Arterial nicotine kinetics during cigarette smoking and intravenous nicotine administration: implications for addiction

Abstract

An understanding of drug addiction requires knowledge of the effective drug concentrations to which receptors in the nervous system are exposed. It has often been thought that smoking of abused substances such as nicotine or cocaine produces much higher drug concentrations in the arterial blood than those achieved following any other route of administration. However, to date no studies have sampled arterial blood following cigarette smoking with the rapidity necessary to evaluate this hypothesis. We measured arterial plasma nicotine concentrations in samples collected every 5 s from 13 cigarette smokers during cigarette smoking and during administration of nicotine by intravenous injections. Our results show that, for both routes of administration, concentrations of nicotine in arterial blood were more than 10 times lower than expected. Thus, the delivery of nicotine into arterial blood is substantially slower than would be predicted if nicotine were absorbed as rapidly as has generally been assumed. A plausible explanation of these results is that lung uptake of nicotine considerably slows the entry of nicotine into the systemic circulation, as has been shown for other amines. These results have significant implications for theories of addiction to nicotine as well as other drugs such as cocaine that may be subject to binding by lung tissue.

Introduction

Cigarette smoking is the leading preventable cause of death in the USA (U.S.D.H.H.S., 1990). Unfortunately, nearly 50 million Americans continue to smoke (Centers for Disease Control, 1993) and with currently available treatment, long-term smoking abstinence rates are generally less than 30% (Fiore et al., 1994). We still know relatively little about the mechanisms underlying tobacco dependence, and a better understanding of these mechanisms may suggest improved treatments.

A great deal of evidence suggests that people continue to smoke because of the reinforcing effects of nicotine (U.S.D.H.H.S., 1988). A widely held version of the nicotine theory of cigarette addiction is the ‘nicotine bolus hypothesis’, which holds that the rapid (5–10 s) transit time of nicotine from lung to brain and high arterial nicotine concentrations following each puff of smoke provide a reinforcing ‘hit’ of nicotine to the brain (Russell and Feyerabend, 1978). Nicotine in sufficient concentrations can activate nicotinic cholinergic receptors that regulate current flow through ion channels (Wonnacott, 1990). Several nicotinic receptor subtypes have been identified, which differ in functional significance and regional distribution in the nervous system as well as in sensitivity to nicotine. Activation of nicotinic receptors triggers a cascade of reinforcing effects, such as dopamine release from mesolimbic reward pathways (Pich et al., 1997) as well as potentiating the release of other neurotransmitters, including acetylcholine, norepinephrine, serotonin and GABA (McGehee et al., 1995).

Since each receptor subtype has a different sensitivity to activation (and desensitization) by nicotine (Olale et al., 1997), it is crucial to know what maximal concentrations of nicotine reach these receptors during cigarette smoking. A few studies have measured nicotine concentrations in arterial blood with reported levels as high as 100 ng/ml (Henningfield et al., 1993), although more often the mean arterial concentrations have been reported to be less than 50 ng/ml (Moreyra et al., 1992, Gourlay and Benowitz, 1997). In these experiments arterial plasma was only sampled intermittently (at most every 2 min) and it has been speculated that peak nicotine levels within the first few seconds of inhalation might be considerably higher than 100 ng/ml (Henningfield et al., 1993, Gourlay and Benowitz, 1997). Indeed, it is often held that the nicotine contained in a puff of cigarette smoke (typically 0.1 mg) is absorbed within a few seconds of contacting the vast surface area of the lungs. If one assumes that the nicotine contained in a puff of smoke is absorbed within 1–2 s of inhalation (Gourlay and Benowitz, 1997), then one can calculate the estimated peak concentration of nicotine in the pulmonary circulation by dividing the nicotine dose by the total blood volume flowing thorough the lungs (which is equal to cardiac output) in 2 s, which is approximately 200 ml in normal healthy adults (Bowman and Rand, 1980). Thus, one might expect a peak nicotine concentration of 0.1 mg/200 ml=500 ng/ml, a peak which may not have been detected in earlier studies that did not sample arterial blood frequently. Assuming that absorption of nicotine through the lung may take as long as 10 s, one might still predict a peak arterial blood nicotine concentration following each puff of smoke of approximately 100 ng/ml (0.1 mg nicotine/1000 ml of blood flowing through the lungs in 10 s).

To evaluate this prediction, we sampled arterial blood every 5 s during cigarette smoking as well as during intravenous nicotine administration. To our knowledge, no previous studies have reported sampling of arterial blood this frequently during cigarette smoking.