Laboratory of Behavioral Neuroscience, Legacy Research Institute, 1225 NE Second Avenue, Portland, OR, 97232, USA.
Psychopharmacology (Berl). 2014 Oct;231(21):4087-98. doi: 10.1007/s00213-014-3548-8. Epub 2014 Apr 12.
Caffeine is a psychostimulant drug that blocks adenosine A₁ and A₂A receptors (A₁Rs and A₂ARs). However, its ability to disrupt early sensory gating as indexed by prepulse inhibition (PPI), which is consistently disrupted by other psychostimulant agents, has never been convincingly demonstrated.
To compare the impact of caffeine on PPI expression in C57BL/6 mice by two dose-response experiments differing in terms of chronicity, regimen, and route of administration. To study separately the acute effect of selective antagonists against A₁R or A₂AR.
Caffeine (10, 30, 100 mg/kg, intraperitoneal (i.p.)) was either administered shortly before testing or via caffeinated drinking water (0.3, 1.0, 2 g/l) in home cages over 3 weeks. Two separate dose-response studies tested the acute effect of the selective A₁R antagonist, 1,3 dipropyl-8 cyclopentyl xanthine (DPCPX), and the selective A₂AR antagonist, 5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c] (SCH 58261) (0.2, 1.0, 5.0 mg/kg, i.p.). The two drugs were combined in a final experiment to identify their potential synergistic interaction.
While the two lower acute doses of caffeine attenuated PPI, the highest dose potentiated PPI. By contrast, chronic caffeine exposure did not affect PPI. Neither DPCPX nor SCH 58261 altered PPI, and no synergism was observed when the two drugs were combined.
This is the first demonstration that acute caffeine disrupts PPI, but the relative contribution of A₁R and A₂AR blockade remains unclear, and possible non-adenosinergic mechanisms cannot be ruled out. The null effect under chronic caffeine exposure might involve the development of tolerance, but the precise receptor subtypes involved also warrant further investigation.
咖啡因是一种精神兴奋剂药物，可阻断腺苷 A₁ 和 A₂A 受体（A₁Rs 和 A₂ARs）。然而，其破坏早期感觉门控的能力（以 prepulse inhibition [PPI] 为指标），其他精神兴奋剂药物一直未能令人信服地证明这一点。
通过两项剂量反应实验比较咖啡因对 C57BL/6 小鼠 PPI 表达的影响，这两项实验在慢性、方案和给药途径方面存在差异。分别研究选择性 A₁R 或 A₂AR 拮抗剂的急性作用。
咖啡因（10、30、100 mg/kg，腹腔内（i.p.））要么在测试前短时间内给药，要么通过含咖啡因的饮用水（0.3、1.0、2 g/l）在家笼中给药 3 周。两项单独的剂量反应研究测试了选择性 A₁R 拮抗剂 1,3-二丙基-8-环戊基黄嘌呤（DPCPX）和选择性 A₂AR 拮抗剂 5-氨基-7-（2-苯乙基）-2-（2-呋喃基）-吡唑并[4,3-e]-1,2,4-三唑[1,5-c]（SCH 58261）（0.2、1.0、5.0 mg/kg，i.p.）的急性作用。在最后一项实验中，将两种药物结合在一起以确定它们的潜在协同作用。
虽然两种较低的急性咖啡因剂量减弱了 PPI，但最高剂量增强了 PPI。相比之下，慢性咖啡因暴露不会影响 PPI。DPCPX 和 SCH 58261 均未改变 PPI，当两种药物联合使用时也未观察到协同作用。
这是首次证明急性咖啡因会破坏 PPI，但 A₁R 和 A₂AR 阻断的相对贡献仍不清楚，也不能排除可能的非腺苷能机制。慢性咖啡因暴露下的无效作用可能涉及到耐受的发展，但涉及的确切受体亚型也需要进一步研究。
