Caffeine acts through neuronal adenosine A2A receptors to prevent mood and memory dysfunction triggered by chronic stress
Caffeine acts through neuronal adenosine A2A receptors to prevent mood and memory dysfunction triggered by chronic stress
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DOI：
10.1073/pnas.1423088112
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发表时间：
2015-06-23
影响因子：
11.1
通讯作者：
Cunha, Rodrigo A.
中科院分区：
文献类型：
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作者：
Kaster, Manuella P.;Machado, Nuno J.;Cunha, Rodrigo A.
咖啡因（一种腺苷受体拮抗剂）的消耗与抑郁症和记忆衰退负相关，腺苷A（2A）受体（A（2A）R）拮抗剂成为候选治疗靶点，因为它们控制异常突触可塑性并提供神经保护。因此，我们测试了A（2A）R控制慢性不可预测应激（CUS）引起的行为、电生理和神经化学改变的能力，慢性不可预测应激改变海马回路，抑制情绪和记忆表现，并增强抑郁症的易感性。连续3周的CUS可诱导成年小鼠产生焦虑和焦虑样行为，并降低记忆能力。这些行为变化伴随着突触改变，典型表现为突触可塑性降低和突触蛋白（突触体相关蛋白25、突触融合蛋白和囊泡谷氨酸转运蛋白1型）密度降低，以及A（2A）R密度增加。海马中谷氨酸能末端。除焦虑外（结果不一），咖啡因（1g/L，饮水，从CUS前3周开始，持续至CUS结束），选择性A（2A）R拮抗剂KW 6002（3 mg/kg，p.o.），(iii)整体A（2A）R缺失;和（iv）前脑神经元中的选择性A（2A）R缺失。值得注意的是，A（2A）R阻断不仅是预防性的，而且是治疗有效的，因为用A（2A）R拮抗剂SCH 58261（0.1 mg/kg，i. p.）逆转CUS引起的情绪和突触功能障碍。这些结果预示着突触A（2A）R在控制慢性应激诱导的修饰中的关键作用，并建议A（2A）R作为候选靶点来减轻慢性应激对脑功能的后果。
The consumption of caffeine (an adenosine receptor antagonist) correlates inversely with depression and memory deterioration, and adenosine A(2A) receptor (A(2A)R) antagonists emerge as candidate therapeutic targets because they control aberrant synaptic plasticity and afford neuroprotection. Therefore we tested the ability of A(2A)R 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 A(2A)R 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 A(2A)R antagonist KW6002 (3 mg/kg, p.o.); (iii) global A(2A)R deletion; and (iv) selective A(2A)R deletion in fore-brain neurons. Notably, A(2A)R blockade was not only prophylactic but also therapeutically efficacious, because a 3-wk treatment with the A(2A)R 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 A(2A)R in the control of chronic stress-induced modifications and suggest A(2A)R as candidate targets to alleviate the consequences of chronic stress on brain function.