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

Manuella P. Kaster, Nuno J. Machado, Henrique B. Silva, Ana Nunes, Ana Paula Ardais, Magda Santana, Younis Baqi, Christa E. Müller, Ana Lúcia S Rodrigues, Lisiane O. Porciúncula, Jiang Fan Chen, Ângelo R. Tomé, Paula Agostinho, Paula M. Canas, Rodrigo A. Cunha

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122 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)7833-7838
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number25
DOIs
Publication statusPublished - Jun 23 2015

Keywords

  • Adenosine A<inf>2a</inf> receptor
  • Caffeine
  • Chronic stress
  • Mood dysfunction
  • Synaptic dysfunction

ASJC Scopus subject areas

  • General

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    Kaster, M. P., Machado, N. J., Silva, H. B., Nunes, A., Ardais, A. P., Santana, M., Baqi, Y., Müller, C. E., Rodrigues, A. L. S., Porciúncula, L. O., Chen, J. F., Tomé, Â. R., Agostinho, P., Canas, P. M., & Cunha, R. A. (2015). Caffeine acts through neuronal adenosine A2A receptors to prevent mood and memory dysfunction triggered by chronic stress. Proceedings of the National Academy of Sciences of the United States of America, 112(25), 7833-7838. https://doi.org/10.1073/pnas.1423088112