Coffee, Tea, Chocolate, and the Brain

Astrid Nehlig

• Publisher: CRC Press
• Year: 2004
• Print ISBN: 9780415306911
• eBook ISBN: 9781134399383
• Topic: Medicine
• Subtopic: Nutrition, Dietics & Bariatrics

Coffee, tea, and chocolate are among the most frequently consumed products in the world. The pleasure that many experience from these edibles is accompanied by a range of favorable and adverse effects on the brain that have been the focus of a wealth of recent research.

Coffee, Tea, Chocolate, and the Brain presents new information on the

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Mechanisms of Action of Caffeine on the Nervous System

John W.Daly and Bertil B.Fredholm

INTRODUCTION

Because of its presence in popular drinks, caffeine is doubtlessly the most widely consumed of all behaviorally active drugs (Serafin, 1996; Fredholm et al., 1999). Although caffeine is the major pharmacologically active methylxanthine in coffee and tea, cocoa and chocolate contain severalfold higher levels of theobromine than caffeine, along with trace amounts of theophylline. Paraxanthine is a major metabolite of caffeine in humans, while theophylline is a minor metabolite. Thus, not only caffeine, but also the other natural methylxanthines are relevant to effects in humans. In animal models, caffeine, theophylline, and paraxanthine are all behavioral stimulants, whereas the effects of theobromine are weak (Daly et al., 1981). Caffeine, theophylline, and theobromine have been or are used as adjuncts or agents in medicinal formulations. Methylxanthines have been used to treat bronchial asthma (Serafin, 1996), apnea of infants (Bairam et al., 1987; Serafin 1996), as cardiac stimulants (Ahmad and Watson, 1990), as diuretics (Eddy and Downes, 1928), as adjuncts with analgesics (Sawynok and Yaksh, 1993; Zhang, 2001), in electroconvulsive therapy (Coffey et al., 1990), and in combination with ergotamine for treatment of migraine (Diener et al., 2002). An herbal dietary supplement containing ephedrine and caffeine is used as an anorectic (Haller et al., 2002). Other potential therapeutic targets for caffeine include diabetes (Islam et al., 1998; Islam, 2002), Parkinsonism (Schwarzschild et al., 2002), and even cancer (Lu et al., 2002). Caffeine has been used as a diagnostic tool for malignant hyperthermia (Larach, 1989). Clinical uses of caffeine have been reviewed (Sawynok, 1995). In the following chapter, we will focus on the actions of caffeine on the nervous system.

POTENTIAL SITES OF ACTION

Three major mechanisms must be considered with respect to the actions of caffeine on the peripheral and central nervous system: (1) blockade of adenosine receptors, A₁-and A_2A-adenosine receptors; (2) blockade of phosphodiesterases, regulating levels of cyclic nucleotides; and (3) action on ion channels, in particular those regulating intracellular levels of calcium and those regulated by the inhibitory neurotransmitters -aminobutyric acid (GABA) and glycine (Fredholm, 1980; Daly, 1993; Nehlig and Debry, 1994; Fredholm et al., 1997, 1999; Daly and Fredholm, 1998).

Caffeine’s effects are biphasic. The stimulatory behavioral effects in humans (and rodents) become manifest with plasma levels of 5 to 20 μM, whereas higher doses are depressant. The only sites of action where caffeine would be expected to have a major pharmacological effect at levels of 5 to 20 μM A₁-and the A_2A-adenosine receptors, where caffeine is a competitive antagonist (Daly and Fredholm, 1998). Major effects at other sites of action, such as phosphodiesterases (inhibition), GABA and glycine receptors (blockade), and intracellular calciumrelease channels (sensitization to activation by calcium) would be expected to require at least tenfold higher in vivo levels of caffeine. At such levels, toxic effects of caffeine, often referred to at nonlethal levels as “caffeinism” in humans, become manifest. Convulsions and death can occur at levels above 300 μM. However, it cannot be excluded that subtle effects of 5 to 20 μM caffeine at sites of action other than adenosine receptors might have some relevance to both acute and chronic effects of caffeine. Extensive in vitro studies of the actions of caffeine at such sites are usually performed at concentrations of caffeine of 1mM or more, clearly levels that in vivo are lethal.

ADENOSINE RECEPTORS: BLOCKADE BY CAFFEINE

Four adenosine receptors have been cloned and pharmacologically characterized: A₁, A_2A-, A_2B-, and A₃-adenosine receptors (Fredholm et al., 2000, 2001a). Of these the A₃-adenosine receptor in rodent species has very low sensitivity to blockade by theophylline, with K_i values of 100 μM or more (Ji et al., 1994). Human A₃- adenosine receptors are somewhat more sensitive to xanthines, but at in vivo levels of 5 to 20 μM caffeine will have virtually no effect even on the human A₃ receptors. By contrast, results from rodents and humans show that caffeine binds to A₁, A_2A, or A_2B receptors with K_d values in the range of 2 to 20 μM (see Fredholm et al., 1999, 2001b). Thus, caffeine at the levels reached during normal human consumption could exert its actions at A₁, A_2A, or A_2B receptors, but not by blocking A₃ receptors.

If caffeine is to exert its actions by blocking adenosine receptors, a prerequisite is that there be a significant ongoing (tonic) activation of A₁, A_2A, or A_2B receptors. All the evidence suggests that at these receptors, adenosine is the important endogenous agonist (Fredholm et al., 1999, 2000, 2001b). Only at A₃ receptors does inosine seem to be a potential agonist candidate (Jin et al., 1997; Fredholm et al., 2001b). In his original proposal of P1 (adenosine) and P2 (ATP) receptors, Burnstock (1978) included the provision that the adenosine receptors would be blocked by theophylline, while the ATP receptors would be insensitive to theophylline. However, there have also been reports of ATP responses that are inhibited by theophylline (Silinksy and Ginsberg, 1983; Shinozuka et al., 1988; Ikeuchi et al., 1996; Mendoza-Fernandez et al., 2000). Such effects have been suggested to indicate novel receptors or to be caused by heteromeric association of A₁-adenosine and P_2Y receptors (Yoshioka et al., 2001). However, the most parsimonious explanation is that the effects are due to rapid breakdown of ATP to adenosine and actions on classical adenosine receptors (Masino et al., 2002). Therefore, caffeine (as well as theophylline and paraxanthine) should act by antagonizing the actions of endogenous adenosine at A₁, A_2A, or A_2B receptors. This requires that the endogenous levels be sufficiently high to ensure an ongoing tonic activation. In the case of A₁ and A_2A receptors, this requirement is fulfilled, at least at those locations where the receptors are abundantly expressed (Fredholm et al., 1999, 2001a, b). By contrast, A_2B receptors may not be sufficiently at sufficiently high abundance to ensure tonic activation by endogenous adenosine during physiological conditions. It must, however, be remembered that the potency of an agonist is not a fixed value but depends on factors such as receptor number and also the effect studied (Kenakin, 1995). It is therefore interesting to note that when activation of mitogen-activated protein kinases is studied, adenosine is as potent on A_2B as on A₁ and A_2A receptors (Schulte and Fredholm, 2000). Hence, the idea that A_2B receptors are “low-affinity” receptors activated only at supraphysiological levels of adenosine may not be absolutely true. Nevertheless, the available evidence suggests that most of the effects of caffeine are best explained by blockade of tonic adenosine activation of A₁ and A_2A receptors.

In chapters to follow, the relative roles of the different adenosine receptor subtypes in mediating in vivo effects of caffeine will be discussed. Here it will suffice to point out that blockade of A₁ receptors by caffeine could remove either a G_i input to adenylyl cyclase or tonic effects mediated through G , on calcium release, potassium channels, and voltage-sensitive calcium channels. Conversely, blockade of A_2A-adenosine receptors could remove stimulatory input to adenylyl cyclase. In the complex neuronal circuitry of the central nervous system, the ultimate effects will depend on the site and nature of physiological input by endogenous adenosine. Hints about the biological roles of adenosine are also provided by the distribution of the receptors.

Adenosine A₁ receptors are found all over the brain and spinal cord (Fastbom et al., 1986; Jarvis et al., 1987; Weaver, 1996; Svenningsson et al., 1997a; Dunwiddie and Masino, 2001). In the adult rodent and human brain, levels are particularly high in the hippocampus, cortex, and cerebellum. By contrast, A_2A receptors have a much more restricted distribution, being present in high amounts only in the dopamine-rich regions of the brain, including the nucleus caudatus, putamen, nucleus accumbens, and tuberculum olfactorium (Jarvis et al., 1989; Parkinson and Fredholm, 1990; Svenningsson et al., 1997b, 1998, 1999a; Rosin et al., 1998). They are virtually restricted to the GABAergic output neurons that compose the so-called indirect pathway and that also are characterized by expressing enkephalin and dopamine D₂ receptors. There is, indeed, very strong evidence for a close functional relationship between A_2A and D₂ receptors (Svenningsson et al., 1999a).

The adenosine A₁ receptors appear to play two major roles: (1) activation of potassium channels leading to hyperpolarization and to decreased rates of neuronal firing and (2) inhibition of calcium channels leading to decreased neurotransmitter release. This will lead to inhibition of excitatory neurotransmission, and there is good evidence for interactions between A₁ and NMDA receptors (Harvey and Lacey, Mendonça de Mendonça and Ribeiro, 1993). Adenosine A_2A receptors regulate the function of GABAergic neurons of the basal ganglia. The effects are opposite those of dopamine acting at D₂ receptors. It is now clear that these receptors are predominantly involved in the stimulant effects of caffeine (Svenningsson et al, 1995; El Yacoubi et al., 2000).

The two caffeine metabolites, theophylline and paraxanthine, are even more potent inhibitors of adenosine receptors than the parent compound (Svenningsson et al., 1999a; Fredholm et al., 2001b). Therefore, the weighted sum of all of them must be considered when evaluating the effective concentration of antagonist at the adenosine receptors.

Investigation of roles of adenosine receptors has been greatly facilitated by the development of a wide variety of potent and/or selective antagonists. Some are xanthines, deriving from caffeine and theophylline as lead compounds, while others are based on other compounds containing instead of a purine other heterocyclic ring systems (Hess, 2001). In addition, the development of receptor knock-out mice has been instrumental in our current understanding. Thus, experiments using A_2A knock-out mice have conclusively shown that blockade of striatal A_2A receptors is the reason why caffeine can induce its behaviorally stimulant effects (Ledent et al., 1997; El Yacoubi et al., 2000) and the mechanisms involved have been clarified in considerable molecular detail (Svenningsson et al., 1999b; Lindskog et al., 2002). In addition, A_2A knock-out mice showed increased aggressiveness and anxiety (Ledent et al., 1997), a characteristic shared by A₁ knock-out mice (Johansson et al., 2001). The fact that elimination of either receptor leads to anxiety could provide the basis for the well-known fact that anxiety is produced by high doses of caffeine in humans (Fredholm et al., 1999); whereas A_2A knockout mice showed hypoalgesia, A₁ knock-out mice showed hyperalgesia. Finally, using A₁ and A_2A knock-out mice it was shown that at least part of the behaviorally depressant effect of higher doses of caffeine depends on a mechanism other than adenosine receptor blockade (Halldner-Henriksson et al., 2002).

INHIBITION OF PHOSPHODIESTERASES BY CAFFEINE

The potentiation of a hormonal response by caffeine or theophylline (Butcher and Sutherland, 1962) was considered for years as a criterion for involvement of cyclic AMP in the response, and such xanthines became the prototypic phosphodiesterase inhibitors. Both caffeine and theophylline now are considered rather weak and nonselective phosphodiesterase inhibitors, requiring concentrations far above 5 to 20 μM for significant inhibition of such enzymes (Choi et al., 1988). In 1970, it was demonstrated that caffeine/theophylline blocked adenosine-mediated cyclic AMP formation (Sattin and Rall, 1970), and attention shifted to the importance of adenosine receptor blockade in the effects of alkylxanthines. Agents have been sought that would be selective either towards phosphodiesterases or towards adenosine receptors (Daly, 2000). It has been proposed that the behavioral depressant effects of xanthines are due to inhibition of phosphodiesterases, while the behavioral stimulation by caffeine and other xanthines is due to blockade of adenosine receptors (Choi et al., 1988; Daly, 1993). Indeed, many nonxanthine phosphodiesterase inhibitors are behavioral depressants (Beer et al., 1972). The depressant effects of high concentrations of caffeine will depend, as with any centrally active agent, on the specific neuronal pathways that are affected. The central pathways where there might be a further elevation of cyclic AMP, due to inhibition of phosphodiesterase by caffeine, have not been defined. A limited number of xanthines and other agents that are selective towards different subtypes of phosphodiesterases are available (Daly, 2000). Unfortunately, many have other activities, such as blockade of adenosine receptors, that decrease their utility as research tools.

ION CHANNELS: I. EFFECTS OF CAFFEINE ON CALCIUM

Caffeine at high concentrations has been reported to have a multitude of effects on calcium channels, transporters, and modulatory sites (Daly, 2000). Caffeine has been known for more than four decades to cause muscle contracture due to release of intracellular calcium. It is now known that caffeine enhances the calciumsensitivity of a cyclic ADP-ribose-sensitive calcium release channel, the so-called ryanodine-sensitive channel, thereby causing release of intracellular c...

Table of contents

• Cover Page
• Title Page
• Copyright Page
• Preface
• Editor
• Contributors
• 1 Mechanisms of Action of Caffeine on the Nervous System
• 2 Effects of Caffeine on Sleep and Wakefulness: An Update
• 3 Arousal and Behavior: Biopsychological Effects of Caffeine
• 4 Coffee, Caffeine, and Cognitive Performance
• 5 Effects of Coffee and Caffeine on Mood and Mood Disorders
• 6 Age-Related Changes in the Effects of Coffee on Memory and Cognitive Performance
• 7 Neurodevelopmental Consequences of Coffee/Caffeine Exposure
• 8 Caffeine’s Effects on the Human Stress Axis
• 9 Dependence upon Coffee and Caffeine: An Update
• 10 Caffeine and Parkinson’s Disease
• 11 Caffeine in Ischemia and Seizures: Paradoxical Effects of Long-Term Exposure
• 12 Relationship with the Effects of Caffeine on Cerebral Blood Flow
• 13 Cerebral Effects of Noncaffeine Constituents in Roasted Coffee
• 14 Can Tea Consumption Protect Against Stroke?
• 15 The Biology and Psychology of Chocolate Craving
• 16 Is There a Relationship Between Chocolate Consumption and Headache?