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Accordingly, the regular intake of moderate doses of caffeine antagonizes adenosine receptors and affords robust neuroprotection. Although caffeine intake alters brain functional connectivity and multi-omics analyses indicate that caffeine intake modifies synaptic and metabolic processes, it is unclear how caffeine intake affects behavior, synaptic plasticity and its modulation by adenosine. We now report that male mice drinking caffeinated water (0.3 g\/L) for 2 weeks were behaviorally indistinguishable (locomotion, mood, memory) from control mice (drinking water) and displayed superimposable synaptic plasticity (long-term potentiation) in different brain areas (hippocampus, prefrontal cortex, amygdala). Moreover, there was a general preservation of the efficiency of adenosine A1 and A2A receptors to control synaptic transmission and plasticity, although there was a tendency for lower levels of endogenous adenosine ensuring A1 receptor-mediated inhibition. In spite of similar behavioral and neurophysiological function, caffeine intake increased the energy charge and redox state of cortical synaptosomes. This increased metabolic competence likely involved a putative increase in the glycolytic rate in synapses and a prospective greater astrocyte\u2013synapse lactate shuttling. It was concluded that caffeine intake does not trigger evident alterations of behavior or of synaptic plasticity but increases the metabolic competence of synapses, which might be related with the previously described better ability of animals consuming caffeine to cope with deleterious stimuli triggering brain dysfunction.<\/jats:p>","DOI":"10.3390\/biom13010106","type":"journal-article","created":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T01:33:30Z","timestamp":1672882410000},"page":"106","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Effects of Chronic Caffeine Consumption on Synaptic Function, Metabolism and Adenosine Modulation in Different Brain Areas"],"prefix":"10.3390","volume":"13","author":[{"given":"C\u00e1tia R.","family":"Lopes","sequence":"first","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"given":"Andreia","family":"Oliveira","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2929-8862","authenticated-orcid":false,"given":"Ingride","family":"Gaspar","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9616-8400","authenticated-orcid":false,"given":"Matilde S.","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2416-8479","authenticated-orcid":false,"given":"Joana","family":"Santos","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"given":"Eszter","family":"Szab\u00f3","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7234-3411","authenticated-orcid":false,"given":"Henrique B.","family":"Silva","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8671-989X","authenticated-orcid":false,"given":"\u00c2ngelo R.","family":"Tom\u00e9","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, 3000-456 Coimbra, Portugal"}]},{"given":"Paula M.","family":"Canas","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"given":"Paula","family":"Agostinho","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"given":"Rui A.","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, 3000-456 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2550-6422","authenticated-orcid":false,"given":"Rodrigo A.","family":"Cunha","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"given":"Ana Patr\u00edcia","family":"Sim\u00f5es","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5122-1802","authenticated-orcid":false,"given":"Jo\u00e3o Pedro","family":"Lopes","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7486-5056","authenticated-orcid":false,"given":"Samira G.","family":"Ferreira","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1056\/NEJMoa1112010","article-title":"Association of coffee drinking with total and cause-specific mortality","volume":"366","author":"Freedman","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1056\/NEJMra1816604","article-title":"Coffee, caffeine, and health","volume":"383","author":"Hu","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1016\/j.mayocp.2017.03.010","article-title":"Association between caffeine intake and all-cause and cause-specific mortality: A population-based prospective cohort study","volume":"92","author":"Tsujimoto","year":"2017","journal-title":"Mayo Clin. Proc."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1093\/advances\/nmaa177","article-title":"Caffeinated coffee consumption and health outcomes in the US population: A dose-response meta-analysis and estimation of disease cases and deaths avoided","volume":"12","author":"Boffetta","year":"2021","journal-title":"Adv. Nutr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"10488","DOI":"10.1038\/s41598-021-89964-0","article-title":"Neuromodulation and neuroprotective effects of chlorogenic acids in excitatory synapses of mouse hippocampal slices","volume":"11","author":"Fernandes","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_6","first-page":"83","article-title":"Actions of caffeine in the brain with special reference to factors that contribute to its widespread use","volume":"51","author":"Fredholm","year":"1999","journal-title":"Pharmacol. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.bcp.2019.06.008","article-title":"The physiological effects of caffeine on synaptic transmission and plasticity in the mouse hippocampus selectively depend on adenosine A1 and A2A receptors","volume":"166","author":"Lopes","year":"2019","journal-title":"Biochem. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1016\/j.neuroscience.2006.07.021","article-title":"Caffeine protects Alzheimer\u2019s mice against cognitive impairment and reduces brain beta-amyloid production","volume":"142","author":"Arendash","year":"2006","journal-title":"Neuroscience"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.expneurol.2006.08.008","article-title":"Caffeine and adenosine A2a receptor antagonists prevent beta-amyloid (25-35)-induced cognitive deficits in mice","volume":"203","author":"Fett","year":"2007","journal-title":"Exp. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"S55","DOI":"10.1212\/01.WNL.0000095214.53646.72","article-title":"Neuroprotection by caffeine and more specific A2A receptor antagonists in animal models of Parkinson\u2019s disease","volume":"61","author":"Schwarzschild","year":"2003","journal-title":"Neurology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/0304-3940(89)90112-2","article-title":"Ischaemic damage in gerbil hippocampus is reduced following upregulation of adenosine A1 receptors by caffeine treatment","volume":"103","author":"Rudolphi","year":"1989","journal-title":"Neurosci Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/0306-4522(91)90157-J","article-title":"The effects of caffeine on ischemic neuronal injury as determined by magnetic resonance imaging and histopathology","volume":"42","author":"Sutherland","year":"1991","journal-title":"Neuroscience"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/0006-8993(93)91672-F","article-title":"Long-term caffeine treatment leads to a decreased susceptibility to NMDA-induced clonic seizures in mice without changes in adenosine A1 receptor number","volume":"612","author":"Georgiev","year":"1993","journal-title":"Brain Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1046\/j.1528-1157.2003.50502.x","article-title":"Prolonged low-dose caffeine exposure protects against hippocampal damage but not against the occurrence of epilepsy in the lithium-pilocarpine model in the rat","volume":"44","author":"Rigoulot","year":"2003","journal-title":"Epilepsia"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1111\/j.1471-4159.2009.06465.x","article-title":"Caffeine and an adenosine A2A receptor antagonist prevent memory impairment and synaptotoxicity in adult rats triggered by a convulsive episode in early life","volume":"112","author":"Cognato","year":"2010","journal-title":"J. Neurochem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1016\/j.neuroscience.2007.11.020","article-title":"Chronic but not acute treatment with caffeine attenuates traumatic brain injury in the mouse cortical impact model","volume":"151","author":"Li","year":"2008","journal-title":"Neuroscience"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.expneurol.2011.12.026","article-title":"Caffeine prevents acute mortality after TBI in rats without increased morbidity","volume":"234","author":"Lusardi","year":"2012","journal-title":"Exp. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1111\/j.1471-4159.2009.06349.x","article-title":"Caffeine consumption attenuates neurochemical modifications in the hippocampus of streptozotocin-induced diabetic rats","volume":"111","author":"Duarte","year":"2009","journal-title":"J. Neurochem."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Duarte, J.M., Agostinho, P.M., Carvalho, R.A., and Cunha, R.A. (2012). Caffeine consumption prevents diabetes-induced memory impairment and synaptotoxicity in the hippocampus of NONcZNO10\/LTJ mice. PLoS One, 7.","DOI":"10.1371\/journal.pone.0021899"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1002\/ana.23866","article-title":"Caffeine and adenosine A2A receptor inactivation decrease striatal neuropathology in a lentiviral-based model of Machado-Joseph disease","volume":"73","author":"Cunha","year":"2013","journal-title":"Ann. Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1002\/ana.24867","article-title":"Caffeine alleviates progressive motor deficits in a transgenic mouse model of spinocerebellar ataxia","volume":"81","author":"Prediger","year":"2017","journal-title":"Ann. Neurol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.brainres.2009.10.054","article-title":"Chronic caffeine treatment attenuates experimental autoimmune encephalomyelitis induced by guinea pig spinal cord homogenates in Wistar rats","volume":"1309","author":"Chen","year":"2010","journal-title":"Brain Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.neuropharm.2014.06.029","article-title":"Chronic caffeine treatment protects against experimental autoimmune encephalomyelitis in mice: Therapeutic window and receptor subtype mechanism","volume":"86","author":"Wang","year":"2014","journal-title":"Neuropharmacology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.bbr.2010.06.022","article-title":"Chronic caffeine treatment during prepubertal period confers long-term cognitive benefits in adult spontaneously hypertensive rats (SHR), an animal model of attention deficit hyperactivity disorder (ADHD)","volume":"215","author":"Pires","year":"2010","journal-title":"Behav. Brain Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.euroneuro.2012.04.011","article-title":"Caffeine regulates frontocorticostriatal dopamine transporter density and improves attention and cognitive deficits in an animal model of attention deficit hyperactivity disorder","volume":"23","author":"Pandolfo","year":"2013","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1097\/FBP.0b013e3283564dd9","article-title":"Effect of long-term caffeine administration on depressive-like behavior in rats exposed to chronic unpredictable stress","volume":"23","author":"Pechlivanova","year":"2012","journal-title":"Behav. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"7833","DOI":"10.1073\/pnas.1423088112","article-title":"Caffeine acts through neuronal adenosine A2A receptors to prevent mood and memory dysfunction triggered by chronic stress","volume":"112","author":"Kaster","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"109776","DOI":"10.1016\/j.pnpbp.2019.109776","article-title":"Caffeine prevents neurodegeneration and behavioral alterations in a mice model of agitated depression","volume":"98","author":"Machado","year":"2020","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"S95","DOI":"10.3233\/JAD-2010-1408","article-title":"Chronic caffeine consumption prevents memory disturbance in different animal models of memory decline","volume":"20","author":"Cunha","year":"2010","journal-title":"J. Alzheimers Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1111\/jnc.13724","article-title":"How does adenosine control neuronal dysfunction and neurodegeneration?","volume":"139","author":"Cunha","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1002\/1531-8249(199907)46:1<95::AID-ANA14>3.0.CO;2-1","article-title":"Epileptogenic action of caffeine during anoxia in the neonatal rat hippocampus","volume":"46","author":"Dzhala","year":"1999","journal-title":"Ann. Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.eplepsyres.2018.10.013","article-title":"Effect of acute caffeine administration on PTZ-induced seizure threshold in mice: Involvement of adenosine receptors and NO-cGMP signaling pathway","volume":"149","author":"Esmaili","year":"2019","journal-title":"Epilepsy Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/0006-8993(95)01153-6","article-title":"The effects of selective A1 and A2a adenosine receptor antagonists on cerebral ischemic injury in the gerbil","volume":"705","author":"Phillis","year":"1995","journal-title":"Brain Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1227\/01.NEU.0000079487.66013.6F","article-title":"Caffeine impairs short-term neurological outcome after concussive head injury in rats","volume":"53","author":"Tariq","year":"2003","journal-title":"Neurosurgery"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1876","DOI":"10.1038\/s41380-018-0110-9","article-title":"Age-related shift in LTD is dependent on neuronal adenosine A2A receptors interplay with mGluR5 and NMDA receptors","volume":"25","author":"Ferreira","year":"2020","journal-title":"Mol. Psychiatry"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1002\/nbm.3080","article-title":"Caffeine alters resting-state functional connectivity measured by blood oxygenation level-dependent MRI","volume":"27","author":"Wu","year":"2014","journal-title":"NMR Biomed."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"14381","DOI":"10.1038\/s41598-021-93849-7","article-title":"Drinking coffee enhances neurocognitive function by reorganizing brain functional connectivity","volume":"11","author":"Kim","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6589","DOI":"10.1038\/s41380-021-01075-4","article-title":"Habitual coffee drinkers display a distinct pattern of brain functional connectivity","volume":"26","author":"Esteves","year":"2021","journal-title":"Mol. Psychiatry"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/0014-2999(86)90340-7","article-title":"Comparative effects of acute and chronic administration of caffeine on local cerebral glucose utilization in the conscious rat","volume":"129","author":"Nehlig","year":"1986","journal-title":"Eur. J. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1176\/ajp.156.2.229","article-title":"Human brain metabolic response to caffeine and the effects of tolerance","volume":"156","author":"Dager","year":"1999","journal-title":"Am. J. Psychiatry"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e149371","DOI":"10.1172\/JCI149371","article-title":"Caffeine intake exerts dual genome-wide effects on hippocampal metabolism and learning-dependent transcription","volume":"132","author":"Paiva","year":"2022","journal-title":"J. Clin. Investig."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1038\/38160","article-title":"Caffeine alters plasma adenosine levels","volume":"389","author":"Conlay","year":"1997","journal-title":"Nature"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1016\/0024-3205(84)90207-8","article-title":"Effects of chronic caffeine on brain adenosine receptors: Regional and ontogenetic studies","volume":"34","author":"Marangos","year":"1984","journal-title":"Life Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/S0006-8993(97)00378-8","article-title":"A1 and A2A adenosine receptors and A1 mRNA in mouse brain: Effect of long-term caffeine treatment","volume":"762","author":"Johansson","year":"1997","journal-title":"Brain Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1126\/science.1222939","article-title":"Synaptic dysfunction in depression: Potential therapeutic targets","volume":"338","author":"Duman","year":"2012","journal-title":"Science"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.arr.2016.04.005","article-title":"Synaptic pathology: A shared mechanism in neurological disease","volume":"28","author":"Henstridge","year":"2016","journal-title":"Ageing Res. Rev."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1111\/jnc.13713","article-title":"Synaptopathies: Synaptic dysfunction in neurological disorders\u2014A review from students to students","volume":"138","author":"Lepeta","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"101801","DOI":"10.1016\/j.pneurobio.2020.101801","article-title":"Presynaptic failure in Alzheimer\u2019s disease","volume":"194","author":"Barthet","year":"2020","journal-title":"Prog. Neurobiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/S0074-7742(05)63007-3","article-title":"Adenosine and brain function","volume":"63","author":"Fredholm","year":"2005","journal-title":"Int. Rev. Neurobiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S0006-8993(03)03247-5","article-title":"Subcellular localization of adenosine A1 receptors in nerve terminals and synapses of the rat hippocampus","volume":"987","author":"Rebola","year":"2003","journal-title":"Brain Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1016\/j.neuroscience.2005.01.014","article-title":"Different synaptic and subsynaptic localization of adenosine A2A receptors in the hippocampus and striatum of the rat","volume":"132","author":"Rebola","year":"2005","journal-title":"Neuroscience"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.neuron.2015.07.010","article-title":"Increased signaling via adenosine A1 receptors, sleep deprivation, imipramine, and ketamine inhibit depressive-like behavior via induction of homer1a","volume":"87","author":"Serchov","year":"2015","journal-title":"Neuron"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"104570","DOI":"10.1016\/j.nbd.2019.104570","article-title":"Synaptic and memory dysfunction in a \u03b2-amyloid model of early Alzheimer\u2019s disease depends on increased formation of ATP-derived extracellular adenosine","volume":"132","author":"Lopes","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/S0028-3908(98)00023-9","article-title":"Synapses in hippocampus occupy only 1\u20132% of cell membranes and are spaced less than half-micron apart: A quantitative ultrastructural analysis with discussion of physiological implications","volume":"37","author":"Rusakov","year":"1998","journal-title":"Neuropharmacology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1038\/nrn.2018.19","article-title":"Lactate in the brain: From metabolic end-product to signalling molecule","volume":"19","author":"Magistretti","year":"2018","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/j.neuron.2020.12.008","article-title":"Behaviorally consequential astrocytic regulation of neural circuits","volume":"109","author":"Nagai","year":"2021","journal-title":"Neuron"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2080","DOI":"10.1523\/JNEUROSCI.3574-05.2006","article-title":"Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers","volume":"26","author":"Ciruela","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.1038\/nn.4649","article-title":"Synapse-specific astrocyte gating of amygdala-related behavior","volume":"20","author":"Jamison","year":"2017","journal-title":"Nat. Neurosci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"133","DOI":"10.3389\/fphar.2018.00133","article-title":"Adenosine A2A receptors control glutamatergic synaptic plasticity in fast spiking interneurons of the prefrontal cortex","volume":"9","author":"Kerkhofs","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1016\/j.neuroscience.2005.12.012","article-title":"Hypoxia-induced desensitization and internalization of adenosine A1 receptors in the rat hippocampus","volume":"138","author":"Coelho","year":"2006","journal-title":"Neuroscience"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1038\/sj.bjp.0703736","article-title":"Modification of adenosine modulation of synaptic transmission in the hippocampus of aged rats","volume":"131","author":"Cunha","year":"2000","journal-title":"Br. J. Pharmacol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.neuron.2007.11.023","article-title":"Adenosine A2A receptors are essential for long-term potentiation of NMDA-EPSCs at hippocampal mossy fiber synapses","volume":"57","author":"Rebola","year":"2008","journal-title":"Neuron"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1146\/annurev.neuro.23.1.649","article-title":"Synaptic plasticity and memory: An evaluation of the hypothesis","volume":"23","author":"Martin","year":"2000","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1002\/hipo.10099","article-title":"Long-term potentiation as a substrate for memory: Evidence from studies of amygdaloid plasticity and Pavlovian fear conditioning","volume":"12","author":"Goosens","year":"2002","journal-title":"Hippocampus"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"111943","DOI":"10.1016\/j.bbr.2019.111943","article-title":"Chronic caffeine exposure in adolescence promotes diurnal, biphasic mood-cycling and enhanced motivation for reward in adult mice","volume":"370","author":"Hinton","year":"2019","journal-title":"Behav. Brain Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"e13597","DOI":"10.1111\/jsr.13597","article-title":"Adenosine, caffeine, and sleep-wake regulation: State of the science and perspectives","volume":"31","author":"Reichert","year":"2022","journal-title":"J. Sleep Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1963","DOI":"10.1007\/s00213-016-4212-2","article-title":"Mechanisms of the psychostimulant effects of caffeine: Implications for substance use disorders","volume":"233","year":"2016","journal-title":"Psychopharmacology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"15904","DOI":"10.1038\/ncomms15904","article-title":"Caffeine inhibits hypothalamic A1R to excite oxytocin neuron and ameliorate dietary obesity in mice","volume":"8","author":"Wu","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"S51","DOI":"10.3233\/JAD-2010-091261","article-title":"Caffeine and the control of cerebral hemodynamics","volume":"20","author":"Pelligrino","year":"2010","journal-title":"J. Alzheimers Dis."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"S127","DOI":"10.3233\/JAD-2010-1376","article-title":"Caffeine protects against disruptions of the blood-brain barrier in animal models of Alzheimer\u2019s and Parkinson\u2019s diseases","volume":"20","author":"Chen","year":"2010","journal-title":"J. Alzheimers Dis."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Stockwell, J., Jakova, E., and Cayabyab, F.S. (2017). Adenosine A1 and A2A receptors in the brain: Current research and their role in neurodegeneration. Molecules, 22.","DOI":"10.3390\/molecules22040676"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1111\/j.1528-1157.1989.tb05276.x","article-title":"Upregulation of adenosine A1 receptors and forskolin binding sites following chronic treatment with caffeine or carbamazepine: A quantitative autoradiographic study","volume":"30","author":"Daval","year":"1989","journal-title":"Epilepsia"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.conb.2017.02.001","article-title":"Epilepsy and synaptic proteins","volume":"45","author":"Fukata","year":"2017","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.yebeh.2017.11.003","article-title":"Caffeine and seizures: A systematic review and quantitative analysis","volume":"80","author":"Bauer","year":"2018","journal-title":"Epilepsy Behav."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1126\/science.1074069","article-title":"Alzheimer\u2019s disease is a synaptic failure","volume":"298","author":"Selkoe","year":"2002","journal-title":"Science"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"103","DOI":"10.3389\/fneur.2018.00103","article-title":"Centrality of early synaptopathy in Parkinson\u2019s disease","volume":"9","author":"Imbriani","year":"2018","journal-title":"Front. Neurol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"602697","DOI":"10.3389\/fnins.2020.602697","article-title":"Caffeine and Parkinson\u2019s disease: Multiple benefits and emerging mechanisms","volume":"14","author":"Ren","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.conb.2017.09.012","article-title":"Control of brain energy supply by astrocytes","volume":"47","author":"Nortley","year":"2017","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1080\/14767058.2017.1419175","article-title":"Caffeine prevents bilirubin-induced cytotoxicity in cultured newborn rat astrocytes","volume":"32","author":"Ergin","year":"2019","journal-title":"J. Matern. Fetal Neonatal. Med."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1203\/00006450-199312000-00004","article-title":"Caffeine decreases glial cell number and increases hyaluronan secretion in newborn rat brain cultures","volume":"34","author":"Marret","year":"1993","journal-title":"Pediatr. Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1016\/j.tins.2006.07.006","article-title":"The brain as a target of inflammation: Common pathways link inflammatory and neurodegenerative diseases","volume":"29","author":"Zipp","year":"2006","journal-title":"Trends Neurosci."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.neuron.2017.07.030","article-title":"The neurovascular unit coming of age: A journey through neurovascular coupling in health and disease","volume":"96","author":"Iadecola","year":"2017","journal-title":"Neuron"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.neulet.2010.06.013","article-title":"Caffeine attenuates lipopolysaccharide-induced neuroinflammation","volume":"480","author":"Brothers","year":"2010","journal-title":"Neurosci. Lett."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.bbr.2016.01.026","article-title":"Caffeine exposure during rat brain development causes memory impairment in a sex selective manner that is offset by caffeine consumption throughout life","volume":"303","author":"Ardais","year":"2016","journal-title":"Behav. Brain Res."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Jee, H.J., Lee, S.G., Bormate, K.J., and Jung, Y.S. (2020). Effect of caffeine consumption on the risk for neurological and psychiatric disorders: Sex differences in human. Nutrients, 12.","DOI":"10.3390\/nu12103080"},{"key":"ref_86","first-page":"39","article-title":"Biological effects of caffeine: Metabolism","volume":"37","year":"1983","journal-title":"Food Technol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2079","DOI":"10.1016\/j.neurobiolaging.2014.03.027","article-title":"Beneficial effects of caffeine in a transgenic model of Alzheimer\u2019s disease-like tau pathology","volume":"35","author":"Laurent","year":"2014","journal-title":"Neurobiol. Aging"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"639322","DOI":"10.3389\/fncel.2021.639322","article-title":"Crosstalk between ATP-P2X7 and adenosine A2A receptors controlling neuroinflammation in rats subject to repeated restraint stress","volume":"15","author":"Dias","year":"2021","journal-title":"Front. Cell Neurosci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1006\/nlme.1997.3746","article-title":"Extension of a new two-trial memory task in the rat: Influence of environmental context on recognition processes","volume":"67","author":"Dellu","year":"1997","journal-title":"Neurobiol. Learn Mem."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1093\/cercor\/bhh165","article-title":"A Three-dimensional MRI atlas of the mouse brain with estimates of the average and variability","volume":"15","author":"Kovacevic","year":"2005","journal-title":"Cereb. Cortex"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1111\/j.1460-9568.2011.07719.x","article-title":"Enhanced role of adenosine A2A receptors in the modulation of LTP in the rat hippocampus upon ageing","volume":"34","author":"Costenla","year":"2011","journal-title":"Eur. J. Neurosci."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2862","DOI":"10.1038\/npp.2016.98","article-title":"Adenosine A2A receptors in the amygdala control synaptic plasticity and contextual fear memory","volume":"41","author":"Machado","year":"2016","journal-title":"Neuropsychopharmacology"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1111\/ejn.13912","article-title":"Adenosine A2A receptors modulate the dopamine D2 receptor-mediated inhibition of synaptic transmission in the mouse prefrontal cortex","volume":"47","author":"Real","year":"2018","journal-title":"Eur. J. Neurosci."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.jneumeth.2006.12.018","article-title":"Capabilities of the WinLTP data acquisition program extending beyond basic LTP experimental functions","volume":"162","author":"Anderson","year":"2007","journal-title":"J. Neurosci. Methods"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1111\/j.1471-4159.1992.tb09420.x","article-title":"Ecto-5\u2032-nucleotidase is associated with cholinergic nerve terminals in the hippocampus but not in the cerebral cortex of the rat","volume":"59","author":"Cunha","year":"1992","journal-title":"J. Neurochem."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1046\/j.1471-4159.2001.00095.x","article-title":"Parallel modification of adenosine extracellular metabolism and modulatory action in the hippocampus of aged rats","volume":"76","author":"Cunha","year":"2001","journal-title":"J. Neurochem."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1007\/BF02260687","article-title":"Separation of adenosine triphosphate and its degradation products in innervated muscle of the frog by reversed phase high-performance liquid chromatography","volume":"28","author":"Cunha","year":"1989","journal-title":"Chromatographia"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.nbd.2007.04.018","article-title":"Blockade of adenosine A2A receptors prevents staurosporine-induced apoptosis of rat hippocampal neurons","volume":"27","author":"Silva","year":"2007","journal-title":"Neurobiol. Dis."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1016\/j.neuroscience.2006.11.027","article-title":"Different metabolism of glutamatergic and GABAergic compartments in superfused hippocampal slices characterized by nuclear magnetic resonance spectroscopy","volume":"144","author":"Duarte","year":"2007","journal-title":"Neuroscience"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/1\/106\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T17:59:10Z","timestamp":1760119150000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/1\/106"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,4]]},"references-count":99,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["biom13010106"],"URL":"https:\/\/doi.org\/10.3390\/biom13010106","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,4]]}}}