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Proc Natl Acad Sci U S A. 2015 Jun 23;112(25):7833-8. doi: 10.1073/pnas.1423088112. Epub 2015 Jun 8.

Caffeine acts through neuronal adenosine A2A receptors to prevent mood and memory dysfunction triggered by chronic stress.

Author information

  • 1CNC-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;
  • 2CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal;
  • 3CNC-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.
  • 4Pharmaceutical Institute, University of Bonn, D-53121 Bonn, Germany; Department of Chemistry, Sultan Qaboos University, 123 Muscat, Oman;
  • 5Pharmaceutical Institute, University of Bonn, D-53121 Bonn, Germany;
  • 6Department of Biochemistry, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil;
  • 7Departament of Biochemistry, Federal University of Rio Grande do Sul, 90035-003 Porto Alegre, Rio Grande do Sul, Brazil.
  • 8Department of Neurology and Pharmacology, Boston University School of Medicine, Boston, MA 02118;
  • 9CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; Department of Life Sciences, University of Coimbra, 3004-517 Coimbra, Portugal;
  • 10CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal.
  • 11CNC-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.

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.

KEYWORDS:

adenosine A2A receptor; caffeine; chronic stress; mood dysfunction; synaptic dysfunction

PMID:
26056314
[PubMed - indexed for MEDLINE]
PMCID:
PMC4485143
Free PMC Article
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