Dear readers of ADxS.org, please forgive the disruption.

ADxS.org needs about $36850 in 2023. In 2022 we received donations from third parties of about $ 13870. Unfortunately, 99.8% of our readers do not donate. If everyone who reads this request makes a small contribution, our fundraising campaign for 2023 would be over after a few days. This donation request is displayed 18,000 times a week, but only 40 people donate. If you find ADxS.org useful, please take a minute and support ADxS.org with your donation. Thank you!

Since 01.06.2021 ADxS.org is supported by the non-profit ADxS e.V..

$7996 of $36850 - as of 2023-05-01
21%
Header Image
Adenosine

Sitemap

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

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 adenosine8485868788

In one study, subjects received 300 mg of caffeine or placebo daily. Mood and subjective effects differed only within the first 4 days. A high dose of caffeine (300 mg twice daily) was able to reduce the effects of

  • Tension / Anxiety
  • jittery / nervous / shaky
  • active / excited / energetic

only in the placebo group. The caffeine group had developed complete tolerance.

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

Details of the interaction of A2A and D2 receptors

A2A / D2 - heteromers cause antagonistic interactions between A2A and D2 at the adenylyl cyclase level
A2A and D2 receptors can be connected in two opposite ways: at the membrane level and intracellularly8

  • Membrane level
    • A2A activation has a balancing effect on D2 stimulation:40
      • Activation has a balancing effect against D2 stimulation115
        • reduced D2 dopamine affinity
        • increased tonic dopamine level in the nucleus accumbens
        • increased extracellular GABA level
          • in the nucleus accumbens
            • but not by dopamine antagonist
          • in the ipsilateral ventral pallidum
            • as well by
              • Dopamine antagonist
              • co-administration of A2A agonist and D2 antagonist at such low doses that each was ineffective alone
        • reduced reward and seeking behavior with cocaine116
      • functional effects induced by D2 stimulation are attenuated
    • Animal models with excessive A2A expression in the brain show reduced D2 numbers in the striatum.
      • A2A activation reduces behavioral responses to psychostimulants
  • synergistic interaction between A2A and D2 at the adenylyl cyclase level in the striatum, upon overexpression of “Activator of G-protein signaling 3” (AGS3)
    • occurs with upregulation of AGS3, e.g., ethanol use or withdrawal from cocaine, ethanol, morphine
    • AGS3 activity
      • stabilizes / inhibits the GDP-bound form of Gi
      • simultaneously increases the βγ-dependent effect of the Gs/olf protein
        –> sharp increase in cAMP-PKA signaling

A2A receptor agonists mediate neuroprotection by increasing NF-κB8

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
  • Memory1305916
  • 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

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.


  1. Borea, Gessi, Merighi, Vincenzi, Varani (2018): Pharmacology of Adenosine Receptors: The State of the Art. Physiol Rev. 2018 Jul 1;98(3):1591-1625. doi: 10.1152/physrev.00049.2017. PMID: 29848236. REVIEW

  2. Quiroz, Orrú, Rea, Ciudad-Roberts, Yepes, Britt, Ferré (2016): Local Control of Extracellular Dopamine Levels in the Medial Nucleus Accumbens by a Glutamatergic Projection from the Infralimbic Cortex. J Neurosci. 2016 Jan 20;36(3):851-9. doi: 10.1523/JNEUROSCI.2850-15.2016.

  3. Hänsel, Sticher (2010): Pharmakognosie - Phytopharmazie, 9. Auflage, S. 1349

  4. Wenzel (2012): Koffeinhaltige Lebensmittel; Eine Zusammenstellung zur Geschichte, Verwendung und Wirkung von koffeinhaltigen Lebensmitteln; Hochschule Weihenstephan

  5. Borbély, Daan, Wirz-Justice, Deboer (2016): The two-process model of sleep regulation: a reappraisal. J Sleep Res. 2016 Apr;25(2):131-43. doi: 10.1111/jsr.12371. PMID: 26762182.

  6. van Diepen, Lucassen, Yasenkov, Groenen, Ijzerman, Meijer, Deboer (2014): Caffeine increases light responsiveness of the mouse circadian pacemaker. Eur J Neurosci. 2014 Nov;40(10):3504-11. doi: 10.1111/ejn.12715. PMID: 25196050.

  7. Borea, Gessi, Merighi, Vincenzi, Varani (2017): Pathological overproduction: the bad side of adenosine. Br J Pharmacol. 2017 Jul;174(13):1945-1960. doi: 10.1111/bph.13763. PMID: 28252203; PMCID: PMC6398520. REVIEW

  8. Ballesteros-Yáñez, Castillo, Merighi, Gessi (2018): The Role of Adenosine Receptors in Psychostimulant Addiction. Front Pharmacol. 2018 Jan 10;8:985. doi: 10.3389/fphar.2017.00985. PMID: 29375384; PMCID: PMC5767594. REVIEW

  9. Chen, Lee, Chern (2014): Adenosine receptor neurobiology: overview. Int Rev Neurobiol. 2014;119:1-49. doi: 10.1016/B978-0-12-801022-8.00001-5. PMID: 25175959. REVIEW

  10. Hu, Adebiyi, Luo, Sun, Le, Zhang, Wu, Zhao, Karmouty-Quintana, Liu, Huang, Wen, Zaika, Mamenko, Pochynyuk, Kellems, Eltzschig, Blackburn, Walters, Huang, Hu, Xia (2016): Sustained Elevated Adenosine via ADORA2B Promotes Chronic Pain through Neuro-immune Interaction. Cell Rep. 2016 Jun 28;16(1):106-119. doi: 10.1016/j.celrep.2016.05.080. PMID: 27320922; PMCID: PMC5662192.

  11. Ferré, Agnati, Ciruela, Lluis, Woods, Fuxe, Franco (2007): Neurotransmitter receptor heteromers and their integrative role in ‘local modules’: the striatal spine module. Brain Res Rev. 2007 Aug;55(1):55-67. doi: 10.1016/j.brainresrev.2007.01.007. PMID: 17408563; PMCID: PMC2039920.

  12. Prasad, de Vries, Elsinga, Dierckx, van Waarde (2021): Allosteric Interactions between Adenosine A2A and Dopamine D2 Receptors in Heteromeric Complexes: Biochemical and Pharmacological Characteristics, and Opportunities for PET Imaging. Int J Mol Sci. 2021 Feb 9;22(4):1719. doi: 10.3390/ijms22041719. PMID: 33572077; PMCID: PMC7915359. REVIEW

  13. Kennedy (2021): ATP as a cotransmitter in sympathetic and parasympathetic nerves - another Burnstock legacy. Auton Neurosci. 2021 Nov;235:102860. doi: 10.1016/j.autneu.2021.102860. PMID: 34340045.

  14. Chen, Eltzschig, Fredholm (2013): Adenosine receptors as drug targets–what are the challenges? Nat Rev Drug Discov. 2013 Apr;12(4):265-86. doi: 10.1038/nrd3955. PMID: 23535933; PMCID: PMC3930074.

  15. Borycz, Pereira, Melani, Rodrigues, Köfalvi, Panlilio, Pedata, Goldberg, Cunha, Ferré (2007): Differential glutamate-dependent and glutamate-independent adenosine A1 receptor-mediated modulation of dopamine release in different striatal compartments. J Neurochem. 2007 Apr;101(2):355-63. doi: 10.1111/j.1471-4159.2006.04386.x. PMID: 17254024.

  16. Chen (2014): Adenosine receptor control of cognition in normal and disease. Int Rev Neurobiol. 2014;119:257-307. doi: 10.1016/B978-0-12-801022-8.00012-X. PMID: 25175970. REVIEW

  17. Pasquini, Contri, Merighi, Gessi, Borea, Varani, Vincenzi (2022): Adenosine Receptors in Neuropsychiatric Disorders: Fine Regulators of Neurotransmission and Potential Therapeutic Targets. Int J Mol Sci. 2022 Jan 22;23(3):1219. doi: 10.3390/ijms23031219. PMID: 35163142; PMCID: PMC8835915. REVIEW

  18. Kashfi, Ghaedi, Baharvand, Nasr-Esfahani, Javan (2017): A1 Adenosine Receptor Activation Modulates Central Nervous System Development and Repair. Mol Neurobiol. 2017 Dec;54(10):8128-8139. doi: 10.1007/s12035-016-0292-6. PMID: 27889899. REVIEW

  19. Carrettiero, Almeida, Fior-Chadi (2008): Adenosine modulates alpha2-adrenergic receptors within specific subnuclei of the nucleus tractus solitarius in normotensive and spontaneously hypertensive rats. Hypertens Res. 2008 Dec;31(12):2177-86. doi: 10.1291/hypres.31.2177. PMID: 19139607.

  20. Prediger, Batista, Takahashi (2004): Adenosine A1 receptors modulate the anxiolytic-like effect of ethanol in the elevated plus-maze in mice. Eur J Pharmacol. 2004 Sep 19;499(1-2):147-54. doi: 10.1016/j.ejphar.2004.07.106. PMID: 15363961.

  21. Prediger, da Silva, Batista, Bittencourt, Takahashi (2006): Activation of adenosine A1 receptors reduces anxiety-like behavior during acute ethanol withdrawal (hangover) in mice. Neuropsychopharmacology. 2006 Oct;31(10):2210-20. doi: 10.1038/sj.npp.1301001. PMID: 16407902.

  22. Massie, O’Connor, Metra, Ponikowski, Teerlink, Cotter, Weatherley, Cleland, Givertz, Voors, DeLucca, Mansoor, Salerno, Bloomfield, Dittrich (2010): PROTECT Investigators and Committees. Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure. N Engl J Med. 2010 Oct 7;363(15):1419-28. doi: 10.1056/NEJMoa0912613. PMID: 20925544.

  23. Poleszak, Malec (2002): Cocaine-induced hyperactivity is more influenced by adenosine receptor agonists than amphetamine-induced hyperactivity. Pol J Pharmacol. 2002 Jul-Aug;54(4):359-66. PMID: 12523489.

  24. Bruns, Katims, Annau, Snyder, Daly (1983): Adenosine receptor interactions and anxiolytics. Neuropharmacology. 1983 Dec;22(12B):1523-9. doi: 10.1016/0028-3908(83)90121-1. PMID: 6199685. REVIEW

  25. Wenzel (2012): Koffein-haltige Lebensmittel; Eine Zusammenstellung zur Geschichte, Verwendung und Wirkung von coffeinhaltigen Lebensmitteln; Hochschule Weihenstephan

  26. Sun, Bachhawat, Chu, Wood, Ceska, Sands, Mercier, Lebon, Kobilka, Kobilka (2017): Crystal structure of the adenosine A2A receptor bound to an antagonist reveals a potential allosteric pocket. Proc Natl Acad Sci U S A. 2017 Feb 21;114(8):2066-2071. doi: 10.1073/pnas.1621423114. PMID: 28167788; PMCID: PMC5338372.

  27. Barnes (2010): Theophylline. Pharmaceuticals (Basel). 2010 Mar 18;3(3):725-747. doi: 10.3390/ph3030725. PMID: 27713276; PMCID: PMC4033977. REVIEW

  28. Quiroz C, Gulyani S, Ruiqian W, Bonaventura J, Cutler R, Pearson V, Allen RP, Earley CJ, Mattson MP, Ferré S (2016): Adenosine receptors as markers of brain iron deficiency: Implications for Restless Legs Syndrome. Neuropharmacology. 2016 Dec;111:160-168. doi: 10.1016/j.neuropharm.2016.09.002. PMID: 27600688; PMCID: PMC5056844.

  29. Rodrigues MS, Ferreira SG, Quiroz C, Earley CJ, García-Borreguero D, Cunha RA, Ciruela F, Köfalvi A, Ferré S (2022): Brain Iron Deficiency Changes the Stoichiometry of Adenosine Receptor Subtypes in Cortico-Striatal Terminals: Implications for Restless Legs Syndrome. Molecules. 2022 Feb 23;27(5):1489. doi: 10.3390/molecules27051489. PMID: 35268590; PMCID: PMC8911604.

  30. Wydra, Gawliński, Gawlińska, Frankowska, Borroto-Escuela, Fuxe, Filip (2020): Adenosine A2AReceptors in Substance Use Disorders: A Focus on Cocaine. Cells. 2020 Jun 1;9(6):1372. doi: 10.3390/cells9061372. PMID: 32492952; PMCID: PMC7348840.

  31. Ravani, Vincenzi, Bortoluzzi, Padovan, Pasquini, Gessi, Merighi, Borea, Govoni, Varani (2017): Role and Function of A2A and A₃ Adenosine Receptors in Patients with Ankylosing Spondylitis, Psoriatic Arthritis and Rheumatoid Arthritis. Int J Mol Sci. 2017 Mar 24;18(4):697. doi: 10.3390/ijms18040697. PMID: 28338619; PMCID: PMC5412283.

  32. Alves, Almeida, Marques, Faé, Machado, Oliveira, Portela, Porciúncula (2020): Caffeine and adenosine A2A receptors rescue neuronal development in vitro of frontal cortical neurons in a rat model of attention deficit and hyperactivity disorder. Neuropharmacology. 2020 Apr;166:107782. doi: 10.1016/j.neuropharm.2019.107782. PMID: 31756336.

  33. Molero, Gumpert, Serlachius, Lichtenstein, Walum, Johansson, Anckarsäter, Westberg, Eriksson, Halldner (2013): A study of the possible association between adenosine A2A receptor gene polymorphisms and attention-deficit hyperactivity disorder traits. Genes Brain Behav. 2013 Apr;12(3):305-10. doi: 10.1111/gbb.12015. PMID: 23332182.

  34. Takahashi, Pamplona, Prediger (2008): Adenosine receptor antagonists for cognitive dysfunction: a review of animal studies. Front Biosci. 2008 Jan 1;13:2614-32. doi: 10.2741/2870. PMID: 17981738. REVIEW

  35. Coelho, Alves, Canas, Valadas, Shmidt, Batalha, Ferreira, Ribeiro, Bader, Cunha, do Couto, Lopes (2014): Overexpression of Adenosine A2A Receptors in Rats: Effects on Depression, Locomotion, and Anxiety. Front Psychiatry. 2014 Jun 13;5:67. doi: 10.3389/fpsyt.2014.00067. PMID: 24982640; PMCID: PMC4055866.

  36. Hohoff, Mullings, Heatherley, Freitag, Neumann, Domschke, Krakowitzky, Rothermundt, Keck, Erhardt, Unschuld, Jacob, Fritze, Bandelow, Maier, Holsboer, Rogers, Deckert (2010): Adenosine A(2A) receptor gene: evidence for association of risk variants with panic disorder and anxious personality. J Psychiatr Res. 2010 Oct;44(14):930-7. doi: 10.1016/j.jpsychires.2010.02.006. PMID: 20334879.

  37. Ledent, Vaugeois, Schiffmann, Pedrazzini, El Yacoubi, Vanderhaeghen, Costentin, Heath, Vassart, Parmentier (1997): Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor. Nature. 1997 Aug 14;388(6643):674-8. doi: 10.1038/41771. PMID: 9262401.

  38. Filip, Frankowska, Zaniewska, Przegaliński, Muller, Agnati, Franco, Roberts, Fuxe (2006): Involvement of adenosine A2A and dopamine receptors in the locomotor and sensitizing effects of cocaine. Brain Res. 2006 Mar 10;1077(1):67-80. doi: 10.1016/j.brainres.2006.01.038. PMID: 16516871.

  39. Prasad, de Vries, Sijbesma, Garcia-Varela, Vazquez-Matias, Moraga-Amaro, Willemsen, Dierckx, van Waarde (2022): Impact of an Adenosine A2A Receptor Agonist and Antagonist on Binding of the Dopamine D2 Receptor Ligand [11C]raclopride in the Rodent Striatum. Mol Pharm. 2022 Jul 18. doi: 10.1021/acs.molpharmaceut.2c00450. PMID: 35849844.

  40. Ferre, von Euler, Johansson, Fredholm, Fuxe (1991): Stimulation of high-affinity adenosine A2 receptors decreases the affinity of dopamine D2 receptors in rat striatal membranes. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7238-41. doi: 10.1073/pnas.88.16.7238. PMID: 1678519; PMCID: PMC52269.

  41. da Silva, Gabriel-Costa, Sudo, Wang, Groban, Ferraz, Nascimento, Fraga, Barreiro, Zapata-Sudo (2017): Adenosine A2A receptor agonist prevents cardiac remodeling and dysfunction in spontaneously hypertensive male rats after myocardial infarction. Drug design, development and therapy, 11, 553–562. https://doi.org/10.2147/DDDT.S113289

  42. Pinna (2014): Adenosine A2A receptor antagonists in Parkinson’s disease: progress in clinical trials from the newly approved istradefylline to drugs in early development and those already discontinued. CNS Drugs. 2014 May;28(5):455-74. doi: 10.1007/s40263-014-0161-7. PMID: 24687255.

  43. Chen, Cunha (2020): The belated US FDA approval of the adenosine A2A receptor antagonist istradefylline for treatment of Parkinson’s disease. Purinergic Signal. 2020 Jun;16(2):167-174. doi: 10.1007/s11302-020-09694-2. PMID: 32236790; PMCID: PMC7367999.

  44. EMA: Nouryant

  45. EMA (2021): Assessment report Nouryant

  46. Jenner (2014): An overview of adenosine A2A receptor antagonists in Parkinson’s disease. Int Rev Neurobiol. 2014;119:71-86. doi: 10.1016/B978-0-12-801022-8.00003-9. PMID: 25175961.

  47. O’Neill, Brown (2007): The effect of striatal dopamine depletion and the adenosine A2A antagonist KW-6002 on reversal learning in rats. Neurobiol Learn Mem. 2007 Jul;88(1):75-81. doi: 10.1016/j.nlm.2007.03.003. PMID: 17467309.

  48. Ko, Camus, Li, Yang, McGuire, Pioli, Bezard (2016): An evaluation of istradefylline treatment on Parkinsonian motor and cognitive deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaque models. Neuropharmacology. 2016 Nov;110(Pt A):48-58. doi: 10.1016/j.neuropharm.2016.07.012. PMID: 27424102.

  49. Li, Silva, Real, Wang, Rial, Li, Payen, Zhou, Muller, Tomé, Cunha, Chen (2015): Inactivation of adenosine A2A receptors reverses working memory deficits at early stages of Huntington’s disease models. Neurobiol Dis. 2015 Jul;79:70-80. doi: 10.1016/j.nbd.2015.03.030. PMID: 25892655.

  50. Zhou, Zhu, Shu, Du, Song, Wang, Zheng, Cai, Chen, He (2009): Preferential enhancement of working memory in mice lacking adenosine A(2A) receptors. Brain Res. 2009 Dec 15;1303:74-83. doi: 10.1016/j.brainres.2009.09.082. PMID: 19785999.

  51. Canas, Porciúncula, Cunha, Silva, Machado, Oliveira, Oliveira, Cunha (2009): Adenosine A2A receptor blockade prevents synaptotoxicity and memory dysfunction caused by beta-amyloid peptides via p38 mitogen-activated protein kinase pathway. J Neurosci. 2009 Nov 25;29(47):14741-51. doi: 10.1523/JNEUROSCI.3728-09.2009. PMID: 19940169; PMCID: PMC6665997.

  52. Mingote, Font, Farrar, Vontell, Worden, Stopper, Port, Sink, Bunce, Chrobak, Salamone (2008): Nucleus accumbens adenosine A2A receptors regulate exertion of effort by acting on the ventral striatopallidal pathway. J Neurosci. 2008 Sep 3;28(36):9037-46. doi: 10.1523/JNEUROSCI.1525-08.2008. PMID: 18768698; PMCID: PMC2806668.

  53. Cho, Choi, Kim, Kim (2018): Association of coffee consumption and non-motor symptoms in drug-naïve, early-stage Parkinson’s disease. Parkinsonism Relat Disord. 2018 May;50:42-47. doi: 10.1016/j.parkreldis.2018.02.016. PMID: 29449185.

  54. Li, He, Chen, Pu, Chen, Li, Li, Li, Huang, Li, Chen (2016): Optogenetic Activation of Adenosine A2A Receptor Signaling in the Dorsomedial Striatopallidal Neurons Suppresses Goal-Directed Behavior. Neuropsychopharmacology. 2016 Mar;41(4):1003-13. doi: 10.1038/npp.2015.227. PMID: 26216520; PMCID: PMC4748425.

  55. Wei, Augusto, Gomes, Singer, Wang, Boison, Cunha, Yee, Chen (2013): Regulation of fear responses by striatal and extrastriatal adenosine A2A receptors in forebrain. Biol Psychiatry. 2014 Jun 1;75(11):855-63. doi: 10.1016/j.biopsych.2013.05.003. PMID: 23820821; PMCID: PMC4058554.

  56. Nagayama, Kano, Murakami, Ono, Hamada, Toda, Sengoku, Shimo, Hattori (2019): Effect of istradefylline on mood disorders in Parkinson’s disease. J Neurol Sci. 2019 Jan 15;396:78-83. doi: 10.1016/j.jns.2018.11.005. PMID: 30423541.

  57. Ning, Yang, Chen, Xiong, Zhang, Li, Zhao, Chen, Liu, Peng, Wang, Chen, Zhou (2013): Adenosine A2A receptor deficiency alleviates blast-induced cognitive dysfunction. J Cereb Blood Flow Metab. 2013 Nov;33(11):1789-98. doi: 10.1038/jcbfm.2013.127. PMID: 23921902; PMCID: PMC3824177.

  58. Batalha, Pego, Fontinha, Costenla, Valadas, Baqi, Radjainia, Müller, Sebastião, Lopes (2013): Adenosine A(2A) receptor blockade reverts hippocampal stress-induced deficits and restores corticosterone circadian oscillation. Mol Psychiatry. 2013 Mar;18(3):320-31. doi: 10.1038/mp.2012.8. PMID: 22371048.

  59. Kaster, Machado, Silva, Nunes, Ardais, Santana, Baqi, Müller, Rodrigues, Porciúncula, Chen, Tomé, Agostinho, Canas, Cunha (2015): Caffeine acts through neuronal adenosine A2A receptors to prevent mood and memory dysfunction triggered by chronic stress. Proc Natl Acad Sci U S A. 2015 Jun 23;112(25):7833-8. doi: 10.1073/pnas.1423088112. PMID: 26056314; PMCID: PMC4485143.

  60. Dall’Igna, Fett, Gomes, Souza, Cunha, Lara (2006): Caffeine and adenosine A(2a) receptor antagonists prevent beta-amyloid (25-35)-induced cognitive deficits in mice. Exp Neurol. 2007 Jan;203(1):241-5. doi: 10.1016/j.expneurol.2006.08.008. PMID: 17007839.

  61. Bonaventura, Navarro, Casadó-Anguera, Azdad, Rea, Moreno, Brugarolas, Mallol, Canela, Lluís, Cortés, Volkow, Schiffmann, Ferré, Casadó (2015): Allosteric interactions between agonists and antagonists within the adenosine A2A receptor-dopamine D2 receptor heterotetramer. Proc Natl Acad Sci U S A. 2015 Jul 7;112(27):E3609-18. doi: 10.1073/pnas.1507704112. PMID: 26100888; PMCID: PMC4500251.

  62. Fahim, Mustafa (2001): Evidence for the presence of A(1) adenosine receptors in the aorta of spontaneously hypertensive rats. Br J Pharmacol. 2001 Dec;134(8):1760-6. doi: 10.1038/sj.bjp.0704433. PMID: 11739253; PMCID: PMC1572910.

  63. Bundesredierung: Koffein: Die Dosis macht’s

  64. Müller, Jacobson (2011): Xanthines as adenosine receptor antagonists. Handb Exp Pharmacol. 2011;(200):151-99. doi: 10.1007/978-3-642-13443-2_6. PMID: 20859796; PMCID: PMC3882893.

  65. Yamada, Kobayashi, Mori, Jenner, Kanda (2013): Antidepressant-like activity of the adenosine A(2A) receptor antagonist, istradefylline (KW-6002), in the forced swim test and the tail suspension test in rodents. Pharmacol Biochem Behav. 2013 Dec;114-115:23-30. doi: 10.1016/j.pbb.2013.10.022. PMID: 24201052.

  66. Cappelletti, Piacentino, Sani, Aromatario (2015): Caffeine: cognitive and physical performance enhancer or psychoactive drug? Curr Neuropharmacol. 2015 Jan;13(1):71-88. doi: 10.2174/1570159X13666141210215655. Erratum in: Curr Neuropharmacol. 2015;13(4):554. Daria, Piacentino [corrected to Piacentino, Daria]. PMID: 26074744; PMCID: PMC4462044. REVIEW

  67. Rogers, Smith (2011): Caffeine, mood and cognition. In: Benton (Hrsg.): Lifetime Nutritional Influences on Cognition, Behaviour and Psychiatric Illness. Woodhead Publishing Ltd; 2011. Seiten 251–271.

  68. Matissek (2016): Alkaloidhaltige Lebensmittel. In: Matissek, Baltes: Lebensmittelchemie, 8. Aufl. S. 557

  69. Matissek (2016): Alkaloidhaltige Lebensmittel. In: Matissek, Baltes: Lebensmittelchemie, 8. Aufl. S. 564

  70. Pandolfo, Machado, Köfalvi, Takahashi, Cunha (2013): Caffeine regulates frontocorticostriatal dopamine transporter density and improves attention and cognitive deficits in an animal model of attention deficit hyperactivity disorder. Eur Neuropsychopharmacol. 2013 Apr;23(4):317-28. doi: 10.1016/j.euroneuro.2012.04.011. PMID: 22561003.

  71. Kubrusly, da Rosa Valli, Ferreira, de Moura, Borges-Martins, Martins, Ferreira, Sathler, de Melo Reis, Ferreira, Manhães, Dos Santos Pereira (2021): Caffeine Improves GABA Transport in the Striatum of Spontaneously Hypertensive Rats (SHR). Neurotox Res. 2021 Dec;39(6):1946-1958. doi: 10.1007/s12640-021-00423-0.PMID: 34637050.

  72. Rogers, Richardson, Dernoncourt (1995): Caffeine use: is there a net benefit for mood and psychomotor performance? Neuropsychobiology. 1995;31(4):195-9. doi: 10.1159/000119192. PMID: 7659200.

  73. Gilliland, Andress (2006): Ad lib caffeine consumption, symptoms of caffeinism, and academic performance. Am J Psychiatry. 1981 Apr;138(4):512-4. doi: 10.1176/ajp.138.4.512. PMID: 7212112.

  74. Fredholm, Bättig, Holmén, Nehlig, Zvartau (1999): Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev. 1999 Mar;51(1):83-133. PMID: 10049999.

  75. Robertson, Wade, Workman, Woosley, Oates (1981): Tolerance to the humoral and hemodynamic effects of caffeine in man. J Clin Invest. 1981 Apr;67(4):1111-7. doi: 10.1172/jci110124. PMID: 7009653; PMCID: PMC370671.

  76. Holtzman, Finn (1988): Tolerance to behavioral effects of caffeine in rats. Pharmacol Biochem Behav. 1988 Feb;29(2):411-8. doi: 10.1016/0091-3057(88)90179-7. PMID: 3362935.

  77. [Fredholm (1982): Adenosine actions and adenosine receptors after 1 week treatment with caffeine. Acta Physiol Scand. 1982 Jun;115(2):283-6. doi: 10.1111/j.1748-1716.1982.tb07078.x. PMID: 6291335.)](https://pubmed.ncbi.nlm.nih.gov/6291335/

  78. Johansson, Ahlberg, van der Ploeg, Brené, Lindefors, Persson, Fredholm (1993): Effect of long term caffeine treatment on A1 and A2 adenosine receptor binding and on mRNA levels in rat brain. Naunyn Schmiedebergs Arch Pharmacol. 1993 Apr;347(4):407-14. doi: 10.1007/BF00165391. PMID: 8510768.

  79. Johansson, Georgiev, Lindström, Fredholm (1997): A1 and A2A adenosine receptors and A1 mRNA in mouse brain: effect of long-term caffeine treatment. Brain Res. 1997 Jul 11;762(1-2):153-64. doi: 10.1016/s0006-8993(97)00378-8. PMID: 9262169.

  80. [Bona, Adén, Fredholm, Hagberg (1995): The effect of long term caffeine treatment on hypoxic-ischemic brain damage in the neonate. Pediatr Res. 1995 Sep;38(3):312-8. doi: 10.1203/00006450-199509000-00007. PMID: 7494652.)](https://pubmed.ncbi.nlm.nih.gov/7494652/

  81. Johansson, Georgiev, Kuosmanen, Fredholm (1996): Long-term treatment with some methylxanthines decreases the susceptibility to bicuculline- and pentylenetetrazol-induced seizures in mice. Relationship to c-fos expression and receptor binding. Eur J Neurosci. 1996 Dec;8(12):2447-58. doi: 10.1111/j.1460-9568.1996.tb01539.x. PMID: 8996794.

  82. Holtzman, Mante, Minneman (1991): Role of adenosine receptors in caffeine tolerance. J Pharmacol Exp Ther. 1991 Jan;256(1):62-8. PMID: 1846425.

  83. Chern, Lai, Fong, Liang (1993): Multiple mechanisms for desensitization of A2a adenosine receptor-mediated cAMP elevation in rat pheochromocytoma PC12 cells. Mol Pharmacol. 1993 Nov;44(5):950-8. PMID: 8246918.

  84. Griffiths, Mumford (1995): Caffeine Reinforcement, Discrimination, Tolerance and Physical Dependence in Laboratory Animals and Humans. In: Schuster, Kihar (Hrsg.): Pharmacological Aspects of Drug Dependence. Toward an Integrated Neurobehavioral Approach. Springer. S. 315 - 369

  85. Biaggioni, Paul, Puckett, Arzubiaga (1991): Caffeine and theophylline as adenosine receptor antagonists in humans. J Pharmacol Exp Ther. 1991 Aug;258(2):588-93. PMID: 1865359.

  86. Ahlijanian, Takemori (1986): Cross-tolerance studies between caffeine and (-)-N6-(phenylisopropyl)-adenosine (PIA) in mice. Life Sci. 1986 Feb 17;38(7):577-88. doi: 10.1016/0024-3205(86)90051-2. PMID: 3003486.

  87. Green, Stiles (1986): Chronic caffeine ingestion sensitizes the A1 adenosine receptor-adenylate cyclase system in rat cerebral cortex. J Clin Invest. 1986 Jan;77(1):222-7. doi: 10.1172/JCI112280. PMID: 3003150; PMCID: PMC423330.

  88. von Borstel, Wurtman, Conlay (1983): Chronic caffeine consumption potentiates the hypotensive action of circulating adenosine. Life Sci. 1983 Mar 7;32(10):1151-8. doi: 10.1016/0024-3205(83)90121-2. PMID: 6827895.)

  89. Finn, Holtzman (1986): Tolerance to caffeine-induced stimulation of locomotor activity in rats. J Pharmacol Exp Ther. 1986 Aug;238(2):542-6. PMID: 3735131.

  90. Holtzman (1983): Complete, reversible, drug-specific tolerance to stimulation of locomotor activity by caffeine. Life Sci. 1983 Aug 22;33(8):779-87. doi: 10.1016/0024-3205(83)90784-1. PMID: 6888193.

  91. Carney (1982): Effects of caffeine, theophylline and theobromine on scheduled controlled responding in rats. Br J Pharmacol. 1982 Mar;75(3):451-4. doi: 10.1111/j.1476-5381.1982.tb09161.x. PMID: 7066599; PMCID: PMC2071561.

  92. Mumford, Neill, Holtzman (1988): Caffeine elevates reinforcement threshold for electrical brain stimulation: tolerance and withdrawal changes. Brain Res. 1988 Aug 30;459(1):163-7. doi: 10.1016/0006-8993(88)90298-3. PMID: 3167574.

  93. Carroll, Hagen, Asencio, Brauer (1988): Behavioral dependence on caffeine and phencyclidine in rhesus monkeys: interactive effects. Pharmacol Biochem Behav. 1988 Dec;31(4):927-32. doi: 10.1016/0091-3057(88)90406-6. PMID: 3252284.

  94. Sinton, Petitjean (1989): The influence of chronic caffeine administration on sleep parameters in the cat. Pharmacol Biochem Behav. 1989 Feb;32(2):459-62. doi: 10.1016/0091-3057(89)90179-2. PMID: 2727004.

  95. Vitiello, Woods (1977): Evidence for withdrawal from caffeine by rats. Pharmacol Biochem Behav. 1977 May;6(5):553-5. doi: 10.1016/0091-3057(77)90116-2. PMID: 561407.

  96. Brunstrom (2004): Does dietary learning occur outside awareness? Conscious Cogn. 2004 Sep;13(3):453-70. doi: 10.1016/j.concog.2004.05.004. PMID: 15336241.

  97. Couturier, Laman, van Duijn, van Duijn (1997): Influence of caffeine and caffeine withdrawal on headache and cerebral blood flow velocities. Cephalalgia. 1997 May;17(3):188-90. doi: 10.1046/j.1468-2982.1997.1703188.x. PMID: 9170342.

  98. Nabbi-Schroeter, Elmenhorst, Oskamp, Laskowski, Bauer, Kroll (2018): Effects of Long-Term Caffeine Consumption on the Adenosine A1 Receptor in the Rat Brain: an In Vivo PET Study with [18F]CPFPX. Mol Imaging Biol. 2018 Apr;20(2):284-291. doi: 10.1007/s11307-017-1116-4. PMID: 28895043.

  99. Matera, Page, Cazzola (2017): Doxofylline is not just another theophylline! Int J Chron Obstruct Pulmon Dis. 2017 Dec 5;12:3487-3493. doi: 10.2147/COPD.S150887. PMID: 29255355; PMCID: PMC5723117.

  100. Spina, Page (2017): Xanthines and Phosphodiesterase Inhibitors. Handb Exp Pharmacol. 2017;237:63-91. doi: 10.1007/164_2016_71. PMID: 27844172.

  101. Jalal, Collin (1976): ESTIMATION OF CAFFEINE, THEOPHYLLINE AND THEOBROMINE IN PLANT MATERIAL

  102. Hänsel, Sticher (2010): Pharmakognosie - Phytopharmazie, 9. Auflage, S. 1359

  103. Barnes PJ. Theophylline. Am J Respir Crit Care Med. 2013 Oct 15;188(8):901-6. doi: 10.1164/rccm.201302-0388PP. PMID: 23672674.

  104. Polson, Krzanowski, Goldman, Szentivanyi (1978): Inhibition of human pulmonary phosphodiesterase activity by therapeutic levels of theophylline. Clin Exp Pharmacol Physiol. 1978 Sep-Oct;5(5):535-9. doi: 10.1111/j.1440-1681.1978.tb00707.x. PMID: 215363.

  105. Estenne, Yernault, De Troyer (1980): Effects of parenteral aminophylline on lung mechanics in normal human. Am Rev Respir Dis. 1980 Jun;121(6):967-71. doi: 10.1164/arrd.1980.121.6.967. PMID: 7416595.

  106. Cushley, Tattersfield, Holgate (1984): Adenosine-induced bronchoconstriction in asthma. Antagonism by inhaled theophylline. Am Rev Respir Dis. 1984 Mar;129(3):380-4. doi: 10.1164/arrd.1984.129.3.380. PMID: 6703496.

  107. Takanashi, Hasegawa, Kanehira, Yamamoto, Fujimoto, Satoh, Okamura (1999): Interleukin-10 level in sputum is reduced in bronchial asthma, COPD and in smokers. Eur Respir J. 1999 Aug;14(2):309-14. doi: 10.1034/j.1399-3003.1999.14b12.x. PMID: 10515406.

  108. Tomita, Chikumi, Tokuyasu, Yajima, Hitsuda, Matsumoto, Sasaki (1999): Functional assay of NF-kappaB translocation into nuclei by laser scanning cytometry: inhibitory effect by dexamethasone or theophylline. Naunyn Schmiedebergs Arch Pharmacol. 1999 Apr;359(4):249-55. doi: 10.1007/pl00005349. PMID: 10344522.

  109. To, Ito, Kizawa, Failla, Ito, Kusama, Elliott, Hogg, Adcock, Barnes (2010): Targeting phosphoinositide-3-kinase-delta with theophylline reverses corticosteroid insensitivity in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010 Oct 1;182(7):897-904. doi: 10.1164/rccm.200906-0937OC. PMID: 20224070; PMCID: PMC2970861.

  110. Eason, Markowe (1989): Aminophylline toxicity–how many hospital asthma deaths does it cause? Respir Med. 1989 May;83(3):219-26. doi: 10.1016/s0954-6111(89)80035-6. PMID: 2595040.

  111. Mohammadi, Kashani, Akhondzadeh, Izadian, Ohadinia (2004): Efficacy of theophylline compared to methylphenidate for the treatment of attention-deficit hyperactivity disorder in children and adolescents: a pilot double-blind randomized trial. J Clin Pharm Ther. 2004 Apr;29(2):139-44. doi: 10.1111/j.1365-2710.2004.00545.x. PMID: 15068402. n = 32

  112. Stein, Lerner (1993): Behavioral and cognitive effect of theophylline: a dose-response study. Ann Allergy. 1993 Feb;70(2):135-40. PMID: 8430921.

  113. Creer, Gustafson (1989): Psychological problems associated with drug therapy in childhood asthma. J Pediatr. 1989 Nov;115(5 Pt 2):850-5. doi: 10.1016/s0022-3476(89)80122-2. PMID: 2681640.

  114. Kennaway (2015): Potential safety issues in the use of the hormone melatonin in paediatrics. J Paediatr Child Health. 2015 Jun;51(6):584-9. doi: 10.1111/jpc.12840. PMID: 25643981. REVIEW

  115. [Ferre, von Euler, Johansson, Fredholm, Fuxe (1Ferré, O’Connor, Snaprud, Ungerstedt, Fuxe (1994): Antagonistic interaction between adenosine A2A receptors and dopamine D2 receptors in the ventral striopallidal system. Implications for the treatment of schizophrenia. Neuroscience. 1994 Dec;63(3):765-73. doi: 10.1016/0306-4522(94)90521-5. PMID: 7898676.

  116. Pintsuk, Borroto-Escuela, Pomierny, Wydra, Zaniewska, Filip, Fuxe (2016): Cocaine self-administration differentially affects allosteric A2A-D2 receptor-receptor interactions in the striatum. Relevance for cocaine use disorder. Pharmacol Biochem Behav. 2016 May;144:85-91. doi: 10.1016/j.pbb.2016.03.004. PMID: 26987369.

  117. Nehlig, Daval, Debry (1992): Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects. Brain Res Brain Res Rev. 1992 May-Aug;17(2):139-70. doi: 10.1016/0165-0173(92)90012-b. PMID: 1356551.

  118. Ioannidis, Chamberlain, Müller (2014): Ostracising caffeine from the pharmacological arsenal for attention-deficit hyperactivity disorder – was this a correct decision? A literature review. Journal of Psychopharmacology, 28(9), 830–836. doi:10.1177/0269881114541014. REVIEW

  119. Ferré (2008): An update on the mechanisms of the psychostimulant effects of caffeine. J Neurochem. 2008 May;105(4):1067-79. doi: 10.1111/j.1471-4159.2007.05196.x. PMID: 18088379.

  120. Barraco, Helfman, Anderson (1996): Augmented release of serotonin by adenosine A2a receptor activation and desensitization by CGS 21680 in the rat nucleus tractus solitarius. Brain Res. 1996 Sep 16;733(2):155-61. doi: 10.1016/0006-8993(96)00279-x. PMID: 8891297.

  121. Castillo-Meléndez, Jarrott, Lawrence (1996): Markers of adenosine removal in normotensive and hypertensive rat nervous tissue. Hypertension. 1996 Dec;28(6):1026-33. doi: 10.1161/01.hyp.28.6.1026. PMID: 8952592.

  122. Pandolfo, Silveirinha, dos Santos-Rodrigues, Venance, Ledent, Takahashi, Cunha, Köfalvi (2011): Cannabinoids inhibit the synaptic uptake of adenosine and dopamine in the rat and mouse striatum. Eur J Pharmacol. 2011 Mar 25;655(1-3):38-45. doi: 10.1016/j.ejphar.2011.01.013. PMID: 21266173.

  123. Mioranzza, Botton, Costa, Espinosa, Kazlauckas, Ardais, Souza, Porciúncula (2010): Adenosine A1 receptors are modified by acute treatment with methylphenidate in adult mice. Brain Res. 2010 Oct 21;1357:62-9. doi: 10.1016/j.brainres.2010.08.004. PMID: 20699089.

  124. Mioranzza, Costa, Botton, Ardais, Matte, Espinosa, Souza, Porciúncula (2011): Blockade of adenosine A(1) receptors prevents methylphenidate-induced impairment of object recognition task in adult mice. Prog Neuropsychopharmacol Biol Psychiatry. 2011 Jan 15;35(1):169-76. doi: 10.1016/j.pnpbp.2010.10.022. PMID: 21044657.

  125. Schmitz, Pierozan, Rodrigues, Biasibetti, Grings, Zanotto, Coelho, Vargas, Leipnitz, Wyse (2017): Methylphenidate Decreases ATP Levels and Impairs Glutamate Uptake and Na+,K+-ATPase Activity in Juvenile Rat Hippocampus. Mol Neurobiol. 2017 Dec;54(10):7796-7807. doi: 10.1007/s12035-016-0289-1. PMID: 27844288.

  126. Sturgess, Ting-A-Kee, Podbielski, Sellings, Chen, van der Kooy (2010): Adenosine A1 and A2A receptors are not upstream of caffeine’s dopamine D2 receptor-dependent aversive effects and dopamine-independent rewarding effects. Eur J Neurosci. 2010 Jul;32(1):143-54. doi: 10.1111/j.1460-9568.2010.07247.x. Epub 2010 Jun 22. PMID: 20576036; PMCID: PMC2994015.

  127. Walker, Abraham, Tercyak (2010): Adolescent caffeineuse, ADHD, and cigarette smoking. Child Health Care 39: 73–90., n = 448

  128. Dosh, Helmbrecht, Anestis, Guenthner, Kelly, Martin (2010): A comparison of the associations of caffeine and cigarette use with depressive and ADHD symptoms in a sample of young adult smokers. J Addict Med. 2010 Mar;4(1):52-4. doi: 10.1097/ADM.0b013e3181b508ec. PMID: 21359163; PMCID: PMC3043357.

  129. Martin, Cook, Woodring, Burkhardt, Guenthner, Omar, Kelly (2008): Caffeine use: association with nicotine use, aggression, and other psychopathology in psychiatric and pediatric outpatient adolescents. ScientificWorldJournal. 2008 May 22;8:512-6. doi: 10.1100/tsw.2008.82. PMID: 18516472; PMCID: PMC3176831.

  130. Vázquez, Martin de la Torre, López Palomé, Redolar-Ripoll (2022): Effects of Caffeine Consumption on Attention Deficit Hyperactivity Disorder (ADHD) Treatment: A Systematic Review of Animal Studies. Nutrients. 2022 Feb 10;14(4):739. doi: 10.3390/nu14040739. PMID: 35215389; PMCID: PMC8875377. REVIEW

  131. Alasmari (2020): Caffeine induces neurobehavioral effects through modulating neurotransmitters. Saudi Pharm J. 2020 Apr;28(4):445-451. doi: 10.1016/j.jsps.2020.02.005. PMID: 32273803; PMCID: PMC7132598., REVIEW

  132. Diukova, Ware, Smith, Evans, Murphy, Rogers, Wise (2012): Separating neural and vascular effects of caffeine using simultaneous EEG-FMRI: differential effects of caffeine on cognitive and sensorimotor brain responses. Neuroimage. 2012 Aug 1;62(1):239-49. doi: 10.1016/j.neuroimage.2012.04.041. PMID: 22561357; PMCID: PMC3778750.

  133. Perault, Griesemann, Bouquet, Lavoisy, Vandel (1989): A study of the interaction of viloxazine with theophylline. Ther Drug Monit. 1989 Sep;11(5):520-2. PMID: 2815226.

  134. Laaban, Dupeyron, Lafay, Sofeir, Rochemaure, Fabiani (1986): Theophylline intoxication following viloxazine induced decrease in clearance. Eur J Clin Pharmacol. 1986;30(3):351-3. doi: 10.1007/BF00541543. PMID: 3732375.

  135. Fraporti, Contini, Tovo-Rodrigues, Recamonde-Mendoza, Rovaris, Rohde, Hutz, Salatino-Oliveira, Genro (2019): Synergistic effects between ADORA2A and DRD2 genes on anxiety disorders in children with ADHD. Prog Neuropsychopharmacol Biol Psychiatry. 2019 Jul 13;93:214-220. doi: 10.1016/j.pnpbp.2019.03.021. PMID: 30946941.

  136. Pires, Pamplona, Pandolfo, Fernandes, Prediger, Takahashi (2009): Adenosine receptor antagonists improve short-term object-recognition ability of spontaneously hypertensive rats: a rodent model of attention-deficit hyperactivity disorder. Behav Pharmacol. 2009 Mar;20(2):134-45. doi: 10.1097/FBP.0b013e32832a80bf. PMID: 19307960.

  137. Prediger, Fernandes, Takahashi (2005): Blockade of adenosine A2A receptors reverses short-term social memory impairments in spontaneously hypertensive rats. Behav Brain Res. 2005 Apr 30;159(2):197-205. doi: 10.1016/j.bbr.2004.10.017. PMID: 15817183.

  138. Prediger, Pamplona, Fernandes, Takahashi (2005): Caffeine improves spatial learning deficits in an animal model of attention deficit hyperactivity disorder (ADHD) – the spontaneously hypertensive rat (SHR). Int J Neuropsychopharmacol. 2005 Dec;8(4):583-94. doi: 10.1017/S1461145705005341. PMID: 15877934.

  139. Pires, Pamplona, Pandolfo, Prediger, Takahashi (2010): Chronic caffeine treatment during prepubertal period confers long-term cognitive benefits in adult spontaneously hypertensive rats (SHR), an animal model of attention deficit hyperactivity disorder (ADHD). Behav Brain Res. 2010 Dec 20;215(1):39-44. doi: 10.1016/j.bbr.2010.06.022. PMID: 20600342.

  140. Leffa, Ferreira, Machado, Souza, Rosa, de Carvalho, Kincheski, Takahashi, Porciúncula, Souza, Cunha, Pandolfo (2019): Caffeine and cannabinoid receptors modulate impulsive behavior in an animal model of attentional deficit and hyperactivity disorder. Eur J Neurosci. 2019 Jun;49(12):1673-1683. doi: 10.1111/ejn.14348. PMID: 30667546.

  141. Ramos, de Mattos Hungria, Camerini, Suiama, Calzavara (2020): Potential beneficial effects of caffeine administration in the neonatal period of an animal model of schizophrenia. Behav Brain Res. 2020 Aug 5;391:112674. doi: 10.1016/j.bbr.2020.112674. PMID: 32417274.

  142. Triche, Grosso, Belanger, Darefsky, Benowitz, Bracken (2008): Chocolate consumption in pregnancy and reduced likelihood of preeclampsia. Epidemiology. 2008 May;19(3):459-64. doi: 10.1097/EDE.0b013e31816a1d17. PMID: 18379424; PMCID: PMC2782959.

  143. Miguel, Bronauth, Deniz, Confortim, de Oliveira, Dalle Molle, Silveira, Pereira (2022): Neonatal hypoxia-ischemia induces dysregulated feeding patterns and ethanol consumption that are alleviated by methylphenidate administration in rats. Exp Neurol. 2022 Apr 7;353:114071. doi: 10.1016/j.expneurol.2022.114071. PMID: 35398338.

  144. Smith, Browne, Jayaraman, Bleickardt, Hodge, Lis, Yao, Rittle, Innocent, Mullins, Boykow, Reynolds, Hill, Parker, Hodgson (2014): Effects of the selective adenosine A2A receptor antagonist, SCH 412348, on the parkinsonian phenotype of MitoPark mice. Eur J Pharmacol. 2014 Apr 5;728:31-8. doi: 10.1016/j.ejphar.2014.01.052. PMID: 24486705.

  145. Basu, Barawkar, Thorat, Shejul, Patel, Naykodi, Jain, Salve, Prasad, Chaudhary, Ghosh, Bhat, Quraishi, Patil, Ansari, Menon, Unadkat, Thakare, Seervi, Meru, De, Bhamidipati, Rouduri, Palle, Chug, Mookhtiar (2017): Design, Synthesis of Novel, Potent, Selective, Orally Bioavailable Adenosine A2A Receptor Antagonists and Their Biological Evaluation. J Med Chem. 2017 Jan 26;60(2):681-694. doi: 10.1021/acs.jmedchem.6b01584. PMID: 28055204.

  146. Weerts, Griffiths (2003): The adenosine receptor antagonist CGS15943 reinstates cocaine-seeking behavior and maintains self-administration in baboons. Psychopharmacology (Berl). 2003 Jul;168(1-2):155-163. doi: 10.1007/s00213-003-1410-5. PMID: 12669180.

  147. O’Neill, Hobson, Levis, Bachtell (2014): Persistent reduction of cocaine seeking by pharmacological manipulation of adenosine A1 and A 2A receptors during extinction training in rats. Psychopharmacology (Berl). 2014 Aug;231(16):3179-88. doi: 10.1007/s00213-014-3489-2. PMID: 24562064; PMCID: PMC4111968.

  148. Moeller, Steinberg, Lane, Kjome, Ma, Ferre, Schmitz, Green, Bandak, Renshaw, Kramer, Narayana (2012): Increased Orbitofrontal Brain Activation after Administration of a Selective Adenosine A(2A) Antagonist in Cocaine Dependent Subjects. Front Psychiatry. 2012 May 28;3:44. doi: 10.3389/fpsyt.2012.00044. PMID: 22654774; PMCID: PMC3361057.

  149. Kubrusly, Bhide (2010): Cocaine exposure modulates dopamine and adenosine signaling in the fetal brain. Neuropharmacology. 2010 Feb;58(2):436-43. doi: 10.1016/j.neuropharm.2009.09.007. PMID: 19765599; PMCID: PMC2813374.

  150. Yao, McFarland, Fan, Jiang, Ueda, Diamond (2006): Adenosine A2a blockade prevents synergy between mu-opiate and cannabinoid CB1 receptors and eliminates heroin-seeking behavior in addicted rats. Proc Natl Acad Sci U S A. 2006 May 16;103(20):7877-82. doi: 10.1073/pnas.0602661103. PMID: 16684876; PMCID: PMC1458620.

  151. Justinová, Ferré, Redhi, Mascia, Stroik, Quarta, Yasar, Müller, Franco, Goldberg (2011): Reinforcing and neurochemical effects of cannabinoid CB1 receptor agonists, but not cocaine, are altered by an adenosine A2A receptor antagonist. Addict Biol. 2011 Jul;16(3):405-15. doi: 10.1111/j.1369-1600.2010.00258.x. PMID: 21054689; PMCID: PMC3115444.