Adenosine

Adenosine is

• a nucleoside
• a compound of adenine and ribose
• a neurotransmitter
• a component of adenosine triphosphate and adenosine diphosphate.

Adenosine is found in almost all body cells. The physiological half-life is in the range of seconds.

Extracellular adenosine levels:¹

• 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) inhibit adenosine and thus dopamine inhibition.³ They 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 dopamine release by stimulating glutamate release at adenosine receptors in the striatum, which increases striatal dopamine levels.⁴

• 1. Behavior regulation through adenosine
• 2. Formation of adenosine
• 3. Effect of adenosine: receptors
  • 3.1. A1 receptor
    • 3.1.1. A1 receptors in the brain
    • 3.1.2. Effect mediated by A1 receptors
      • 3.1.2.1. Neurophysiological effect in the brain
      • 3.1.2.2. Behavior influenced by A1
      • 3.1.2.3. Physiological effect in the body
    • 3.1.3. A1 receptor ligands
      • 3.1.3.1. A1 agonists
      • 3.1.3.2. A1 antagonists
  • 3.2. A2A receptor
    • 3.2.1. A2A receptors in the brain
    • 3.1.2. Effect mediated by A2A receptors
      • 3.1.2.1. Neurophysiological effect in the brain of A2A
      • 3.1.2.2. Behavior influenced by A2A
    • 3.2.2. A2A receptor ligands
    • 3.2.2.1. A2A agonists
    • 3.2.2.2. A2A antagonists
  • 3.3. A2B receptor
  • 3.4. A3 receptor
  • 3.5. Receptor heteromers
  • 3.6. Agonists and antagonists
    • 3.6.1. Agonists
    • 3.6.2. Antagonists
      • 3.6.2.1. Caffeine
        • 3.6.2.1.1. General information on caffeine
        • 3.6.2.1.2. Long-term caffeine consumption and habituation
        • 3.6.2.1.2.1. Tolerance development
        • 3.6.2.1.2.2. Withdrawal
      • 3.6.2.2. Theophylline
        • 3.6.2.2.1. Theophylline for asthma and COPD
        • 3.6.2.2.2. Theophylline for ADHD
• 4. Adenosine and neurotransmitters
  • 4.1. Adenosine and dopamine
    • 4.1.1. Adenosine inhibits dopamine at A1 receptors
    • 4.1.2. Adenosine and adenosine antagonists inhibit D2 receptors in A2A-D2 heteromers
    • 4.1.3. Equilibrative nucleoside transporter (ENT) influences dopamine balance
  • 4.2. Adenosine inhibits noradrenaline
  • 4.3. Adenosine and glutamate, acetylcholine, serotonin, histamine
• 5. Degradation of adenosine
  • 5.1. ENT transporter
  • 5.2. Adenosine deaminase (ADA)
• 6. Regulation of adenosine
• 7. Adenosine and ADHD
  • 7.1. Methylphenidate and adenosine
  • 7.2. Caffeine and ADHD
  • 7.3. Adenosine antagonist theophylline possibly equivalent to MPH for ADHD
  • 7.4. ADHD drug viloxazine increases theophylline
  • 7.5. A2A receptor gene and ADHD
  • 7.6. Adenosine system altered in SHR
  • 7.7. Some comorbidities associated with ADHD show elevated adenosine levels
  • 7.8. Some ADHD risk factors show increased adenosine levels
  • 7.9. ADHD symptoms that are promoted by adenosine
    • 7.9.1. Hypermotor skills
    • 7.9.2. Motivation problems
• 8. Outlook - Adenosine (A2A) antagonists as ADHD medications?

1. Behavior regulation through adenosine¶

Adenosine:

• Energy regulation of the cells
  • 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.⁵
• Sleep
  • has a dampening / sedative effect⁵
  • via A1 receptors⁶
  • Together with melatonin, adenosine regulates sleep depending on neuronal activity and energy metabolism.⁷⁵
  • 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,⁸ suggesting an interaction between adenosine and glutamate⁷
• Vascular dilation⁹
  • increased adenosine causes vasodilation
• Pain¹⁰
  • Inhibition of pain via A1 receptors⁵
  • increased pain sensation via A2A receptors⁵
• Inflammation⁹
  • increased adenosine reduces inflammation
• Neuromodulation in the CNS¹⁰
  • reduces the spontaneous activity of neurons in many regions of the brain
  • inhibits in the CNS:
    • Glutamate⁷
    • Acetylcholine⁵
    • Noradrenaline⁵
    • Dopamine⁵
      • especially in the mesolimbic dopamine system
    • GABA⁵
    • Serotonin⁵
• Control of voluntary movements (via A2A receptor)¹¹
• Motivation (via A2A receptor)¹¹
• Emotion (via A2A receptor)¹¹
• Cognition (via A2A receptor)¹¹
• Arousal⁹
• Learning⁹
• Memory⁹
• cerebral blood flow⁹
• increases the cramp threshold⁵
• is released from heart muscle cells during a heart attack⁵
  • has a cardioprotective effect via A1 and A3 receptors
  • overexpressed A1 receptors reduce the risk of heart attack
  • overexpressed A3 receptors increase cardiomyopathies.

Chronic overproduction of adenosine is pathological, e.g. in:⁹

• Parkinson’s disease
  • Caffeine has a protective effect against Parkinson’s disease
• Fibrosis
• Hepatic steatosis
• Colitis
• Asthma
  • For asthma:⁵
    • increased release of adenosine at the bronchial vessels
    • activates bronchial A1 receptors
    • these inhibit adenylyl cyclase
    • cAMP drop has a constrictive effect in bronchial muscles
• Diabetes
• Cancer
• epileptic convulsions (via A2A receptor and neurotrophins)
• chronic pain¹²
  • via A2B receptors and IL-6
• increased sensitivity¹²
  • via A2B receptors and IL-6

2. Formation of adenosine¶

Adenosine is formed in two ways:

• intracellular adenosine synthesis¹³ (physiologically predominant synthesis pathway in a healthy state)¹ e.g. in the striatum
  • AMP is hydrolyzed to adenosine by cytoplasmic 5′-nucleotidase (stronger)
  • S-adenosyl-homocysteine (SAH) hydrolyzed to adenosine by SAH hydrolase (lower)¹⁴
  • Release of adenosine into the extracellular space by bidirectional equilibrative nucleoside transporters (ENT)
• extracellular adenosine synthesis¹⁰ (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.¹⁵¹⁶

Adenosine is a degradation product of ATP. High ATP consumption by the cells (due to high neuronal activity) leads to high levels of adenosine.¹⁴ 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.

3. Effect of adenosine: receptors¶

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).¹⁶

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.

3.1. A1 receptor¶

• inhibits adenylyl cyclase via Gi/o proteins¹⁰
• encoded by the ADORA1 gene on chromosome 1 (1q32.1)

3.1.1. A1 receptors in the brain¶

• Cortex¹⁰
• Hippocampus¹⁰
• Cerebellum¹⁰
• Nerve endings¹⁷
• Spinal cord¹⁷
• Glial cells¹⁷
• Striatum
  • at the neck of dendritic spines, where they can interact with extrasynaptic dopamine and metabotropic glutamate receptors as heteromers ¹³
  • presynaptically at glutamatergic axon terminals, where they modulate glutamate release¹³
  • presynaptically at dopaminergic synapses, where they inhibit dopamine release¹⁸
    • the modulation of dopamine release mediated by A1 receptors in the striatum is complex and differs in different striatal compartments

3.1.2. Effect mediated by A1 receptors¶

3.1.2.1. Neurophysiological effect in the brain¶

• Inhibition of the release of neurotransmitters¹⁰¹⁹

• Reduction of neuronal excitability¹⁰¹⁹

• Reduction of dopamine D1 signaling²⁰

• Synaptic plasticity

  • Brain development²¹
  • Long-term potentiation (LTP, “learning”) primarily via agonists, long-term depression (LTD, “forgetting”) primarily via antagonists in¹⁹
    • Hippocampus
    • Striatum
    • Hypothalamus
    • Cerebellum

• Increase in Homer1a expression²⁰

• presynaptic:²⁰

  • Inhibition of the release of
    • Dopamine
    • Glutamate
    • Serotonin
    • Acetylcholine

• postsynaptic:²⁰

  • Impairment of neuronal signal transmission due to
    • Hyperpolarization of the neuron membrane
    • Reduction in the excitability of potassium channels

• Promotion of self-adaptive changes to regulate neuronal plasticity by heteromers with A2A and D1 receptors²⁰

• 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.²²

3.1.2.2. Behavior influenced by A1¶

• Learning¹⁹
• Memory¹⁹
• Movement activity¹⁰
• Discrimination¹⁰
• Search¹⁰
• Reward¹⁰
• Regulation of sleep¹⁰
• Sedation¹⁰
• anticonvulsant¹⁰
• anxiolytic¹⁰
  • Adenosine A1 receptors modulate the anxiolytic effect of ethanol²³²⁴
• Sensation of pain¹⁰

Studies confirm the potential of A1 agonists as an effective strategy to combat the effects caused by psychostimulants.

3.1.2.3. Physiological effect in the body¶

• reduces renal blood flow²⁵
• reduces glomerular filtration rate (GFR)²⁵
• stimulates the release of renal renin²⁵
• increases proximal tubular sodium reabsorption²⁵

3.1.3. A1 receptor ligands¶

3.1.3.1. A1 agonists¶

• 2-chloro-N6-cyclopentyladenosine (CCPA)²³
• N6-cyclopentyladenosine (CPA) is an A1 agonist²⁶²⁷
• 5’-N-Ethylcarboxamidoadenosine (NECA) is an A2/A1 agonist²⁶
• N6-R-phenylisopropyladenosine (L-PIA) (selective)¹⁴

3.1.3.2. A1 antagonists¶

• Caffeine (non-selective)²⁶
  • Binding to A1R stronger than to A2R³
  • Antagonization 25 to 50%³
  • 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.²⁸
• Rolofylline²⁵
• [3H]-DPCPX (8-cyclopentyl-1,3-dipropylxanthine)²⁹²⁷
• Theophylline (3-methyxanthine)
• CPT (8-cyclopentyltheophylline)²⁶
• Doxofylline (7-(1,3-dioxalan-2-yl-methyl) theophylline)
  • similar efficacy to theophylline with lower adenosine receptor affinity³⁰

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:³¹³²

• Downregulaton from A1R
• Relative upregulation of A2AR

3.2. A2A receptor¶

Former name: RDC8
Activation of the A2A receptor activates adenylyl cyclase via Gi/o proteins.¹⁰
Encoded by the ADORA2A gene on chromosome 22 (22q11.23)

3.2.1. A2A receptors in the brain¶

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.³³

• Striatum¹⁰
  • A2A is mainly found in the striatum and less in other brain regions.¹⁴ In the entire striatum:
    • Caudate nucleus³³
    • dorsal striatum³³
    • ventral striatum³³
    • Nucleus accumbens¹⁴
  • Distribution In the striatum³³
    • up to 3 % on astrocytes
    • to 90 % on neurons, of which
      • 70 % postsynaptic
        • mainly in the GABAergic medium spiny neurons of the indirect pathway (which project to the external segment of the globus pallidus) and which simultaneously express a high density of D2 receptors and enkephalin, with A2A receptors located close to 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
        • presynaptic
      • 3 % extrasynaptic
      • In the dorsal striatum¹⁴
        • 95-96 % of A2A is co-expressed with D2
        • 3-6 % of A2A co-express D1 or substance P mRNA.
      • In the ventral striatum¹⁴
        • 89-92 % of A2A co-express with preproenkephalin-A
        • 93-95 % of A2A co-express with D2 receptors
    • in medium, but not in large neurons¹⁴
  • in particular at the perisynaptic ring of the glutamatergic synapse in enkephalin neurons, where they can interact with D2 and mGlu5 receptors as heteromers.¹³
  • at the neck of dendritic spines, where they can interact with extrasynaptic dopamine and metabotropic glutamate receptors as heteromers.¹³
  • presynaptically at glutamatergic axon terminals, where they modulate glutamate release¹³
• Olfactory bulb¹⁰
• optical cortex (low)³³
• Amygdala (low)³³
• Hippocampus (low)³³
• Substantia nigra (low)³³
• Cerebellum (low)³³

Stimulation of the A2A receptor could be a potential therapeutic target for the treatment of drug addiction.¹⁰

3.1.2. Effect mediated by A2A receptors¶

3.1.2.1. Neurophysiological effect in the brain of A2A¶

• Reduction of dopamine D2 signaling²⁰
  • Conversely, inhibition of adenosine by dopamine. These interactions arise (at least in part) through allosteric receptor-receptor interactions within heteromeric A2AR/D2R complexes¹⁴
• Increase in the release of excitatory neurotransmitters²⁰
• Regulation of neuroinflammation²⁰⁹
  • 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.³⁴
• Modulation of neuronal glutamate release⁹
  • Increase in mGLUR5 signaling²⁰
  • Potentiation of NMDA-mediated effects⁹
  • Release of glutamate from glutamatergic endings⁹
  • Inhibition of the glutamate-1 transporter (GLT-1) in astrocytes⁹
• Modulation of glial reactivity⁹
• Modulation of the permeability of the blood-brain barrier⁹
• Infiltration of peripheral immune cells⁹
• Ischemic damage⁹
• Influence on neurite branching, neurite length and axonal growth in PFC neurons³⁵

3.1.2.2. Behavior influenced by A2A¶

• Regulation of vigilance³⁶
• ADHD-like behavior³⁶
• Synaptic plasticity
  • Corticoaccumbens and hippocampus
    • reduced long-term potentiation (LTP, “learning”) due to antagonists¹⁹
  • Hippocampus
    • increased kainate and BDNF-modulated LTP in the hippocampus by A2A agonists
  • Striatum
• Learning³⁷¹⁹
• Memory³⁷¹⁹
  • 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
• Cognition¹⁹

A2A overexpression correlates with³⁸

• Fear
• Depression

A2A polymorphisms correlate with:³⁹

• Fear
• Panic disorders

A2A knockout mice (mice without A2A receptor):⁴⁰

• Aggressiveness strongly increased (males)
• Increased anxiety
• Exploratory behavior reduced
  • Caffeine further reduced this
• Pain sensation reduced
• Increased blood pressure
• Increased heart rate
• Increased platelet aggregation

3.2.2. A2A receptor ligands¶

3.2.2.1. A2A agonists¶

• 2-p-(2-carboxyethyl)phenethylamino-5’-N-ethylcarboxamidoadenosine (CGS 21680) is an A2A agonist²⁶
• 5’-N-Ethylcarboxamidoadenosine (NECA) is an A2/A1 agonist²⁶
• CGS 21680⁴¹³⁵
  • causes a two- to threefold decrease in the affinity of D2 receptors for dopamine receptor agonists ¹⁴
  • reduced the availability of D2 receptors in the striatum in a study in rats.⁴²
  • reduced effect at very high, saturating doses, presumably due to A2A downregulation⁴³
• 3,4-Methylenedioxybenzoyl-2-thienylhydrazone (LASSBio-294)⁴⁴
  • lowered blood pressure and prevented heart defects in SHR after myocardial infarction

3.2.2.2. A2A antagonists¶

• Caffeine
  • Binding to A1R stronger than to A2R³
  • Antagonization 25 to 50%³
• Istradefylline (KW 6002)¹⁴⁴⁵
  • Approval in 2019 in the USA (first ever approved A2A antagonist) for the treatment of Parkinson’s disease (brand name: Nourianz®),⁴⁶ but only when the drug’s target was restricted from Parkinson’s disease as a whole to Parkinson’s disease with off-episodes.
  • Approval refused in the EU.⁴⁷⁴⁸
  • The most frequently reported side effects were⁴⁸
    • Dyskinesia
    • Hallucinations
    • Constipation
    • Dizziness
    • Nausea
    • Vomiting
  • Patent expires in 2024⁴⁶
  • Istradefylline did not reduce the availability of D2 receptors in the striatum in a study in rats.⁴²
• Preladenant (SCH 420814)⁴⁹⁴⁵
  • Development discontinued after no more effective than placebo in phase III
• Tozadenant (RO-449351, SYN-115; 4-hydroxy-N-(4-methoxy-7-(4-morpholinyl)benzo[d]thiazol-2-yl)-4-methylpiperidine-l-carboxamide)⁴⁹⁴⁵
  • several phase III trials discontinued prematurely
  • 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.⁴⁶
• Vipadenant⁴⁹⁴⁵
• KW-6356 (2nd generation, selective)⁴⁶
  • is to become a successor to Istradefylline
  • positive results in phase II test
• KW-6002⁵⁰
• ST 1535⁴⁹⁴⁵
• PBF-509⁴⁵
• ST4206⁴⁵
• V81444⁴⁵
• DMPX (3,7-dimethyl-1-propargylxanthine) is a selective A2 antagonist²⁶
• MSX-3⁴¹
• SCH 58261 (selective)³⁵
• ZM241385 (4-(2-[7-amino-2-[2-furyl][1,2,4]triazolo-[2,3-a][1,3,5]triazin-5-yl-amino]ethyl)phenol)²³²⁹
• SCH58261 (selective)¹⁴
• SCH-412348¹⁴
• Cmpd-1²⁹
  • is a dual antagonist of A2AR / NR2B.
  • has a 15-fold higher affinity to the A2AR than to the A1R
  • binds NR2B with high affinity (pKi = 8.25)
  • is therefore a potential Parkinson’s drug
• AZD4635 (HTL1071, Imaradenant)⁵¹
  • a 5,6-diaryl-1,2,4-triazine-3-amine derivative
  • is currently undergoing clinical trials for cancer immunotherapy
  • had previously been considered for the treatment of ADHD
  • Ki value: 1.7 nM for the human A2A receptor
  • more than 30 times the selectivity of other adenosine receptors

A2A antagonists have been shown to be helpful in:

• Working memory problems⁵²⁵³⁵⁴
• Memory disorders⁵⁵
• Reverse learning⁵⁰
• Motivation ⁵⁶⁵⁷
• goal-oriented behavior⁵⁸
• Task change⁴⁶
• Fear conditioning⁵⁹
• Improvement in cognitive performance⁵⁷
  • The effect of istradefylline on cognition was not assessed in its clinical trials in Parkinson’s patients
• Mood (depression) in Parkinson’s disease (here due to Istradefylline)⁶⁰
• Anhedonia⁵⁷
• traumatic brain injuries⁶¹
  • this is also reported for ADHD stimulants
• acute and chronic stress⁶²⁶³
• Restless legs syndrome (RLS)⁹
  • RLS is a common comorbidity of ADHD
• Huntington’s disease⁵³
• Alzheimer’s disease⁶⁴
• severe depression⁹
• Schizophrenia⁹
• Epilepsy⁹

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:³¹³²

• Downregulation of A1R
• Relative upregulation of A2AR

3.3. A2B receptor¶

Encoded by the ADORA2B gene on chromosome 17 (17p12)

Occurrence in the brain in¹⁰

• Astrocytes
• Nerve cells
• Microglia

The A2B receptor

• stimulates adenylyl cyclase via Gi/o proteins¹⁰
• barely represented in the brain¹⁰¹³
• 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)¹⁴

Ligands:

• 5’-N-Ethylcarboxamidoadenosine (NECA) is an A2/A1 agonist²⁶

3.4. A3 receptor¶

Occurs in the brain only in small quantities¹³ in:¹⁰
Encoded by the ADORA3 gene on chromosome 1 (1p13.2)

• Cortex
• Thalamus
• Hypothalamus
• Hippocampus
• Motor nerve endings
• Retinal ganglion cells
• Pial and intracerebral arteries
• Glia

The A3 receptor

• inhibits adenylyl cyclase via Gi/o proteins¹⁰
• barely represented in the brain
• influences synaptic plasticity in the hippocampus¹⁹
• 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.³⁴
• 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)¹⁴

Agonists:

Cl-IBMECA is a selective A3 agonist¹⁹

• increased theta burst-induced LTP and attenuated LTD

Antagonists

MRS-1191 is a selective A3R antagonist¹⁹

• reduced theta burst-induced LTP and attenuated LTD

3.5. Receptor heteromers¶

Adenosine receptors also occur as monomers, heteromers and omnimers:¹⁰

• with each other (e.g. A1 / A2A)¹
  • low adenosine preferentially stimulates A1 –> inhibition of glutamatergic transmission
  • high adenosine stimulates A2A –> blockade of A1-mediated effects –> potentiation of glutamate release
• with other receptors (e.g. A2A / D2 heteroidmer)
  • A2A / D2 heterodimers appear to be partly responsible for the psychomotor and reinforcing effects of psychostimulants such as cocaine and amphetamine¹⁰

In the striatum³³

• A2A / A2A (on the cell surface)
• A2A / A1
• A2A / A2B
• A2A / A3
• A2A / CB1
• A2A / D2
  • mainly in GABAergic medium spiny neurons (MSN) of the indirect pathway¹⁴
    • striatopallidal: motor control
    • Nucleus accumbens: reward-related behavior
  • in astrocytes¹⁴
  • in Glia¹⁴
  • in cholinergic interneurons¹⁴
  • 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 entirety¹⁴
• A2A / D3
• A2A / mGlu5
• A2A / FGFR1 (fibroblast growth factor receptor)
• A2A / Sigma1 receptors
• A1 / A2A (presynaptic in glutamate axon terminals)
• 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.⁶⁵

In the hippocampus
found in moderate to high density in the dorsal hippocampus, mainly in the pyramidal cell layer³³

• A1 / A2A
• A2A / A2B
• A2A / A3

3.6. Agonists and antagonists¶

3.6.1. Agonists¶

• 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 agonist⁶⁶

3.6.2. Antagonists¶

• Xanthine
  • Caffeine (A2A and A1 antagonist)
    • Recommended daily dose max 5.7 mg/kg⁶⁷
  • Theophylline (A1 and A2 antagonist; only minor A3 antagonist)
  • Paraxanthin (caffeine metabolite)⁶⁸
  • 1-methylxanthine (caffeine and theophylline metabolite)⁶⁸
  • Theobromine (weak antagonist)⁶⁸
• Istradefylline (A2A antagonist; used for Parkinson’s disease)¹ (possibly also for depression)⁶⁹
• Regadenoson¹
• Doxofylline¹³⁰
• Bamifylline¹

Relative potency of methylxanthines:⁵

Effect	Caffeine	Theophylline	Theobromine
CNS stimulation	+++	+++	-
Heart	+	+++	++
Bronchodilation and vasodilation	+	+++	++
Skeletal muscle stimulation	+++	++	+
Diuresis	+	+++	++

3.6.2.1. Caffeine¶

Due to the special importance of caffeine, we dedicate a separate section to it.

3.6.2.1.1. General information on caffeine¶

1.6 billion cups of coffee are consumed worldwide every day.⁷⁰ 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 smokers⁷¹

The values per portion (cup, jar, can, 50 g bar)⁷¹

• 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.⁷²
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.⁷³

3.6.2.1.2. Long-term caffeine consumption and habituation¶

Chronic (long-term) caffeine consumption causes adaptations of the adenosine system that counteract the effects of isolated caffeine intake.⁷¹

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) induced⁷⁴

• 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).⁷⁵

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 ⁷⁶⁷¹

One study found that increased caffeine consumption in students correlated with increased anxiety and depression symptoms and poorer academic performance.⁷⁷ 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 caffeine⁷⁸⁷⁹⁸⁰
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,⁸¹ 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.⁸² Other studies found no increase in A1 receptors in the hippocamus, cerebral cortex or cerebellum.⁸³
    • The inhibition of lipolysis in fat cells by adenosine remained unchanged
  • chronic doses below 50 mg / kg / day:
    • Number of receptors unchanged⁸⁴⁸⁵
    • Tolerance development, possibly by means of altered gene transcription⁸⁶
• A2A
  • Receptor number not or barely changed by chronic high doses⁸⁷⁸⁶
    • A1 is easily downregulated in vitro, whereas A2A is not
  • 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 number⁸⁷
• increased functional sensitivity to adenosine^8889909192

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.

3.6.2.1.2.1. Tolerance development¶

Tolerance to caffeine developed within 1 to 3 days and ended 3 to 4 days after cessation of chronic caffeine administration⁹³
Tolerance development in rats from a dose of 6 mg/kg/day⁸⁸

Repeated daily caffeine intake can reduce the physiological effects of a single dose of caffeine within a few days. A single dose of caffeine has the following effects⁸⁸

• 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.^89909192 In contrast, such receptor adaptation does not occur with D-amphetamine.⁹⁴
It remains to be seen whether moderate or daily alternating caffeine consumption can achieve a reduction in adenosine without sensitization to adenosine.

3.6.2.1.2.2. Withdrawal¶

Symptoms of withdrawal from chronic high caffeine intake are described:⁸⁸

• reduced locomotor skills⁹⁴⁹³
  • single caffeine administration increased locomotion, chronic caffeine administration did not, while D-amphetamine increased locomotion with both single and chronic administration⁹⁴
  • 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 administration⁹⁴
  • 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.⁹³ ) Withdrawal from 190 mg/kg/day of caffeine over 7 weeks showed a reduction in locomotion to one fifth on the first day⁹⁴
• reduced operant behavior⁹⁵⁹⁶⁹⁷
  • Caffeine was more effective than thephylline than theobromine in this respect⁹⁵
• reduced amplification threshold for electrical brain stimulation⁹⁶
• relatively longer sleep phases I and II⁹⁸
• Avoidance of previously preferred flavors if they are now presented without caffeine⁹⁹
  • 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”.¹⁰⁰
• 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.¹⁰¹

The withdrawal period in rats was approx. 10 days,⁹⁶ whereby individual behaviors only returned to normal after 30 days.⁹⁸
A study in rats with chronic caffeine consumption of 30 mg/kg/day (equivalent 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.¹⁰²

In humans, after 3 x 250 mg/day of caffeine over 7 days, the blood plasma was free of caffeine after 60 hours⁸⁹
The withdrawal period in humans appears to be around 14 days.⁸⁸

3.6.2.2. Theophylline¶

Theophylline is an A1 and A2 antagonist; weaker A3 antagonist. The affinity to human adenosine receptors is (from strong to weak):¹⁰³¹⁰⁴

• A2A: 2-10 µM
• A1: 10-30 µM
• A2B: 10-30 µM
• A3 receptor: 20-100 µM

Theophylline also has the following effects⁵

• an inhibition of phosphodiesterases
  • Phosphodiesterases break down the regulatory substance cyclic adenosine monophosphate (cAMP)
  • cAMP acts as a second information carrier (“second messenger”) and has a number of functions:
    • Hormone stimulation
    • Mediation of reactions to neurotransmitters
    • Triggering chemotactic behavior
    • act on effector cells that are 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 - approx. 0.03 % dry weight¹⁰⁵ to 0.1 %⁷²
black tea 0.02 to 0.04 %¹⁰⁶
Mate leaves - unclear:
0 to 0.004 % ¹⁰⁶
approx. 0.05 to 0.1 %⁷²
Cocoa - traces¹⁰⁵ up to approx. 0.05 %
Coffee bean - Traces¹⁰⁵
Kola nut - Traces

3.6.2.2.1. Theophylline for asthma and COPD¶

• Use for asthma and COPD)¹
• subject to prescription in D, A, CH
• Theophylline is able to reduce corticosteroid resistance via genetic pathways. This is the pathway by which theophylline is helpful in COPD and asthma.¹⁰⁷³⁰
  • this apparently already at low levels of 5mg/L¹⁰³
• weak, non-selective inhibitor of PDE³⁰
  • PDE degrade the cyclic nucleotides in the cell
    • leads to an increase in intracellular
      • cyclic 3’5’-adenosine monophosphate (AMP)
      • cyclic 3’,5’-guanosine monophosphate (GMP)
  • PDE inhibition at therapeutically relevant doses only low (5 - 10 % in human lung extracts)¹⁰⁸
  • PDE inhibition stronger in asthma¹⁰⁹
• prevents the bronchoconstrictor effect of adenosine at therapeutic doses¹¹⁰
• IL10 increasing
  • IL-10 is reduced in asthma and COPD¹¹¹
  • unclear whether this is also relevant for therapeutic doses
• Inhibits NF-κB¹¹²
  • prevents translocation of NF-kB into the cell nucleus
  • possible pathway to prevent expression of inflammatory genes in asthma and COPD
• Inhibits phosphoinositie-3-kinases directly, but weakly
  • pI3K (p110)-δ subtype (IC50 75 μM) still strongest
    • involved in reactions to oxidative stress
  • the ability of theophylline to reverse corticosteroid resistance appears to be based on this mechanism¹¹³
    • important for its clinical effect in severe asthma and COPD
• Plasma concentrations above 20 mg/L often show side effects³⁰
  • Headache
    • through inhibition of PDE4
  • Nausea and vomiting
    • through inhibition of PDE4 in the vomiting center
  • Stimulation
    • could be the desired effect for ADHD
    • via A1 antagonism
  • Discomfort in the abdomen
  • Restlessness
  • increased gastric acid secretion
    • via A1 antagonism
  • gastroesophageal reflux
  • Diuresis
    • via A1 antagonism
  • increased inflammation
    • via A2A antagonism¹⁰³
• at even higher levels
  • Cramps
  • Cardiac arrhythmia
    • through inhibition of PDE3
    • via A1 antagonism
• Deaths after additional intravenous administration of aminophylline, e.g. in the emergency room for severe asthma.¹¹⁴

Asthma treatment³⁰

• Theophylline is recommended as an additional bronchodilator if high doses of inhaled corticosteroids are not sufficient
• higher side effects than long-acting inhaled β2 agonists, which are also more effective

3.6.2.2.2. Theophylline for ADHD¶

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).¹¹⁵ 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. ¹¹⁶

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.¹¹⁷ Since the studies involved children without ADHD, the causation of ADHD symptoms is an indication that theophylline affects these symptoms. Given the inverted-U effect¹¹⁸¹¹⁹ 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.¹²⁰ Melatonin in turn deactivates the HPA axis, although this has probably only been investigated at extremely high doses in rats.

4. Adenosine and neurotransmitters¶

4.1. Adenosine and dopamine¶

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.¹⁰

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.¹⁰

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.¹⁰

In the striatum¹⁰

• antagonistic relationship between A2A and D2
  • 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.¹³

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.⁶⁵¹⁴ If, on the other hand, a D2 agonist binds to a D2 heteromer, the binding of A2A agonists is suppressed¹⁴
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.¹⁴

4.1.3. Equilibrative nucleoside transporter (ENT) influences dopamine balance¶

There is evidence that the equilibrative nucleoside transporter (ENT) family may play a role in dopaminergic signaling changes in ADHD.²

4.2. Adenosine inhibits noradrenaline¶

The adenosine A1 and A2A antagonist caffeine promotes noradrenaline.¹²³ in the nucleus coeruleus.¹²⁴

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 synapse¹³

A1 and A2A receptors in cholinergic nerve terminals appear to modulate striatal acetylcholine release.¹²⁵
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.¹²⁵ A2A antagonists cause serotonin release in the tractus solitarius.¹²⁶
Adenosine is able to modulate the ascending histaminergic excitation system via A2A receptors in the hypothalamus.¹²⁵

5. Degradation of adenosine¶

5.1. ENT transporter¶

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:⁹

• ENT1
• ENT2

Adenosine reuptake inhibitors:

• [3H]nitrobenzylthioinosine ([3H]NBMPR)¹²⁷
• Cannabinoids inhibit the reuptake of¹²⁸
  • Adenosine (stronger)
  • 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.

5.2. Adenosine deaminase (ADA)¶

Conversion of adenosine:¹⁰

• Adenosine kinase (AK) to AMP (phosphorylation)
  • AK has a higher affinity for adenosine than ADA.
  • predominant intracellular degradation pathway in a healthy state
• Adenosine deaminase (ADA) to inosine (deamination)
  • predominant intracellular degradation pathway in the pathological state
  • also extracellular

6. Regulation of adenosine¶

Adenosine is increased by:⁹

• Hypoxia (lack of oxygen)
• Ischemia
• Tissue damage

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.

7. Adenosine and ADHD¶

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.

7.1. Methylphenidate and adenosine¶

Several studies indicate that MPH - at least at extreme doses - also appears to act via A1 receptors.¹²⁹¹³⁰

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%.¹³¹ Since adenosine inhibits dopamine, the reduction in ATP could contribute to the increase in dopamine.

7.2. Caffeine and ADHD¶

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.¹²⁴ There are indications that caffeine also exerts its dopamine-related effects independently of adenosine receptors.¹³²

Caffeine is consumed twice as often by adolescents with ADHD than by those without the disorder¹³³
Caffeine consumption also correlates positively with the severity of ADHD symptoms,¹³⁴¹³⁵ which indicates possible “self-medication”.¹²⁴

Caffeine improves:

• Attention¹³⁶
• Learning ability¹³⁶
• Memory^1366319
• Odor discrimination¹³⁶
• Reactions to chronic stress⁶³
• cognitive performance¹³⁷ in an auditory oddball test¹³⁸
• Mood¹³⁷

Caffeine does not cause any change in:¹³⁶

• Blood pressure
• Body weight

The effect of caffeine is unclear:¹³⁶

• Hyperactivity
  • Increase with naive caffeine input⁸⁶
  • 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 dose⁸⁶
• Impulsiveness

PFC neurons of the SHR show fewer neurite branches, a shorter maximum neurite length and less 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)³⁵

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,

7.4. ADHD drug viloxazine increases theophylline¶

Viloxazine significantly increases the plasma level of the adenosine A1 and A2 antagonist theophylline.¹³⁹¹⁴⁰
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.

More about viloxazine at =&gt Viloxazine for ADHD

7.5. A2A receptor gene and ADHD¶

A study found a possible link between the polymorphism SNP rs35320474 of the ADORA2A gene (A2A receptor gene) and ADHD³⁶
A combination of certain A2A and D2 receptor genes appears to increase the risk of anxiety disorders in children with ADHD.¹⁴¹

7.6. Adenosine system altered in SHR¶

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 =&gt Adenosine system altered in SHR In the article =&gt ADHD in animal models

The amount of A2A receptors in frontocortical axon terminals is increased in SHR⁷⁴

Adenosine antagonists improve various ADHD symptoms in SHR

• Caffeine (non-selective A1 and A2A antagonist)
  • Object recognition¹⁴²
  • social recognition¹⁴³
  • spatial learning¹⁴⁴
  • no influence on high blood pressure¹⁴⁴
• DPCPX (8-cyclopenthyl-1,3-dipropylxanthine, A1 antagonist)
  • Object recognition¹⁴²
  • no influence on high blood pressure¹⁴⁴
• ZM241385 (4-(2-[7-amino-2-[2-furyl][1,2,4]triazolo-[2,3-a][1,3,5]triazin-5-yl-amino]ethyl) phenol, A2A-Antagonist)
  • Object recognition¹⁴²
  • social recognition¹⁴³
  • no influence on high blood pressure¹⁴⁴

Chronic caffeine input⁷⁴

• normalized the dopaminergic function
• improved memory and attention deficits
• 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 rats¹⁴⁵

There is evidence of an interaction between the cannabinoid and adenosine systems in relation to impulsive behavior in SHR:¹⁴⁶

• WIN55212-2 (cannabinoid receptor agonist) increased impulsive behavior
• 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 levels⁹
A co-occurrence of these comorbidities with ADHD thus increasingly indicates an elevated 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 rats¹⁴⁷
• High levels of the (weak) adenosine antagonist theobromine correlated negatively with pre-eclampsia in humans.¹⁴⁸
• 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).¹⁴⁹

7.9. ADHD symptoms that are promoted by adenosine¶

7.9.1. Hypermotor skills¶

striatopallidal: motor control

• mainly in GABAergic medium spiny neurons (MSN) of the indirect pathway¹⁴¹⁵⁰
• mainly via A2A, barely via A1¹⁴¹⁵⁰

7.9.2. Motivation problems¶

Adenosine inhibits dopaminergic neurotransmission and thus the reward system in the striatum via

• A1¹⁰
• A2A¹⁰¹⁴

primarily in the nucleus accumbens,

• here mainly in GABAergic medium spiny neurons (MSN) of the indirect pathway¹⁴

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.¹⁵¹ 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 effects¹⁰

A2A antagonists can have a similar effect to psychostimulants at low doses, as long as they are not given together with A2A agonists.^{152 153} 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.
Blocking A2A receptors led (here: in cocaine-dependent subjects) to an increase in dopamine in the striatum, which triggered a strong stimulation of the PFC.¹⁵⁴ 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.¹⁵⁵ Systemic administration of A2A antagonists reduced addictive behavior in rats with respect to heroin and THC, but not with respect to cocaine.¹⁵⁶¹⁵⁷

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®).⁴⁶ The EMA has so far refused approval for Europe, citing contradictory study results.