Simulating early steps in nicotine dependence: Pharmacokinetics, activation, and chaperoning of nicotinic receptors.

Nicotine App is a publicly accessible web-based simulator for the pharmacokinetics and pharmacodynamics of human smoking or vaping. The simulator exploits observations that nicotine has nearly equal concentrations in the plasma, cerebrospinal fluid, and endoplasmic reticulum, with time delays of just a few seconds. The simulations describe 2 nicotine-dependent processes. First, nicotine activates nicotinic acetylcholine receptor (nAChR) channels on the plasma membrane. Second, nicotine pharmacologically chaperones nAChRs, with an EC50 much lower than that for channel activation. Beyond the scope of the stimulations, chaperoning leads to nAChR upregulation on the plasma membrane and to nicotine dependence. The simulated "Default Parameters" correspond to a moderate level of smoking: 14 cigarettes per day, 1 mg ingested per cigarette. The simulations explain how people who smoke and have slow nicotine metabolism consume fewer cigarettes per day, but they remain approximately as dependent on nicotine. With instructions from a user-supplied dose table, Nicotine App can also simulate an observed ad libitum pattern of smoking, variable puffing frequency, a transdermal nicotine patch, or other nicotine consumption. The simulations lead to the inference, from reports that nicotine dependence is minimal at nicotine levels <0.3 mg per cigarette, that these levels correspond to a chaperoned receptor fraction of 0.26. Nicotine App may be used for further research or for teaching about nicotine dependence. In the future, Nicotine App can also be used to support a wearable continuous nicotine monitor. SIGNIFICANCE STATEMENT: This study honors the memory of Bill Catterall by describing a web-based simulator of nicotine dependence. The simulator will find use along the spectrum ranging from public knowledge about nicotine dependence to further research on the topic.