CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
Biochem Pharmacol. 2019 Aug;166:313-321. doi: 10.1016/j.bcp.2019.06.008. Epub 2019 Jun 12.
Caffeine is the most consumed psychoactive drug worldwide and its intake in moderate amounts prevents neurodegenerative disorders. However, the molecular targets of caffeine to modulate activity in brain circuits are ill-defined. By electrophysiologically recording synaptic transmission and plasticity in Schaffer fibers-CA1 pyramid synapses of mouse hippocampal slices, we characterized the impact of caffeine using a concentration reached in the brain parenchyma upon moderate caffeine consumption. Caffeine (50 µM) facilitated synaptic transmission by 40%, while decreasing paired-pulse facilitation, and also decreased by 35% the amplitude of long-term potentiation (LTP). Clearance of extracellular adenosine with adenosine deaminase (2 U/mL) blunted all the effects of caffeine on synaptic transmission and plasticity. The AR antagonist DPCPX (100 nM) only eliminated caffeine-induced facilitation of synaptic transmission while not affecting caffeine-induced depression of LTP; conversely, the genetic (using AR knockout mice) or the pharmacological blockade (with SCH58261, 50 nM) of AR eliminated the effect of caffeine on LTP while not affecting caffeine-induced facilitation of synaptic transmission. Finally, blockade of GABA or of ryanodine receptors with bicuculline (10 μM) or dantrolene (10 μM), respectively, did not affect the ability of caffeine to alter synaptic transmission or plasticity. These results show that the effects of caffeine on synaptic transmission and plasticity in the hippocampus are selectively mediated by antagonizing adenosine receptors, where AR are responsible for the impact of caffeine on synaptic transmission and AR regulate the impact of caffeine on LTP.
咖啡因是全球范围内使用最广泛的精神活性药物，适量摄入可以预防神经退行性疾病。然而，咖啡因调节大脑回路活动的分子靶点尚未明确。通过在小鼠海马脑片的 Schaffer 纤维-CA1 锥体神经元突触上进行电生理记录，我们用达到中度咖啡因摄入时脑实质内的浓度来描述咖啡因的影响。咖啡因（50µM）使突触传递增强了 40%，同时降低了成对脉冲易化，也使长时程增强（LTP）的幅度降低了 35%。用腺苷脱氨酶（2U/mL）清除细胞外腺苷，可使咖啡因对突触传递和可塑性的所有作用减弱。AR 拮抗剂 DPCPX（100nM）仅消除了咖啡因诱导的突触传递易化作用，而不影响咖啡因诱导的 LTP 抑制；相反，AR 的遗传（使用 AR 敲除小鼠）或药理学阻断（用 SCH58261，50nM）消除了咖啡因对 LTP 的作用，而不影响咖啡因诱导的突触传递易化作用。最后，用毒蕈碱型乙酰胆碱受体拮抗剂（10μM）或肌醇 1,4,5-三磷酸受体拮抗剂（10μM）阻断 GABA 或肌浆网钙释放通道受体，均不能影响咖啡因改变突触传递或可塑性的能力。这些结果表明，咖啡因对海马体突触传递和可塑性的影响是通过拮抗腺苷受体选择性介导的，其中 AR 负责咖啡因对突触传递的影响，AR 调节咖啡因对 LTP 的影响。
