Continuous Nicotine Monitors for Personal Nicotine Pharmacokinetics: A Receptor-Aware Research Agenda.

A minimally invasive "continuous nicotine monitor" (CNM) would resolve the dynamic nicotine concentration, [nicotine]t, faced by high-sensitivity nicotinic acetylcholine receptors (nAChRs) during and after nicotine intake by individual subjects. Motivations: "Know the potential enemy at an individual level." Smoking or vaping produces an initial "bolus" of nicotine in the blood and brain, lasting ~5 minutes with a peak concentration of ~100-200 nM. The bolus largely governs reinforcement, reward, and cognitive enhancement. A prolonged declining phase of [nicotine], with a half-time of 1-4 hours, largely suppresses withdrawal symptoms and governs the known cell biology of addiction. Next, "Know the potential therapy," because individual [nicotine]t records will be useful during research on the effectiveness of nicotine replacement therapy. Finally, "Know the physiology." The only three known effects on nAChRs in cerebrospinal fluid at the relevant [nicotine]t are activation, desensitization, and chaperoning/upregulation. Therefore, additional mechanistic insights will arise from correlating [nicotine]t with readily measurable physiological data on those effects in molecular, cellular, and brain slice systems and animal models. Interstitial fluid is the appropriate compartment for a CNM. The molecular sensor technology could employ fluorescence, as shown by progress on measuring [nicotine]t with improved variants of intensity-based nicotine-sensing fluorescent reporters (iNicSnFRs). Electrochemical measurements of [nicotine]t may also be possible. Studies like the Population Assessment of Tobacco Health would contextualize [nicotine]t measurements during each subject's ad libitum nicotine intake, hopefully at a cost <$100 for a 24-hour record.