Nicotine, Caffeine and Social Drinking: Behaviour and Brain Function

Monicque Lorist, Jan Snel

• Publisher: Taylor & Francis
• Year: 2013
• eBook ISBN: 9781134409457
• Edition: 1
• Topic: Psychology
• Subtopic: Addiction in Psychology
• Index: Psychology

Often, people use nicotine, caffeine, and some level of alcohol in varying combinations at different times of the day in order to optimize their functioning and feelings of well-being, whether at work, in leisure time, or in a social context. However, until now, studies on the effects of this everyday practice have been diverse, widespread, and insufficiently summarized. Recently developed methods to study the effects in more detail have received little attention, especially among a nonscientific readership. Nicotine, Caffeine and Social Drinking focuses readers' attention on the effects of normal, socially accepted psychoactive substances on cognitive performance and on the brain. Divided into three sections, this book studies each substance individually before examining the effects of their combined usage.

Part I — Nicotine

ONE	Pharmacokinetics and Pharmacodynamics of Nicotine Jacques Le Houezec
TWO	Effects of Nicotine on Human Performance Walter S. Pritchard and John H. Robinson
THREE	Nicotinic and Non-Nicotinic Aspects of Smoking: Motivation and Behavioural Effects †Karl Bättig
FOUR	Functional Utility of Nicotine: Arousal, Mood and Performance Verner J. Knott, Anne Harr and Stacey Lusk-Mikkelsen
FIVE	Nicotine and the Situation X Trait Adaptive Response (STAR) Model: Emotional States and Information Processing David G. Gilbert and Brenda O. Gilbert

CHAPTER ONE

Pharmacokinetics and Pharmacodynamics of Nicotine

Jacques Le HOUEZEC

INTRODUCTION

Nicotine acts on nearly every physiological system of the human body. The effects of nicotine on the peripheral nervous system have been extensively studied and are now quite well understood. The effects of nicotine on the central nervous system are more complex and our understanding of their effects is limited. This chapter reviews the pharmacokinetics and pharmacodynamics of nicotine with an emphasis on the psychopharmacological basis of nicotine dependence.

In South America, seeking for psychoactive effects of nicotine might be as old as the origin of horticulture, beginning some eight thousand years before present. Ritual tobacco use in Shamanism aimed to achieve acute nicotine intoxication, which induced in the Shamans catatonic states representing symbolic death. The effects of large doses of nicotine on the autonomic and central nervous systems gave the impression of a gradual death of the Shaman, who then returned miraculously to life (Wilbert, 1987).

Nicotine, the major alkaloid of tobacco, was first isolated in a pure form by Posselt and Reimann in 1828. Nicotine and other alkaloids (atropine, muscarine, curare alkaloids) have played a key role in the development of knowledge and understanding of the functional organization of the autonomic nervous system. At the turn of the 19th century, Langley and his colleagues used nicotine to determine the nature of the autonomic innervation and the location of ganglionic synapses for many organs. The concept of receptor arose from Langley’s experiments. In, 1914, Dale developed the concept of two different sites of action of acetylcholine, termed muscarinic and nicotinic, based on the relative selectivity of the response to muscarine and nicotine (see Le Houezec and Benowitz, 1991 for references).

Tobacco smoking is a unique and highly addictive form of systemic drug administration in that entry into the circulation is through the pulmonary rather than the portal or systemic venous circulations. Nicotine reaches the brain in less than 10 seconds, faster than after intravenous administration. Nicotine is distributed throughout the brain, with highest concentrations in the hypothalamus, hippocampus, thalamus, midbrain, brain stem and in areas of the cerebral cortex. Nicotine also binds to nigrostriatal and mesolimbic dopaminergic neurons. Brain nicotine concentrations increase sharply after completion of smoking, then decline over 20 to 30 minutes as nicotine redistributes to other tissues (Benowitz et al., 1990). This results in transient high brain concentrations of nicotine which act on many neurotransmitters and produce reinforcing psychological effects (Le Houezec and Benowitz, 1991). Subsequently, venous blood concentrations decline more slowly, reflecting redistribution from body tissues and the rate of elimination (half-life averaging 2 hours). In contrast to inhalation, other routes of absorption result in gradual increase in nicotine concentration in the brain, and a lower brain-to-blood ratio. These routes are considered as less addictive forms of administration.

BASIC AND CLINICAL PHARMACOLOGY OF NICOTINE

Because after tobacco use nicotine is present in the body in very low concentrations, analytic methodology sensitive enough to routinely assay nicotine in biological fluids has been available for only the past 15 to 20 years (Feyerabend et al., 1975; Jacob et al., 1981). The possibility of measuring levels of nicotine in the body gave rise to research on the human pharmacology of tobacco dependence. Many studies have shown that smokers tend to maintain constant their blood nicotine levels from day to day. However, blood nicotine levels are not highly correlated with the nicotine or tar ‘yield’ of cigarettes, determined with a smoking machine under standard smoking procedures. This body of evidence suggests a ‘finger-tip control’ of the smoker on his, or her, own nicotine intake.

Chemical properties of nicotine

Research on tobacco dependence has mainly focused on nicotine effects because nicotine is the major alkaloid of tobacco, representing 90 to 95% of the total alkaloid content. In addition to nicotine, there are several related alkaloids in tobacco that may be of pharmacological importance. There is, however, no information on their pharmacological effects in humans as yet. Nornicotine and anabasine have pharmacological activity qualitatively similar to that of nicotine (Clark et al., 1965). In addition, some of the minor alkaloids may also influence the effects of nicotine (Stålhandske and Slanina, 1982). The minor alkaloids represent 8 to 12% of the total alkaloid content of commercial tobacco products, which are mainly derived from Nicotiana tabacum. In some other varieties of tobacco, nornicotine (N. tomentosa) or anabasine (N. glauca) are present in concentrations exceeding those of nicotine (Wilbert, 1987). Alkaloids are synthesized in the roots and transported to the leaves with a concentration gradient. Leaves that are higher on the stalk have higher concentrations of nicotine than those lower on the stalk. Combining different varieties of tobacco and different parts of the plant is a way to control the nicotine concentration of tobacco products.

The alkaloid content of tobacco products also depends on the way tobacco is processed after being harvested. Blond tobaccos are dried in ovens under specific hygrometric conditions (flue curing). Such treatment makes the tobacco smoke acidic (pH 5–6). Dark tobaccos, such as those used for pipe or cigar tobacco in the United States, are smoked in cigarettes as well in other countries. They are sun or air dried (air curing) after a fermentation period aimed to reduce the alkaloid content, naturally higher in dark than in blond tobaccos. This process makes the smoke more alkaline (pH 6–7 for cigarettes, pH 8 for pipe or cigars).

Nicotine is a tertiary amine composed of a pyridine and a pyrrolidine ring. The natural stereo-isomer of tobacco is the 1-nicotine, which is from 5 to 100 times (depending on which specific activity) more potent pharmacologically than the d-isomer (Jacob et al., 1988). The latter is present in tobacco smoke only (up to 10% of the nicotine smoke content), indicating that some racemization occurs during the combustion process. Nicotine is a volatile and colourless weak base (pK_a = 7.9), which acquires a brown colour and the characteristic odour of tobacco when in contact with the air. Under atmospheric pressure, nicotine boils at 246°C, and is consequently volatilized in the cone of burning tobacco (800°C). Nicotine in freshly inhaled smoke is suspended in tar droplets (0.3–0.5 μm). Nicotine free base is readily absorbed across membranes because of its lipophilicity.

The nicotinic receptors

The pharmacologically active form of nicotine is a positively charged ion protonated on the pyrrolidine nitrogen. This active form resembles acetylcholine in the spacing of positive and negative charges (Cynoweth et al., 1973). Because of its flexibility, acetylcholine can bind to both nicotinic and muscarinic receptors. Nicotine and muscarine molecules are less flexible and are, therefore, specific agonists of only one type of cholinergic receptors, hence the names.

The nicotinic receptors are member of the super-family of ligand-gated ion channels, and are made up of five subunits. Although the muscle (peripheral) nicotinic receptors present four types of subunits (α, β, γ, and δ in 2:1:1:1 ratio), the neuronal (central) receptors are made of only two types; α and β. The binding site of the receptor is located on the two alpha subunits. When nicotine binds to the receptor, it changes its conformation, opening the ion channel and allowing sodium to enter the cell; depolarization.

Two kinds of nicotinic receptors appear to co-exist in the brain according to their affinity to different ligands. One population is labelled with ³H-nicotine or ³H-acetylcholine and corresponds to a high affinity site, while another population, labelled with ¹²⁵I-α-BTX (bungarotoxin), corresponds to a low affinity site. The two receptor populations may mediate different effects. Until recently, the mechanism of the nicotinic receptor was only partially known. Many research groups are now studying the receptor extensively (Picciotto et al., 1995). Their results will help to better understand some of its properties which might be directly related to the psychoactive effects and to nicotine dependence.

PHARMACOKINETICS OF NICOTINE

Absorption

The pH is important in determining the absorption of nicotine across cell membranes (pKa = 7.9). In acidic environments, nicotine is in its ionized state and does not readily cross membranes. However, at physiological pH (7.4), about 31% of nicotine is non-ionised such that it rapidly crosses membranes. The methods by which tobacco is processed and used result in considerable differences in the extent and rate of absorption of nicotine. Nicotine is readily absorbed through oral mucous membranes because of the thin epithelium and rich blood supply of these membranes. Nicotine that is swallowed (smokeless tobacco or nicotine polacrilex gum) is absorbed by the small bowel. After absorption into the portal venous circulation, nicotine undergoes presystemic metabolism by the liver so that its bioavailability is relatively low (30–40%). Consequently, buccal (mucous) absorption results in higher blood nicotine levels because nicotine bypasses the liver first pass effect.

The pH of smoke from flue-cured tobaccos found in most cigarettes is acidic. In contrast with some other tobacco products such as chewing tobacco, oral snuff tobacco, pipe or cigar tobacco smoke, there is little buccal absorption from cigarette smoke, even when it is held in the mouth. Inhalation is required to allow nicotine to be absorbed by the huge surface of the alveolar epithelium. Absorption into the systemic circulation is facilitated because pulmonary capillary blood flow is high, representing passage of the entire blood volume through the lung every minute. As we will see in the pharmacodynamics section, the kinetics of absorption of nicotine are important when considering the psychological or subjective effects which may play a role in nicotine dependence. Blood nicotine concentration rises quickly during cigarette smoking and peaks at the completion of smoking. Thus, nicotine absorbed from tobacco smoke can quickly reach various parts of the body, including the brain (Benowitz et al., 1988). In contrast, input from smokeless tobacco has a small lag time, peaks and declines during a 30 minute period of administration, then continues to be absorbed for more than 30 minutes after tobacco is removed from the mouth. The later phase probably reflects delayed absorption of swallowed nicotine. Individual data of this study show that absorption of nicotine varies widely, both in extent and rate, among people.

Smoking behaviour is complex and smokers can manipulate the dose of nicotine delivered to the circulation on a puff-by-puff basis. The intake of nicotine varies considerably with the intensity, duration and number of puffs, depth of inhalation, and the degree of mixing of smoke with air. Because of the complexity of this process the dose of nicotine cannot be predicted from the nicotine content of the tobacco. In one study, the range of intake of nicotine among research subjects was 0.4–1.6 mg per cigarette, and was unrelated to the nominal nicotine yield of the cigarettes (Benowitz and Jacob, 1984).

The same complexity is observed with chewing tobacco or polacrilex gum. The rate of chewing, amount swallowed and local (buccal) factors can influence the absorption of nicotine. A threefold variation was found in a study of gum chewers asked to chew 10 pieces of gum, each for 30 minutes, daily (Benowitz et al., 1987). However, since absorption from chewing gum is slow and persists even after the chewing stops, adjustments of the dose cannot be as precise as when smoking cigarettes (Benowitz et al., 1988).

Because nicotine is readily absorbed through the skin, transdermal delivery systems (nicotine patches) have been developed for use in smoking cessation therapy. Absorption of nicotine from transdermal systems is slow, reaching maximum blood levels in 6 to 8 hours, but allow sustained concentrations of nicotine to be delivered over 24 h. The new generation of nicotine delivery systems is represented by nasal nicotine spray and nasal nicotine aerosol. Absorption of nicotine through the nasal route results in kinetic profiles similar to absorption from tobacco smoke (Sutherland et al., 1992a). Besides their potential value in smoking cessation therapy, these systems present a potential use to deliver safely quantified doses of nicotine to smokers and non-smokers in experimental studies.

Distribution

Smoking is a unique form of systemic drug administration in that it delivers the drug into the pulmonary rather than the portal or systemic venous circulations. Based on physiological considerations nicotine is expected to reach the brain in about 10 seconds (Benowitz, 1990), faster than when nicotine is given intravenously. The drug is then extensively and quickly distributed to other body tissues with a steady state volume of distribution averaging 180 litres (2.6 litre/kg).

Simulation of nicotine concentrations in various organs after smoking a cigarette has been performed, using tissue distribution data derived from experiments in rabbits (Benowitz et al., 1990). Arterial blood and brain concentrations increase sharply following exposure then decline over 20 to 30 minutes as nicotine redistributes to other body tissues, particularly skeletal muscle. In the minutes during and immediately following nicotine absorption, levels of nicotine are much higher in arterial than in venous blood. The discrepancy between arterial and venous blood concentrations has been observed in rabbits after rapid intravenous injection of nicotine (Porchet et al., 1987) and in people after cigarette smoking (Henningfield et al., 1990). Subsequently venous blood concentrations decline more slowly, reflecting redistribution from body tissues and the rate of elimination. The ratio of the concentration of nicotine in the brain to that in venous blood is highest during and at the end of the exposure period, and gradually decreases as the elimination phase is entered.

In contrast to inhalation, the oral and transdermal routes of absorption result in a gradual increase in nicotine concentrations in the brain, with relatively lower brain-to-blood ratio and little arterial-venous disequilibrium. Nicotine nasal spray and aerosol systems are probably in an intermediate situation between inhalation and these slow delivery systems.

Elimination

Nicotine is extensively metabolized in the liver, but also to a small extent in the lungs and kidneys (for a review see Benowitz et al., 1990). Renal excretion of unchanged nicotine depends on urinary pH and urine flow, typically accounting for 5–10% of total elimination. The elimination half-life of nicotine averages 2 hours, although there is considerable interindividual variability. The primary metabolites of nicotine are cotinine (70%) and nicotine-N′-oxide (4%). Seventeen per cent of nicotine is not accounted for by metabolism to cotinine or nicotine-N′-oxide and may be metabolized in nicotine isomethonium ion and nornicotine.

Cotinine is formed in the liver in a two-step process involving cytochrome P-450 and aldehyde oxidase enzymes. Cotinine is further metabolized, with only about 17% of cotinine excreted unchanged in the urine. Trans-3′-hydroxycotinine is the major meta...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• CONTENTS
• Preface
• Notes on Contributors
• Part I — Nicotine
• Part II — Coffee and Caffeine
• Part III — Social Drinking
• References
• Subject Index
• Author Index