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Antagonism of adenosine receptors by caffeine and caffeine metabolites in equine forebrain tissues.
Abstract: To determine the presence of adenosine receptor subtypes A1 and A2a in equine forebrain tissues and to characterize the interactions of caffeine and its metabolites with adenosine receptors in the CNS of horses. Methods: Brain tissue specimens obtained during necropsy from 5 adult male research horses. Methods: Membrane-enriched homogenates from cerebral cortex and striatum were evaluated by radioligand binding assays with the A1-selective ligand [3H]DPCPX and the A2a-selective ligand [3H]ZM241385. Functional responses to adenosine receptor agonists and antagonists were determined by a nucleotide exchange assay using [35S]-guanosine 5'-(gamma-thio) triphosphate ([35S]GTPgammaS). Results: Saturable high affinity [3H]DPCPX binding (A1) sites were detected in cerebral cortex and striatum, whereas high-affinity [3H]ZM241385 binding (A2a) sites were detected only in striatum. Caffeine and related methylxanthines had similar binding affinities at A1 and A2a sites with rank orders of drug binding affinities (theophylline > paraxanthine > or = caffeine >> theobromine) similar to other species. [35S]GTPgammaS exchange revealed that caffeine and its metabolites act as pure adenosine receptor antagonists at concentrations that correspond to A1 and A2a receptor binding affinities. Conclusions: Results of our study affirm the presence of guanine nucleotide binding protein linked adenosine receptors (ie, high-affinity A1 and A2a adenosine receptors) in equine forebrain tissues and reveal the antagonistic actions by caffeine and several biologically active caffeine metabolites. Antagonism of adenosine actions in the equine CNS by these stimulants may be responsible for some central actions of methylxanthine drugs, including motor stimulation and enhanced racing performance.
Publication Date: 2003-02-27 PubMed ID: 12602592DOI: 10.2460/ajvr.2003.64.216Google Scholar: Lookup The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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This research paper explores the presence of adenosine receptor subtypes A1 and A2a in horse forebrain tissues and describes how caffeine and its metabolites interact with these receptors. The findings confirm that these receptors exist in the equine brain and also reveal that caffeine and its metabolites can counteract the function of adenosine in the horse’s central nervous system. This interaction could possibly affect the horse’s locomotion and racing performance.
Methods
- Brain tissue samples were collected post-mortem from five adult male research horses.
- The researchers focused on the membrane-enriched homogenates from the cerebral cortex and striatum of the horse’s brain.
- Radioligand binding assays using A1-selective ligand [3H]DPCPX and A2a-selective ligand [3H]ZM241385 were carried out to measure the presence and number of adenosine receptors.
- A nucleotide exchange assay was done to determine the functional response of the adenosine receptors to agonists and antagonists using [35S]-guanosine 5′-(gamma-thio) triphosphate ([35S]GTPgammaS).
Results
- [3H]DPCPX binding (A1) sites were found in cerebral cortex and striatum, proving the presence of adenosine A1 receptors.
- [3H]ZM241385 (A2a) binding sites were found only in striatum, validating the presence of adenosine A2a receptors.
- The caffeine-based compounds studied had comparable binding affinities at both A1 and A2a sites.
- The rank orders of drug binding affinities (theophylline > paraxanthine > or = caffeine >> theobromine) were found to be similar to that in other species.
- The nucleotide exchange study revealed that caffeine and its metabolites function purely as adenosine receptor antagonists at concentrations matching the receptor binding affinities.
Conclusions
- The research confirmed the presence of high-affinity A1 and A2a adenosine receptors linked to guanine nucleotide-binding proteins in equine forebrain tissues.
- Caffeine and several of its metabolites were found to function as antagonists, counteracting the function of adenosine in the equine central nervous system.
- The research provides evidence that caffeine and its metabolites may influence the motor functioning and racing performance of horses by antagonizing the function of adenosine in the central nervous system.
Cite This Article
APA
Chou CC, Vickroy TW.
(2003).
Antagonism of adenosine receptors by caffeine and caffeine metabolites in equine forebrain tissues.
Am J Vet Res, 64(2), 216-224.
https://doi.org/10.2460/ajvr.2003.64.216 Publication
Researcher Affiliations
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610-0144, USA.
MeSH Terms
- Animals
- Caffeine / metabolism
- Caffeine / pharmacology
- Central Nervous System Stimulants / metabolism
- Central Nervous System Stimulants / pharmacology
- Cerebral Cortex / metabolism
- Horses
- Male
- Neostriatum / metabolism
- Prosencephalon / metabolism
- Purinergic P1 Receptor Antagonists
- Receptors, Purinergic P1 / metabolism
- Theobromine / metabolism
- Theophylline / metabolism
Citations
This article has been cited 9 times.- Szlapinski SK, Charrette A, Guthrie N, Hilmas CJ. Paraxanthine safety and comparison to caffeine. Front Toxicol 2023;5:1117729.
- Reichert CF, Deboer T, Landolt HP. Adenosine, caffeine, and sleep-wake regulation: state of the science and perspectives. J Sleep Res 2022 Aug;31(4):e13597.
- Jäger R, Purpura M, Wells SD, Liao K, Godavarthi A. Paraxanthine Supplementation Increases Muscle Mass, Strength, and Endurance in Mice. Nutrients 2022 Feb 20;14(4).
- Xing D, Yoo C, Gonzalez D, Jenkins V, Nottingham K, Dickerson B, Leonard M, Ko J, Faries M, Kephart W, Purpura M, Jäger R, Wells SD, Sowinski R, Rasmussen CJ, Kreider RB. Dose-Response of Paraxanthine on Cognitive Function: A Double Blind, Placebo Controlled, Crossover Trial. Nutrients 2021 Dec 15;13(12).
- Yoo C, Xing D, Gonzalez D, Jenkins V, Nottingham K, Dickerson B, Leonard M, Ko J, Faries M, Kephart W, Purpura M, Jäger R, Wells SD, Sowinski R, Rasmussen CJ, Kreider RB. Acute Paraxanthine Ingestion Improves Cognition and Short-Term Memory and Helps Sustain Attention in a Double-Blind, Placebo-Controlled, Crossover Trial. Nutrients 2021 Nov 9;13(11).
- Manalo RVM, Medina PMB. Caffeine Protects Dopaminergic Neurons From Dopamine-Induced Neurodegeneration via Synergistic Adenosine-Dopamine D2-Like Receptor Interactions in Transgenic Caenorhabditis elegans. Front Neurosci 2018;12:137.
- Johnson IM, Prakash H, Prathiba J, Raghunathan R, Malathi R. Spectral analysis of naturally occurring methylxanthines (theophylline, theobromine and caffeine) binding with DNA. PLoS One 2012;7(12):e50019.
- Okuro M, Fujiki N, Kotorii N, Ishimaru Y, Sokoloff P, Nishino S. Effects of paraxanthine and caffeine on sleep, locomotor activity, and body temperature in orexin/ataxin-3 transgenic narcoleptic mice. Sleep 2010 Jul;33(7):930-42.
- Tsutsui S, Schnermann J, Noorbakhsh F, Henry S, Yong VW, Winston BW, Warren K, Power C. A1 adenosine receptor upregulation and activation attenuates neuroinflammation and demyelination in a model of multiple sclerosis. J Neurosci 2004 Feb 11;24(6):1521-9.
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