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20 to 300 nM under normal physiological conditions
Increase to low micromolar values under extreme physiological conditions, e.g:
intensive sports
low oxygen content in the air at high altitude
Increase to high micromolar values (30 µM) under pathological conditions, e.g:
Ischemia
The adenosine system is closely linked to the dopaminergic system.2 Adenosine receptors are located in particular in the brain regions involved in ADHD. Adenosine receptors are closely linked to dopamine receptors and form heteromers with them.
Adenosine inhibits dopamine. Adenosine antagonists (primarily A2A antagonists) are currently being researched for the treatment of Parkinson’s disease and, in our opinion, could also be considered for the 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.3
Among other things, adenosine is used for autoregulation in the event of impending energy deficiency in the cell (e.g. if the cell is overstressed or lacks oxygen): If the ATP content in a cell drops, more adenosine is produced as a hydrolysis product. Some of this adenosine is released from the cell and binds to adenosine receptors of neighboring cells, which is intended to compensate for the disturbed balance between energy consumption and energy supply.4
Together with melatonin, adenosine regulates sleep depending on neuronal activity and energy metabolism.64
Through this mechanism, the increased adenosine level after sleep deprivation could influence 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,7 suggesting an interaction between adenosine and glutamate6
intracellular adenosine synthesis12 (physiologically predominant synthesis pathway in a healthy state)1 in the striatum, among other places
AMP is hydrolyzed to adenosine by cytoplasmic 5′-nucleotidase (stronger)
S-adenosyl-homocysteine (SAH) hydrolyzed to adenosine by SAH hydrolase (lower)13
Release of adenosine into the extracellular space by bidirectional equilibrative nucleoside transporters (ENT)
extracellular adenosine synthesis9 (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 converted to adenosine by a specific ecto-5′-nucleotidase enzyme (CD73).1
ATP itself appears to be a neurotransmitter and to have an inhibitory effect in the intestine and an exitatory effect in the autonomic nervous system.1415
Adenosine is a degradation product of ATP. High ATP consumption by the cells (due to high neuronal activity) leads to high adenosine.13 This mechanism serves to regulate the energy level of the cells.
Rising adenosine levels increase sleep pressure and thus promote recovery. Sleeping at night reduces adenosine and thus lowers sleep pressure.
Neurodegenerative diseases release high concentrations of ATP from the damaged neuronal and non-neuronal brain cells, which is then enzymatically degraded to adenosine. Neurodegenerative diseases (dementia, Alzheimer’s, Parkinson’s, Huntington’s) appear to cause two-stage damage: primarily through various protein aggregates, resulting in secondary superimposed damage, particularly through P2X7 and A2AR activation. Small molecule antagonists can efficiently prevent or attenuate this damage. P2X7 and A2AR also appear to be involved in ADHD, depression and obsessive-compulsive disorder.15
Adenosine receptors are G-protein-coupled and occur frequently in almost all human tissues and organs.
They are a subgroup of purinoceptors (purinergic receptors), which are divided into ATP receptors (P2 receptors) and adenosine receptors (P1 receptors).15
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 in the excitability of potassium channels
Promotion of self-adaptive changes to regulate neuronal plasticity by heteromers with A2A and D1 receptors19
The A1 agonist CPA increased the binding of the alpha2-adrenoceptor in the nucleus tractus solitarius. The increase in binding was around 10 times greater with SHR than with WKY.21
Caffeine is a non-selective adenosine receptor antagonist25
Adenosine A1 receptors in the brain regulate the need for sleep. Adenosine A1 receptors inhibit the enzyme adenylyl cyclase, which is required for the conversion of ATP into cAMP. This inhibition is prevented by caffeine, the cAMP level remains high. This increases alertness.27
similar efficacy to theophylline with lower adenosine receptor affinity29
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:3031
Former name: RDC8
Activation of the A2A receptor activates adenylyl cyclase via Gi/o proteins.9
Encoded by the ADORA2A gene on chromosome 22 (22q11.23)
A2A receptors are most commonly found in the striatum of the brain in both humans and rats. In other areas of the brain, they are found much less frequently.32
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.
barely in neurons of the direct striato-nigral pathway (which selectively express D1 receptors and the peptide dynorphin)
23 % presynaptic
mainly at cortico-thalamic glutaminergic axon terminals that were in contact with medium spiny neurons of the direct and indirect GABAergic pathways and at cholinergic neurons that modulate acetylcholine release
in particular at the perisynaptic ring of the glutamatergic synapse in enkephalin neurons, where they can interact with D2 and mGlu5 receptors as heteromers.12
at the neck of dendritic spines, where they can interact with extrasynaptic dopamine and metabotropic glutamate receptors as heteromers.12
presynaptically at glutamatergic axon terminals, where they modulate glutamate release12
Conversely, inhibition of adenosine by dopamine. These interactions arise (at least in part) through allosteric receptor-receptor interactions within heteromeric A2AR/D2R complexes13
Increase in the release of excitatory neurotransmitters19
In chronic autoimmune rheumatic diseases, A2A and A3 receptors are overexpressed in lymphocytes. A2A and A3 agonists inhibited the activation of NF-κB, the release of typical proinflammatory cytokines and the concentration of metalloproteinases, which are involved in the inflammatory reactions in chronic autoimmune rheumatic diseases.33
Caffeine (as a non-selective adenosine antagonist) as well as selective adenosine A2A antagonists can improve memory performance in rodents and protect against memory impairment
Approval in 2019 in the USA (first ever approved A2A antagonist) for the treatment of Parkinson’s disease (brand name: Nourianz®),45 but only when the drug’s overall target was restricted from Parkinson’s to Parkinson’s with off-episodes.
Death of 5 patients in a Phase III study with 409 participants due to drug-induced agranulocytosis (formation of antibodies against neutrophil membrane glycoproteins, which leads to the destruction of neutrophils). Other approved drugs also have this side effect. Has not yet been observed with Istradefylline.45
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:3031
weak adenosine binding. Only activated when extracellular adenosine levels are very high (micromolar), e.g. after tissue damage (e.g. inflammation, hypoxia, ischemia, brain injury)13
Ligands:
5’-N-Ethylcarboxamidoadenosine (NECA) is an A2/A1 agonist25
influences synaptic plasticity in the hippocampus18
In chronic autoimmune rheumatic diseases, A2A and A3 receptors are overexpressed in lymphocytes. A2A and A3 agonists inhibited the activation of NF-κB, the release of typical proinflammatory cytokines and the concentration of metalloproteinases, which are involved in the inflammatory reactions in chronic autoimmune rheumatic diseases.33
weak adenosine binding. Only activated when extracellular adenosine levels are very high (micromolar), e.g. after tissue damage (e.g. inflammation, hypoxia, ischemia, brain injury)13
The mutual inhibition of adenosine and dopamine in mammals is mediated by A2A / and D2 receptors, at least parts of which are mediated 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. mechanisms such as downregulation do not affect one part of the heteromer alone, but the entirety13
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. Consequences are that A2A antagonists at high concentrations act in the same way as A2A agonists, namely by reducing D2 receptor-mediated activity in neurons.64
In the hippocampus
found in moderate to high density in the dorsal hippocampus, mainly in the pyramidal cell layer32
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 agonist65
1.6 billion cups of coffee are consumed worldwide every day.69 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 longer in pregnant women and shorter in smokers70
The values per portion (cup, jar, can, 50 g bar)70
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 releases caffeine immediately after contact with stomach acid. Coffee caffeine therefore works quickly.
Caffeine from tea is bound to polyphenols. The caffeine is only produced through fermentation and is released in the intestine, so it has a later and longer-lasting effect.71
Tea is therefore preferable to coffee when it comes to treating ADHD.
Green tea contains just as much caffeine as black tea. However, the same source states 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.72
3.6.2.1.2. Long-term caffeine consumption and habituation¶
Chronic (long-term) caffeine consumption causes adaptations in the adenosine system that counteract the effects of isolated caffeine intake.70
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) induced73
normalized dopaminergic function (reduced in SHR per se)
improved memory and attention deficits (which are typical in SHR)
upregulation of A2A in frontocortical nerve endings
Caffeine further improved in vitro in the striatum of SHR the
GABA release (reduced with SHR per se)
GABA reuptake via GAT1 transporter (reduced in SHR per se)
whereas this was not the case with Wistar rats (which are not an ADHD animal model).74
This result could be an indication of a positive effect of caffeine on ADHD.
In contrast, other studies suggest that the effects of caffeine on alertness and cognitive performance do not represent a net benefit for 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 7570
One study found that increased caffeine consumption in students correlated with increased anxiety and depression symptoms and poorer academic performance.76 It remains to be seen 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, of the effects of caffeine777879
Note: The following doses 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,80 and also in the hippocampus (CA3), without changes in gene transcription, apparently due to a blockade of downregulation caused by adenosine in the absence of caffeine.81 Other studies found no increase in A1 receptors in the hippocamus, cerebral cortex or cerebellum.82
The inhibition of lipolysis in fat cells by adenosine remained unchanged
Tolerance development, possibly by means of altered gene transcription85
A2A
Receptor number not or barely changed by chronic high doses8685
A1 can be easily downregulated in vitro, whereas A2A cannot
basal adenylyl cyclase activity and cyclase activities stimulated by adenosine agonists, GTP gamma S or forskolin are reduced in cells desensitized by chronic caffeine administration, but also in ways other than changes in receptor number86
increased functional sensitivity to adenosine8788899091
In one study, subjects were given 300 mg of caffeine or placebo daily. Mood and subjective effects only differed within the first 4 days. A high dose of caffeine (300 mg twice a day) was able to improve the effects of caffeine
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 administration92
Tolerance development in rats from a dose of 6 mg/kg/day87
Repeated daily caffeine intake can reduce the physiological effects of a single dose of caffeine within a few days. A single dose of caffeine causes87
increased water excretion
Salivation
increased metabolic rate (oxygen consumption)
increased blood pressure
increased noradrenaline and adrenaline plasma levels
increased renin plasma level activity
Sleep disorders
After 7 days of caffeine consumption, total sleep time, sleep efficiency and frequency of awakenings no longer differed from the initial value.
Little is known about the mechanisms of caffeine tolerance formation. Therefore, the question of whether long-term high caffeine consumption has advantages or disadvantages in relation to ADHD will have to be discussed in greater depth. A concern seems to be that chronic caffeine consumption increases sensitivity to adenosine and thus counteracts the desired effect of reducing adenosine in order to reduce the inhibition of dopamine by adenosine.88899091 In contrast, such receptor adaptation does not occur with D-amphetamine.93
It remains to be seen whether moderate or daily alternating caffeine consumption can achieve a reduction in adenosine without sensitization to adenosine.
single caffeine administration increased locomotion, chronic caffeine administration did not, while D-amphetamine increased locomotion with both single and chronic administration93
locomotion normalized within 4 days after the end of chronic caffeine administration. Then even a single dose of caffeine had the same effect as before chronic caffeine administration93
Rats showed no withdrawal effects with regard to locomotor activity after withdrawal from 19 mg/kg/day or 36 mg/kg/day. Only at 67 mg/kg/day did locomotion halve on the first day of withdrawal.92 ) Withdrawal from 190 mg/kg/day of caffeine over 7 weeks showed a reduction in locomotion to one fifth on the first day93
Avoidance of previously preferred flavors if they are now presented without caffeine98
A positive assessment of the taste of caffeinated foods is directly caused by the effect of the caffeine itself. A test with two novel-tasting fruit juices, which were initially judged as equally positive, with which either a capsule containing caffeine or a placebo was taken, showed a clearly positive assessment of the taste by the test subjects who received caffeine - but mainly by those test subjects who were used to caffeine and were currently in “withdrawal”.99
Headache frequent withdrawal effect
Caffeine causes vasoconstriction. After chronic caffeine consumption, vasodilation occurs on cessation, leading to increased cerebral blood flow, which appears to be a common cause of headaches.100
The withdrawal period in rats was approx. 10 days,95 whereby individual behaviors only returned to normal after 30 days.97
A study in rats with chronic caffeine consumption of 30 mg/kg/day (corresponding to 4-5 cups of coffee/day in humans) over 12 weeks found a decrease in A1 receptors in the brain by around a third on the first day of withdrawal, which had returned to normal after 27 hours on average. In contrast to the other brain regions, the nucleus accumbens and hypothalamus showed no change in A1 receptors.101
In humans, after 3 x 250 mg/day of caffeine over 7 days, the blood plasma was free of caffeine after 60 hours88
The withdrawal period in humans appears to be around 14 days.87
Theophylline is able to reduce corticosteroid resistance via genetic pathways. This is the pathway by which theophylline is helpful in COPD and asthma.10629
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 study over 6 weeks. A dose of 3 mg/kg/day in children up to 11 years 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).114 The fact that the results were obtained over a period of 6 weeks indicates that theophylline (unlike caffeine) does not show any habituation effects.
In a double-blind crossover study of 14 (asymptomatic) children with asthma, theophylline showed an improvement in behavior in the second week of treatment after parent rating. Cognitive improvements were not observed. 115
A meta-analysis found an effect on ADHD symptoms in 10 studies of theophylline in people with ADHD (without ADHD). Hyperactivity was mentioned most frequently, as were distractibility, inattention, irritability and sleep problems.116 Since the studies involved children without ADHD, the causation of ADHD symptoms is an indication that theophylline affects these symptoms. In light of the inverted-U effect117118 of neurotransmitters and dopamine in particular (too little dopamine causes similar symptoms to too much dopamine), the causation of ADHD symptoms in people without ADHD could be explained by the fact that an increase in dopamine levels caused too much dopamine in these people. Since ADHD is characterized by a dopamine deficiency, use in people with ADHD could compensate for this deficit.
Due to its degradation mechanism, theophylline increases the plasma level and bioavailability of melatonin.119 Melatonin in turn deactivates the HPA axis, although this has probably only been studied at extremely high doses in rats.
The adenosine system is closely linked to the dopamine system.2
A1 receptors form heteromers with D1 receptors.
A2A receptors form heteromers with D2 receptors.9
4.1.1. Adenosine inhibits dopamine at A1 receptors¶
Adenosine inhibits dopaminergic neurotransmission via adenosine A1 and A2 receptors. Since A1 receptors primarily form heteromers with D1 receptors, which are located outside the striatum, adenosine inhibits D1 receptors in particular. Since A2A receptors primarily form heteromers with D2 receptors within the striatum, adenosine on the latter inhibits dopaminergic transmission in the striatum, the reward system.9
Adenosine A1 receptor antagonists have the effect of increasing dopamine levels.
4.1.2. Adenosine and adenosine antagonists inhibit D2 receptors in A2A-D2 heteromers¶
A2A-D2 heteromers occur primarily in the striatum, especially in the GABA-ergic striatopallidal neurons. Here, A2A activation increases GABA release and counteracts the effects induced by D2 receptors.9
predominant (due to the higher distribution of adenylyl cyclase type V)
upon upregulation of “Activator of G-protein signaling 3” (AGS3):
increasingly synergistic interaction
e.g. 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.12
At least in A2A / D2 heteromers, A2A ligands (agonists as well as antagonists alone, but not when agonists and antagonists occur simultaneously) cause a reduced affinity and signaling effect of D2 agonists.6413 If, on the other hand, a D2 agonist binds to a D2 heteromer, the binding of A2A agonists is suppressed13
The A2A / D2 interaction may influence 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.13
Details on 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 intracellularly9
Membrane level
A2A activation has a balancing effect on D2 stimulation:42
Activation has a balancing effect compared to D2 stimulation120
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
also through
Dopamine antagonist
joint administration of A2A agonist and D2 antagonist in such low doses that they were ineffective on their own
reduced reward and addictive behavior with cocaine121
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, with overexpression of the “Activator of G-protein signaling 3” (AGS3)
occurs with upregulation of AGS3, e.g. with ethanol consumption 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
–> strong increase in cAMP-PKA signaling
A2A receptor agonists mediate neuroprotection by increasing NF-κB9
The adenosine A1 and A2A antagonist caffeine promotes noradrenaline.122 in the nucleus coeruleus.123
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 synapse12
A1 and A2A receptors in cholinergic nerve terminals appear to modulate striatal acetylcholine release.124
A1 and A2A receptors modulate the release of serotonin. It is possible that A1 / A2A receptor heteromers exist that control both acetylcholine and serotonin release.124 A2A antagonists cause serotonin release in the tractus solitarius.125
Adenosine is able to modulate the ascending histaminergic excitation system via A2A receptors in the hypothalamus.124
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:8
Dopamine (weaker)
in the striatum. This applies to a large number of endogenous and exogenous cannabinoid ligands. The maximum strength of reuptake inhibition often corresponded to that of the dopamine reuptake inhibitor GBR12783 and the equilibrative nucleoside reuptake inhibitor dipyridamole. The inhibition was apparently not through the cannabinoid-1 receptor.
Adenosine, dopamine and endocannabinoids modulate the release of each other in the dorsolateral striatum and thus control synaptic plasticity.
At a second level of interaction, they regulate each other’s action via the formation of receptor heteromers.
So far, little information has been found on the link 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 areas of the brain that are particularly involved in ADHD. If we look at the areas of action of A2A antagonists, we find 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, thus increasing adenosine and dopamine.
Several studies indicate that MPH - at least at extreme doses - also appears to act via A1 receptors.128129
MPH appears to reduce ATP. ATP is the precursor of adenosine in extracellular adenosine synthesis. In mice, chronic MPH administration resulted in a reduction of ATP in the hippocampus by approximately 12 %.130 Since adenosine inhibits dopamine, the reduction in ATP could contribute to the increase in dopamine.
Caffeine is a strong adenosine A1 and A2A receptor antagonist.
In contrast, the other effects (A2B antagonist, A3 antagonist, GABAA antagonist, calcium mobilization and phosphodiesterase inhibition) appear to be negligible. In addition, caffeine increases noradrenaline turnover in the nucleus coeruleus.123 There are indications that caffeine also exerts its dopamine-related effects independently of adenosine receptors.131
Caffeine is consumed twice as often by adolescents with ADHD than by those without the disorder132
Caffeine consumption also correlates positively with the severity of ADHD symptoms,133134 which indicates possible “self-medication”.123
no increase in hyperactivity after habituation to caffeine (60 mg/kg/day - far above the recommended dosage for humans of 5.7 mg/kg/day), not even by increasing the dose85
Impulsiveness
PFC neurons of the SHR show fewer neurite branches, a shorter maximum neurite length and a lower axonal growth than PFC neurons of the WKY.
Caffeine restored neurite branching and elongation in SHR neurons via both PKA and PI3K signaling. The A2A agonist CGS 21680 improved neurite branching via PKA signaling. The selective A2A antagonist SCH 58261 restored axonal growth of SHR neurons via PI3K signaling (not PKA signaling)34
Unfortunately, caffeine causes a strong tolerance build-up and increased sensitivity of adenosine receptors, so it is doubtful whether caffeine has any benefit in relation to ADHD beyond alternating use of small doses (1-2 cups of coffee every 2 days).
7.3. Adenosine antagonist theophylline possibly equivalent to MPH for ADHD¶
A smaller study found an equivalent effect of theophylline compared to MPH in children with ADHD. As this study ran for 6 weeks, this could indicate that theophylline has a lower tolerance than caffeine,
Viloxazine significantly increases the plasma level of the adenosine A1 and A2 antagonist theophylline.138139
It is quite conceivable that part of the effect of viloxazine in ADHD could be due to the dopamine-increasing effect of the adenosine antagonist theophylline.
A study found a possible link between the polymorphism SNP rs35320474 of the ADORA2A gene (A2A receptor gene) and ADHD35
A combination of certain A2A and D2 receptor genes appears to increase the risk of anxiety disorders in children with ADHD.140
The Spontaneously Hypertensive Rat (SHR) is a genetic animal model for ADHD-HI with hyperactivity.
An altered adenosine system was detected in the SHR. Find out more at => Adenosine system altered in SHR In the article => ADHD in animal models
The amount of A2A receptors in frontocortical axon terminals is increased in SHR73
Adenosine antagonists improve various ADHD symptoms in SHR
induced upregulation of A2AARs in frontocortical nerve endings
Chronic administration of caffeine or MPH before puberty improved object recognition in adult SHR, while the same treatment worsened it in adult Wistar rats144
There is evidence of an interaction between the cannabinoid and adenosine systems in relation to impulsive behavior in SHR:145
acute pre-treatment with caffeine canceled this out
chronic caffeine intake increased impulsivity
7.7. Some comorbidities associated with ADHD show elevated adenosine levels¶
Asthma, inflammatory disorders (such as neurodermatitis) and diabetes often occur comorbidly with ADHD. These 3 disorders are often associated with highly elevated adenosine levels8
A co-occurrence of these comorbidities with ADHD thus increasingly indicates an excessive adenosine level. While we know that dopamine deficiency in ADHD can be a consequence of elevated adenosine and that ADHD can therefore 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 increased adenosine levels¶
Pre-eclampsia (gestational gestosis, high blood pressure disease during pregnancy) increases the risk of ADHD by 30 to 188%. Pre-eclampsia is associated with changes in the adenosine system including adenosine transporters and adenosine receptors. SHR are born in a pre-eclampsia-like situation due to adult maternal hypertension. Caffeine (an adenosine antagonist) in 7-day-old SHR prevented the negative Consequences of preeclampsia (hyperactivity, worsened social interaction, worsened contextual fear conditioning), while it enhanced these symptoms in Wistar rats146
High levels of the (weak) adenosine antagonist theobromine correlated negatively with pre-eclampsia in humans.147
Hypoxia (lack of oxygen) increases adenosine.
Adenosine antagonists can prevent or remedy the negative Consequences of hypoxia (see above).
Methylphenidate can also remedy the ADHD symptoms triggered by hypoxia (here: addictive behavior).148
7.9. ADHD symptoms that are promoted by adenosine¶
here mainly in GABAergic medium spiny neurons (MSN) of the indirect pathway13
8. Outlook - Adenosine (A2A) antagonists as ADHD medications?¶
There is some evidence that adenosine antagonists may have positive effects on ADHD symptoms. They are therefore being considered as ADHD medications.150 In addition to the empirical evidence of increased caffeine consumption by people with ADHD reported above, this is based on neurophysiological findings.
A2A / D2 heteromers are involved in reward mechanisms. They are found in particular in GABAergic neurons of the ventral striatopallidal area, which are responsible for reward and motivational effects9
A2A antagonists can have a similar effect to psychostimulants at low doses, as long as they are not given together with A2A agonists.151152 The fact that they could possibly have a drug-like effect at very high doses corresponds to the stimulants methylphenidate and amphetamine drugs used as ADHD medications: here, too, the dose makes the poison.
A blockade of A2A receptors led (here: in cocaine-dependent subjects) to an increase in dopamine in the striatum, which triggered a strong stimulation of the PFC.153 This corresponds to the desired effect pathways of ADHD drugs at medical doses.
At the same time, A2A antagonists offer the potential of addiction therapy or withdrawal support and the treatment of children with Consequences of fetal drug intoxication.154 Systemic administration of A2A antagonists reduced addictive behavior in rats with respect to heroin and THC, but not with respect to cocaine.155156
So far, adenosine antagonists have only been researched from the perspective of Parkinson’s treatment. It is to be hoped that research will also look at 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®).45 The EMA has so far refused approval for Europe, citing contradictory study results.
[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/ ↥
