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

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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 affects the vigilance decrement of Trite planiceps jumping spiders (Salticidae).
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“Caffeine is a natural product that interacts with the dopamine neurotransmitter signaling pathway in mammals, in which it has been well-studied, via several mechanisms (Fredholm, Bättig, Holmén, Nehlig, & Zvartau, 1999; Cauli & Morelli, 2005; Ferré, 2008).”
Background
Effects of oral caffeine pretreatment on response to intravenous nicotine and cocaine.
Johnson, M. W., Strain, E. C., & Griffiths, R. R. (2010) · Experimental and Clinical Psychopharmacology · doi:10.1037/a0020509 · Cited by 9
“…of results may relate to the differential involvement of adenosine receptor subtypes between caffeine with and without caffeine tolerance (e.g., Ferre, 2008; Ferre et al., 2008; Karcz-Kubicha et al., 2003; Quarta et al., 2004), and/or to the observations that chronic caffeine administration…”
Background
Distinct Personality Traits Associated with Intake of Coffee, Tea, and Cola Drinks and Smoking
Lara, D. R., Antoniolli, E., Frozi, J., Schneider, R., & Ottoni, G. L. (2011) · Journal of Caffeine Research · doi:10.1089/jcr.2011.0006 · Cited by 10
The MAO-A inhibitor clorgyline reduces ethanol-induced locomotion and its volitional intake in mice
Ledesma, J. C., Escrig, M. A., Pastor, R., & Aragón, C. M. G. (2013) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2013.11.012 · Cited by 9
Association Between Plasma Caffeine and Other Methylxanthines and Metabolic Parameters in a Psychiatric Population Treated With Psychotropic Drugs Inducing Metabolic Disturbances
Delacrétaz, A., Vandenberghe, F., Glatard, A., Levier, A., Dubath, C., Ansermot, N., Crettol, S., Gholam‐Rezaee, M., Guessous, I., Bochud, M., et al. (2018) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2018.00573 · Cited by 9
“Thus, theobromine has two- to three-fold lower affinity than caffeine for adenosine receptors A1 and A2A (58) and penetrates the blood-brain barrier less readily than caffeine (59).”
Background
Effect of chronic administration and withdrawal of caffeine on motor function, cognitive functions, anxiety, and the social behavior of BLC57 mice.
Mahdi, S., Almosawi, S., Baksh, H., Qareeballa, A. A., Alsaleh, B., Falamarzi, F., Alrabaani, M., Alkalbani, A., & Kamal, A. (2019) · Europe PMC (PubMed Central) · Cited by 9
Using caffeine as a chemical means to induce flow states
Reich, N., Mannino, M., & Kotler, S. (2024) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2024.105577 · Cited by 9
“It is well established that especially high and daily caffeine admin-istrations induce desensitization (tolerance), and various mechanisms have been suggested (see Ferre, 2008).”
Influential
Coffee and mental disorders: How caffeine affects anxiety and depression
Meamar, M., Raise‐Abdullahi, P., Rashidy‐Pour, A., & Raeis-Abdollahi, E. (2024) · Progress in brain research · doi:10.1016/bs.pbr.2024.06.015 · Cited by 13
Role of various lifestyle and behavioral strategies in positive mental health across a preventive to therapeutic continuum
Prakash, J., Chatterjee, K., Srivastava, K., Chauhan, V. S., & Chail, A. (2020) · Industrial Psychiatry Journal · doi:10.4103/ipj.ipj_126_20 · Cited by 11
“While short-term use of caffeine is associated with better mood, alertness, and performance, the harm far outweighs the benefits.[23,24] High intake of caffeine has been found to be associated with anxiety, elation, panic, irritability, restlessness, psychomotor agitation, dysphoria, mixed mood state, etc.”
Background
The therapeutic potential of exercise and caffeine on attention-deficit/hyperactivity disorder in athletes
Sogard, A. S., & Mickleborough, T. D. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.978336 · Cited by 8
“It is postulated in humans, and shown in multiple animal studies that acute and chronic CAF ingestion selectively antagonizes adenosine receptors (Ferré, 2008; Pandolfo et al., 2013; Cunha, 2016; Frontiers in Neuroscience 07 frontiersin.org FIGURE 2 The effects of caffeine on adenosine receptors.”
BackgroundInfluential
Effects of Caffeine on Main Symptoms in Children with ADHD: A Systematic Review and Meta-Analysis of Randomized Trials
Perrotte, G., Moreira, M. M. G., de Vargas, A., Filho, A. T., & Castaldelli-Maia, J. M. (2023) · Brain Sciences · doi:10.3390/brainsci13091304 · Cited by 8
Contribution of Caffeine to the Psychostimulant, Neuroinflammatory and Neurotoxic Effects of Amphetamine-Related Drugs
Frau, L., Simola, N., & Morelli, M. (2013) · Journal of Caffeine Research · doi:10.1089/jcr.2013.0007 · Cited by 8
“40 It is known that caffeine may also affect targets other than the adenosine receptors, such as the inhibition of phosphodiesterase and the activation of ryanodine Ca 2 + channels, which would result in effects that are not dependent on dopaminergic mechanisms.”
Tea consumption maybe an effective active treatment for adult attention deficit hyperactivity disorder (ADHD)
Liu, K., Liang, X., & Kuang, W. (2011) · Medical Hypotheses · doi:10.1016/j.mehy.2010.08.049 · Cited by 8
Caffeine and attentional control: improved and impaired performance in healthy older adults and Parkinson’s disease according to task demands
Sharma, K., Fallon, S. J., Davis, T., Ankrett, S., Munro, G., Christopher, G., & Coulthard, E. J. (2022) · Psychopharmacology · doi:10.1007/s00213-021-06054-9 · Cited by 11
“Adenosine A2A receptors are also colocalised with dopaminergic D2 receptors on GABAergic neurons and have antagonising effects (Benarroch 2008; Ferré 2008; Fredholm & Svenningsson 2003).”
Background
Caffeine improved spatial learning and memory deficit in sleep deprived female rat
Esmaeilpour, K., Sheibani, V., & Saadati, H. (2015) · Cited by 8
Quantitative Proteomic Analysis of the Orbital Frontal Cortex in Rats Following Extended Exposure to Caffeine Reveals Extensive Changes to Protein Expression: Implications for Neurological Disease
Franklin, J. L., Mirzaei, M., Wearne, T. A., Homewood, J., Goodchild, A. K., Haynes, P. A., & Cornish, J. L. (2016) · Journal of Proteome Research · doi:10.1021/acs.jproteome.5b01043 · Cited by 8
Caffeine alters the dynamics of ocular accommodation depending on the habitual caffeine intake
Redondo, B., Vera, J., Molina, R., Luque‐Casado, A., & Jiménez, R. (2019) · Experimental Eye Research · doi:10.1016/j.exer.2019.05.003 · Cited by 10
Possible synergies between isatin, an endogenous MAO inhibitor, and antiparkinsonian agents on the dopamine release from striatum of freely moving rats.
Faro, L. R. F., Justo, L., Alfonso, M., & Durán, R. (2020) · Neuropharmacology · doi:10.1016/j.neuropharm.2020.108083 · Cited by 8
Improvement of postural adjustment steps in hemiparkinsonian rats chronically treated with caffeine is mediated by concurrent blockade of A1 and A2A adenosine receptors
Bata-García, J. L., Tun-Cobá, L., Álvarez-Cervera, F. J., Villanueva-Toledo, J. R., Heredia-López, F. J., & Góngora-Alfaro, J. L. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2009.12.072 · Cited by 8
Bayesian Nonparametric Analysis of Residence Times for Protein–Lipid Interactions in Molecular Dynamics Simulations
Sexton, R., Fazel, M., Schweiger, M., Pressé, S., & Beckstein, O. (2025) · Journal of Chemical Theory and Computation · doi:10.1021/acs.jctc.4c01522 · Cited by 7
Adenosine A2A receptors in the nucleus accumbens regulate stress resilience and predict susceptibility to stress-induced affective disturbances
Bevilacqua, L. M., Neto, F. D. S., Rosado, A. F., Pinho, C. M., Platt, N., & Kaster, M. P. (2026) · Purinergic Signalling · doi:10.1007/s11302-025-10118-2 · Cited by 7
“Adenosine receptors, particularly the A1 and A2A, are abundantly expressed in the NAc, where they play key modulatory roles in synaptic transmission, neuronal excitability, and reward-related behaviors [12, 13].”
Integrative Biological, Cognitive and Affective Modeling of Caffeine Use on Stress
de Haan, R. E., Blankert, M., & Ziabari, S. S. M. (2019) · Advances in intelligent systems and computing · doi:10.1007/978-3-030-23887-2_9 · Cited by 7
The Performance Effect of Scheduled Carbohydrate and Caffeine Intake during Simulated Team Sport Match-Play
Keane, J., Shovlin, A., Devenney, S., Malone, S., Young, D., Coratella, G., Collins, K. D., & Shortall, M. (2020) · Nutrients · doi:10.3390/nu12071926 · Cited by 7
“Previously, the primary mechanism of action was related to the antagonism of adenosine receptors in the brain [14].”
Background
Caffeine intake is associated with less severe depressive symptoms in noncancer populations: an analysis based on NHANES 2007-2016.
Yang, L.-S., Zhang, Z.-Y., Yan, L.-J., Yan, Y.-C., Tan, S., Wang, D.-X., Dong, Z.-R., & Li, T. (2023) · Nutrition Research · doi:10.1016/j.nutres.2023.07.004 · Cited by 7
Cognitive Enhancement in Humans
Dresler, M., & Repantis, D. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-417042-1.00011-5 · Cited by 6
Impact of Caffeine on Ethanol‐Induced Stimulation and Sensitization: Changes in ERK and DARPP‐32 Phosphorylation in Nucleus Accumbens
Porru, S., López‐Cruz, L., Carratalá‐Ros, C., Salamone, J. D., Acquas, E., & Correa, M. (2021) · Alcoholism Clinical and Experimental Research · doi:10.1111/acer.14553 · Cited by 7
Peripheral Administration of a μ-Opioid Receptor Agonist DAMGO Suppresses the Anxiolytic and Stimulatory Effects of Caffeine
Sudakov, S. K., Nazarova, G. A., Alekseeva, E. V., & Kolpakov, A. A. (2015) · Bulletin of Experimental Biology and Medicine · doi:10.1007/s10517-015-2744-9 · Cited by 7
The Role of Adenosine in the Ventral Striatal Circuits Regulating Behavioral Activation and Effort-Related Decision Making: Importance for Normal and Pathological Aspects of Motivation
Salamone, J. D., Correa, M., Randall, P. A., Nunes, E. J., Pardo, M., & López‐Cruz, L. (2012) · Springer eBooks · doi:10.1007/978-1-4614-3903-5_23 · Cited by 7
Phytochemicals for the Improvement of Cognitive Function through Cholinergic Anti-inflammatory Pathway
Singh, D. K., Kumari, B., Sinha, S., & Fatima, K. (2024) · Current Indian Science · doi:10.2174/012210299x309791240914125655 · Cited by 6
Effects of isolated or combined carbohydrate and caffeine supplementation on tennis training performance: single-blind randomized placebo-controlled crossover session
Abdioğlu, M., Mor, A., Alexe, D. I., Todor, R. M., Panaet, E. A., Alexe, C. I., & Akça, F. (2025) · Frontiers in Nutrition · doi:10.3389/fnut.2025.1608893 · Cited by 6
“This ergogenic factor is that caffeine easily crosses the blood–brain barrier thanks to its special chemical structure and acts on adenosine receptors (A1, A2), thus blocking pain-producing receptors in the body (45).”
Tightrope or Slackline? The Neuroscience of Psychoactive Substances
Coulon, P., & Gorji, A. (2016) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2016.04.004 · Cited by 6
Genotoxic effect of caffeine in Yarrowia lipolytica cells deficient in DNA repair mechanisms
Quiñones-González, C. A., Arredondo-Mendoza, G. I., Jiménez‐Salas, Z., Larriba-Calle, G., Ruíz-Herrera, J., & Campos‐Góngora, E. (2019) · Archives of Microbiology · doi:10.1007/s00203-019-01658-4 · Cited by 6
“2004; Ferre 2008).”
Effects of aripiprazole on caffeine-induced hyperlocomotion and neural activation in the striatum
Batista, L. A., Viana, T. G., da Silveira, V. T., de Aguiar, D. C., & Moreira, F. A. (2015) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-015-1170-x · Cited by 6
“Caffeine is somewhat different from other psychostimulants since it has weak reinforcing properties and controversy exists regarding its effects upon dopamine release in the ventral striatum (Daly and Fredholm 1998; Quarta et al. 2004; De Luca et al. 2007; Ferre 2008).”
BackgroundInfluential
Nutrition and Psychiatric Disorders
Mohamed, W. M. Y., & Kobeissy, F. H. (2022) · Nutritional neurosciences · doi:10.1007/978-981-19-5021-6 · Cited by 6
“Forte et al. (2016) in their writing suggested that for people adapting to a diet that induces ketosis, there is inhibition of glycolysis in the brain that reduces the excitation of the neuron by potentiation of GABA transmission via the steroid pathway.”
Background
CAFFEINE AND CHLOROGENIC ACIDS IN COFFEE AND EFFECTS ON SELECTED NEURODEGENERATIVE DISEASES
Santos, R. M. M., Hunter, T., Wright, N., & Lima, D. R. A. (2013) · Journal of Pharmaceutical and Scientific Innovation · doi:10.7897/2277-4572.02443 · Cited by 7
Caffeine
Evatt, D. P., & Griffiths, R. R. (2013) · Elsevier eBooks · doi:10.1016/b978-0-12-375083-9.00033-7 · Cited by 6
Novel kombucha-based energy drinks: Supplementation, efficacy, and safety
Zhao, T., Ter, Z. Y., Sermwittayawong, D., Chang, L. S., Fazry, S., & Lim, S. J. (2025) · Journal of Food Composition and Analysis · doi:10.1016/j.jfca.2025.107696 · Cited by 7
The association of caffeine consumption with positive affect but not with negative affect changes across the day
Hachenberger, J., Li, Y., Realo, A., & Lemola, S. (2025) · Scientific Reports · doi:10.1038/s41598-025-14317-0 · Cited by 8
The Issue of “Smart Drugs” on the Example of Modafinil: Toxicological Analysis of Evidences and Biological Samples
Nowak, K., Chłopaś‐Konowałek, A., Szpot, P., & Zawadzki, M. (2025) · Journal of Xenobiotics · doi:10.3390/jox15010015 · Cited by 7
The orexinergic system mediates the excitatory effects of caffeine on the arousal and sympathetic activity
Li, Y., Guo, Z., Cai, C., Liu, D., Kang, Y., & Liu, P. (2023) · Heliyon · doi:10.1016/j.heliyon.2023.e14170 · Cited by 5
“Caffeine is a non-selective adenosine receptor antagonist, targeting mainly adenosine A1 and A2A receptors in the brain [1,2].”
Background

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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