Opposite modulatory roles for adenosine A1and A2Areceptors on glutamate and dopamine release in the shell of the nucleus accumbens. Effects of chronic caffeine exposure
Abstract
Previous studies have demonstrated opposing roles for adenosine A1 and A2A receptors in the modulation of extracellular levels of glutamate and dopamine in the striatum. In the present study, acute systemic administration of motor-activating doses of the A2A receptor antagonist MSX-3 significantly decreased extracellular levels of dopamine and glutamate in the shell of the rat nucleus accumbens (NAc) and counteracted both dopamine and glutamate release induced by systemic administration of motor-activating doses of either the A1 receptor antagonist CPT or caffeine. Furthermore, exposure to caffeine in the drinking water (1 mg/mL, 14 days) resulted in tolerance to the effects of systemic injection of CPT or caffeine, but not MSX-3, on extracellular levels of dopamine and glutamate in the NAc shell. The present results show: first, the existence of opposite tonic effects of adenosine on extracellular levels of dopamine and glutamate in the shell of the NAc mediated by A1 and A2A receptors; second, that complete tolerance to caffeine's dopamine- and glutamate-releasing effects which develops after chronic caffeine exposure is attributable to an A1 receptor-mediated mechanism. Development of tolerance to the dopamine-releasing effects of caffeine in the shell of the NAc may explain its weak addictive properties and atypical psychostimulant profile.
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Caffeine antagonism of adenosine receptors can result in enhanced dopaminergic signaling due to increased dopamine release, upregulation of dopamine receptors, and increased affinity of dopamine receptors for dopamine in the striatum and nucleus accumbens.
“Caffeine antagonism of adenosine receptors can result in enhanced dopaminergic signaling, thought to be due to a combination of increased dopamine release (200, 201), upregulation of dopamine receptors, and increased affinity of dopamine receptors for dopamine in the striatum and nucleus accumbens (202).”
From The Safety of Ingested Caffeine: A Comprehensive Review (2017) · cites this paper as [201]
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- Authors
- Quarta, D., Ferré, S., Solinas, M., You, Z., Hockemeyer, J., Popoli, P., & Goldberg, S. R.
- Affiliations
- United States Department of Health and Human Services (US)
- National Institutes of Health (US)
- University of Bonn (DE)
- Istituto Superiore di Sanità (IT)
- Corresponding author
- Goldberg, Steven R.
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2004-02-04
- Volume
- 88
- Issue
- 5
- Pages
- 1151-1158
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W1529567719
- Cited by
- 163
- References
- 33
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 7 · 2023: 4 · 2022: 6 · 2021: 12 · 2020: 6 · 2019: 6 · 2018: 3 · 2017: 5 · 2016: 4 · 2015: 10 · 2014: 5 · 2013: 11 · 2012: 12
- FWCI
- 6.25
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- adenosine A1 receptor, adenosine A2A receptor, nucleus accumbens shell, glutamate release, dopamine release, caffeine, caffeine tolerance, MSX-3, CPT, extracellular neurotransmitter levels, caffeine addiction
- MeSH terms
- Animals, Caffeine, Dopamine, Male, Nucleus Accumbens, Theophylline, Time, Xanthines, Rats, Sprague-Dawley, Microdialysis, Glutamic Acid, Receptor, Adenosine A1, Receptor, Adenosine A2A, Rats, Adenosine A1 Receptor Antagonists, Adenosine A2 Receptor Antagonists
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