Caffeine acts through neuronal adenosine A 2A receptors to prevent mood and memory dysfunction triggered by chronic stress

作者：Manuella P. Kaster, Nuno J. Machado, Henrique B. Silva, Ana F. Nunes, Ana Paula Ardais, Magda M. 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 · 发表于：Proceedings of the National Academy of Sciences · 年份：2015 · DOI：10.1073/pnas.1423088112 · 被引用次数：314 · 研究领域：Tryptophan and brain disorders、Stress Responses and Cortisol、Neuroendocrine regulation and behavior

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 anta...