title: Caffeine acts through neuronal adenosine A2A receptors to prevent mood and memory dysfunction triggered by chronic stress.
abstract: The consumption of caffeine (an adenosine receptor antagonist) correlates inversely with depression and memory deterioration, and adenosine A2A receptor (A2AR) antagonists emerge as candidate therapeutic targets because they control aberrant synaptic plasticity and afford neuroprotection. Therefore we tested the ability of A2AR to control the behavioral, electrophysiological, and neurochemical modifications caused by chronic unpredictable stress (CUS), which alters hippocampal circuits, dampens mood and memory performance, and enhances susceptibility to depression. CUS for 3 wk in adult mice induced anxiogenic and helpless-like behavior and decreased memory performance. These behavioral changes were accompanied by synaptic alterations, typified by a decrease in synaptic plasticity and a reduced density of synaptic proteins (synaptosomal-associated protein 25, syntaxin, and vesicular glutamate transporter type 1), together with an increased density of A2AR in glutamatergic terminals in the hippocampus. Except for anxiety, for which results were mixed, CUS-induced behavioral and synaptic alterations were prevented by (i) caffeine (1 g/L in the drinking water, starting 3 wk before and continued throughout CUS); (ii) the selective A2AR antagonist KW6002 (3 mg/kg, p.o.); (iii) global A2AR deletion; and (iv) selective A2AR deletion in forebrain neurons. Notably, A2AR blockade was not only prophylactic but also therapeutically efficacious, because a 3-wk treatment with the A2AR antagonist SCH58261 (0.1 mg/kg, i.p.) reversed the mood and synaptic dysfunction caused by CUS. These results herald a key role for synaptic A2AR in the control of chronic stress-induced modifications and suggest A2AR as candidate targets to alleviate the consequences of chronic stress on brain function.
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; Department of Biochemistry, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil;
authors.forename: Manuella P
authors.initials: MP
authors.lastname: Kaster
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal;
authors.forename: Nuno J
authors.initials: NJ
authors.lastname: Machado
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal;
authors.forename: Henrique B
authors.initials: HB
authors.lastname: Silva
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal;
authors.forename: Ana
authors.initials: A
authors.lastname: Nunes
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; Departament of Biochemistry, Federal University of Rio Grande do Sul, 90035-003 Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Ardais
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal;
authors.forename: Magda
authors.initials: M
authors.lastname: Santana
authors.affiliation: Pharmaceutical Institute, University of Bonn, D-53121 Bonn, Germany; Department of Chemistry, Sultan Qaboos University, 123 Muscat, Oman;
authors.forename: Younis
authors.initials: Y
authors.lastname: Baqi
authors.affiliation: Pharmaceutical Institute, University of Bonn, D-53121 Bonn, Germany;
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
authors.affiliation: Department of Biochemistry, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil;
authors.forename: Ana Lúcia S
authors.initials: AL
authors.lastname: Rodrigues
authors.affiliation: Departament of Biochemistry, Federal University of Rio Grande do Sul, 90035-003 Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Lisiane O
authors.initials: LO
authors.lastname: Porciúncula
authors.affiliation: Department of Neurology and Pharmacology, Boston University School of Medicine, Boston, MA 02118;
authors.forename: Jiang Fan
authors.initials: JF
authors.lastname: Chen
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; Department of Life Sciences, University of Coimbra, 3004-517 Coimbra, Portugal;
authors.forename: Ângelo R
authors.initials: ÂR
authors.lastname: Tomé
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal.
authors.forename: Paula
authors.initials: P
authors.lastname: Agostinho
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal;
authors.forename: Paula M
authors.initials: PM
authors.lastname: Canas
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal cunharod@gmail.com.
authors.forename: Rodrigo A
authors.identifier: http://orcid.org/0000-0003-2550-6422
authors.initials: RA
authors.lastname: Cunha
mesh_terms: D000818:Animals; D002110:Caffeine / Q000494:pharmacology*; D008297:Male; D008569:Memory Disorders / Q000209:etiology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D019964:Mood Disorders / Q000209:etiology / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000187:drug effects*; D013315:Stress, Psychological / Q000150:complications*
chemical_list: D043705:Receptor, Adenosine A2A; D002110:Caffeine
keywords: adenosine A2A receptor; caffeine; chronic stress; mood dysfunction; synaptic dysfunction