Coffee and cigarettes: Modulation of high and low sensitivity?4?2 nicotinic acetylcholine receptors by n-MP, a biomarker of coffee consumption

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 coapplied with PNU-120596, a positive allosteric modulator (PAM), the coffees stimulated currents from cells expressing alpha 7 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 alpha 7 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 alpha 4132 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 alpha 4132 receptors, but were PAMs for LS alpha 4132 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.