Dear readers of ADxS.org, please forgive the disruption.
ADxS.org needs about $36850 in 2023. In 2022 we received donations from third parties of about $
13870. Unfortunately, 99.8% of our readers do not donate. If everyone who reads this request makes a small contribution, our fundraising campaign for 2023 would be over after a few days. This donation request is displayed 18,000 times a week, but only 40 people donate. If you find ADxS.org useful, please take a minute and support ADxS.org with your donation. Thank you!
Since 01.06.2021 ADxS.org is supported by the non-profit ADxS e.V..
20 to 300 nM under normal physiological conditions
Increase to low micromolar levels under extreme physiological conditions, e.g.:
intensive sport
low atmospheric oxygen content at high altitude
Increase to high micromolar levels (30 µM) under pathological conditions, e.g.:
Ischemia
The adenosine system is closely linked to the dopaminergic system. Adenosine receptors are particularly located in brain regions that are insoluble in ADHD. Adenosine receptors are closely associated with dopamine receptors and form heteromers with them.
Adenosine inhibits dopamine. Adenosine antagonists (primarily A2A antagonists) are currently being investigated for treatment of Parkinson’s disease and, in our opinion, could also be considered for treatment of ADHD. At the same time, adenosine modulates striatal DA release by stimulating glutamate release at adenosine receptors in the striatum, which increases dopamine levels.2
Among other things, adenosine is used for autoregulation in the event of an imminent lack of energy in the cell (e.g. when the cell’s performance is overloaded or when there is a lack of oxygen): If the ATP content in a cell drops, more adenosine is produced as a hydrolysis product. Part of this adenosine is discharged from the cell and binds to adenosine receptors of neighboring cells, which is supposed to compensate for the disturbed balance between energy consumption and energy supply.3
Adenosine, together with melatonin, regulates sleep in relation to neuronal activity and energy metabolism.53
Through this mechanism, the increased level of adenosine after sleep deprivation could affect the light sensitivity of the circadian clock. 6-hour sleep deprivation reduced the light response in the SCN. Caffeine almost completely restored this SCN light response,6 suggesting an interaction between adenosine and glutamate5
intracellular adenosine synthesis11 (physiologically predominant synthesis pathway in healthy state)1 a.o. in striatum
AMP is hydrolyzed to adenosine by cytoplasmic 5′-nucleotidase (stronger)
S-adenosyl homocysteine (SAH) hydrolyzed to adenosine by SAH hydrolase (minor)12
Release of adenosine by bidirectional equilibrative nucleoside transporters (ENT) into the extracellular space
extracellular adenosine synthesis8 (predominant in cellular stress such as injury, hypoxia, neurodegeneration, neuroinflammation, or excitotoxicity)1
ATP from neurons or glial cells is dephosphorylated to ADP and AMP by the enzyme ectonucleoside triphosphate diphosphohydrolase (CD39). ADP and AM are then and converted to adenosine by a specific ecto-5′-nucleotidase enzyme (CD73).1
ATP appears to be a neurotransmitter itself, acting inhibitory in the gut and exitatory in the autonomic nervous system.13
Adenosine is a degradation product of ATP. High ATP consumption by the cells (due to high neuronal activity) leads to high adenosine.12 This mechanism serves to regulate the energy level of the cells.
Rising adenosine levels increase sleep pressure and thus promote recovery. Night sleep breaks down adenosine and thus lowers sleep pressure.
Adenosine receptors are G protein-coupled and are abundant in almost all human tissues and organs.
They are a subgrouper of the purinoceptors, which are divided into ATP receptors (P2 receptors) and adenosine receptors (P1 receptors).
Affinity:1
Under normal conditions, adenosine has a higher affinity for A1 and A2A receptors. Only at higher adenosine levels are A2B and A3 receptors also addressed.
Reduction of the excitability of potassium channels
Promotion of self-adaptive changes to regulate neuronal plasticity by heteromers with A2A and D1 receptors17
The A1 agonist CPA increased alpha2-adrenoceptor binding in the nucleus tractus solitarius. The increase in binding was about 10 times greater in SHR than in WKY.19
Caffeine is a nonselective adenosine receptor antagonist23
Adenosine A1 receptors in the brain regulate the need for sleep. Adenosine A1 receptors inhibit the enyzm adenylyl cyclase, which is needed for the conversion of ATP into cAMP. This inhibition is prevented by caffeine, and cAMP levels remain high. This increases alertness.25
similar efficacy to theophylline with lower adenosine receptor affinity27
One side effect of A1 antagonists is (epileptic) seizures.
Iron deficiency appears to be related to an alteration in the expression of adenosine receptor subtypes in the cortico-striatal glutamatergic terminals:2829
Former name: RDC8
Activation of the A2A receptor activates adenylyl cyclase via Gi/o proteins.8
Encoded by the ADORA2A gene on chromosome 22 (22q11.23)
mainly in the GABAergic medium spiny neurons of the indirect pathway (projecting to the external segment of the globus pallidus) and which simultaneously express a high density of D2 receptors and enkephalin, with A2A receptors located near the D2 receptors.
hardly in neurons of the direct striato-nigral pathway (which selectively express D1 receptors and the peptide dynorphin)
23 % presynaptic
primarily at cortico-thalamic glutaminergic axon terminals that contacted medium-sized spiny neurons of direct and indirect GABAergic pathways, and at cholinergic neurons that modulate acetylcholine release
particularly at the perisynaptic ring of the glutamatergic synapse in enkephalin neurons, where they can interact with D2 and mGlu5 receptors as heteromers.11
at the neck of dendritic spines, where they can interact with extrasynaptic dopamine and metabotropic glutamate receptors as heteromers.11
presynaptically at glutamatergic axon terminals, where they modulate glutamate release11
Conversely, inhibition of adenosine by dopamine. These interactions arise (at least in part) from allosteric receptor-receptor interactions within heteromeric A2AR/D2R complexes12
Increase in the release of excitatory neurotransmitters17
In chronic autoimmune rheumatic diseases, A2A and A3 receptors are overexpressed in lymphocytes. A2A and A3 agonists inhibited NF-κB activation, the release of typical proinflammatory cytokines, and the concentration of metalloproteinases involved in the inflammatory responses in chronic autoimmune rheumatic diseases.31
Caffeine (as a nonselective adenosine antagonist) as well as selective adenosine A2A antagonists can improve memory performance in rodents and protect against memory impairment
Approved in 2019 in the U.S. (first A2A antagonist ever approved) for the treatment of Parkinson’s disease (brand name: Nourianz®),43 but not until the drug’s target was narrowed from Parkinson’s overall to Parkinson’s with off-episodes.
several Phase III studies discontinued prematurely
Death of 5 patients in a phase III study of 409 participants from drug-induced agranulocytosis (formation of antibodies to neutrophil membrane glycoproteins leading to destruction of neutrophils). Other, approved, drugs also have this side effect. Has not been observed with Istradefylline.43
Iron deficiency, which is also a cause of RLS, appears to be related to an alteration in the expression of adenosine receptor subtypes in the cortico-striatal glutamatergic terminals:2829
weak adenosine binding. Activated only when extracellular adenosine levels are very high (micromolar), e.g. after tissue damage (e.g. inflammation, hypoxia, ischemia, brain injury)12
Ligands:
5’-N-Ethylcarboxamidoadenosine (NECA) is an A2/A1 agonist23
influences synaptic plasticity in the hippocampus16
In chronic autoimmune rheumatic diseases, A2A and A3 receptors are overexpressed in lymphocytes. A2A and A3 agonists inhibited NF-κB activation, the release of typical proinflammatory cytokines, and the concentration of metalloproteinases involved in the inflammatory responses in chronic autoimmune rheumatic diseases.31
weak adenosine binding. Activated only when extracellular adenosine levels are very high (micromolar), e.g. after tissue damage (e.g. inflammation, hypoxia, ischemia, brain injury)12
low adenosine preferentially stimulates A1 –> inhibition of glutamatergic transmission
high adenosine stimulates A2A –> blockade of A1mediated effects –> potentiation of glutamate release
with other receptors (e.g., A2A / D2 heteroid inhibitors)
A2A / D2 heterodimers appear to be partially responsible for the psychomotor and reinforcing effects of psychostimulants such as cocaine and amphetamine8
Mutual inhibition of adenosine and dopamine is mediated in mammals by A2A / and D2 receptors; at least parts of it by A2A / D2 heteromeret.
A2A agonists inhibit and A2A antagonists enhance D2-mediated locomotor activation (including in striatopallidal GABAergic medium spiny neurons (MSN) of the indirect pathway) and goal-directed behavior.
A2A / D2 co-aggregate, co-internalize, and co-desensitize, i.e., even mechanisms such as downregulation do not affect one part of the heteromer alone, but the entirety12
A2A / D3
A2A / mGlu5
A2A / FGFR1 (fibroblast growth factor receptor)
A2A / Sigma1 receptors
A1 / A2A (in glutamate axon terminals presynaptic)
A2A-D2 heterodimers in equilibrium with trimeric A1-A2A-D2 heteroreceptor complexes
A2A/ D2 receptor heterodimers appear to form heterotetramers. It follows that A2A antagonists at high concentrations act in the same way as A2A agonists, namely reducing D2 receptor-mediated activity in neurons.61
In the hippocampus
found in moderate to high density in the dorsal hippocampus, mainly in the pyramidal cell layer30
Adenosine (A1 and A2A antagonist; used as A1 antagonist in Aroxysmal Supraventricular Tachycardia (PSVT); used as A2A antagonist in Myocardial Perfusion)1
2-chloroadenosine (CAD) is a non-specific adenosine receptor agonist62
Worldwide, 1.6 billion cups of coffee are consumed every day.66 Coffee was first mentioned in a medical text in 1025.
Caffeine is an A2A and A1 antagonist.
The highest blood caffeine level occurs approx. 30 to 40 minutes after consumption. The half-life is approx. 3 to 6 hours and is prolonged in pregnant women and shortened in smokers67
The values per serving (cup, glass, can, 50 g bar)67
ground coffee 105 mg
Energy drinks 80 mg
Instant coffee 54 mg
Tea (bags, loose leaves, instant tea, green tea) 40 mg
Cola 16 to 30 mg
Chocolate 8 to 27 mg
Caffeine from coffee and black tea is released differently.
Caffeine from roasted coffee is bound to a chlorogenic acid-potassium complex and immediately releases caffeine upon contact with stomach acid. Coffee caffeine therefore acts quickly.
Caffeine from tea is bound to polyphenols. The caffeine is only formed through fermentation and is released in the intestine, thus having a later and longer-lasting effect.68
Tea is therefore preferable to coffee in the treatment of ADHD.
Green tea contains as much caffeine as black tea. However, the same source says that caffeine is only released during fermentation. Green tea is unfermented, black tea is fermented. Young tea leaves (pekoe) contain particularly high levels of caffeine.69
3.6.2.1.2. Continuous caffeine consumption and habituation¶
Chronic (sustained) caffeine consumption causes adjustments in the adenosine system that counteract the effects of isolated caffeine intake.67
Chronic caffeine administration in SHR (a genetic animal model of ADHD-HI) of 2 mg/kg for 21 days (which should be sufficient for receptor adaptation regulation) produced70
normalized dopaminergic function (reduced in SHR per se)
improved memory and attention deficits (which are typical in SHR per se)
an upregulation of A2A in frontocortical nerve terminals
Caffeine further improved in vitro in the striatum of SHR the
GABA release (intrinsically reduced in SHR)
GABA reuptake via GAT1 transporter (reduced in SHR per se)
whereas this was not the case in Wistar rats (which are not an ADHD animal model).71
This result could be an indication for a positive effect of caffeine in ADHD.
In contrast, other studies suggest that the effects of caffeine on alertness and cognitive performance are not a net benefit to functioning, but merely a reversal of withdrawal effects. Acute caffeine withdrawal (e.g., overnight) worsens alertness, cognitive performance, and mood; caffeine consumption restores these to normal levels but does not improve them beyond that 7267
One study found that increased caffeine consumption in college students correlated with increased anxiety and depression symptoms and poorer academic performance.73 It is open whether these symptoms are causally caused by caffeine or whether caffeine is used as (inadequate) self-medication due to a dopamine deficit.
Humans and laboratory animals develop tolerance to some, but not all, effects of caffeine747576
Note: The doses listed below are 10 times the maximum recommended dose for humans of 5.7 mg/kg/day.
A1
chronic doses above 50 mg / kg / day: upregulation of A1 receptors in the cerebral cortex,77 and also in the hippocampus (CA3), without changes in gene transcription, apparently due to a blockade of downregulation arising without caffeine by adenosine.78 Other studies found no increase in A1 receptors in the hippocampus, cerebral cortex, or cerebellum.79
Inhibition of lipolysis in fat cells by adenosine remained unchanged
Development of tolerance, possibly by means of altered gene transcription82
A2A
Receptor number not or hardly changed by chronic high doses8382
In vitro, A1 is easily downregulated, whereas A2A is not
basal adenylyl cyclase activity and cyclase activities stimulated by adenosine agonists, GTP gamma S, or forskolin are decreased in cells desensitized by chronic caffeine administration, but also by means other than changes in receptor number83
increased functional sensitivity to adenosine8485868788
In one study, subjects received 300 mg of caffeine or placebo daily. Mood and subjective effects differed only within the first 4 days. A high dose of caffeine (300 mg twice daily) was able to reduce the effects of
Tension / Anxiety
jittery / nervous / shaky
active / excited / energetic
only in the placebo group. The caffeine group had developed complete tolerance.
Tolerance to caffeine developed within 1 to 3 days and ended 3 to 4 days after cessation of chronic caffeine administration89
Tolerance formation in rats already from a dose of 6 mg/kg/day84
Repeated daily caffeine intake can reduce the physiological effects of single caffeine intake within a few days. Single caffeine administration causes84
increased water excretion
Salivation
increased metabolic rate (oxygen consumption)
increased blood pressure
increased plasma levels of norepinephrine and epinephrine
increased renin plasma activity
Sleep disorders
After 7 days of caffeine consumption, total sleep time, sleep efficiency, and frequency of awakenings no longer differed from baseline.
Little is known about the mechanisms of action of caffeine tolerance formation. Therefore, the question whether permanent high caffeine consumption has rather advantages or disadvantages in relation to ADHD will have to be discussed in more detail. Of concern seems to be that chronic caffeine consumption increases sensitivity to adenosine, thus counteracting the desired effect of decreasing adenosine to decrease inhibition of dopamine by adenosine.85868788 In contrast, no such receptor adaptation occurs with D-amphetamine.90
It is open whether adenosine reduction without sensitization to adenosine can be achieved by moderate or alternate-day caffeine consumption.
single caffeine administration increased locomotion, chronic caffeine administration did not, whereas D-amphetamine increased locomotion with both single and chronic administration90
locomotion normalized within 4 days after cessation of chronic caffeine administration. Then, even a single dose of caffeine had the same effect as before chronic caffeine administration90
Rats showed no withdrawal effects with respect to locomotion when previously withdrawn at 19 mg/kg/day or 36 mg/kg/day. Only at 67 mg/kg/day did a halved locomotion occur on the first day of withdrawal.89 ) Withdrawal from 190 mg/kg/day of caffeine for 7 weeks showed a reduction in locomotion to one-fifth on the first day90
Avoidance of previously preferred flavors when they are now presented without caffeine95
A positive assessment of the taste of foods containing caffeine is directly caused by the effect of the caffeine itself. A test with two novel-tasting fruit juices, initially judged to be equally positive, to which either a capsule with caffeine or placebo was added, showed a clearly positive assessment of the taste by the subjects who received caffeine - but mainly by those subjects who were used to caffeine and were currently undergoing “withdrawal”.96
Headache frequent withdrawal effect
Caffeine causes vasoconstriction. After chronic caffeine consumption, vasodilation occurs upon discontinuation, resulting in increased cerebral blood flow, which appears to be a common cause of headaches.97
The withdrawal period in rats approximately 10 days,92 with individual behaviors not normalizing until 30 days.94
One study found a decrease in A1 receptors in the brain of about one-third on the first day of withdrawal in rats with chronic caffeine consumption of 30 mg/kg/day (equivalent to 4-5 cups of coffee/day in humans) over 12 weeks, which returned to normal after an average of 27 hours. Nucleus accumbens and hypothalamus, in contrast to the other brain regions, showed no change in A1 receptors.98
In humans, after 3 x 250 mg/day of caffeine for 7 days, blood plasma was free of caffeine after 60 hours85
The withdrawal period in humans seems to be about 14 days.84
Phosphodiesterases degrade the regulatory substance cyclic adenosine monophosphate (cAMP)
cAMP acts as a second messenger and has several functions:
Hormone stimulation
Mediation of neurotransmitter responses
Triggering chemotactic behavior
act on effector cells involved in the pathogenesis of type I allergies
the mobilization of intracellular Ca2+ depots by means of ryanodine receptors.
Theophylline occurs naturally in
Guarana - up to 0.25
Tea leaves - about 0.03% dry weight101 up to 0.1%68
black tea 0,02 - 0,04 %102
Mate leaves - unclear:
0 to 0.004 % 102
approx. 0.05 to 0.1 %68
Cocoa - traces101 to approx. 0.05 %
Coffee bean - traces101
Kola nut - tracks
Theophylline is able to reduce corticosteroid resistance through genetic pathways. This is the pathway by which theophylline is helpful in COPD and asthma.10327
Theophylline was shown to be equivalent to methylphenidate in the treatment of ADHD in children in parent and teacher ratings in a small double-blind randomized trial over 6 weeks. A dose of 3 mg/kg/day in children 11 years and younger and 4 mg/kg/day in children 12 years and older produced equivalent results to 1 mg/kg/day of methylphenidate. The side effects of theophylline were lower than those of MPH (headache and dropout rate).111 That the results were obtained over a 6-week period suggests that theophylline (unlike caffeine) does not show habituation effects.
Theophylline showed improvement in behavior at the second week of treatment after parent rating in a double-blind crossover study of 14 (asymptomatic) children with asthma. Cognitive improvements were not noted. 112
A meta-study found an effect on ADHD symptoms in 10 trials of theophylline in asthma sufferers (without ADHD). Hyperactivity was most frequently cited, as were distractibility, inattention, irritability, and sleep problems.113 Because the studies involved children without ADHD, the causation of ADHD symptoms is evidence that theophylline affects these symptoms. Given the inverted-U effect of neurotransmitters and especially dopamine (too little dopamine causes similar symptoms to too much dopamine), the causation of ADHD symptoms in those not affected by ADHD could be explained by the fact that an increase in dopamine levels in them caused too much dopamine. Since ADHD is characterized by a lack of dopamine, use in ADHD sufferers could compensate for this deficit.
Theophylline increases the plasma level and bioavailability of melatonin due to its degradation mechanism.114 For its part, melatonin deactivates the HPA axis, although this has probably only been studied at extremely high doses in rats.
A1 receptors form heteromers with D1 receptors.
A2A receptors form heteromers with D2 receptors.8
4.1.1. Adenosine inhibits dopamine at A1 receptors¶
Adenosine inhibits dopaminergic neurotransmission via adenosine A1 and A2A receptors. Since A1 receptors primarily form heteromers with D1 receptors located outside the striatum, adenosine inhibits D1 receptors in particular. Since A2A receptors primarily form heteromers with D2 receptors within the striatum, adenosine at the latter inhibits dopaminergic transmission in the striatum, the reward system.8
Adenosine A1- receptor antagonists have a resultant dopamine-increasing effect.
4.1.2. Adenosine and adenosine antagonists inhibit D2 receptors in A2A-D2 heteromers¶
A2A-D2 heteromers occur primarily in the striatum, and there mainly in the GABA-ergic striatopallidal neurons. Here, A2A activation increases GABA release and counteracts the effects induced by D2 receptors.8
predominant (due to the higher distribution of adenylyl cyclase type V)
upon upregulation of “Activator of G-protein signaling 3” (AGS3), however:
increasingly synergistic interaction
e.g. in case of chronic exposure to addictive substances
Spine neurons in the striatum are predominantly controlled by dopamine, glutamate, acetylcholine, and adenosine. Adenosine is released inside and outside the synapse, from where it addresses extrasynaptic and intrasynaptic adenosine receptors in and near glutamatergic synapses.11
At least in A2A / D2 - heteromers, A2A ligands (agonists as well as antagonists alone, but not when agonists and antagonists occur simultaneously) cause reduced affinity and signaling of D2 agonists.6112 In contrast, when a D2 agonist binds to a D2 heteromer, A2A agonist binding is suppressed12
The A2A / D2 interaction possibly influences the intracellular formation of cyclic AMP not only at the membrane level but also at the second messenger level. This could even be the decisive effect.12
Details of the interaction of A2A and D2 receptors
A2A / D2 - heteromers cause antagonistic interactions between A2A and D2 at the adenylyl cyclase level
A2A and D2 receptors can be connected in two opposite ways: at the membrane level and intracellularly8
Membrane level
A2A activation has a balancing effect on D2 stimulation:40
Activation has a balancing effect against D2 stimulation115
reduced D2 dopamine affinity
increased tonic dopamine level in the nucleus accumbens
increased extracellular GABA level
in the nucleus accumbens
but not by dopamine antagonist
in the ipsilateral ventral pallidum
as well by
Dopamine antagonist
co-administration of A2A agonist and D2 antagonist at such low doses that each was ineffective alone
reduced reward and seeking behavior with cocaine116
functional effects induced by D2 stimulation are attenuated
Animal models with excessive A2A expression in the brain show reduced D2 numbers in the striatum.
A2A activation reduces behavioral responses to psychostimulants
synergistic interaction between A2A and D2 at the adenylyl cyclase level in the striatum, upon overexpression of “Activator of G-protein signaling 3” (AGS3)
occurs with upregulation of AGS3, e.g., ethanol use or withdrawal from cocaine, ethanol, morphine
AGS3 activity
stabilizes / inhibits the GDP-bound form of Gi
simultaneously increases the βγ-dependent effect of the Gs/olf protein
–> sharp increase in cAMP-PKA signaling
A2A receptor agonists mediate neuroprotection by increasing NF-κB8
The adenosine A1 and A2A antagonist caffeine promotes norepinephrine.117 in the nucleus coeruleus.118
4.3. Adenosine and glutamate, acetylcholine, serotonin, histamine¶
Adenosine correlates with increased glutamatergic neurotransmission. Stimulation of glutamate NMDA receptors releases adenosine at the postsynapse of striatal neurons. Presynaptically, increased glutamate input (presumably through increased release of synaptic ATP) causes a rapid increase in adenosine at the glutamatergic synapse11
A1 and A2A receptors in cholinergic nerve terminals appear to modulate striatal acetylcholine release.119
A1 and A2A receptors modulate serotonin release. It is possible that A1 / A2A receptor heteromers exist that control both acetylcholine and serotonin release.119 A2A antagonists cause serotonin release in the tractus solitarius.120
Adenosine is able to modulate the ascending histaminergic arousal system via A2A receptors in the hypothalamus.119
Under resting conditions, adenosine is approximately equally abundant intracellularly and extracellularly.
In pathophysiological conditions (inflammation, ischemia, and hypoxia) characterized by high adenosine concentrations, reuptake by ENTs is the main mechanism of extracellular adenosine degradation.
There are two adenosine transporters:7
Dopamine (weaker)
in the striatum. This involved a large number of both endogenous and exogenous cannabinoid ligands. The maximal strength of reuptake inhibition was often equivalent to that of the dopamine reuptake inhibitor GBR12783 and the equilibrative nucleoside reuptake inhibitor dipyridamole. Inhibition did not appear to be through the cannabinoid-1 receptor.
Adenosine, dopamine, and endocannabinoids modulate the release of each other in the dorsolateral striatum, thereby controlling synaptic plasticity.
At a second level of interaction, they regulate each other’s action via the formation of receptor heteromers.
To date, little information can be found on the relationship between adenosine and ADHD.
It should be emphasized that adenosine inhibits dopamine and adenosine antagonists promote dopamine. Adenosine and dopamine receptors are closely linked, especially in the brain areas that are particularly involved in ADHD. Looking at the areas of action of A2A antagonists, one finds a considerable range of typical ADHD symptoms and ADHD comorbidities.
Cannabinoids, which also act as ADHD medications, inhibit adenosine and dopamine reuptake in the striatum, and thus have an increasing effect on adenosine and dopamine.
Several studies suggest that MPH - at least at extreme doses - also appears to act via A1 receptors.123124
MPH appears to decrease ATP. ATP is the precursor of adenosine in extracellular adenosine synthesis. In mice, chronic MPH administration caused a reduction of ATP in the hippocampus by approximately 12%.125 Since adenosine inhibits dopamine, the reduction in ATP could contribute to the increase in dopamine.
Caffeine is a potent adenosine A1 and A2A receptor antagonist.
In contrast, the other effects (A2B antagonist, A3 antagonist, GABAA antagonist, calcium mobilization, and phosphodiesterase inhibition) seem negligible. In addition, caffeine increases norepinephrine turnover in the nucleus coeruleus.118 There is evidence that caffeine also exerts its dopamine-related effects independently of adenosine receptors.126
Caffeine is consumed twice as often by adolescents with ADHD as by those not affected127
Caffeine consumption also correlates positively with ADHD symptom severity,128129 suggesting possible “self-medication.”118
no increase in hyperactivity after habituation to caffeine (60 mg/kg/day - well above the recommended dosage for humans of 5.7 mg/kg/day), even with dose increase82
Impulsivity
PFC neurons of SHR show fewer neurite branches, shorter maximum neurite length, and lower axonal growth than PFC neurons of WKY.
Caffeine restored neurite branching and extension in SHR neurons via both PKA and PI3K signaling. The A2A agonist CGS 21680 enhanced neurite branching via PKA signaling. The selective A2A antagonist SCH 58261 restored axonal growth of SHR neurons via PI3K signaling (not PKA signaling)32
Unfortunately, caffeine causes strong tolerance formation and increased sensitivity of adenosine receptors, so it is doubtful that caffeine has any benefit in ADHD beyond alternate use of small doses (1-2 cups of coffee every 2 days).
7.3. Adenosine antagonist theophylline possibly equivalent to MPH in ADHD¶
A smaller study found an equivalent effect of theophylline compared to MPH in children with ADHD. Since this study was conducted over 6 weeks, this may indicate that theophylline has a lower tolerance formation than caffeine,
Viloxazine markedly increases plasma levels of the adenosine A1 and A2 antagonist theophylline.133134
It is quite conceivable that part of the effect of viloxazine in ADHD may be due to the dopaminergic enhancing effect of the adenosine antagonist theophylline.
One study found a possible association between the polymorphism SNP rs35320474 of the ADORA2A gene (A2A receptor gene) and ADHD33
A combination of certain A2A and D2 receptor genes appears to increase the risk of anxiety disorders in children with ADHD.135
The Spontaneously Hypertensive Rat (SHR) is a genetic animal model of ADHD-HI with hyperactivity.
An altered adenosine system was detected during SHR. More about this at =&gt Adenosine system changed in SHR In the article =&gt ADHD in animal models
The amount of A2A receptors in frontocortical axon terminals is increased in SHR70
Adenosine antagonists improve various ADHD symptoms in SHR
induced upregulation of A2AARs in frontocortical nerve terminals
Chronic administration of caffeine or MPH before puberty improved object recognition in adult SHR, whereas the same treatment worsened it in adult Wistar rats139
Evidence exists for an interaction between the cannabinoid and adenosine systems in relation to impulsive SHR behavior:140
7.7. Some comorbidities elevated in ADHD show elevated adenosine levels¶
Asthma, inflammatory disorders (such as atopic dermatitis) and diabetes are often comorbid with ADHD. These 3 disorders are often associated with highly elevated adenosine levels7
A concurrence of these comorbidities with ADHD thus increasingly points to an excessive adenosine level. While in ADHD we know that dopamine deficiency can be a consequence of elevated adenosine and therefore ADHD can be a consequence of elevated adenosine (although there are many other possible causes), the causality in asthma, neurodermatitis and diabetes is unknown.
7.8. Some ADHD risk factors show elevated adenosine levels¶
Preeclampsia (gestational gestosis, hypertensive disease during pregnancy) increases the risk of ADHD by 30% to 188%. Preeclampsia is associated with changes in the adenosine system including adenosine transporters and adenosine receptors. SHR are born in a preeclampsia-like situation due to hypertension in adult mothers. Caffeine (an adenosine antagonist) in 7-day-old SHR prevented the negative consequences of preeclampsia (hyperactivity, worsened social interaction, worsened contextual fear conditioning), whereas it exacerbated these symptoms in Wistar rats141
High levels of the (weak) adenosine antagonist theobromine correlated negatively with preeclampsia in humans.142
Hypoxia (lack of oxygen) increases adenosine.
Adenosine antagonists can prevent or resolve the adverse effects of hypoxia (see above).
Methylphenidate can also resolve ADHD symptoms (Here: addictive behavior) triggered by hypoxia.143
here mainly in GABAergic medium spiny neurons (MSN) of the indirect pathway12
8. Outlook - Adenosine (A2A) antagonists as ADHD drugs?¶
There is some evidence that adenosine antagonists may have beneficial effects on ADHD symptoms. They are therefore being considered as ADHD medications.145 In addition to the empirical evidence of increased caffeine consumption by ADHD sufferers reported above, this is based on neurophysiological findings.
A2A / D2 - heteromers are involved in reward mechanisms. In particular, they are found in GABAergic neurons of the ventral striatopallidal area, which are responsible for reward and motivation effects8
A2A antagonists can act similarly to psychostimulants at appropriately low doses, as long as they are not given together with A2A agonists.146147 The fact that at very high doses they could possibly act as drugs corresponds to the stimulants methylphenidate and amphetamine drugs used as ADHD medications: here, too, the dose makes the poison.
Blockade of A2A receptors led (here: in cocaine-dependent subjects) to a dopamine increase in the striatum, which triggered a strong stimulation of the PFC.148 This corresponds to the desired effect pathways of ADHD drugs at medicinal doses.
At the same time, A2A antagonists offer the potential of addiction therapy or withdrawal support and treatment of children with consequences of fetal drug intoxication.149 Systemic administration of A2A antagonists reduced addictive behavior in rats with respect to heroin and THC, but not with respect to cocaine.150151
So far, adenosine antagonists are only being researched from the perspective of Parkinson’s disease treatment. It is to be hoped that research will also address their use in relation to ADHD.
Istradefylline, the first A2A antagonist for the treatment of Parkinson’s disease, was approved in the USA in 2019 (brand name: Nourianz®).43 The EMA has so far refused to grant approval for Europe, citing conflicting study data.
[Bona, Adén, Fredholm, Hagberg (1995): The effect of long term caffeine treatment on hypoxic-ischemic brain damage in the neonate. Pediatr Res. 1995 Sep;38(3):312-8. doi: 10.1203/00006450-199509000-00007. PMID: 7494652.)](https://pubmed.ncbi.nlm.nih.gov/7494652/ ↥
