• Key preliminary clinical data and preclinical findings are reviewed.
• We propose adenosine-related therapeutics to treat schizophrenia.

If anyone is interested here are some various adenosine studies.

AMPHETAMINES-
http://www.ncbi.nlm.nih.gov/pubmed/24312250 - Adenosine A₂A receptors in striatal glutamatergic terminals and GABAergic neurons oppositely modulate psychostimulant action and DARPP-32 phosphorylation.
http://www.ncbi.nlm.nih.gov/pubmed/25301277
http://www.ncbi.nlm.nih.gov/pubmed/25975203
http://www.ncbi.nlm.nih.gov/pubmed/25296982
http://www.ncbi.nlm.nih.gov/pubmed/22961480
OPIATES-
http://www.ncbi.nlm.nih.gov/pubmed/19934879 - Opioid-induced decreases in rat brain adenosine levels are reversed by inhibiting adenosine deaminase.
http://www.ncbi.nlm.nih.gov/pubmed/23098802
EPILEPSY-
http://www.ncbi.nlm.nih.gov/pubmed/21635241
http://www.ncbi.nlm.nih.gov/pubmed/18634566
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943589/
NEUROTRANSMITTERS/SLEEP -
http://www.ncbi.nlm.nih.gov/pubmed/25979489 - Comorbidities in Neurology: Is adenosine the common link?
http://www.ncbi.nlm.nih.gov/pubmed/24147740
http://www.ncbi.nlm.nih.gov/pubmed/25236726 - Adenosine and glutamate in neuroglial interaction: implications for circadian disorders and alcoholism.
http://www.ncbi.nlm.nih.gov/pubmed/17646043 - Adenosine A2A receptors and basal ganglia physiology
http://www.ncbi.nlm.nih.gov/pubmed/22997174
http://www.hindawi.com/journals/ecam/2013/840134/
http://rstb.royalsocietypublishing.o.../1654/20130594 - Astrocytic adenosine: from synapses to psychiatric disorders
http://www.ncbi.nlm.nih.gov/pubmed/22754033 - "No thanks, coffee keeps me awake": individual caffeine sensitivity depends on ADORA2A genotype.
http://www.ncbi.nlm.nih.gov/pubmed/16221767 - A functional genetic variation of adenosine deaminase affects the duration and intensity of deep sleep in humans.
http://www.ncbi.nlm.nih.gov/pubmed/22540145
http://www.sciencedirect.com/science...65032710002879
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2141681/ -- A2A receptors in ventral striatum, hypothalamus and nociceptive circuitry implications for drug addiction, sleep and pain.
THERAPEUTIC ADENOSINE STUDIES –
http://www.researchgate.net/publicat...ase_inhibitors
http://www.ncbi.nlm.nih.gov/pubmed/11223861
http://www.ncbi.nlm.nih.gov/pubmed/23592612 - Adenosine kinase: exploitation for therapeutic gain.
ASTROGLIOSIS-
http://www.sciencedirect.com/science...0439401400041X - Astrogliosis as a therapeutic target for neurodegenerative diseases

 

[dopamimetic]

This is really really interesting. Thanks for sharing Realize I have to read up about adenosine ...

My mother suffers from schizophrenia (but got also diagnosed with ADHD lately, don't know what's the reality because I've lost contact with her for several years now).

hyper-dopamine and hypo-glutamate theories

With my limited understanding of the matter, I have the strong feeling that I'm the opposite. Hypo-dopamine and hyper-glutamate. Just didn't find yet a sustainable, working re-balancing agent ... but the tendency is that increased dopamine helps half and decreased glutamate does the other half, whilst doing the opposite exacerbates things . Each adjustment alone (well, I know there are always downstream mechanisms of course) doesn't do the trick. And I hate caffeine.

Would be great if an adenosine adjusting agent could balance all this out...!! (with the obligatory catch hidden somewhere within)

 

[clubcard]

Thank you for putting so much effort into the above. As you know, I lost a friend of 17 years to an RSU (regional secure unit) about 20 years ago. When you see someone every day, it takes longer to realize that they have a big problem. He was initially arrested for beating up a petrol-pump attendant but the police phones a doctor within an hour so 2:30PM he was free, driving from Dover & by 7:30 PM he was in a secure unit. He was let out after a couple of months but it was plain to see he was still very unwell and 3 months later, his house was up for sale (by his parents, I presume).

A friend who had worked at the RSU asked colleagues about him and a senior member of staff was visiting and told us all 'he's going to be in a secure unit for a LONG TIME'. Well, 20 years and still waiting.

ALL knowledge is good and when I find a way of distributing my papers on the subject, the better informed everyone will be. I mean, they discovered that serine would bind to NMDA receptors and Neboglamine is a PAM for NMDA. I mean, it's such a simple drug - glutamate bound to 4,4-dimethyl cyclohexane.

I think I suggested that serine suppliments MAY help some people. Wouldn't remove the need for a neuroleptic but might lower the dose so that antipyramidal & other issues show up less. My sane friend who needs clozapine has had his health ruined by it BUT because it's treating such a serious condition, compounds pass the FDA & NICE that would fail for most purposes.

Once again, THANK YOU - I hope I can repay the debt.

 

[dopamimetic]

Flumazenil, the BZD / GABA-A antagonist has some weird effects.

In Italy, the gold standard for treatment of high-dose benzodiazepine dependency is 8–10 days of low dose, slow infusion of flumazenil.

Epileptic patients who have become tolerant to the anti-seizure effects of the benzodiazepine clonazepam became seizure-free for several days after treatment with 1.5 mg flumazenil.[13] Similarly, patients who were dependent on high doses of benzodiazepines (median dosage 333 mg diazepam-equivalent) were able to be stabilised on a low dose of clonazepam after 7–8 days of treatment with flumazenil.

Flumazenil has been tested against placebo in dependent subjects, whereby typical benzodiazepine effects were reversed with little to no withdrawal symptoms. Flumazenil was shown to produce significantly less withdrawal symptoms than saline in a randomized, placebo-controlled study with benzodiazepine dependent subjects. Additionally, relapse rates were much less during subsequent follow-up.

Flumazenil was found to be more effective than placebo in reducing feelings of hostility and aggression in patients who had been free of benzodiazepines for 4–266 weeks.

An antagonist that causes less w/d than saline. Treating high-dose BZD dependencies ... w/o seizures (not even talking of the terror of mind)?

... it turns out to be an adenosine reuptake inhibitor. Unfortunately I don't have access to the source (Goldfrank, Lewis R.; Neal Flomenbaum; Mary Ann Howland; Robert S. (2006). Goldfrank's toxicologic emergencies. p. 243) but all that's really remarkable.

So does this mean that adenosine is able to readily overpower the adverse effects from antagonizing high-dose BZD dependency? Wow. I wanna try flumazenil (and think to remember that flubromazolam has been suggested to be an AdRI, too!)

And sad to see they are still and once more not applying science to treat masses of suffering individuals (at least outside of some Italian addiction clinics).
Why on earth are docs and drug rehab clinics still doing cold turkey if such effective pharmacological treatments are available!!?? You can reverse opioid tolerance. You can reverse BZD tolerance. And so on. Really, I believe somewhat every day spent in acute or protracted withdrawal is potentially causing permanent harm or at least psychical damage. There is some evidence for that. And they are still ignorant. The more I learn, the less I can believe why the world is how it is..

 

[Cotcha Yankinov]

Hi guys, Club I'm so sorry to hear about your friend in the RSU, that must be absolute hell for him. Any idea what meds he's on? If theoritically he's not getting better and they've just got him sedated I would love to see his doctors try him on a couple things... Not saying we should totally Guinea pig people off label but Jesus if they're doing miserable or the person is not all there because yknow Thorazine type shit, then might as well try for example antagonizing the shit out of 5-HT2A. Not all the way to trying him on the adenosine kinase/deanimase inhibitors just yet they sound pretty bad, leukemia drug type stuff.

Thats really interesting Dopa all the old literature I first read on adenosine was related to epileptics because where they first found the adenosine kinase over expression was in epileptics. I started digging because a part of me logically extrapolated epilepsy, an over firing of neurons and hyper excitability, with the same in things like ADHD/insomnia/shizophrenia even though that excitability is all at a sub seizure threshold usually. When I first looked into this matter a while ago I couldn't believe how many meds were adenosine re uptake inhibitors, the tricyclics even but if I remember right the benzos were the main powerful ones, however it seems to me that in some of these disorders the problem with the tone of adenosine might be related to over expression of adenosine kinase (ADK) in astrocytes so I don't know how precise a reputake inhibitor would be.. Increasing the adenosine extracellular concentration whilst adenosine kinase is still going nuts and breaking it down might not work too well but who knows, I wonder where in the cellular space adenosine is most prone to metabolization. Id love to see how much of the therapeutic effects of different drugs can be isolated to adenosine though.

My other thought is along the lines of there being an adenosine kinase over expression in a specific part of the brain/cognitive faculties that you need working well for rational thought etc. (mainly in epilepsy models was the ADK over expression found but ADK is made from astrocytes in adults, strangely made in neurons in young children then it transfers over to astrocytes) but anyways in my thinking astrogliosis in a specific area could lead to this ADK over expression. If it's a specific part of the brain having a problem with ADK then increasing adenosine globally with an reuptake inhibitor might not pinpoint the exact location that the brain is having a problem with adenosine kinase over expression. So basically it would be hard to truly correct a problem of adenosine kinase without directly inhibiting it, and even then it wouldn't be inhibiting it just in the "problem area" assuming there is such a problem area.

The agonists/antagonists aimed at the specific adenosine receptors in question could do some good though right?? I suspect they would be highly addicting if they worked, in theory the brain would still be making adenosine at the exact same pace but the receptor down regulation would be real. Would probably have some very real effects on sleep, the reason why I'm cautious of increasing adenosine globally too much is that it is actually really confusing what adenosine receptor does what in different parts of the brain when it comes to sleep. Agonists in one part of the brain even cause insomnia if I remember right, then adenosine in another increases slow wave sleep and is really necessary for circadian rhythms.. Though I wonder when using a reuptake inhibitor if it wouldn't reach enough concentrations in that part of the brain that the injection of agonists caused insomnia in and the brain would benefit from the overall increased adenosine. It also seems to me that increasing adenosine via injection in just one area might not be reliable to study the overall effects because it throws that part of the brain's cells out of balance with the other parts, maybe you could get different effects depending on if you did multiple injections in different locations that ended up being entirely different effects than the injections in isolation. It seems we do have some adenosine agonists/antagonists available when it comes to straight up brain injections. It sucks that adenosine itself has such a short half life though.

Now for some mega-theory crafting and blabbing of mine, I don't know if this has ever really been suggested before and this will probably be obsolete by the time we are capable of this in a thousand years but here it goes.. It seems there is a problem with getting a specific chemical into a specific part of the brain, correct me if I'm wrong please but I don't think we have much selectivity in where a chemical makes its way through the brain other than receptor affinity. Let's say you needed to get ADK into a specific part of the brain that had just for example a lot of adenosine-dopamine heterodimers. What would be really interesting is if you could design a chemical that is initially an adenosine affinitive molecule so it makes its way specifically where you want it near the adenosine but when there due to some method of reacting it (perhaps yet another adenosine or dopamine affinitive molecule that because it's designed for the same receptors when it meets with and reacts with the first molecule it becomes an ADK inhibitor, or maybe when a molecule it is metabolized) it becomes what you really wanted to deliver to that part of the brain. So you get the ADK inhibition precisely where you want it. Obviously this technique if it was possible wouldn't just apply to adenosine. Could really be used to deliver anything to a specific part of the brain assuming it was something that both molecules had some affinity but after they're reacted together or a singular molecule is metabolized etc. it becomes what you really wanted. Sorta similar to conjugation I guess. But the general idea is you use receptor affinity to deliver a drug to a specific part of the brain and after that you find a way to react it so it becomes the real drug. I.e starts out as an adenosine agonist but ends up as an ADK inhibitor just delivered to the perfect place of A2Ar etc.

I realize this is mega theorycrafting but the reason why I mentioned it is that some mental disorder might have problems with specific structures of the brain and if it's an astrogliosis problem it could be a different area for different people so finding a way to target those structures could help cut down on extra pyramidal side effects and depersonalization, for example if there's too much dopamine in an area and that's the area responsible for schizophrenia then antagonizing dopamine globally would take away too much personality as well as the schizophrenia, in general I think a way to leave the personality intact is try to to get more specific in fighting the mental illness.

On that note if these various dopamine and glutamate related mental illness are for some people really adenosine problems what the fuck have we been doing since all these studies have come out?? I feel like its taking absolutely forever for practiced medicine to keep up with the research. There is a big disconnect. People pretty much just learn what they learn in school and that's it in my experience. I theorize adenosine based sleeping meds are the future as well, they do a really good job of promoting slow wave sleep anyways, but likely combined with some other meds (5-HT2A inverse agonist etc.) they would be amazing. Sorry for wall of txt Peaceout

 

[SKL]

The adenosine stuff is really interesting, but drug development seems pretty far off, and not for lack of interest, I'm sure, by "Big Pharma," schizophrenia/major mental illness drugs are a goldmine.

Flumazenil, the BZD / GABA-A antagonist has some weird effects.

It also lowers the seizure threshold, whether or not the patient is on BZDs but especially if they are. In fact we do this all the time clinically, on purpose, in ECT.

clozapine

Has a unique clinical and pharmacological profile with some unpleasant side effects and is not good for you but ought not to be demonized, it truly is a miracle drug in a lot of patients particularly with respect to treating refractory symptoms, and particularly with regards to reducing violence and suicide. Now, if someone isn't benefiting, they shouldn't stay on, this is common sense; if they are but it's not entirely benign, then it's a cost/benefit analysis type thing, this is inherent in medicine. Don't be so quick to villianize an important part of our armamentarium (I say this because I'm pretty sure it was you I saw posting about clozapine elsewhere ...)

 

[dopamimetic]

Consumption of RNA-rich foods may lead to high levels of purines (adenosine and guanosine) in blood. (wikipedia - dietary sources of uridine)

The problem is the bioavailability and possibly also (in)ability to cross the blood brain barrier ...? But could yeast in the end make a game-changing supplement for GABAergic withdrawal!?

It also lowers the seizure threshold, whether or not the patient is on BZDs but especially if they are. In fact we do this all the time clinically, on purpose, in ECT.

Yes, would be obvious for a GABA antagonist, but it seems that with slow enough infusion the adenosine reuptake inhibition is possibly able to overpower this (and then of course using a more potent AdRI and less potent GABA-ant. would make a great treatment.)

 

[Neuroprotection]

Hi dopamimetic, its sad to hear your mother has psychitsaphrenia, but I hope she recovers soon. Just interested, have you ever considered giving her emoxepine or another safe but strong antioxidant, I am not suggesting you test random compounds on people, but just consider alternatives or even add ons to traditional antipsychotics which can have unpleasant side affects. Also, antioxidents, or enhancing antioxidant defences tends to lead to reduced psychotic symptoms as well as enhanced emotional responsiveness to pleasure and positive aspects of life.

 

[dopamimetic]

Thanks, she won't recover probably because she has this condition for more than two decades now and she doesn't accept any treatment (probably good that she isn't on strong neuroleptics, but well I could imagine quite a few things that would help her, but she doesn't want and at the moment I have to take care for myself ...) Sarcosine has some interesting results for schizophrenia, emoxypine I don't know but I like this compound as it literally erases the rebound and dopamine 'depletion' from stimulants like isopropylphenidate, with no negatives at all ... even memantine might be promising against delusions resulting from over-excitation ...

 

[Neuroprotection]

How do you get hold of isopropyl phenidate, is it not restricted by drug laws

 

[dopamimetic]

Depends on where you live, in the EU there aren't true analogue laws (yet), so it's legally obtainable from RC vendors. In Germany they wanted to introduce a new RC analogue law and it was ruled illegal by the constitution court. The same for their attempt to declare anything psychoactive as 'medicine'. Sometimes complicated systems have their plus points too ... Switzerland, being a small country, has a catch-all clause since 2011 where anything considered a 'designer drug' (and there is no real possibility to complain against their arbitrarily decisions) is treated as if you have had that amount of heroine ... crazy.

 

[anubis23]

Adenosine and epilepsy

http://www.ncbi.nlm.nih.gov/pubmed/17350481?dopt=Abstract


Unfortunately that allopurinol is potentially teratogenic but may be interesting to study its mechanism for other uses. I was surprised to learn that tianeptine also interacts with adenosine, then I found some information on its more specific mechanisms.

http://www.nature.com/npp/journal/v32/n2/full/1301143a.html

All the more reason for those interested in tianeptine not to attempt to chase the transitory mu agonism, as aside from its low efficacy at that effect, and rapid tolerance compounded by tianeptines effects with glutamate receptor complexes, rapid cessation from

Your reasoning is sound, for instance many people with Tourette's or schizophrenia and epilepsy report that too much caffeine will aggravate their symptoms.

http://www.ncbi.nlm.nih.gov/pubmed/9865523

I would say that ginseng deserves more research in the field of opioid cessation. You may find adenosine more promising in yet another scope of research.

(Ginseng and adenosine : http://www.ncbi.nlm.nih.gov/pubmed/16212227 ) I also read it has the chemical itself in the roots, however I am unsure at the moment towards its metabolism and permeability.

You can find more research about ginseng being used in morphine withdrawal easily.