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 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

• 1. Behavioral regulation by adenosine
• 2. Formation of adenosine
• 3. Action 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 about caffeine
        • 3.6.2.1.2. Continuous 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 in asthma and COPD
        • 3.6.2.2.2. Theophylline for ADHD
• 4. Adenosine and neurotransmitter
  • 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
  • 4.2. Adenosine inhibits norepinephrine
  • 4.3. Adenosine and glutamate, acetylcholine, serotonin, histamine
• 5. Adenosine degradation
  • 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 in 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 elevated in ADHD show elevated adenosine levels
  • 7.8. Some ADHD risk factors show elevated adenosine levels
  • 7.9. ADHD symptoms promoted by adenosine
    • 7.9.1. Hypermotor
    • 7.9.2. Motivation problems
• 8. Outlook - Adenosine (A2A) antagonists as ADHD drugs?

1. Behavioral regulation by adenosine¶

Adenosine:

• Energy regulation of the cells
  • 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
• Sleep
  • has a depressant / sedative effect³
  • via A1 receptors⁴
  • 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
• Vascular dilation⁷
  • increased adenosine causes vasodilatation
• Pain⁸
  • Inhibition of pain via A1 receptors³
  • increased pain sensation via A2A receptors³
• Inflammation⁷
  • increased adenosine reduces inflammation
• Neuromodulation in the CNS⁸
  • reduces the spontaneous activity of neurons in many brain regions
  • inhibits in the CNS:
    • Glutamate⁵
    • Acetylcholine³
    • Norepinephrine³
    • Dopamine³
      • especially in the mesolimbic dopamine system
    • GABA³
    • Serotonin³
• Control of voluntary movements (via A2A receptor)⁹
• Motivation (via A2A receptor)⁹
• Emotion (via A2A receptor)⁹
• Cognition (via A2A receptor)⁹
• Arousal⁷
• Learning⁷
• Memory⁷
• cerebral blood flow⁷
• increases the seizure threshold³
• is released from heart muscle cells during myocardial infarction³
  • has a cardioprotective effect via A1 and A3 receptors
  • overexpressed A1 receptors reduce risk of infarction
  • overexpressed A3 receptors exacerbate cardiomyopathies.

Chronic overproduction of adenosine is pathological, e.g., in:⁷

• Parkinson’s
  • Caffeine has protective effect against Parkinson’s disease
• Fibrosis
• Hepatic steatosis
• Colitis
• Asthma
  • For asthma:³
    • increased adenosine release at the bronchial vessels
    • activates bronchial A1 receptors
    • these inhibit adenylyl cyclase
    • cAMP drop has a constrictor effect in bronchial muscles
• Diabetes
• Cancer
• epileptic seizures (via A2A receptor and neurotrophins)
• chronic pain¹⁰
  • via A2B receptors and IL-6
• increased sensitivity¹⁰
  • via A2B receptors and IL-6

2. Formation of adenosine¶

Adenosine is formed in two ways:

• 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.

3. Action of adenosine: receptors¶

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.

3.1. A1 receptor¶

• inhibits adenylyl cyclase via Gi/o proteins⁸
• encoded by the ADORA1 gene on chromosome 1 (1q32.1)

3.1.1. A1 receptors in the brain¶

• Cortex⁸
• Hippocampus⁸
• Cerebellum⁸
• Nerve endings¹⁴
• Spinal cord¹⁴
• Glial cells¹⁴
• Striatum
  • 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
  • presynaptically at dopaminergic synapses, where they inhibit dopamine release¹⁵
    • 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 neurotransmitters⁸¹⁶

• Reduction of neuronal excitability⁸¹⁶

• Reduction of dopamine D1 signaling¹⁷

• Synaptic plasticity

  • Brain development¹⁸
  • Long-term potentiation (LTP, “learning”) mainly via agonists, long-term depression (LTD, “forgetting”) mainly via antagonists in¹⁶
    • Hippocampus
    • Striatum
    • Hypothalamus
    • Cerebellum

• Increase of Homer1a expression¹⁷

• presynaptic:¹⁷

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

• postsynaptic:¹⁷

  • Impairment of neuronal signal transmission due to
    • Hyperpolarization of the neuron membrane
    • 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

3.1.2.2. Behavior influenced by A1¶

• Learning¹⁶
• Memory¹⁶
• Movement activity⁸
• Discrimination⁸
• Search⁸
• Reward⁸
• Sleep regulation⁸
• Sedation⁸
• anticonvulsant⁸
• anxiolytic⁸
  • Adenosine A1 receptors modulate the anxiolytic effect of ethanol²⁰²¹
• Pain sensation⁸

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

3.1.2.3. Physiological effect in the body¶

• reduces renal blood flow²²
• reduces glomerular filtration rate (GFR)²²
• stimulates the release of renal renin²²
• increases proximal tubular sodium reabsorption²²

3.1.3. A1 receptor ligands¶

3.1.3.1. A1 agonists¶

• 2-chloro-N6-cyclopentyladenosine (CCPA)²⁰
• N6-cyclopentyladenosine (CPA) is an A1 agonist²³²⁴
• 5’-N-ethylcarboxamidoadenosine (NECA) is an A2/A1 agonist²³
• N6-R-phenylisopropyladenosines (L-PIA) (selective)¹²

3.1.3.2. A1 antagonists¶

• 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
• Rolofylline²²
• [3H]-DPCPX (8-cyclopentyl-1,3-dipropylxanthine)²⁶²⁴
• Theophylline (3-methyxanthine)
• CPT (8-cyclopentyltheophylline)²³
• Doxofylline (7-(1,3-dioxalan-2-yl-methyl) theophylline)
  • 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

• 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.⁸
Encoded by the ADORA2A gene on chromosome 22 (22q11.23)

3.2.1. A2A receptors in the brain¶

A2A receptors are most abundant in the striatum of the brain in both humans and rats. They are found much less frequently in other brain areas.³⁰

• Striatum⁸
  • A2A are found primarily in the striatum and less so in other brain regions.¹² Throughout the striatum:
    • Caudate nucleus³⁰
    • dorsal striatum³⁰
    • ventral striatum³⁰
    • Nucleus accumbens¹²
  • Distribution In striatum³⁰
    • to 3 % on astrocytes
    • 90% on neurons, of which
      • 70 % postsynaptic
        • 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
        • presynaptic
      • 3 % extrasynaptic
      • In the dorsal striatum¹²
        • 95-96% of A2A are expressed together with D2
        • 3-6% of A2A co-express D1 or substance P mRNA.
      • In the ventral striatum¹²
        • 89-92% of A2A co-express with preproenkephalin-A
        • 93-95% of A2As co-express with D2 receptors
    • in medium, but not in large neurons¹²
  • 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
• Olfactory bulb⁸
• optical cortex (low)³⁰
• Amygdala (low)³⁰
• Hippocampus (low)³⁰
• Substantia nigra (low)³⁰
• Cerebellum (low)³⁰

Stimulation of the A2A receptor could be a potential therapeutic target for the treatment of drug addiction.⁸

3.1.2. Effect mediated by A2A receptors¶

3.1.2.1. Neurophysiological effect in the brain of A2A¶

• Reduction of dopamine D2 signaling¹⁷
  • 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
• Regulation of neuroinflammation¹⁷⁷
  • 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
• Modulation of neuronal glutamate release⁷
  • Increase mGLUR5 signaling¹⁷
  • Potentiation of NMDA-mediated effects⁷
  • Release of glutamate from glutamatergic terminals⁷
  • Inhibition of the glutamate-1 transporter (GLT-1) in astrocytes⁷
• Modulation of glial reactivity⁷
• Modulation of the permeability of the blood-brain barrier⁷
• Infiltration of peripheral immune cells⁷
• Ischematic damage⁷
• Influencing neurite branching, neurite length, and axonal growth in PFC neurons³²

3.1.2.2. Behavior influenced by A2A¶

• Regulation of vigilance³³
• ADHD-like behavior³³
• Synaptic plasticity
  • Corticoaccumbens and hippocampus
    • reduced long-term potentiation (LTP, “learning”) due to antagonists¹⁶
  • Hippocampus
    • increased kainate- and BDNF-modulated LTP in the hippocampus by A2A agonists
  • Striatum
• Learning³⁴¹⁶
• Memory³⁴¹⁶
  • Caffeine (as a nonselective adenosine antagonist) as well as selective adenosine A2A antagonists can improve memory performance in rodents and protect against memory impairment
• Cognition¹⁶

A2A overexpression correlates with³⁵

• Fear
• Depression

A2A polymorphisms correlate with:³⁶

• Fear
• Panic disorders

A2A knockout mice (mice lacking A2A receptor) showed:³⁷

• Agressivity strongly increased (males)
• Anxiety increased
• Exploratory behavior reduced
  • Caffeine reduced this further
• Pain sensation reduced
• Blood pressure increased
• Heart rate increased
• Platelet aggregation increased

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 agonist²³
• 5’-N-Ethylcarboxamidoadenosine (NECA) is an A2/A1 agonist²³
• CGS 21680³⁸³²
  • causes a two- to threefold decrease in the affinity of D2 receptors for dopamine receptor agonists ¹²
  • decreased the availability of D2 receptors in the striatum in a study in rats.³⁹
  • reduced effect at very high, saturating doses, probably due to A2A downregulation⁴⁰
• 3,4-Methylenedioxybenzoyl-2-thienylhydrazone (LASSBio-294)⁴¹
  • acted to lower blood pressure and prevent cardiac defects in SHR after myocardial infarction

3.2.2.2. A2A antagonists¶

• Istradefylline (KW 6002)¹²⁴²
  • 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.
  • Approval denied in the EU.⁴⁴⁴⁵
  • The most common adverse events reported were:⁴⁵
    • Dyskinesia
    • Hallucinations
    • Constipation
    • Dizziness
    • Nausea
    • Vomiting
  • Patent expires in 2024⁴³
  • Istradefylline did not decrease D2 receptor availability in the striatum in a study in rats.³⁹
• Preladenant (SCH 420814)⁴⁶⁴²
  • Development discontinued after Phase III not more effective than placebo
• Tozadenant (RO-449351, SYN-115; 4-hydroxy-N-(4-methoxy-7-(4-morpholinyl)benzo[d]thiazol-2-yl)-4-methylpiperidine-l-carboxamide)⁴⁶⁴²
  • 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
• Vipadenant⁴⁶⁴²
• KW-6356 (2nd generation, selective)⁴³
  • is to become a successor to Istradefylline
  • positive results in phase II test
• KW-6002⁴⁷
• ST 1535⁴⁶⁴²
• PBF-509⁴²
• ST4206⁴²
• V81444⁴²
• DMPX (3,7-dimethyl-1-propargylxanthine) is a selective A2 antagonist²³
• MSX-3³⁸
• SCH 58261 (selective)³²
• ZM241385 (4-(2-[7-amino-2-[2-furyl][1,2,4]triazolo-[2,3-a][1,3,5]triazin-5-yl-amino]ethyl)phenol)²⁰²⁶
• SCH58261 (selective)¹²
• SCH-412348¹²
• Cmpd-1²⁶
  • is a dual antagonist of A2AR / NR2B.
  • has 15 times higher affinity to A2AR than to A1R
  • binds NR2B with high affinity (pKi = 8.25)
  • is thus a potential Parkinson’s drug

A2A antagonists were shown to be helpful in:

• Working memory problems⁴⁸⁴⁹⁵⁰
• Memory disorders⁵¹
• Reverse learning⁴⁷
• Motivation ⁵²⁵³
• purposeful behavior⁵⁴
• Task change⁴³
• Fear conditioning⁵⁵
• Improvement of cognitive performance⁵³
  • The effect of Istradefylline on cognition was not assessed in its clinical trials in Parkinson’s disease patients
• Mood (depression) in Parkinson’s disease (here caused by Istradefylline)⁵⁶
• Anhedonia⁵³
• traumatic brain injuries⁵⁷
  • this is also reported from ADHD stimulants
• acute and chronic stress⁵⁸⁵⁹
• Restless Legs Syndrome (RLS)⁷
  • RLS is a common comorbidity of ADHD
• Huntington’s chorea⁴⁹
• Alzheimer⁶⁰
• major depression⁷
• Schizophrenia⁷
• Epilepsy⁷

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

• Downregulation of A1R
• Relative upregulation of A2AR

3.3. A2B receptor¶

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

Occurrence in the brain in⁸

• Astrocytes
• Nerve cells
• Microglia

The A2B receptor

• stimulates adenylyl cyclase via Gi/o proteins⁸
• hardly represented in the brain⁸¹¹
• 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

3.4. A3 receptor¶

Occurs in the brain only in small amounts¹¹ in:⁸
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 proteins⁸
• hardly represented in the brain
• 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

Agonists:

Cl-IBMECA is a selective A3 agonist¹⁶

• increased theta burst-induced LTP and attenuated LTD

Antagonists

MRS-1191 is a selective A3R antagonist¹⁶

• reduced theta burst-induced LTP and attenuated LTD

3.5. Receptor heteromers¶

Adenosine receptors also occur as monomers, heteromers, and omnimers:⁸

• with each other (e.g. A1 / A2A)¹
  • 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

In the striatum³⁰

• 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 pathway¹²
    • striatopallidal: motor control
    • Nucleus accumbens: reward-related behavior
  • in astrocytes¹²
  • in Glia¹²
  • in cholinergic interneurons¹²
  • 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

• 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 agonist⁶²

3.6.2. Antagonists¶

• Xanthine
  • Caffeine (A2A and A1 antagonist)
    • Recommended daily dose max 5.7 mg/kg⁶³
  • Theophylline (A1 and A2 antagonist; only minor A3 antagonist)
  • Paraxanthin (caffeine metabolite)⁶⁴
  • 1-methylxanthine (caffeine and theophylline metabolite)⁶⁴
  • Theobromine (weak antagonist)⁶⁴
• Istradefylline (A2A antagonist; used in Parkinson’s disease)¹ (possibly also used in depression)⁶⁵
• Regadenoson¹
• Doxofylline¹²⁷
• Bamifylline¹

Relative potency of methylxanthines:³

Effect	Caffeine	Theophylline	Theobromine
CNS Stimulation	+++	+++	-
Heart	+	+++	++
Broncho- 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 about caffeine¶

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
  • chronic doses below 50 mg / kg / day:
    • Receptor number unchanged⁸⁰⁸¹
    • 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 adenosine^8485868788

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.

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 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.

3.6.2.1.2.2. Withdrawal¶

Symptoms of withdrawal from chronic high caffeine intake have been described as:⁸⁴

• reduced locomotor activity⁹⁰⁸⁹
  • 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
• reduced operant behavior⁹¹⁹²⁹³
  • Caffeine was more effective than thephylline in this regard than theobromine⁹¹
• reduced gain threshold for electrical brain stimulation⁹²
• relatively longer sleep phases I and II⁹⁴
• 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

3.6.2.2. Theophylline¶

Theophylline is an A1 and A2 antagonist; weaker A3 antagonist. Affinity for human adenosine receptors is (from strong to weak):⁹⁹¹⁰⁰

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

Besides, theophylline causes³

• an inhibition of phosphodiesterases
  • 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

3.6.2.2.1. Theophylline in asthma and COPD¶

• Use in asthma and COPD)¹
• prescription only in D, A, CH
• Theophylline is able to reduce corticosteroid resistance through genetic pathways. This is the pathway by which theophylline is helpful in COPD and asthma.¹⁰³²⁷
  • this apparently already at low levels of 5mg/L⁹⁹
• weak, non-selective inhibitor of PDE²⁷
  • PDE degrade the cyclic nucleotides in the cell
    • leads to increase of 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)¹⁰⁴
  • PDE inhibition stronger in asthma¹⁰⁵
• prevents the bronchoconstrictor effect of adenosine at therapeutic doses¹⁰⁶
• IL10 increasing
  • IL-10 is reduced in asthma and COPD¹⁰⁷
  • unclear whether this is also relavant at therapeutic doses
• Inhibits NF-κB¹⁰⁸
  • prevents translocation of NF-kB into the cell nucleus
  • possible pathway to prevent expression of inflammatory genes in asthma and COPD
• Inhibits phosphoinositol 3-kinases directly but weakly
  • strongest still PI3K (p110)-δ subtype (IC50 75 μM)
    • involved in oxidative stress responses
  • the ability of theophylline to reverse corticosteroid resistance appears to be based on this mechanism¹⁰⁹
    • important for its clinical effect in severe asthma and COPD
• Plasma concentrations above 20 mg/L frequently show side effects²⁷
  • Headache
    • through inhibition of PDE4
  • Nausea and vomiting
    • by inhibition of PDE4 in the vomiting center
  • Stimulation
    • could be the desired effect for ADHD
    • via A1 antagonism
  • Abdominal discomfort
  • Unrest
  • increased gastric acid secretion
    • via A1 antagonism
  • gastroesophageal reflux
  • Diuresis
    • via A1 antagonism
  • increased inflammations
    • via A2A antagonism⁹⁹
• with even higher mirrors
  • Cramps
  • Cardiac arrhythmias
    • through inhibition of PDE3
    • via A1 antagonism
• Deaths after additional intravenous administration of aminophylline, e.g., in the emergency department for severe asthma.¹¹⁰

Asthma treatment²⁷

• Theophylline is recommended as an additional bronchodilator when 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 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.

4. Adenosine and neurotransmitter¶

4.1. Adenosine and dopamine¶

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

In the striatum⁸

• 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), 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

4.2. Adenosine inhibits norepinephrine¶

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

5. Adenosine degradation¶

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:⁷

• ENT1
• ENT2

Adenosine reuptake inhibitors:

• [3H]nitrobenzylthioinosine ([3H]NBMPR)¹²¹
• Cannabinoids inhibit the reuptake of¹²²
  • Adenosine (stronger)
  • 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.

5.2. Adenosine deaminase (ADA)¶

Conversion of adenosine by:⁸

• Adenosine kinase (AK) to AMP (phosphorylation)
  • AK is more affine to adenosine than ADA.
  • predominant intracellular degradation pathway in healthy state
• Adenosine deaminase (ADA) to inosine (deamination)
  • predominant intracellular degradation pathway in pathological state
  • also extracellular

6. Regulation of adenosine¶

Adenosine is increased by:⁷

• Hypoxia (oxygen deficiency)
• Ischemia
• Tissue damage

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.

7. Adenosine and ADHD¶

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.

7.1. Methylphenidate and adenosine¶

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.

7.2. Caffeine and ADHD¶

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

Caffeine improves:

• Attention¹³⁰
• Ability to learn¹³⁰
• Memory^1305916
• Odor discrimination¹³⁰
• Reactions to chronic stress⁵⁹
• cognitive performance¹³¹ in an auditory oddball test¹³²
• Mood¹³¹

Caffeine does not cause any change in:¹³⁰

• Blood pressure
• Body weight

The effect of caffeine is unclear regarding:¹³⁰

• Hyperactivity
  • Increase with naive caffeine input⁸²
  • 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,

7.4. ADHD drug viloxazine increases theophylline¶

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.

More about viloxazine at =&gt Viloxazine for ADHD

7.5. A2A receptor gene and ADHD¶

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

7.6. Adenosine system altered in SHR¶

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

• Caffeine (non-selective A1 and A2A antagonist)
  • Object detection¹³⁶
  • social recognition¹³⁷
  • spatial learning¹³⁸
  • no influence on high blood pressure¹³⁸
• DPCPX (8-cyclopenthyl-1,3-dipropylxanthine, A1 antagonist)
  • Object detection¹³⁶
  • no influence on high blood pressure¹³⁸
• 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 detection¹³⁶
  • social recognition¹³⁷
  • no influence on high blood pressure¹³⁸

Chronic Caffeine Input⁷⁰

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

• WIN55212-2 (cannabinoid receptor agonist) increased impulsive behavior
• acute pretreatment with caffeine reversed this
• chronic caffeine intake increased impulsivity

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

7.9. ADHD symptoms promoted by adenosine¶

7.9.1. Hypermotor¶

striatopallidal: motor control

• mainly in GABAergic medium spiny neurons (MSN) of the indirect pathway¹²¹⁴⁴
• mainly via A2A, hardly any via A1¹²¹⁴⁴

7.9.2. Motivation problems¶

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

• A1⁸
• A2A⁸¹²

primarily in the nucleus accumbens,

• 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.^{146 147} 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.