Department of Pharmacology and Therapeutics, University of Florida, PO Box 100267, Gainesville, FL, 32610-0267, (RLP, MK, CS), USA.
Department of Pharmacology and Therapeutics, University of Florida, PO Box 100267, Gainesville, FL, 32610-0267, (RLP, MK, CS), USA.
Neuropharmacology. 2022 Sep 15;216:109173. doi: 10.1016/j.neuropharm.2022.109173. Epub 2022 Jun 27.
Smokers report particular appreciation for coffee with their first cigarettes of the day. We investigated with voltage-clamp experiments, effects of aqueous extracts (coffees) of unroasted and roasted coffee beans on the activity of human brain nicotinic acetylcholine receptor (nAChR) subtypes expressed in Xenopus oocytes, looking at complex brews, low molecular weight (LMW) fractions, and specific compounds present in coffee. When co-applied with PNU-120596, a positive allosteric modulator (PAM), the coffees stimulated currents from cells expressing α7 nAChR that were larger than ACh controls. The PAM-dependent responses to green bean coffee were three-fold greater than those to dark roasted coffee, consistent with α7 receptor activation by choline, a component of coffee that is partially degraded in the roasting process. Coffees were tested on both high sensitivity (HS) and low sensitivity (LS) forms of α4β2 nAChR, which are associated with nicotine addiction. To varying degrees, these receptors were both activated and inhibited by the coffees and LMW extracts. We also examined the activity of nine small molecules present in coffee. Only two compounds, 1-methylpyridinium and 1-1-dimethylpiperidium, produced during the process of roasting coffee beans, showed significant effects on nAChR. The compounds were competitive antagonists of the HS α4β2 receptors, but were PAMs for LS α4β2 receptors. HS receptors in smokers are likely to progressively desensitize through a day of smoking but may be hypersensitive in the mornings when brain nicotine levels are low. A smoker's first cup of coffee may therefore balance the effects of the day's first cigarette in the brain.
吸烟者特别喜欢在一天中的第一支香烟后喝咖啡。我们通过电压钳实验研究了未烘焙和烘焙咖啡豆的水提物（咖啡）对在非洲爪蟾卵母细胞中表达的人脑中烟碱型乙酰胆碱受体（nAChR）亚型活性的影响，研究了复杂的酿造物、低分子量（LMW）部分以及咖啡中存在的特定化合物。当与阳性变构调节剂（PAM）PNU-120596 共同应用时，咖啡刺激了表达α7 nAChR 的细胞中的电流，其大小超过 ACh 对照。与深烘焙咖啡相比，绿咖啡豆咖啡引起的 PAM 依赖性反应是三倍，这与咖啡中的胆碱有关，胆碱是咖啡在烘焙过程中部分降解的成分，可激活α7 受体。在高灵敏度（HS）和低灵敏度（LS）形式的α4β2 nAChR 上测试了咖啡，这两种受体都与尼古丁成瘾有关。在不同程度上，这些受体都被咖啡和 LMW 提取物激活和抑制。我们还研究了咖啡中存在的九种小分子的活性。只有两种化合物，在烘焙咖啡豆过程中产生的 1-甲基吡啶和 1-1-二甲基哌啶，对 nAChR 表现出显著的作用。这些化合物是 HS α4β2 受体的竞争性拮抗剂，但对 LS α4β2 受体是 PAMs。吸烟者的 HS 受体在一天的吸烟过程中可能会逐渐脱敏，但在大脑尼古丁水平较低的早晨可能会过度敏感。因此，吸烟者的第一杯咖啡可能会平衡大脑中第一支香烟的影响。
