An Update on the Mechanisms of the Psychostimulant Effects of Caffeine

Ferré, Sergi

doi:10.1111/j.1471-4159.2007.05196.x

Cited by 440Adenosine and Purinergic SignalingNeuroscience and Neuropharmacology ResearchNeurotransmitter Receptor Influence on Behavior

An Update on the Mechanisms of the Psychostimulant Effects of Caffeine

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Ferré, Sergi·2008·Journal of Neurochemistry

DOI 10.1111/j.1471-4159.2007.05196.x

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Abstract

There has been a long debate about the predominant involvement of the different adenosine receptor subtypes and the preferential role of pre‐ versus post‐synaptic mechanisms in the psychostimulant effects of the adenosine receptor antagonist caffeine. Both striatal A 1 and A 2A receptors are involved in the motor‐activating and probably reinforcing effects of caffeine, although they play a different role under conditions of acute or chronic caffeine administration. The present review emphasizes the key integrative role of adenosine and adenosine receptor heteromers in the computation of information at the level of the striatal spine module (SSM). This local module is mostly represented by the dendritic spine of the medium spiny neuron with its glutamatergic and dopaminergic synapses and astroglial processes that wrap the glutamatergic synapse. In the SSM, adenosine acts both pre‐ and post‐synaptically through multiple mechanisms, which depend on heteromerization of A 1 and A 2A receptors among themselves and with D 1 and D 2 receptors, respectively. A critical aspect of the mechanisms of the psychostimulant effects of caffeine is its ability to release the pre‐ and post‐synaptic brakes that adenosine imposes on dopaminergic neurotransmission by acting on different adenosine receptor heteromers localized in different elements of the SSM.

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Caffeine's central stimulant effects likely arise from broader disinhibition of a multi-neurotransmitter network driven by concurrent antagonism of A1 and A2A receptors, rather than from blockade of a single receptor pathway alone.
“In addition, functional interactions between A2A receptors and dopaminergic signaling pathways suggest that caffeine’s central stimulant effects likely arise from the broader disinhibition of a multi-neurotransmitter network, driven by concurrent antagonism of A1 and A2A receptors, rather than from blockade of a single receptor pathway alone [37,38].”
From Pre-Exercise Caffeine as a Modulator of Exercise-Induced Acute Cardiometabolic Responses: A Narrative Review (2026) · cites this paper as [37]
The ‘Adenosine A1 or A2A receptor antagonism?’ section (page unavailable) concludes that both receptors contribute to caffeine’s motor-activating effects. The ‘Pre-synaptic mechanisms’ section (page unavailable) describes effects on dopamine and glutamate and says other neurotransmitters may also be involved. It does not establish broad disinhibition of a multi-neurotransmitter network as the mechanism; its account of receptor effects on neurotransmitter release is more varied. (LLM, conf=0.82)
Experimental — accuracy not yet measured
High concentrations of caffeine inhibit phosphodiesterase activity and stimulate dopamine D2 receptors.
“In addition, high concentrations of caffeine inhibit phosphodiesterase activity 3 and stimulate dopamine D2 receptors.9”
From Theanine maintains sleep quality in healthy young women by suppressing the increase in caffeine-induced wakefulness after sleep onset (2023) · cites this paper as [9]
Caffeine excites neural circuits that project from the basal ganglia to the striatum and cerebral cortex.
“Furthermore, caffeine excites neural circuits that project from the basal ganglia to the striatum and cerebral cortex.9”
From Theanine maintains sleep quality in healthy young women by suppressing the increase in caffeine-induced wakefulness after sleep onset (2023) · cites this paper as [9]

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Determination of the effects of caffeine and carbamazepine on striatal dopamine release by in vivo microdialysis
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Reciprocal interactions between adenosine A2A and dopamine D2 receptors in Chinese hamster ovary cells co-transfected with the two receptors
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Adenosine receptor‐mediated modulation of dopamine release in the nucleus accumbens depends on glutamate neurotransmission and N‐methyl‐ d ‐aspartate receptor stimulation
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Differential glutamate‐dependent and glutamate‐independent adenosine A1 receptor‐mediated modulation of dopamine release in different striatal compartments
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Adenosine A1 Receptor-mediated Modulation of Dopamine D1 Receptors in Stably Cotransfected Fibroblast Cells
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Role of adenosine receptors in caffeine tolerance.
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Neurotransmitter receptor heteromers and their integrative role in ‘local modules’: The striatal spine module
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Dose–response study of caffeine effects on cerebral functional activity with a specific focus on dependence
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Postsynaptic dopamine/adenosine interaction: II. Postsynaptic dopamine agonism and adenosine antagonism of methylxanthines in short-term reserpinized mice
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Adenosine receptor antagonists potentiate dopamine receptor agonist-induced rotational behavior in 6-hydroxydopamine-lesioned rats
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Adenosine agonists can both inhibit and enhance in vivo striatal dopamine release
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Genetic or pharmacological inactivation of the dopamine D1 receptor differentially alters the expression of regulator of G‐protein signalling (Rgs) transcripts
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Qualitative differences in the discriminative stimulus effects of low and high doses of caffeine in the rat.
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Blocking Striatal Adenosine A2A Receptors: A New Strategy for Basal Ganglia Disorders
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Electrophysiological and behavioural evidence for an antagonistic modulatory role of adenosine A2A receptors in dopamine D2 receptor regulation in the rat dopamine‐denervated striatum
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Basal Ganglia
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Evidence for adenosine A2 receptor involvement in the hypomobility effects of adenosine analogues in mice
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Cocaine and Caffeine Conditioned Place Preference, Locomotor Activity, and Additivity
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Adenosine A1 receptor blockade selectively potentiates the motor effects induced by dopamine D1 receptor stimulation in rodents
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Striatal A2A adenosine receptor antagonism differentially modifies striatal glutamate outflow in vivo in young and aged rats
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Presynaptic adenosine A2A receptors enhance GABAergic synaptic transmission via a cyclic AMP dependent mechanism in the rat globus pallidus
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A detailed behavioral analysis of the acute motor effects of caffeine in the rat: involvement of adenosine A1 and A2A receptors
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Psychostimulants and monoamine transporters: upsetting the balance
Elliott, J. M., & Beveridge, T. J. R. (2004) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2004.09.005 · Cited by 65 · see citing works
Adenosine A1 and A2A receptor antagonists stimulate motor activity: evidence for an increased effectiveness in aged rats
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Inhibition of nigrostriatal release of dopamine in the rat by adenosine receptor agonists: A1 receptor mediation
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Caffeine and accumbens shell dopamine
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Lack of tolerance to motor stimulant effects of a selective adenosine A2A receptor antagonist
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Caffeine place conditioning in rats: comparison with cocaine and ethanol
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Involvement of adenosine A1 receptors in the discriminative-stimulus effects of caffeine in rats
Solinas, M., Ferré, S., Antoniou, K. M., Quarta, D., Justinová, Z., Hockemeyer, J., Pappas, L. A., Segal, P. N., Wertheim, C. E., Müller, C. E., et al. (2005) · Psychopharmacology · doi:10.1007/s00213-004-2081-6 · Cited by 52 · see citing works
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ROLE OF ADENOSINE IN THE CONTROL OF HOMOSYNAPTIC PLASTICITY IN STRIATAL EXCITATORY SYNAPSES
Ferré, S., Borycz, J., Goldberg, S. R., Hope, B. T., Morales, M., Lluı́s, C., Franco, R., Ciruela, F., & Cunha, R. A. (2005) · Journal of Integrative Neuroscience · doi:10.1142/s0219635205000987 · Cited by 50 · see citing works
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Effect of locally infused 2-chloroadenosine, an A1 receptor agonist, on spontaneous and evoked dopamine release in rat neostriatum
Ballarín, M., Reiriz, J., Ambrosio, S., & Mahy, N. (1995) · Neuroscience Letters · doi:10.1016/0304-3940(94)11217-7 · Cited by 49 · see citing works
Heterodimerization of G-protein-coupled receptors in the CNS
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Combination of adenosine A1 and A2A receptor blocking agents induces caffeine-like locomotor stimulation in mice
Kuzmin, A., Johansson, B. A., Giménez‐Llort, L., Ögren, S. O., & Fredholm, B. B. (2005) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2005.07.001 · Cited by 48 · see citing works
Subchronic Caffeine Exposure Induces Sensitization to Caffeine and Cross-Sensitization to Amphetamine Ipsilateral Turning Behavior Independent from Dopamine Release
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Effects of SCH 58261, an Adenosine A2A Receptor Antagonist, on Quinpirole-Induced Turning in 6-Hydroxydopamine-Lesioned Rats Lack of Tolerance after Chronic Caffeine Intake
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Psychomotor stimulant effects of methylxanthines in squirrel monkeys: relation to adenosine antagonism
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Immunohistochemical localization of caffeine-induced c-Fos protein expression in the rat brain
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Adenosine receptor expression and function in rat striatal cholinergic interneurons
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The differential role of A1 and A2 adenosine receptor subtypes in locomotor activity and place conditioning in rats
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Behavioral effects of adenosine analogs in squirrel monkeys: relation to adenosine A2 receptors
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Adenosine receptors--the role in modulation of dopamine and glutamate release in the rat striatum.
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Stimulation of adenosine A1 receptors attenuates dopamine D1 receptor‐mediated increase of NGFI‐A, c‐fos and jun‐B mRNA levels in the dopamine‐denervated striatum and dopamine D1 receptor‐mediated turning behaviour
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Psychostimulants and Vesicle Trafficking: A Novel Mechanism and Therapeutic Implications
Hanson, G. R., Sandoval, V., Riddle, E. L., & Fleckenstein, A. E. (2004) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1316.019 · Cited by 31 · see citing works
Adenosinergic modulation of the discriminative-stimulus effects of methamphetamine in rats
Munzar, P., Justinová, Z., Kutkat, S. W., Ferré, S., & Goldberg, S. R. (2002) · Psychopharmacology · doi:10.1007/s00213-002-1075-5 · Cited by 31 · see citing works
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How habitual caffeine consumption and dose influence flavour preference conditioning with caffeine
Tinley, E. M., Durlach, P. J., & Yeomans, M. R. (2004) · Physiology & Behavior · doi:10.1016/j.physbeh.2004.03.018 · Cited by 23 · see citing works
Reinforcing and aversive effects of caffeine measured by flavor preference conditioning in caffeine-naive and caffeine-acclimated rats
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Caffeine-reinforced conditioned flavor preferences in rats.
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Addition of a 5-HT receptor agonist to methylphenidate potentiates the reduction of [123I]FP-CIT binding to dopamine transporters in rat frontal cortex and hippocampus
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[46]46. Gine ´s S., Hillion J., Torvinen M. et al. (2000) Dopamine D1 and adenosine A1 receptors form functionally interacting heteromeric complexes. Proc. Natl Acad. Sci. USA 97, 8606-8611.
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The 2.6 Angstrom Crystal Structure of a Human A 2A Adenosine Receptor Bound to an Antagonist
Jaakola, V., Griffith, M. T., Hanson, M. A., Cherezov, V., Chien, E. Y. T., Lane, J. R., IJzerman, A. P., & Stevens, R. C. (2008) · Science · doi:10.1126/science.1164772 · Cited by 1,786 · see citing works
Caffeine (1, 3, 7‐trimethylxanthine) in Foods: A Comprehensive Review on Consumption, Functionality, Safety, and Regulatory Matters
Heckman, M. A., Weil, J., & de Mejı́a, E. G. (2010) · Journal of Food Science · doi:10.1111/j.1750-3841.2010.01561.x · Cited by 1,072 · see citing works
“The blockage of adenosine to the neurons causes the sleep promoting effects of adenosine to stop, resulting in the neurons speeding up instead of slowing down (Ferre 2008).”
Background
Herbal extracts and phytochemicals: Plant secondary metabolites and the enhancement of human brain function
Kennedy, D. O., & Wightman, E. L. (2011) · Advances in Nutrition · doi:10.3945/an.110.000117 · Cited by 684 · see citing works
“Similarly, in mammals, caffeine is a competitive antagonist of inhibitory adenosine A1 and A2 receptors, which in turn leads to activation via increased dopaminergic and glutamatergic activity (64).”
Background
Interindividual Differences in Caffeine Metabolism and Factors Driving Caffeine Consumption
Nehlig, A. (2018) · Pharmacological Reviews · doi:10.1124/pr.117.014407 · Cited by 632 · see citing works
Scientific Opinion on the safety of caffeine
EFSA Panel on Dietetic Products, N. A. A. (. (2015) · EFSA Journal · doi:10.2903/j.efsa.2015.4102 · Cited by 613 · see citing works
“Prolonged administration of an adenosine A2A receptor antagonist does not induce tolerance to its motor stimulant effect, suggesting that caffeine tolerance may be dependent on blockade of A1, rather than A2A, receptors (Ferre, 2008).”
Background
Caffeine and Adenosine
Ribeiro, J. A., & Sebastião, A. M. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-1379 · Cited by 584 · see citing works
“Caffeine improves cognition [1]; however, it also affects sleep [3].”
Quercetin increases brain and muscle mitochondrial biogenesis and exercise tolerance
Davis, J. M., Murphy, E. A., Carmichael, M. D., & Davis, B. (2009) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.90925.2008 · Cited by 486 · see citing works
“Quercetin, like caffeine, has been shown to be an adenosine A1 receptor antagonist in vitro (1), which is at least partially responsible for the psychostimulant and ergogenic effects of caffeine (1, 5, 7, 9).”
Background
Adenosine receptors and brain diseases: neuroprotection and neurodegeneration
Gomes, C. V., Kaster, M. P., Tomé, A. R., Agostinho, P. M., & Cunha, R. A. (2011) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2010.12.001 · Cited by 419 · see citing works
Energy Drinks: An Assessment of Their Market Size, Consumer Demographics, Ingredient Profile, Functionality, and Regulations in the United States
Heckman, M. A., Sherry, K., & de Mejı́a, E. G. (2010) · Comprehensive Reviews in Food Science and Food Safety · doi:10.1111/j.1541-4337.2010.00111.x · Cited by 384 · see citing works
“The blockage of adenosine to the neurons causes the sleep promoting effects of adenosine to stop, resulting in the neurons speeding up instead of slowing down (Ferre 2008).”
Background
The effect of caffeine on subsequent sleep: A systematic review and meta-analysis
Gardiner, C., Weakley, J., Burke, L. M., Roach, G. D., Sargent, C., Maniar, N., Townshend, A., & Halson, S. L. (2023) · Sleep Medicine Reviews · doi:10.1016/j.smrv.2023.101764 · Cited by 315 · see citing works
Genetics of caffeine consumption and responses to caffeine
Yang, A., Palmer, A. A., & de Wit, H. (2010) · Psychopharmacology · doi:10.1007/s00213-010-1900-1 · Cited by 310 · see citing works
“The psychomotor stimulant effects of caffeine are due to antagonism of adenosine's inhibitory actions on the striatal D 2 transmission (Ferre 2008).”
Adenosine Receptors and the Central Nervous System
Sebastião, A. M., & Ribeiro, J. A. (2009) · Handbook of experimental pharmacology · doi:10.1007/978-3-540-89615-9_16 · Cited by 271 · see citing works
“The broad caffeine intake associated with common beverages, together with the impact of xanthines on biomedical research, prompted many studies that have focused on specific caffeine effects rather than using it as a tool to antagonize ARs (Daly 2007; Ferré 2008).”
BackgroundInfluential
Coffee, Caffeine, and Risk of Depression Among Women
Lucas, M. (2011) · Archives of Internal Medicine · doi:10.1001/archinternmed.2011.393 · Cited by 270 · see citing works
“Caffeine affects brain function mainly by its antagonist action on the adenosine A2A receptor and, therefore, plays a role in the modulation of dopaminergic transmission.(30,33) The antagonist effect of caffeine on adenosine also might imply nondopaminergic mechanisms, such as modulation of the release of acetylcholin…”
Background
Caffeine, Mental Health, and Psychiatric Disorders
Lara, D. R. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-1378 · Cited by 236 · see citing works
“dopamine, glutamate, and acetylcholine [4,5].”
Chronic Caffeine Consumption Prevents Memory Disturbance in Different Animal Models of Memory Decline
Cunha, R. A., & Agostinho, P. M. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-1408 · Cited by 233 · see citing works
“Furthermore, evidence is accumulating suggesting that the chronic consumption of caffeine mostly acts by antagonizing A2A rather than A1 receptors [107,108], as first suggested by Daly and Fredholm [58].”
Background
Genome-Wide Meta-Analysis Identifies Regions on 7p21 (AHR) and 15q24 (CYP1A2) As Determinants of Habitual Caffeine Consumption
Cornelis, M. C., Monda, K. L., Yu, K., Paynter, N., Azzato, E. M., Bennett, S. N., Berndt, S. I., Boerwinkle, E., Chanock, S., Chatterjee, N., et al. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1002033 · Cited by 228 · see citing works
“Genetic association studies focused on candidate genes related to the pharmacokinetic and pharmacodynamic properties of caffeine have identified genes encoding cytochrome P-450 (CYP)1A2, as the primary enzyme involved in caffeine metabolism [3,4].”
Caffeine as an Attention Enhancer: Reviewing Existing Assumptions
Einöther, S. J. L., & Giesbrecht, T. (2013) · Psychopharmacology · doi:10.1007/s00213-012-2917-4 · Cited by 215 · see citing works
“Caffeine is the single most widely consumed psychoactive ingredient (Ferre 2008).”
Caffeine Use Disorder: A Comprehensive Review and Research Agenda
Meredith, S. E., Juliano, L. M., Hughes, J. R., & Griffiths, R. R. (2013) · Journal of Caffeine Research · doi:10.1089/jcr.2013.0016 · Cited by 210 · see citing works
“Importantly, caffeine has been shown to stimulate dopaminergic activity by removing the negative modulatory effects of adenosine at dopamine receptors.(28) Studies suggest that dopamine release in the nucleus accumbens shell may be a specific neuropharmacological mechanism underlying the addictive potential of caffein…”
Background
Mechanisms of the psychostimulant effects of caffeine: implications for substance use disorders
Ferré, S. (2016) · Psychopharmacology · doi:10.1007/s00213-016-4212-2 · Cited by 209 · see citing works
“2006) and postsynaptic A1 receptors that form heteromers with D1 receptors in the GABAergic striato-nigral neuron (Ferré et al. 1997; Ferré 2008).”
BackgroundSelf-citation
Using caffeine and other adenosine receptor antagonists and agonists as therapeutic tools against neurodegenerative diseases: A review
Rivera-Oliver, M., & Díaz‐Ríos, M. (2014) · Life Sciences · doi:10.1016/j.lfs.2014.01.083 · Cited by 204 · see citing works
“Caffeine has been described to have the ability to influence dopaminergic neurotransmission and potentiate dopamine receptor-mediated behavioral responses, such as locomotion and cognitive functions (Ferré, 2008; Xie et al., 2007).”
BackgroundInfluential
Potential Therapeutic Interest of Adenosine A2A Receptors in Psychiatric Disorders
Cunha, R. A., Ferré, S., Vaugeois, J., & Chen, J. (2008) · Current Pharmaceutical Design · doi:10.2174/138161208784480090 · Cited by 187 · see citing works
“Regarding the dopaminergic involvement in schizophrenia, it is noteworthy that activation of adenosine A2A receptors reduces the affinity of dopaminergic D2 receptors for dopamine, being the probable mechanism underlying the antipsychotic-like profile of adenosine agonists [213], the hyperdopaminergic effect of caffei…”
BackgroundSelf-citation
Caffeine consumption and self-assessed stress, anxiety, and depression in secondary school children
Richards, G., & Smith, A. (2015) · Journal of Psychopharmacology · doi:10.1177/0269881115612404 · Cited by 179 · see citing works
“Dose-dependent effects of caffeine on behaviour Short-term effects of caffeine consumption include enhanced mood and alertness (Ferré, 2008; Kaplan et al., 1997; Lorist and Tops, 2003), improved exercise performance (Doherty and Smith, 2004), increased blood pressure (Riksen et al., 2009), improved…”
Background
Non-pharmacological cognitive enhancement
Dresler, M., Sandberg, A., Ohla, K., Bublitz, C., Trenado, C., Mroczko-Wąsowicz, A., Kühn, S., & Repantis, D. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.07.002 · Cited by 181 · see citing works
“Caffeine is an adenosine receptor antagonist; it reduces inhibition of neural firing by large through an increased turnover of noradrenaline in the brain (Smith et al., 2003; Ferre, 2008).”
Background
Coffee and caffeine consumption and depression: a meta-analysis of observational studies
Wang, L., Shen, X., Wu, Y., & Zhang, D. (2016) · Australian & New Zealand Journal of Psychiatry · doi:10.1177/0004867415603131 · Cited by 180 · see citing works
“Second, caffeine, as a nonspecific adenosine A1/ A2A receptor antagonist, generates psychostimulant effects through modulating dopaminergic transmission(Ferre, 2008; Morelli et al., 2010), and major metabolites of caffeine act on adenosine receptors in the brain (Morelli et al.”
Background
Adenosine receptor antagonists including caffeine alter fetal brain development in mice
Silva, C. G., Métin, C., Fazeli, W., Machado, N. J., Darmopil, S., Launay, P.-S., Ghestem, A., Nesa, M.-P., Bassot, E., Szabó, E., et al. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3006258 · Cited by 177 · see citing works
“A2ARs may control the migration of GABA neurons Chronic consumption of caffeine exerts its central action mostly via its antagonistic action onA2ARs (27, 28).”
Background
G protein-coupled receptors in neurodegenerative diseases and psychiatric disorders
Wong, T., Li, G., Li, S., Gao, W., Chen, G., Gan, S., Zhang, M., Li, H., Wu, S., & Du, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01427-2 · Cited by 168 · see citing works
“The psychoactive function of caffeine is mediated via the non-selective antagonistic action on A1/A2A receptors.(144) How A1/A2A receptors regulate depression-like behaviour remains unclear.”
Background
Allosteric interactions between agonists and antagonists within the adenosine A 2A receptor-dopamine D 2 receptor heterotetramer
Bonaventura, J., Navarro, G., Casadó-Anguera, V., Azdad, K., Rea, W. P., Moreno, E., Brugarolas, M., Mallol, J., Canela, E. I., Lluı́s, C., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1507704112 · Cited by 149 · see citing works
“It has been hypothesized that the allosteric interactions between A2AR and D2R agonists within the A2AR-D2R heteromer provide a mechanism responsible not only for the depressant effects of A2AR agonists, but also for the psychostimulant effects of adenosine A2AR antagonists and the nonselective adenosine receptor anta…”
BackgroundSelf-citation
The Dietary Flavonoid Quercetin Increases VO2max and Endurance Capacity
Davis, J. M., Carlstedt, C. J., Chen, S., Carmichael, M. D., & Murphy, E. A. (2010) · International Journal of Sport Nutrition and Exercise Metabolism · doi:10.1123/ijsnem.20.1.56 · Cited by 146 · see citing works
“Quercetin, like caffeine, is an adenosine-A1-receptor antagonist, at least in vitro (Alexander), and the delay in fatigue that occurs with caffeine results at least in part from its ability to block adenosine receptors in the brain (Davis et al., 2003; Ferre, 2008).”
Background
Caffeine Consumption Prevents Memory Impairment, Neuronal Damage, and Adenosine A2A Receptors Upregulation in the Hippocampus of a Rat Model of Sporadic Dementia
Espinosa, J., Rocha, A., Nunes, F., Costa, M. S., Schein, V., Kazlauckas, V., Kalinine, E., Souza, D., Cunha, R., & Porciúncula, L. (2013) · Journal of Alzheimer's Disease · doi:10.3233/jad-111982 · Cited by 136 · see citing works
“Another major argument to dismiss this hypothesis is the observation that chronic caffeine mostly affects central adenosine A2A receptors (A2AR) [35, 61], which do not seem Fig.”
Background
Nucleus Accumbens Adenosine A 2A Receptors Regulate Exertion of Effort by Acting on the Ventral Striatopallidal Pathway
Mingote, S., Font, L., Farrar, A. M., Vontell, R., Worden, L. T., Stopper, C. M., Port, R. G., Sink, K. S., Bunce, J. G., Chrobak, J. J., et al. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.1525-08.2008 · Cited by 141 · see citing works
Caffeine prevents disruption of memory consolidation in the inhibitory avoidance and novel object recognition tasks by scopolamine in adult mice
Botton, P. H., Costa, M. S., Ardais, A. P., Mioranzza, S., Souza, D. O., da Rocha, J. B. T., & Porciúncula, L. O. (2010) · Behavioural Brain Research · doi:10.1016/j.bbr.2010.05.034 · Cited by 140 · see citing works
Adenosine Receptor Control of Cognition in Normal and Disease
Chen, J. (2014) · International review of neurobiology · doi:10.1016/b978-0-12-801022-8.00012-x · Cited by 137 · see citing works
Role of the Central Ascending Neurotransmitter Systems in the Psychostimulant Effects of Caffeine
Ferré, S. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-1400 · Cited by 133 · see citing works
“[3,22]) Particularly influential were the experiments with A2A receptor knockout (A2AKO) mice, which showed a lack of motor-activating effects of caffeine [49].”
Self-citation
Antioxidants in Sport Nutrition
Lamprecht, M. (2014) · CRC Press eBooks · doi:10.1201/b17442 · Cited by 133 · see citing works
Adenosine A2A receptor antagonism and genetic deletion attenuate the effects of dopamine D2 antagonism on effort-based decision making in mice
Pardo, M., López‐Cruz, L., Valverde, O., Ledent, C. A., Baqi, Y., Müller, C. E., Salamone, J. D., & Correa, M. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.12.033 · Cited by 128 · see citing works
Sleep deprivation prevents stimulation-induced increases of levels of P-CREB and BDNF: Protection by caffeine
Alhaider, I. A., Aleisa, A. M., Tran, T. T., & Alkadhi, K. A. (2011) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2011.02.006 · Cited by 127 · see citing works
Caffeine prevents age-associated recognition memory decline and changes brain-derived neurotrophic factor and tirosine kinase receptor (TrkB) content in mice
da Costa, M. S., Botton, P. H. S., Mioranzza, S., Souza, D. O., & Porciúncula, L. O. (2008) · Neuroscience · doi:10.1016/j.neuroscience.2008.03.038 · Cited by 124 · see citing works
Caffeine Regulates Frontocorticostriatal Dopamine Transporter Density and Improves Attention and Cognitive Deficits in an Animal Model of Attention Deficit Hyperactivity Disorder
Pandolfo, P., Machado, N. J., Köfalvi, A., Takahashi, R. N., & Cunha, R. A. (2013) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2012.04.011 · Cited by 118 · see citing works
Caffeine and Selective Adenosine Receptor Antagonists as New Therapeutic Tools for the Motivational Symptoms of Depression
López‐Cruz, L., Salamone, J. D., & Correa, M. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00526 · Cited by 117 · see citing works
“Caffeine actions on A1 and A2A adenosine receptors (Ferré, 2008), has promoted its study as an alternative preventive or therapeutic tool for parkinsonian symptoms (Prediger, 2010).”
Background
Green tea and coffee consumption is inversely associated with depressive symptoms in a Japanese working population
Pham, N. M., Nanri, A., Kurotani, K., Kuwahara, K., Kume, A., Sato, M., Hayabuchi, H., & Mizoue, T. (2013) · Public Health Nutrition · doi:10.1017/s1368980013000360 · Cited by 115 · see citing works
“Finally, caffeine can increase excitatory neurotransmitters through modulating dopaminergic transmission((11)) and facilitate the release of acetylcholine and serotonin((12)).”
Drosophila D1 dopamine receptor mediates caffeine-induced arousal
Waldowski, R. A., Kim, Y.-C., Jones, F. S., Han, K., & Greenspan, R. J. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0806776105 · Cited by 109 · see citing works
“CAFF acting through AdoR on dopaminergic neurons could stimulate dopamine synthesis or release through protein kinase A dependent mechanisms similar to the A2A receptor in mammals (4).”
Background
Neuroprotective and Therapeutic Effect of Caffeine on the Rat Model of Parkinson's Disease Induced by Rotenone
Khadrawy, Y. A., Salem, A. M. H., El-Shamy, K. A., Ahmed, E. K., Fadl, N. N., & Hosny, E. N. (2017) · Journal of Dietary Supplements · doi:10.1080/19390211.2016.1275916 · Cited by 106 · see citing works
“Caffeine, 1,3,7-trimethylxanthine, is the world’s most consumed psychoactive substance (Ferre´, 2008).”
Background
Differential actions of adenosine A1 and A2A antagonists on the effort-related effects of dopamine D2 antagonism
Salamone, J. D., Farrar, A. M., Font, L., Patel, V. B., Schlar, D. E., Nunes, E. J., Collins, L. E., & Sager, T. N. (2009) · Behavioural Brain Research · doi:10.1016/j.bbr.2009.02.021 · Cited by 105 · see citing works
“Furthermore, the modest effects of caffeine are consistent with reports indicating that caffeine, despite its some-what mixed pattern of binding to adenosine receptors, does show some degree of preference for adenosine A1 receptors over A2A receptors [23].”
Background
Psychopharmacology of theobromine in healthy volunteers
Baggott, M. J., Childs, E., Hart, A. B., de Bruin, E. A., Palmer, A. A., Wilkinson, J. E., & de Wit, H. (2013) · Psychopharmacology · doi:10.1007/s00213-013-3021-0 · Cited by 106 · see citing works
“The highest dose of theobromine decreased alertness and increased response times on the ANT task.”
MethodInfluential
Skill execution and sleep deprivation: effects of acute caffeine or creatine supplementation - a randomized placebo-controlled trial
Cook, C. J., Crewther, B. T., Kilduff, L. P., Drawer, S., & Gaviglio, C. M. (2011) · Journal of the International Society of Sports Nutrition · doi:10.1186/1550-2783-8-2 · Cited by 104 · see citing works
Coffee, caffeine, and risk of completed suicide: Results from three prospective cohorts of American adults
Lucas, M., O’Reilly, E. J., Pan, A., Mirzaei, F., Willett, W. C., Okereke, O. I., & Ascherio, A. (2014) · The World Journal of Biological Psychiatry · doi:10.3109/15622975.2013.795243 · Cited by 103 · see citing works
“Caffeine has complex effects in the central nervous system, largely mediated by antagonism of adenosine A2a and A1 receptors, including an increased turnover of several monoamine transmitters, such as serotonin, dopamine, and noradrenaline (Fredholm et al. 1999; Ferre 2008; Ferre et al. 2008).”
Background
Allosteric mechanisms within the adenosine A2A–dopamine D2 receptor heterotetramer
Ferré, S., Bonaventura, J., Tomasi, D. G., Navarro, G., Moreno, E., Cortés, A., Lluı́s, C., Casadó, V., & Volkow, N. D. (2015) · Neuropharmacology · doi:10.1016/j.neuropharm.2015.05.028 · Cited by 99 · see citing works
“…effects of adenosine analogues and for the psychostimulant effects of selective adenosine A2AR antagonists and the non-selective adenosine receptor antagonist caffeine, with implications for several neuropsychiatric disorders (Ferré et al., 2004, 2008; Ferré, 2008; Bonaventura et al., 2015).”
BackgroundSelf-citation
Essential Control of the Function of the Striatopallidal Neuron by Pre-coupled Complexes of Adenosine A2A-Dopamine D2 Receptor Heterotetramers and Adenylyl Cyclase
Ferré, S., Bonaventura, J., Zhu, W., Hatcher-Solis, C., Taura, J., Quiroz, C., Cai, N.-S., Moreno, E., Casadó-Anguera, V., Kravitz, A. V., et al. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00243 · Cited by 100 · see citing works
“…in the A2AR-D2R heteromer, a reduction in the affinity of agonists for the D2R, contradicts the hypothesis of a key role of allosteric interactions within the A2AR-D2R heteromer as a main mechanism involved in the opposite behavioral effects of A2AR agonists and antagonists (Ferré, 2008, 2016).”
BackgroundSelf-citation
Tuning and Fine-Tuning of Synapses with Adenosine
Sebastião, A. M., & Ribeiro, J. A. (2009) · Current Neuropharmacology · doi:10.2174/157015909789152128 · Cited by 97 · see citing works
“This A2A/D2 interaction seems to be essential for the behavioural effects of adenosine agonists and antagonists, like caffeine [56].”
Background
Green Tea, Coffee, and Caffeine Consumption Are Inversely Associated with Self-Report Lifetime Depression in the Korean Population
Kim, J., & Kim, J. (2018) · Nutrients · doi:10.3390/nu10091201 · Cited by 95 · see citing works
“Caffeine is well known to have psychostimulant effects [35].”
Background
The Role of Adenosine Receptors in Psychostimulant Addiction
Ballesteros-Yáñez, I., Castillo, C. A., Merighi, S., & Gessi, S. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00985 · Cited by 80 · see citing works
“CREB phosphorylation then increases transcription of immediate early genes such as c-fos and other genes like preproenkephalin (Ferré, 2008).”
Background
Involvement of Adenosine A2A Receptors in Depression and Anxiety
Yamada, K., Kobayashi, M., & Kanda, T. (2014) · International review of neurobiology · doi:10.1016/b978-0-12-801022-8.00015-5 · Cited by 93 · see citing works
“itor at concentrations higher than the physiological conditions (Ferré, 2008).”
Background
Differential effects of selective adenosine antagonists on the effort-related impairments induced by dopamine D1 and D2 antagonism
Nunes, E. J., Randall, P. A., Santerre, J. L., Given, A. M., Sager, T. N., Correa, M., & Salamone, J. D. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2010.05.068 · Cited by 91 · see citing works
Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
Froestl, W., Muhs, A., & Pfeifer, A. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-121186 · Cited by 91 · see citing works
“neurotransmission [374].”
Psychostimulant pharmacological profile of paraxanthine, the main metabolite of caffeine in humans
Orrù, M., Guitart, X., Karcz‐Kubicha, M., Solinas, M., Justinová, Z., Barodia, S. K., Zanoveli, J. M., Cortés, A., Lluı́s, C., Casadó, V., et al. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.11.029 · Cited by 89 · see citing works
“It is generally believed that caffeine exerts psychostimulant effects acting as a nonselective adenosine A1 receptor (A1R) and A2A receptor (A2AR) antagonist (Fredholm and Persson 1982; Nehlig et al., 1992; Fredholm and Lindstrom, 1999; Fisone et al., 2004; Ferré, 2008).”
BackgroundSelf-citation
Adenosine and related drugs in brain diseases: present and future in clinical trials.
Lopes, L. V., Sebastião, A., & Ribeiro, J. (2011) · Current Topics in Medicinal Chemistry · doi:10.2174/156802611795347591 · Cited by 94 · see citing works
“A2A receptor reduces affinity for dopamine D2 receptors [123, 124]”
Background
Caffeine promotes wakefulness via dopamine signaling in Drosophila
Nall, A. H., Shakhmantsir, I., Cichewicz, K., Birman, S., Hirsh, J., & Sehgal, A. (2016) · Scientific Reports · doi:10.1038/srep20938 · Cited by 85 · see citing works
Caffeine and adenosine A2A receptor inactivation decrease striatal neuropathology in a lentiviral‐based model of Machado–Joseph disease
Gonçalves, N., Simões, A., Cunha, R. A., & de Almeida, L. P. (2013) · Annals of Neurology · doi:10.1002/ana.23866 · Cited by 90 · see citing works
Caffeine and seizures: A systematic review and quantitative analysis.
Koert, R. R. V., Bauer, P., Schuitema, I., Sander, J. W., & Visser, G. (2018) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2017.11.003 · Cited by 79 · see citing works
“Chronic administration of caffeine does not affect seizure susceptibility as strongly as acute administration[3,16–26,29,30,45,46,49,57], suggesting the development of tolerance to A1- and A2Areceptor blockade by caffeine.[45,54,56,58,64,100,104] Chronic or acute administration of caffeine did not affect the sensitivi…”
Blockade of adenosine A2A receptors recovers early deficits of memory and plasticity in the triple transgenic mouse model of Alzheimer's disease
Silva, A. C., Lemos, C., Gonçalves, F. Q., Pliássova, A., Machado, N. J., Silva, H. B. L., Canas, P. M., Cunha, R. A., Lopes, J. P., & Agostinho, P. M. (2018) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.05.024 · Cited by 85 · see citing works
Caffeine prevents sleep loss‐induced deficits in long‐term potentiation and related signaling molecules in the dentate gyrus
Alhaider, I. A., Aleisa, A. M., Tran, T. T., & Alkadhi, K. A. (2010) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2010.07175.x · Cited by 84 · see citing works
“Caffeine, a commonly used central nervous system stimulant (Nicholson & Stone, 1980; Nehlig et al., 1992; Ferre, 2008), is an important pharmacological research tool for studying the involvement of adenosine receptors in cognitive function (Kopf et al., 1999; Dall’ Igna et al., 2004).”
Background
Neuroprotection by caffeine in the MPTP model of parkinson’s disease and its dependence on adenosine A2A receptors
Xu, K., Luca, D. G. D., Orrù, M., Xu, Y., Chen, J., & Schwarzschild, M. A. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2016.02.035 · Cited by 84 · see citing works
“Several studies have indicated that caffeine exerts its psychostimulant effects acting as a nonselective adenosine A1R and A2AR receptor antagonist (Fredholm and Persson, 1982; Nehlig et al., 1992; Fredholm and Lindström, 1999; Fisone et al., 2004; Ferré, 2008).”
Background
Risk assessment of energy drinks with focus on cardiovascular parameters and energy drink consumption in Europe
Ehlers, A., Marakis, G. N., Lampen, A., & Hirsch‐Ernst, K. I. (2019) · Food and Chemical Toxicology · doi:10.1016/j.fct.2019.05.028 · Cited by 82 · see citing works
Pharmacologic interventions for the prevention and treatment of retinopathy of prematurity
Beharry, K. D. A., Valencia, G. B., Lazzaro, D. R., & Aranda, J. V. (2016) · Seminars in Perinatology · doi:10.1053/j.semperi.2015.12.006 · Cited by 82 · see citing works
“Caffeine also stimulates dopaminergic activity by removing the negative modulatory effects of adenosine at dopamine receptors.(112) Caffeine was first demonstrated to be effective for treatment of apnea of prematurity (AOP) in the 1970s by Aranda et al.”
The Relationship of Caffeine Intake with Depression, Anxiety, Stress, and Sleep in Korean Adolescents
Jin, M.-J., Yoon, C.-H., Ko, H., Kim, H.-M., Kim, A., Moon, H., & Jung, S.-P. (2016) · Korean Journal of Family Medicine · doi:10.4082/kjfm.2016.37.2.111 · Cited by 80 · see citing works
Astrocyte regulation of synaptic signaling in psychiatric disorders
Kruyer, A., Kalivas, P. W., & Scofield, M. D. (2022) · Neuropsychopharmacology · doi:10.1038/s41386-022-01338-w · Cited by 76 · see citing works
“Gi-coupled A1 and Gs-coupled A2A adenosine receptors have received the most attention for their regulation of synaptic physiology in recent years [95, 107, 108].”
Background
Recent advances in the utilization of tea active ingredients to regulate sleep through neuroendocrine pathway, immune system and intestinal microbiota
Wei, Y., Xu, J., Miao, S., Wei, K., Peng, L., Wang, Y., & Wei, X. (2022) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2022.2048291 · Cited by 73 · see citing works
Acute effects of tea consumption on attention and mood
Einöther, S. J. L., & Martens, V. E. G. (2013) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.113.058248 · Cited by 74 · see citing works
“Caffeine is present in a range of beverages (eg, tea, coffee, soft drinks, energy drinks) and in some foods (eg, chocolate) and is the most consumed psychoactive ingredient worldwide (24).”
Background
A comparison of the effects of caffeine following abstinence and normal caffeine use
Addicott, M. A., & Laurienti, P. J. (2009) · Psychopharmacology · doi:10.1007/s00213-009-1668-3 · Cited by 69 · see citing works
“At normal dietary concentrations, caffeine produces a mild neurostimulant effect by antagonizing adenosine, thus disinhibiting neuronal firing throughout the brain (for review, see Nehlig 1999; Ferre 2008).”
Background
Adenosine receptors as markers of brain iron deficiency: Implications for Restless Legs Syndrome
Quiroz, C., Gulyani, S., Ruiqian, W., Bonaventura, J., Cutler, R. G., Pearson, V., Allen, R. P., Earley, C. J., Mattson, M. P., & Ferré, S. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.09.002 · Cited by 69 · see citing works
“…A1R could be involved in the pathogenesis of PLMS in RLS. Postsynaptic A1R form heteromers with D1R and their activation or blockade leads to a respective selective decrease or increase in D1R-mediated activation of D1R-expressing striato-nigral neurons (Ferré et al., 1997; Ferré, 2008, 2010).”
BackgroundSelf-citation
The effect of caffeine on working memory load-related brain activation in middle-aged males
Klaassen, E. B., de Groot, R. H. M., Evers, E. A. T., Snel, J., Veerman, E. C. I., Ligtenberg, A. J. M., Jolles, J., & Veltman, D. J. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.06.026 · Cited by 68 · see citing works
“This finding is consistent with both the neurostimulant and arousal enhancing effects on caffeine primarily via the dopamine (Ferre, 2008; Pelligrino et al., 2010) and histaminergic arousal (Ferre, 2008) systems respectively.”
BackgroundResultInfluential
Caffeine Expectancy Questionnaire (CaffEQ): Construction, psychometric properties, and associations with caffeine use, caffeine dependence, and other related variables.
Huntley, E. D., & Juliano, L. M. (2011) · Psychological Assessment · doi:10.1037/a0026417 · Cited by 69 · see citing works
Pharmacological recruitment of the GABAergic tail of the ventral tegmental area by acute drug exposure
Kaufling, J., Waltisperger, E., Bourdy, R., Valera, A. M., Veinante, P., Freund‐Mercier, M. J., & Barrot, M. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.00984.x · Cited by 66 · see citing works
“Due to caffeine’s low affinity for phophodiesterases, its in vivo action, particularly its psychostimulant effect, is thought to be mediated through its inhibitory effects on adenosine receptors (Ferré, 2008).”
Background
Adenosine A2A Receptors in Psychopharmacology: Modulators of Behavior, Mood and Cognition
Shen, H., & Chen, J. (2009) · Current Neuropharmacology · doi:10.2174/157015909789152191 · Cited by 66 · see citing works
“The activation of A2ARs can reduce D2R affinity and function, which may potentially underlie the antipsychotic-like profile of adenosine agonists [56], the hyperdopaminergic effect of caffeine [53, 56] and the exacerbation of psychotic symptoms by caffeine in schizophrenic patients [132].”
Background
Caffeine triggers behavioral and neurochemical alterations in adolescent rats
Ardais, A. P., Borges, M. F., da Rocha, A. S., Sallaberry, C., Cunha, R. A., & Porciúncula, L. O. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2014.04.003 · Cited by 64 · see citing works
“…adenosine receptor antagonist with similar in vitro affinities for A1 receptors (A1R) and A2AR (Fredholm et al., 1999), the main adenosine receptors involved in memory normalization (Cunha and Agostinho, 2010) and in the motor-activating, reinforcing and arousal effects of this drug (Ferré, 2008).”
Explaining Human Recreational Use of ‘pesticides’: The Neurotoxin Regulation Model of Substance Use vs. the Hijack Model and Implications for Age and Sex Differences in Drug Consumption
Hagen, E. H., Roulette, C. J., & Sullivan, R. J. (2013) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2013.00142 · Cited by 64 · see citing works
“interacts with the central dopaminergic systems via antagonism of endogenous adenosine (135).”
Background
Separating neural and vascular effects of caffeine using simultaneous EEG–FMRI: Differential effects of caffeine on cognitive and sensorimotor brain responses
Diukova, A., Ware, J. J., Smith, J. E., Evans, J., Murphy, K., Rogers, P. J., & Wise, R. G. (2012) · NeuroImage · doi:10.1016/j.neuroimage.2012.04.041 · Cited by 64 · see citing works
“In addition, y, Park Place, Cardiff University, license. there is also evidence showing that caffeine has secondary effects on other neurotransmitter systems including dopamine, acetylcholine and noradrenaline (Ferre, 2008; Fredholm et al., 1999; Latini and Pedata, 2001).”
BackgroundInfluential
Caffeine Caused a Widespread Increase of Resting Brain Entropy
Chang, D., Song, D., Zhang, J., Shang, Y., Ge, Q., & Wang, Z. (2018) · Scientific Reports · doi:10.1038/s41598-018-21008-6 · Cited by 62 · see citing works
Plant-derived nootropics and human cognition: A systematic review
Lorca, C., Mulet, M., Arévalo‐Caro, C., Sanchez, M. Á., Perez, A., Perrino, M., Bach-Faig, A., Aguilar, A., Vilella, E., Gallart‐Palau, X., et al. (2022) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2021.2021137 · Cited by 64 · see citing works
Development of the Caffeine Withdrawal Symptom Questionnaire: Caffeine withdrawal symptoms cluster into 7 factors
Juliano, L. M., Huntley, E. D., Harrell, P. T., & Westerman, A. T. (2012) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2012.01.009 · Cited by 61 · see citing works
The effects of energy drink in combination with alcohol on performance and subjective awareness
Alford, C., Hamilton-Morris, J., & Verster, J. C. (2012) · Psychopharmacology · doi:10.1007/s00213-012-2677-1 · Cited by 60 · see citing works
“Blockade of the A2A receptor by caffeine inhibits the sleeppromoting effect with adenosine levels increasing across the hours of wakefulness (Davis et al. 2003; Ferré 2008; Huang et al. 2007; Landolt 2008; Sturgess et al. 2010).”
Background
Induced Alkalosis and Caffeine Supplementation: Effects on 2,000-m Rowing Performance
Carr, A. J., Gore, C. J., & Dawson, B. (2011) · International Journal of Sport Nutrition and Exercise Metabolism · doi:10.1123/ijsnem.21.5.357 · Cited by 72 · see citing works
“Caffeine supplementation can improve short-term (5–10 min) endurance performance (Jackman, Wendling, Friars, & Graham, 1996; Wiles, Bird, & Hopkins, 1992) via enhanced voluntary muscle activation (Ferré, 2008; Kalmar, 2005), reduced rating of perceived exertion (RPE) and pain perception during exercise (Ganio, Klau, C…”
Background
Caffeine Protects Dopaminergic Neurons From Dopamine-Induced Neurodegeneration via Synergistic Adenosine-Dopamine D2-Like Receptor Interactions in Transgenic Caenorhabditis Elegans
Manalo, R. V. M., & Medina, P. M. B. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00137 · Cited by 55 · see citing works
“For the most part, its enhancing effects are attributed to the antagonism of adenosine A2A receptors (A2ARs)—ligands of which, like adenosine, bind to induce sleepiness—which may explain the psychostimulatory effects of caffeine (Ferré, 2008a).”
BackgroundResult
New Developments on the Adenosine Mechanisms of the Central Effects of Caffeine and Their Implications for Neuropsychiatric Disorders
Ferré, S., Díaz-Ríos, M., Salamone, J. D., & Prediger, R. D. (2018) · Journal of Caffeine and Adenosine Research · doi:10.1089/caff.2018.0017 · Cited by 52 · see citing works
Self-citation
Stimulant effects of adenosine antagonists on operant behavior: differential actions of selective A2A and A1 antagonists
Randall, P. A., Nunes, E. J., Janniere, S. L., Stopper, C. M., Farrar, A. M., Sager, T. N., Baqi, Y., Hockemeyer, J., Müller, C. E., & Salamone, J. D. (2011) · Psychopharmacology · doi:10.1007/s00213-011-2198-3 · Cited by 56 · see citing works
“Nonselective adenosine antagonists such as caffeine act as minor stimulants and are commonly consumed by humans drinking coffee, tea, and “energy drinks” (Antoniou et al. 2005; Ferré 2008; Ferré et al. 2008a; Reissig et al. 2009).”
Caffeine intake exerts dual genome-wide effects on hippocampal metabolism and learning-dependent transcription
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“In addition, current evidence suggests that the psychostimulant and reinforcing effects of caffeine may be the result of increased activity of dopaminergic neurotransmission, perhaps via adenosine–dopamine interactions (Powell et al., 2001; Ferré, 2008).”
Background
Dopamine dysregulation in a mouse model of paroxysmal nonkinesigenic dyskinesia
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“Pharmacological mechanisms underlying caffeine effects are primarily via a nonselective antagonism of adenosine receptors, with A1 and A2A receptors as preferential targets (Fredholm et al., 1999; Ferre, 2008).”
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Modulation of adenosine signaling prevents scopolamine-induced cognitive impairment in zebrafish
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“The psychostimulant effect of caffeine on the central nervous system (CNS) is primarily due to the antagonism of adenosine receptors A1 and A2A (Ferré, 2008; Fredholm, Bättig, Holmén, Nehlig, & Zvartau, 1999).”
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Caffeine and a selective adenosine A2A receptor antagonist induce sensitization and cross-sensitization behavior associated with increased striatal dopamine in mice
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“Caffeine causes a diverse range f pharmacological effects that are time- and concentrationependent and reversible (Ferre et al., 2008; Ferre, 2008; Bode Abbreviations: SR, serine/arginine-rich; ACTN, alpha actinin; KLF6, Krüppel-like actor 6; EMT, epithelial-mesenchymal-transition; HIF-1 , hypoxia…”
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Caffeine and cognitive performance: Persistent methodological challenges in caffeine research
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Background

Adenosine A1-A2A receptor heteromers: New targets for caffeine in the brain
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Self-citation
Role of the Central Ascending Neurotransmitter Systems in the Psychostimulant Effects of Caffeine
Ferré, S. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-1400 · Cited by 133 · see citing works
Self-citation
Review Article Role of the Central Ascending Neurotransmitter Systems in the Psychostimulant Effects of Caffeine
(2016)
New Developments on the Adenosine Mechanisms of the Central Effects of Caffeine and Their Implications for Neuropsychiatric Disorders
Ferré, S., Díaz-Ríos, M., Salamone, J. D., & Prediger, R. D. (2018) · Journal of Caffeine and Adenosine Research · doi:10.1089/caff.2018.0017 · Cited by 52 · see citing works
Self-citation
DARPP Chocolate: A Caffeinated Morsel of Striatal Signaling
Bastia, E., & Schwarzschild, M. A. (2003) · Science s STKE · doi:10.1126/stke.2003.165.pe2 · Cited by 11 · see citing works

Authors: Ferré, S.
Affiliations: National Institutes of Health (US)
Corresponding author: Ferré, Sergi
ORCID: Ferré, Sergi
Venue: Journal of Neurochemistry
Publisher: Wiley
Published: 2007-12-18
Volume: 105
Issue: 4
Pages: 1067-1079
ISSN: 0022-3042 (ISSN-L)
1471-4159
DOI: 10.1111/j.1471-4159.2007.05196.x
OpenAlex: W1994970739
Cited by: 440
References: 129
Citations by year: 2026: 12 · 2025: 19 · 2024: 14 · 2023: 23 · 2022: 31 · 2021: 30 · 2020: 15 · 2019: 26 · 2018: 24 · 2017: 18 · 2016: 32 · 2015: 32 · 2014: 25 · 2013: 34 · 2012: 29
FWCI: 1.52
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Journal of Neurochemistry (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
National Institute on Drug Abuse
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords: caffeine, psychostimulant effects, adenosine receptors, adenosine A1 receptor, adenosine A2A receptor, receptor heteromers, dopamine signaling, glutamatergic synapses, dopamine D1 receptor, dopamine D2 receptor, motor activation, reinforcement, adenosine
MeSH terms: Adenosine, Central Nervous System Stimulants, Animals, Caffeine, Humans, Receptors, Purinergic P1, Purinergic P1 Receptor Agonists

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An Update on the Mechanisms of the Psychostimulant Effects of Caffeine

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