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An update on the mechanisms of the psychostimulant effects of caffeine
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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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“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]
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“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]
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“Furthermore, caffeine excites neural circuits that project from the basal ganglia to the striatum and cerebral cortex.9”
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“Notably, A2AR are now recognized as the main targets operated by chronic caffeine consumption to generate its psychoactive effects (Cunha and Agostinho 2010; Ferré 2008; Prediger 2010).”
BackgroundGomes, C. A., George, J., Chen, J., & Cunha, R. A. (2015) · Current topics in neurotoxicity · doi:10.1007/978-3-319-20273-0_5
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Food and Beverages Fortified with Phytonutrients
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“produce a mild neurostimulant effect by antagonizing adenosine, thus disinhibiting neuronal firing throughout the brain.(25,26) This counter effect on adenosine receptors will improve attention, reaction time, memory and verbal reasoning.”
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Adaji, R. I. (2016) · Michigan State University Libraries · doi:10.25335/9p6b-j935
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Libman, B. M. (2016) · doi:10.12794/metadc849709
“However, while both the pharmacodynamic and -kinetic interactions of caffeine with the CNS have been well documented (Ferré, 2008), less is understood about”
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Leong, X. (2016) · UTAS Research Repository · doi:10.25959/23239499
Segura, N. S. M. (2017) · Tesis Doctorals en Xarxa (Consorci de Serveis Universitaris de Catalunya) · doi:10.6035/14023.2017.237485
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Metadata
- 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
- 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
- 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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