Caffeine: Chemistry, Analysis, Function and Effects / Edition 1

by T A Astorino, K A Alkadhi, Merideth Addicott, A Farah, F Balssa

Overview

Caffeine is known to stimulate the central nervous system but what other functions does it have? This book covers the latest scientific knowledge in a uniquely structured format and is specifically designed to link chemistry with health and nutrition to provide a broad, appealing book. Coverage begins with caffeine in relation to nutrition focussing on beverages, then concentrates on chemistry, crystal structures of complexes in caffeine and biochemistry. In the analysis chapters, assays are conducted by LC-MS, capillary electrophoresis, automated flow methods and immunoassay methods. The effects of caffeine on the brain, cognitive performance, sleep, oxidative damage, exercise and pulmonary function are all considered in the closing section of the book. Delivering high quality information, this book will be of benefit to anyone researching this area of health and nutritional science. It will bridge scientific disciplines so that the information is more meaningful and applicable to health in general. Part of a series of books, it is specifically designed for chemists, analytical scientists, forensic scientists, food scientists, dieticians and health care workers, nutritionists, toxicologists and research academics. Due to its interdisciplinary nature it could also be suitable for lecturers and teachers in food and nutritional sciences and as a college or university library reference guide.

Product Details

ISBN-13:	9781849733670
Publisher:	RSC
Publication date:	09/03/2012
Series:	ISSN , #2
Pages:	424
Product dimensions:	6.20(w) x 9.40(h) x 1.30(d)

About the Author

Victor Preedy is currently Professor of Nutritional Biochemistry and Director of Genomics Centre, King's College London and Professor of Clinical Biochemistry at King's College Hospital London. After graduating with a BSc degree in Physiology with Pharmacology and Biology, Professor Preedy carried out a period of research on protein metabolism in the Department of Nutrition at the London School of Hygiene and Tropical Medicine. After the successful award of his PhD he studied aspects of cardiac protein metabolism at the National Heart Hospital. After 4 years, he then moved to the MRC Clinical Research Centre in Harrow, which was followed by his appointment as a lecturer to Kings College in 1988. He was promoted to Reader in 1995 and Professor in 2003. Professor Preedy has published over 550 articles, which includes over 160 peer-reviewed manuscripts based on original research and 90 reviews as well as 35 books.

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Caffeine

Chemistry, Analysis, Function and Effects

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By Victor R. Preedy

The Royal Society of Chemistry

Copyright © 2012 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-1-84973-367-0

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CHAPTER 1

Caffeine and Nutrition: an Overview

RUBEM CARLOS ARAUJO GUEDES, MARLISON JOSE LIMA DE AGUIAR AND CILENE REJANE RAMOS ALVES-DE-AGUIAR

1.1 Introduction: Caffeine Consumption and its Effects on the Organism

Caffeine is extracted on a large scale from the plant Coffea arabica (Figure 1.1 (A)), which originated in Ethiopia and spread to other regions of the world between the twelfth and fifteenth centuries A.D. The daily consumption of caffeine (1,3,7-trimethylxanthine; Figure 1.1 (B)) is common in modern society. In most parts of the world, people largely consume caffeine regardless of age and economic status. The chemical is present in our diet in the form of beverages like coffee (Figure 1.1 (C)), tea, soft drinks and energy drinks, chocolate, and other foods, and also in medicines (Table 1). All of these products are characterized by containing substances from the group of the xanthines (caffeine, theophylline, and theobromine), the most potent of which is caffeine. This substance can be ingested through infusions, medications, or caffeine-laced soft drinks (McKim, 1996) and acts on brain function to produce both positive and negative effects.

The frequent consumption of drugs like caffeine, as well as malnutrition induced by the dietary deficiency of protein, can disrupt the behavioral and electrophysiological organization of brain function. This disruption is especially severe if occurring early in life, during the period of intense brain development (Guedes, 2011). The capacity that normal organisms have of focusing attention to optimally perform a task, as well as the production of normal brain electrical activity, are basic neural functions that caffeine and the nutritional status of the organism can influence. The relevance of this theme and the lack of studies on the caffeine–nutrition interface highlight the need for systematic investigation with clinical and experimental approaches. In this chapter, we present experimental results on the behavioral phenomenon designated as "latent inhibition (LI) and on the brain electrophysiological phenomenon known as "cortical spreading depression" (CSD). We demonstrate how LI and CSD can be used in studies, comparing their features in malnourished and well-nourished rats.

Although the relationships between caffeine and normal and abnormal function of the brain are detailed in specific sections of this book, we briefly comment here on the two experimental models mentioned above that we have used to explore the theme "caffeine and nutrition." With the use of the LI behavioral model, it is possible to study the effects of behaviorally active substances like caffeine and to observe disturbances in behavioral parameters (Bakshi et al, 1995; Aguiar et al, 2011). Recent studies have targeted verifying the effect of caffeine on attention deficit and hyperactivity disorder and suggest that caffeine acts on cognitive performance by improving the state of concentration in novel environments (Caballero et al, 2011; Mahoney et al, 2011).

Caffeine at moderate doses seems to produce several behavioral effects in humans. Among these, we can highlight (i) increased alertness and reduced fatigue, especially under conditions of little stimulation, such as working at night, and (ii) improved performance on tasks that involve vigilance, or long-lasting responses when the alertness has been reduced (Smith, 2002). Furthermore, caffeine enables users to have control over its consumption; i.e., users seem to use caffeine when they need to benefit from its positive effects on, for instance, mental performance and fatigue (Dagan and Doljansky, 2006; Giesbrecht et al, 2010).

The excessive consumption of caffeine can produce negative effects in the organism. Under these conditions, attenuation of the effect of sedatives, increased anxiety, and worsening of the symptoms of anxiety disorders have been reported (Pan and Chen, 2007). The action of caffeine on cognition and memory still requires further investigation; it seems to depend on the type of task used. In activities involving operational skills (operating machinery, car driving), caffeine intake appears to be beneficial. In the execution of complex cognitive tasks (involving intelligence, memory, and learning), data are not yet clear. Studies reveal that the time of day in which these tasks are carried out seems to strongly influence mental performance (e.g., Adan et al 2008).

With regard to the effects of caffeine abstinence, abstinence symptoms have been suggested to be related to the uncontrolled and excessive use of compounds containing caffeine. This intake seems to produce some withdrawal symptoms, which include headache, stress, fatigue, decreased alertness, depression and anxiety, and changes in EEG activity (Sigmon et al 2009). Recently, Heatherley (2011) has discussed the possibility that improvements in alertness and driving performance after caffeine intake would represent withdrawal reversal rather than a net effect of caffeine. All of these effects may be related to the action of caffeine as a psychostimulant of the central nervous system in humans, in an age-independent way (Mahoney et al 2011; McKim, 1996).

Several studies indicate that the action of caffeine on the organism of mammals is also dose-dependent. To produce stimulant effects in rodents, caffeine should be administered in doses ranging from 10 to 40 mg kg-1 (Fredholm et al 1999; McKim, 1996). In animal models, several behavioral effects of caffeine have been described, including (i) increased spontaneous locomotor activity in the open-field paradigm, (ii) difficulty in the discrimination of stimuli in visual discrimination models, and (iii) decreased perception under negative stimuli, e.g., electric shock through the conditioned avoidance model (Fredholm et al 1999; McKim 1996; Mahoney 2011). Other evidence indicates that caffeine could produce an effect known as conditioned place preference, which suggests a reinforcing action of this drug in animals (Brockwell et al 1991). However, doses above 40 mg kg-1 can produce a state of insomnia, irritability, headache, vertigo, and tinnitus in humans (Fredholm et al 1999; McKim 1996). Recent studies have reported that caffeine-containing compounds can elicit chronic energetic effects, mainly by increasing alertness and decreasing sleep in adolescents and children when taken in doses above 50 mg per day (Warzark et al 2011).

The most consumed caffeine-containing products are listed in the left column of Table 1, and their content ranges of caffeine are presented on the right column on a "per 100 mL", or "per 100 g" or "per tablet" basis, respectively, in the case of liquids (coffee, tea and energy drinks), solids (chocolate bar), or medication (tablets) products. The sometimes wide range of caffeine content depends on variations in analytical methods, in the varieties of the caffeine-source plants, and the methods of product preparation (mainly in the case of coffee and tea beverages preparation). For more details, the reader is advised to see the reports by Barone and Roberts (1996), and Stavric et al, (1988). For recommendations about consumption of caffeine-containing energy drinks, see Higgins et al (2010).

1.2 Pharmacodynamics and Pharmacokinetics of Caffeine

After ingestion, caffeine is rapidly absorbed in the gastrointestinal tract in both humans and in laboratory animals (Magkos and Kavouras 2005). When plasma caffeine concentrations after caffeine oral intake are compared with those after intravenous administration, they vary over time with comparable features, suggesting similar pharmacokinetics in the two routes of administration (Arnaud 1993). Concerning its action on the central nervous system, caffeine seems to pass freely from blood to brain and also exerts a dose-dependent, protective effect against the blood–brain barrier disruption found in degenerative diseases of the central nervous system, like Alzheimer's disease and Parkinson's disease (Chen et al 2010). The stimulant effects of caffeine on the central nervous system are primarily the result of its role in the blockade of adenosine receptors (mostly on the high-affinity A1 and A2A receptors), the inhibition of cAMP phosphodiesterase activity, the intracellular mobilization of calcium, and the binding to benzodiazepine receptors (Chen et al 2010; Lee and Chung 2010).

When administered orally or intravenously in humans or rats, caffeine acts with reinforcing properties in response to electrophysiological and behavioral stimulation (Griffiths and Mumford 1995). However, the bitter taste of caffeine can interfere with administration, especially in behavioral studies, as experiments in rats have shown that the animals freely ingest only low doses of caffeine (Heppner et al 1986). Thus, the immediate consequence of consuming caffeine orally would be a trend to generate aversion (because of its bitter taste). Other studies show that caffeine intake in the form of medication can cause nausea and gastric irritation, especially in children (e.g., McKim, 1996). Furthermore, caffeine can interfere with a subsequent reinforcing effect in animal models of oral self-administration. Similar findings have been observed in humans; the reinforcing effect of caffeine varies with dose, i.e., low and medium doses maintain the behavior of oral self-administration and high doses can even produce aversion (Griffiths and Mumford 1995). Other routes, while less explored, may also be used for caffeine administration, such as intramuscular injection and application in the form of suppositories.

Caffeine is absorbed primarily by the stomach and intestine (absorption reaches 99% in the intestinal tract; see Fredholm et al., 1999, for details), with higher affinity for lipids compared to water; the peak plasma of caffeine occurs 15–45 minutes after ingestion, and the half-life is approximately 5–6 hours (Smith 2002). Caffeine is distributed through the blood, with 10 to 30 percent being transported by proteins (McKim 1996). In addition to its relative facility in passing the blood–brain barrier, caffeine has a lipophilic character and, for this reason, is also found in all organs and can be present in breast milk (Arnaud 1993; Fredholm et al 1999; McKim 1996). The excretion of the products of caffeine metabolism is performed by the liver (Fredholm et al 1999), and only 2% is excreted by the kidneys without being metabolized (Arnaud 2011).

The selective antagonism of A1 and A2A receptors that is involved in the mechanism of action of caffeine has been the focus of recent investigations regarding behavioral outcomes (Randall et al 2011). Authors have shown that increased locomotor activity and high frequency of lever pressing in rats result from the caffeine stimulating effect mediated by blockade of A2A receptors, whereas the anxiogenic effect is probably related to action on the A1 receptor antagonist. However, additional investigation is required to better clarify the specific action of adenosine receptors on behavioral alterations.

1.3 Caffeine–Nutrition Interaction: Effects on Physiological Processes

In this part of the chapter, we address the possible interaction between caffeine and changes in the nutritional status of the organism. This discussion is based on data from our lab on an experimental model of attention designated as LI, and on an electrophysiological phenomenon designated as CSD as described in the following text.

1.4 Caffeine–Nutrition Interaction: Latent Inhibition Model of Attention

Attention is defined as a basic psychological process that is the focus of our consciousness in only a limited aspect of the totality of our experience. According to the cognitive interpretation, attention is seen as a "filtering" process that controls the afferent passage of information through the sensory system. In behavioral analysis, however, the complex information processing required for simple acts of perception, language, and thought involves selection of relevant stimuli, so that the behavior becomes controlled by a narrow range of stimuli that are related to important consequences. Therefore, deficient filtering of information from the outside world results in an inability to ignore irrelevant stimuli. Because of these characteristics, attention is considered a selective process (Alves et al 2002). An animal model of simulation of a cognitive process that uses the manipulation of environmental variables for the behavioral study of selective attention is the LI model. In LI, the animal is first repeatedly exposed to a neutral stimulus, without consequence, and thereafter is submitted to a conditioning paradigm in which the neutral stimulus now functions as a conditioned stimulus. The pre-exposure to this conditioned stimulus impairs the subsequent conditioning (Aguiar et al 2011).

In our experiments, LI was assessed using a conditioned taste-aversion paradigm. Briefly, we measured the effectiveness of sucrose pre-exposure in preventing subsequent acquisition of a conditioned taste aversion to sucrose. The LI procedure consisted of three phases, conducted on five successive days, at the same time of the day during the morning. During phase 1 (pre-exposure to sucrose, days 1 to 3), animals were individually placed in the experimental chamber (Figure 1.2) and given access to either 50 mL of a 5% sucrose solution (sucrose pre-exposed group, PE) or 50 mL of tap water (non–pre-exposed group, NPE) for 30 minutes. On day 4 (phase 2; "conditioning" day), all animals were given access to 50 mL of a 5% sucrose solution for 30 minutes, immediately followed by an intraperitoneal injection of LiCl (50 mg kg-1 in 1 mL kg-1 distilled water) as an aversive stimulus to produce the conditioned taste aversion. Finally, on day 5 (phase 3; testing day), each animal was placed again in the experimental chamber and given simultaneous access to both 5% sucrose and water for 30 minutes. In PE and NPE animals, LI, expressed as the sucrose suppression ratio (SSR), was assessed by comparing the amount of sucrose versus water consumed on day 5, according to the following formula: SSR = [mL sucrose consumed/(mL sucrose consumed + mL water consumed)]. Both caffeine and saline rats were subdivided into PE and NPE groups, and these substances were administered to the respective groups 20 minutes prior to the pre-exposure and conditioning phases.

(Continues...)

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Table of Contents

Caffeine in Context; Chemistry, Structure and Biochemistry; Analysis; Function and Effects; Subject Index