Caffeine and the central nervous system: mechanisms of ... · Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects Astrid

Brain Research Reuiews, 17 (19921139-170 0 1992 Elsevier Science Publishers B.V. Ail rights reserved 01650173/92/$05.00

139

BRESR 90147

Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects

Astrid Nehlig a, Jean-Luc Daval a and GCrard Debry b

’ INSERM U 272 Uniuersite’ de Nancy I and b Centre de Nutrition Humaine, Nancy (France)

(Accepted 2 June 1992)

Key work Caffeine; Methybranthine; Adenosine; Psychostimulant effect; Anxiety; Sleep; Monoamine; Dependence

CONTENTS

1.

2.

3.

4.

5.

6.

7.

Introduction ........................................................................................

Mechanisms of action of caffeine on the central nervous system ................................................... 2.1. Mobilization of intracellular calcium ................................................................... 2.2. Inhibition of phosphodiesterases ...................................................................... 2.3. Antagonism at the level of adenosine receptors ........................................................... 2.4. Interactions with benzodiazepine binding sites ............................................................

Effects of chronic caffeine consumption on density of cerebral receptors ............................................. 3.1. Effects on adenosine receptors ....................................................................... 3.2. Effects on benzodiazepine receptors ...................................................................

Effects of caffeine on neurotransmitters .................................................................... 4.1. Catecholamines 4.2. Serotonin

.................................................................................. ......................................................................................

4.3. Acetylcholine ................................................................................... 4.4. Aminoacids ....................................................................................

Effects of caffeine on cerebral blood flow and metabolism .......................................................

Effects of caffeine on cerebral electrical activity 6.1.Animalstudies

..............................................................

6.2. Humanstudies .................................................................................. ..................................................................................

Effects of caffeine on behavior .......................................................................... 7.1. Spontaneous motor activity. ......................................................................... 7.2. Learning, memory and mental performance .............................................................. 7.3. Simple and complex coordination activities and vigilance 7.4. Endurance and athletic performance

.................................................... ...................................................................

7.5. Social behavior, aggressivity and mood 7.6. Effects of caffeine on anxiety

.................................................................

7.7. Effects of caffeine on sleep ........................................................................

7.7.1. Animalstudies.. ......................................................................... .

7.7.2. Humanstudies ............................................................................

..............................................................................

140

140 141 141 142 142

142 142 143

143 143 144 144 14.5

145

146 146 146

146 147 147 148 148 149 150 151 151 151

Correspondence to: A. Nehlig, INSERM U 272, Pathologie et Biologie du Developpement Humain,Universiti de Nancy I, 30, rue Lionnois, Boite Postale 3069, 54013 Nancy Cedex, France. Fax: (33) 83.32.95.90.

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7.x. 7.0.

Caffeine intoxication or caffeinism . Individual variability and age-related variations in the effects of caffeine

7.Y.l. Variations in the effects of caffeine among individuals

7.Y.2. Age-related variations . .

X. Tolerance and dependence towards the effects of caffeine . . 8.1. Tolerance . . . . . . . . . . . . . . . . . . . . . . . 8.2. Dependence and withdrawal . . . . . . .

9. Conclusion . . . . . . . . . . . . . . . . . I . . . . .

IO. Summary . . . . . . . . . . . . . . . . . . . . . .

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . .

References . . . . . . . . . . . . . . . . . . . . . . . .

I .

.

. .

...................

...................

...................

1. INTRODUCTION

Methylxanthines, and especially caffeine, can be considered as the central nervous system stimulants

most widely consumed by man414,497~510. As a compo-

nent of tea, coffee and cola drinks, caffeine is the most commonly ingested methylxanthine. Moreover, caffeine, as well as related methylxanthines such as theophylline and aminophylline, are widely used as medications to treat asthma497~5L0 and apnea in the newborn’4$1”*6”. Caffeine is also present in many over- the-counter medications, such as in headache prepara- tions in association with aspirin and in appetite sup- pressants.

Caffeine is usually absorbed in small or moderate doses and, only occasionally, in relatively high doses. Moderate doses of caffeine are generally considered to have the effect of a “mild stimulant, helpful in tem- porarily relieving minor fatigue and boredom with little risk of any harmful effects”237. The amount of caffeine consumed by most people in coffee, tea or cola drinks produces effects that are difficult to detect or so subtle as to go unnoticed; thus, interpreting the influence of caffeine on the central nervous system is complex. Moreover, since caffeine is quite often absorbed in coffee, its various and complex pharmacological effects are even more complex, i.e., modified or sometimes enhanced by the presence of numerous other components in coffee. In fact, most of the results obtained to date remain ambiguous or inconsistent’48-150~174~4’5~569. Other factors that make interpretation difficult are individual differences in sensitivity to the psychotropic effects of caffeine and to the action of methylxanthine on parameters such as sleep, vigilance, anxiety and depression’49323’. Finally, when interpreting the data, it must be kept in mind that acquired tolerance to the effects of caffeine could also account for variations in the resultss’4.

In addition, no animal species metabolizes caffeine in a way similar to that of humans570, It is therefore very difficult to extrapolate the results obtained from animal studies to humans; it is especially difficult because some metabolites of caffeine, more active and potentially more toxic than the methylxanthine itself, can result in very great variations in the pharmacological and toxic effects of caffeine from one species to another5”. In humans, the metabohsm of methylxanthines also varies with age. Indeed, premature babies are able to synthesize caffeine from theophyllinei416’.

Caffeine, either ingested or administered, diffuses throughout the entire organism, has a volume of distri- bution similar to that of body waters2j and quickly penetrates into the brain 26. Since caffeine is highly soluble in lipids, it rapidly crosses the blood-brain barrier both by diffusion and by a saturable transport system397. Experiments in the dog have shown that caffeine concentration in cerebrospinal fluid reaches one-half of its level in plasma within onIy 4-8 minsK8, and that brain concentration of caffeine remains stable for at least 1 h58y, According to a recent study, average concentrations of caffeine in plasma and brain are proportional to the dose of caffeine administered I h

before. This correlation between plasma and brain concentrations of caffeine and the administered dose is highly significant. The authors conclude that plasma concentration of caffeine and its metabolites could be a precise indicator of the concentration of these substances in the brain, both in animals and man324.

2. MECHANISMS OF ACTION OF CAFFEINE ON THE

CENTRAL NERVOUS SYSTEM

Several hypotheses have been formulated concerning possible mechanisms of action of caffeine at the cellular level. Three main mechanisms of action have been described which are, in chronological order of

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their discovery: intracellular mobilization of calcium, inhibition of phosphodiesterases, and antagonism at the level of adenosine receptors. These different mechanisms of action have been the topic of numerous revie.s12~79~93~207~209~329~446,465,491~498~559~ A hypothesis has

been formmated suggesting a fourth mechanism of action of caffeine on the central nervous system, the binding of caffeine to benzodiazepine receptors61*387.

2.1. Mobilization of intracellular calcium The effect of methylxanthines on mobilization of

intracellular calcium has been first demonstrated in

skeletal muscle. Caffeine, at a concentration of 1-2 mM lowers the excitability threshold and prolongs duration of the active period of muscle contraction by promoting translocation of calcium through plasma membrane and sarcoplasmic reticulum4g-51. Similar observations have been made subsequently on mammal cardiac muscleZ3 and on sarcoplasmic reticulum in vitro530q620+621. The effect of caffeine also depends on intra- and extracellular concentrations of calcium330. Recently, it has been shown that caffeine sensitizes the muscular contractile apparatus to the concentration of intracellular calcium136~1~~4s4*419; the direct interaction of methylxanthine with calcium channels has been observed in the sarcoplasmic reticulum524.

Synaptic transmission in central and peripheral nervous systems requires controlled release of neurotrans; mitters, which in turn depends on the influx of calcium into nerve endings. In the sympathetic neuron of bull- frogs, the presence of caffeine induces rhythmic hyper- polarizations resulting from increased intracellular calcium concentration343,344*558. In this preparation, meth- y~anthine in concentrations ranging from 6 to 30 m&I acts on four different types of ion channels, all of which are affected by calcium release from intracellular stores, probably the endoplasmic reticulum5T416. In arterial ceils of rabbit ear, caffeine blocks the voltage- dependent calcium channels by direct interaction at the level of the calcium channe13”. Caffeine has a biphasic effect on calcium shifts in the isolated cerebral endoplasmic reticulum. Small or moderate concentrations of methylxanthine stimulate both the uptake and release of calcium by the endoplasmic reticu- lum407. High concentration of caffeine inhibits calcium uptake by the endoplasmic reticulum407*592. These effects are not due to adenosine 3’5’~cyclic monophosphate (cAMP)~~~. Also, it has been recently reported that stores of calcium that are sensitive to the effects of caffeine might be located in the cell bodies, are not coupled with release of neurotransmitters like noradrenaline611, and may or may not affect the GARA, response . 145 Three intracellular pools of cal-

cium can indeed be distinguished by their turnover and

mechanisms of Ca2+ a~umulation, storage and re- Iease’80~568. One pool is exclusively sensitive to inositol 1,4,5_triphosphate, one is sensitive to both inositol 1,4,5triphosphate and caffeine, and the third one is only caffeine-sensitive’80,4”,568,64g.

A minimal concentration of 250 FM of caffeine seems necessary to produce detectable effects on calcium shifts263,530. The circulating plasma concentration of caffeine after ingestion of coffee is usually less than 100 PM. Toxic effects are observed with concentration of this methy~anthine above 200 FM, and lethal intox- ications are observed with blood concentrations higher than 500 FM 209Y497. Thus, the mechanisms responsible

for the pharmacological effects of caffeine are probably activated by concentrations lower than 100 PM. Given these conditions, it is unlikely that mobilization of intracellular calcium represents an essential mechanism of caffeine action in the central nervous system.

2.2. Inhibition of phosphodiesterases The inhibiting properties of methylxanthines on

cyclic nucleotide phosphodiesterases activity were dis- covered by Sutherland’s group39$s4 who used theophylline and caffeine in their research on regulation of glycogen metabolism and on peripheral lipolysis. After identifying the major role of CAMP in the regulation of these processes, the authors observed that methylxanthine prevents enzymatic breakdown of CAMP by inhibiting cyclic nucleotide phosphodiesterase3g,84. This discovery represents a possible mechanism of action of methylxanthines, i.e., accumulation of CAMP and po- tentialization of its effects in order to stimulate the action of substances such as catecholamines2~.

Methylxanthines inhibiting effects on phosphodiesterase have been later demonstrated in the central nervous system606. Cerebral cyclic nucleotide phosphodiesterases are found in various molecular forms599*600 which are distributed in a non-homogeneous way and are affected to varying degree by number of inhibi- tors626. Methylxanthines, which have a structure related to that of cyclic nucleotides, competitively inhibit the various isoenzymes of phosphodiesterases to variable degrees depending on the region of the brain. However, this inhibition is produced only with millimo- lar concentration of methylxanthines, i.e., a toxic concentration that is never found in situ93,610,626. Hence, it seems very difficult to establish a link between phosphodiesterase inhibition and pharmacological properties of caffeine in concentrations usually found in the circulating blood. Thus, chronic treatment of caffeine at a dose of 25 mg/kg/day does not increase intracerebral concentration of CAMP and does not decrease

142

specific activity of the specific phosphodiesterases of cerebral cyclic nucleotides in vivox3.

2.3. Antagonism at the leuel of adenosine receptors The hypothesis concerning this third mechanism of

action of methylxanthines comes from the studies of Sattin and Ra11s34. These authors made the surprising

discovery that, under several conditions, theophylline reduces the accumulation of CAMP in cerebral slices instead of increasing it as would be expected from a phosphodiesterase inhibitor. Therefore, they suggested that theophylline could block stimulation of CAMP formation by endogenous adenosine.

The possibility that central stimulant effects of methylxanthines result from competitive antagonism of the depressant effects of endogenous adenosine is ap- pealing for many reasons. Most pharmacologic effects of adenosine in nerve tissue can be suppressed by relatively low concentration of circulating methylxanthines, e.g., less than 100 PM, which is attained after drinking l-3 cups of coffee. This concentration apparently has no direct effect on CAMP metabolism nor on calcium shifts’26,s6”. Administration of adenosine and its derivatives usually produces effects opposite to those of caffeine or theophylline446. These effects include depression of spontaneous electrical activity of the neurons340,477, inhibition of synaptic transmission4s1~sss and release of neurotransmitters210,286. Adenosine and its derivatives also influence behavior644. Injection of adenosine into the cerebral ventricles is favorable to the onset of slow-wave sleep and reduces vigilance in various animal species 183,268,390*483. In humans, therapeutic administration of deoxycoformycin increases the blood concentration of adenosine, and probably its brain concentration as well, and has side effects of lethargy and drowsiness 382; this substance, used in the treatment of leukemia, is an inhibitor of adenosine deaminase which is the enzyme responsible for the breakdown of adenosine into inosine. Adenosine derivatives also cause a dose-dependent decrease in locomotor activity that can be eliminated by small doses of caffeine or theophylline1s8~ss9~s60. The relative efficacy of various xanthine compounds in stimulating locomotor activity is related to the relative affinity of these substances for adenosine receptorss6’. Caffeine and theophylline also act as adenosine receptor antagonists in humans4’.

There are two main sub-classes of adenosine receptors, Al receptors have high affinity for adenosine and A2 have low affinity371,46s,603. Adenosine, via these two types of receptors, regulates a number of physiological functions either by inhibition (Al receptors) or by stimulation (A2 receptors) of adenylate cyclase. Caf-

feine and theophylline exert antagonist actions on these two types of receptors127~ss”.

2.4. Interactions with benzodiazepine binding sites

Caffeine also binds to benzodiazepine receptor sites although the affinity is rather weak61,387. This binding has been suggested as a possible mechanism of action of methylxanthines because caffeine antagonizes or modifies the effects of benzodiazepines on anima113s~4”0 and on human behavior 188~221~284~368~39s~s’2. However, caffeine and theophylline are much more potent antagonists of adenosine receptors than of benzodiazepine site8’. Moreover, the interaction between caffeine and benzodiazepines might not be due to competition of the two substances at the level of benzodiazepine receptors, but could imply action on adenosine recep- tors133,287,447*480. Finally, some experimental data suggest that only the toxic effects of high doses of methylxanthines would be due to interaction with benzodiazepine receptors 62s Nevertheless, it is advisable to . decrease rather than increase caffeine and benzodiazepine consumption in order to maintain an even mood”“.

3. EFFECTS OF CHRONIC CAFFEINE CONSUMPTION ON DENSITY OF CEREBRAL RECEPTORS

Methylxanthines interfere with mainly two types of receptors, i.e., adenosine and benzodiazepine receptors which, subsequently to chronic treatment, can modify their number in the brain.

3.1. Effects on adenosine receptors

Numerous studies have shown that chronic administration of caffeine or theophylline by intraperitoneal injection (20-100 mg/kg/day), in food (50-600 mg/kg of food), in drinking water (1 g/l), or by implantation (37.5 mg/week), for periods ranging from 1 to 6 weeks, increases the number of adenosine receptors in rat or mouse ~~~~~62,130,181,208~270~378,384~434~500,519,585~640~653 in

most studies, the increase in the number of adenosine receptors is not accompanied by a modification in their affinity 62,130,208,378,384,434,585,640,653

Modification in the number of adenosine receptors does not necessarily reflect functional changes393. Thus, neither accumulation of cyclic AMP in hippocampal slices nor in isolated adipose tissue nor inhibiting effects of adenosine on lipolysis are modified by chronic exposure to caffeine, in spite of the increased number of adenosine receptors 208,6s2. However, chronic caffeine treatment increases sensitivity to adenosine both in cerebral slices and in the whole anima124s,364s609, and decreases sensitivity to acetylcholine36s. This last effect

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could be linked to a decrease in the number of cholin-

ergic receptors 365. Also, reduced sensitivity to convul-

sants after chronic theophylline treatment was attributed to increased number of cw-adrenoreceptors585 and to decreased number of /3-adrenoreceptors21”229 induced by this type of treatment.

Chronic administration of caffeine in the food of pregnant mice (400 mg/kg of food) produces a long- term increase in the number of adenosine receptors in the brains of their offspring. This increase lasts until adult age385. On the other hand, when juvenile rats are given caffeine (50 mg/kg i.p.> between days 4 and 27 after birth, the increase in the number of adenosine receptors does not last more than 2 weeks after the treatment is discontinued3%. In adult mice, the effects vary with cerebral regions. The increase in the number of adenosine receptors in the cerebellum is still observed 2 weeks after caffeine treatment is stopped, while the number of receptors in the forebrain returns to normal value within 8 days59.

3.2. Effects on benzodiazepine receptors A double blind clinical study on 51 students showed

that 250 mg of caffeine could neutralize effects resulting from administration of 10 mg of diazepam, such as lowered cognitive ability and increased muscle relaxa- tion395. Similar results were obtained in another

study ls8. These results prove that caffeine absorption can

lower the clinical effectiveness of benzodiazepines. Doses used in this study (125-500 mg of caffeine) correspond to 2-6 cups of coffee. Conversely, benzodiazepines can neutralize the stimulant effects of 5 to 20 mg of caffeine in animals . 135 However, the depressant effect of diazepam on cerebral energy metabolism is not decreased in the rat after 15 days of chronic exposure to caffeine . 295 It has also been suggested that patients suffering from some anxiety disorders might have developed a hypersensitivity to caffeine65.

However, even though the interaction between caffeine and benzodiazepine receptors has been demon- strated61T439, results of studies on the effects of methylxanthines on benzodiazepine receptors are contradictory. Thus, after intraperitoneal administration of 5-40 mg of caffeine of after addition of caffeine to food at a dose of 600 mg/kg, some authors report an increase62,386Y639, others a decrease131, and still others no change at a11229,306 in the number of benzodiazepine receptors. Caffeine increases the binding of benzodiazepines to their receptor sites in vivo338@‘1 but decreases this binding in cultured neurons324. It would appear that caffeine may alter the function of the chloride channel associated with the benzodiazepine

receptors516. These divergences can be explained in

two ways. On the one hand, stress affects the number of benzodiazepine receptors while caffeine added to food has no effect373. In some studies, animals were treated with daily intraperitoneal injection of caffeine; this requires handling and thus creates a stressful situ- ation. Moreover, different types of stress can affect the benzodiazepine receptors in completely opposite

wayP. On the other hand, the antagonistic effect of caf-

feine on benzodiazepine receptors requires concentrations 5-10 times higher than those that block action of adenosine receptors439*560. It is probably these concen-

trations that can be attained with intraperitoneal injection but not with oral ingestion of caffeine. Finally, part of the effects of methylxanthines on the benzodiazepines could be linked to the interaction of the latter with endogenous adenosine4”. In fact, benzodiazepines inhibit uptake of adenosine by isolated nerve endings69V474 and stimulate release of adenosine476,M8. Therefore, it seems that caffeine does not interact with benzodiazepine receptors in vivo at the non-toxic doses usually ingested by man318,364,625.

4. EFFECTS OF CAFFEINE ON NEUROTRANSMIT-

TERS

The effects of caffeine on the formation and release of neurotransmitters have been the subject of in-depth studies. Several studies have suggested that some effects of methylxanthines could be due to enhanced release of endogenous catecholamines24,46*140,579,631. However, it must be kept in mind that these animal studies were performed in vitro using caffeine concentrations much greater than those found in humans after intake of several cups of coffee, and that, conversely to the studies on the effects of caffeine on phosphodiesterase inhibition, Ca*+ mobilization or adenosine antagonism, little is known at present on the threshold concentrations of caffeine necessary to induce changes in neurotransmitter metabolism and function. A primary role of adenosine in the central nervous system appears to be to inhibit the release of various neurotransmitters, and possibly glutamate in

particular, through presynaptic receptors. Therefore adenosine antagonists, such as methylxanthines, can be expected to increase the release of neurotransmitters.

4.1. Ca techolamines In most studies, methylxanthines, caffeine and theo-

phylline in doses varying between 2.5 and 100 mg/kg do not seem to have any effect on intracerebral noradrenaline concentration46~‘05~12’~328~538~612~614. They in-

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crease the rates of synthesis and turnover of ~~~ad~ena]in~46~‘“~122,328~5”8,612,6~4

. They increase spontaneous electrical activity of noradrenaline-containing

neuronsz3’, inducing increased rates of synthesis and turnover of monoamine’s6. However, the mechanism by which caffeine activates the noradrenaline neurons is not known’86,238. Methylxanthines also decrease the density of #?-adrenoreceptors in the brain in response to increased release of noradrenaline22”*37’.

On the other hand, the effects of caffeine and other metylxanthines on dopamine are not as clear. Caffeine increases intracerebral dopamine concentration167,375, 4’3,573,6’4, but it can either increase or decrease or leave unchanged the release, uptake and turnover of dopa- mine46,92,167,216,229,238,2’9,413 Catecholamine synthesis has

been reported to increase 30 min after administration of caffeine, 50 or 100 mg/kg, but to decrease 2 h after exposure to the same dose of methylxanthinez5.

More recently, in vitro studies have shown in animals that caffeine affects local release of catecholamines, especially dopamine. Indeed, methylxanthine selectively depresses the firing rate of dopamine neurons of the ventral tegmental area that projects to the frontal cortex and limbic structures, but has no significant effect on the firing rate of dopamine neurons in substantia nigra pars compacta that projects to the caudate nucleuss74. Therefore, it appears that, in the rat, caffeine administration inhibits mesolimbic and mesocortical projecting dopamine neurons, but has no effect on dopamine neurons that project to the stria- turn. In addition to providing a possible site of action for the effects of caffeine on attention and vigilance, these results also may explain the clinical observations of exacerbation of schizophrenic symptoms574. In addition, caffeine decreases local release of dopamine in the caudate nucleus in a dose-dependent way423. The latter effects can be linked to the stimulant action of caffeine on locomotor activity. Caffeine at a dose of 10 to 50 mg/kg is able to prevent the appareance of akinesia induced by catecholamine depletion in mice484. Both dopamine and noradrenaline are necessary for manifestation of caffeine-induced motor stimulation, although it is unclear which cate~holamine is most important i94,578.

4.2. Serotonin Caffeine increases in vitro serotonin concentration

in the brainstem, especially in raphe nuclei, and in cerebral cortex and cerebellum44*578. When caffeine (0.3%), green or roasted coffee, or tea (10%) are incorporated into the food of rats, cerebral concentrations of tryptophan, serotonin and its main metabolite, 5-hydro~indoleacetic acid, are increased in the brain

starting from the 1st day of exposurem7. On the other hand, decaffeinated coffee has no effect. These same variations are observed after animals are injected with lo- 100 mg/kg caffeine’X”~220~“27~h46.

Conversely, data on the rates of release, uptake, synthesis, and turnover of serotonin are less consistent. Indeed, rates are either increased or decreased or

unchanged by doses of methylxanthines ranging from 10 to 100 mg/kg 91~105~121~125~328~4S6~527~538~602~ These modi_

fications of serotonin cerebral concentration and metabolism suggest that this neurotransmitter could play a role in the pharmacological activity of caffeine4’. The intensity of the effect of methylxanthine on intracerebral serotonin concentration and on behavior varies as a function of the basis emotional level of the animal”*. This variability is also observed in man231,3h3. However, it is difficult to link these biochemical effects to the stimulant action of methylxanthines in man, especially in view of the high doses used in most animal studies.

Caffeine reduces serotonin availability at postsynap- tic receptor sites”‘; this elicits a reduction in the sedative effect of the amine on activity, and has re- percussions on sleep mechanisms, motor function, and functional regulation of cerebral blood vessels, all of which are influenced by serotonin’20~137~2’y~262*265~290* 322,333,348,435,463~461,478,505~618, Thus, it is highly probable

that serotonin plays an important role in the mechanism of action of caffeine on the central nervous sys-

tem27R. Recent studies performed on rodents show that

caffeine increases concentrations and rates of cerebral utilization of noradrenaline, dopamine, and serotonin, specially in some structures belonging to the limbic system. The authors suggest that if similar limbic effects on neurotransmitters exist in man, they could have important clinical consequences; theoretically, they could predispose some individuals to the beneficial psychological effects linked to absorption of cof- fee265,333. The majority of these neurochemical studies also confirm the results of behavioral studies showing that caffeine is only a mild stimuiant compared to amphetamines and to cocaine505.

4.3. Acetylcholine Few studies have been performed on the effects of

caffeine on the cholinergic system. Caffeine and theophylline, at doses of 15 and 30 mg/kg i.p. in anes- thetized rats, increase the outflow of acetylcholine from the cerebral cortex . 478 Acetylcholine turnover in

the hippocampus also is increased by intracerebral injection of theophylline . 435 However, methy~anthines can produce either activating or inhibiting effects on

145

acetylcholine release in brain slices; these effects vary as a function of both caffeine concentration and frequency of electrical stimulation of the slices463,464. Fi- nally, chronic consumption of high doses of caffeine modifies the sensitivity of cholinergic neurons to methylxanthine. This modification is not linked to adenosine receptors’*‘.

4.4. Amino acids Caffeine, administered first at a dose of 0.5 mg/ml

in drinking water for 1 week then at 1.0 mg/ml for the following 2 weeks, increases the amount of glutamine in the whole brain of mice, while the amounts of GABA and glycine are decreased, particularly in poste- rior areas of the brain 348. Modifications in the concentration of these two inhibitory neurotransmitter amino acids could be the source of an increased excitability of the central nervous system348. On the other hand, caffeine has little or no effect on cerebral transport systems of neurotransmitter amino acids13’. Rats given drinking water containing gradually increasing concentrations of caffeine until they exhibit symptoms of self-mutilation, similar to those described in the Lesch-Nyhan syndrome , 4oo have increased amounts of taurine, histidine, ornithine and aspartate in their brains, while tyrosine is unchanged and the amounts of GARA and glutamate are decreased”7*486. According to the authors, changes in the concentration of amino acids in the cortex could be responsible for behavioral abnormalities observed in these animals. Furthermore, these variations are similar to those observed in experimental uremiaa6.

Cerebral tyrosine concentration is increased in the brain of newborn rats whose mothers were exposed to caffeine (0.04% in drinking water) during gestation and/or during lactation 586 Hence, maternal intake of .

caffeine could induce disturbances in the metabolism of catecholamines, of which tyrosine is the precursor, as well as behavioral abnormalities in developing rats586.

5. EFFECTS OF CAFFEINE ON CEREBRAL BLOOD

FLOW AND METABOLISM

The stimulant effects of caffeine on the central nervous system are associated with changes in local rates of cerebral energy metabolism. Administration of an acute dose of 10 mg/kg caffeine or continuous perfusion of methylxanthine, at a rate of 0.30 mg/kg/min, induces an increase in the rates of local cerebral glucose utilization; this increase is significant in monoaminergic cell groupings, like substantia nigra and ventral tegmental area, which are rich in dopamine,

medial and dorsal raphe nuclei, which contain sero-

tonin and locus coeruleus, rich in noradrenaline. Caf- feine increases the rates of energy metabolism in the structures of the extrapyramidal motor system and in numerous thalamic nuclei and motor or limbic relays, as well as in limbic areas such as the hippocam-

Pus 257,258,438@o-443. These local increases of cerebral

glucose utilization in structures which are involved in the control of locomotor activity and especially in the sleep/wake cycle, correlate very well with the methylxanthine-induced behavioral modifications described in detail in this chapter. Finally, the increase in glucose utilization rates is of the same amplitude after acute or 2-week chronic administration of 10 mg/kg caffeine. Thus, cerebral energy metabolism does not seem to develop tolerance to the stimulant effects of methyl- xanthine438.

Methylxanthines such as caffeine or theophylline induce vasodilation, except in the central nervous system where they raise cerebrovascular resistance; this actually contributes to a reduction in cerebral blood flow. The vasoconstrictive properties of methylxanthines have been demonstrated in man89*236,381,391. 393,394,427,549,622 and in animals257,258,440,443,492. Caffeine

induces a decrease in local cerebral blood flow, mainly in the areas where it increases metabolism, i.e., in monoaminergic cell groupings, in the motor and limbic systems, and in the thalamus257,258,444.

In most situations, cerebral blood flow and glucose utilization are closely coupled in all cerebral regions 147,495,516, so that modifications in cerebral activity elicit parallel changes in glucose utilization and in cerebral blood flow256,331,346Y398,561. In general, changes in cerebral blood flow are the consequence of variations in cerebral energy metabolism256,331*398. Contrary

to the majority of pharmacological agents to which man is frequently exposed, caffeine has the property of inducing cerebral hypoperfusion accompanied by simultaneous increase in glucose utilization256,438+r0-443; in other words, it resets the level of coupling between cerebral blood flow and energy metabolism. Methybt- anthines thus seem to modify the regulating mechanism between blood flow and cerebral metabolism. Although this mechanism is not yet well understood, adenosine, with which methylxanthines compete, is known to be one of the modulators of regulation in the

relationship of blood flow to metabolism in the central nervous system47*346,635.

Caffeine is very frequently used in the treatment of idiopathic apnea in the preterm infant 14J6,66. Several studies have shown that modifications of cerebral blood flow in the premature newborn play a very important role in the pathology of intraventricular hemorrhage

146

and in the development of periventricular leuco- malacia’6”~4’2. Ho wever, a recent study showed that a bolus dose of caffeine usually used for treatment of apnea in the preterm neonate, i.e., 20 mg/kg, does not modify the velocity of cerebral blood flow in the premature infant and therefore can be administrated without risk”2x. The innocuousness of aminophylline, another methylxanthine used in the treatment of apnea in the premature infant, has been proven. In fact, this substance reduces cerebral blood flow but does not affect cerebral functions4”“.

6. EFFECTS OF CAFFEINE ON CEREBRAL ELECTRI- CAL ACTIVITY

6.1. Animal studies

Caffeine has long been believed to have an overall stimulant effect on the central nervous system, especially on the cerebral cortex5”, by increasing vigilance and lessening the feeling of weariness. Electrophysio- logical studies in the rat have shown that cortical electrical activity is stimulated by intravenous administration of lo-100 mg/kg of caffeine20,475. In the cat, a dose of 10 mg/kg of caffeine produces an activation of the cortical EEG similar to the activity recorded at the time of physiological awakening or to the activity produced by direct stimulation of the reticular formation323,544, a structure which plays an important role in vigilance and awakening42h. However, stimulation of spontaneous electrical activity in neurons of the reticular formation appears with much lower doses of caffeine, l-2.5 mg/kg i.v. 200,2R1. On the other hand, this structure does not seem to be indispensable for the activating effects of caffeine to be seen on the EEG ‘99,s44,591. The response of reticular formation neurons to caffeine is dose-dependent, and the duration of activation lengthens in proportion to the dose given2s’.

Caffeine and other methylxanthines also elevate the excitability observed in vitro in rat hippocampal slices1”7,24” and activate the B-rhythm of the EEG in

rabbit hippocampus . 48s Caffeine lengthens the post-firing duration in the hippocampus and this effect lasts longer than the changes induced by caffeine on the EEG 157,246,48s,601. High doses of caffeine provoke electrical modifications in the hippocampus similar to those that are recorded during generalized seizures4s5. The great stimulant effect of caffeine on the hippocampus shows the importance of the limbic system in development of the convulsant and anxiogenic effects of this methylxanthine4s5. Caffeine also elevates reinforcement threshold for electrical brain self-stimulation, perhaps corresponding to the anxiogenic component of

action of caffeine that predominates at high doses in

humans4”-43”. This effect does not seem to be mediated by adenosine systems432.

At the same time that caffeine increases cortical electrical activity, it induces a significant decrease in electrical activity in thalamic neurons, even in very small doses, 0.1 mg/kg i.v.“‘“.“‘7.‘99. This lowering of thalamic activity correlates well with sleep disturbances induced by caffeine’~‘7~‘yy~27H~h”‘. Similarly, direct ion- tophoretic administration of caffeine decreases the spontaneous electrical activity of neurons in the caudate nucleus of the rat59x. Thus, the methylxanthine seems capable of activating the nigrostriatal pathway, resulting in decreased activity in the caudate nucleus subsequent to stimulation of dopamine release by the nigrostriatal nerve endings2’“.

6.2. Human studies

In man, stimulant agents of the central nervous system generally increase the number of p-waves and decrease 8- and a-activity on thk’ EEG19’. However, the observed effects of caffeine on resting EEG are variable and quite conflicting. Caffeine administration has been reported to cause either ,a decrease235 or an increase”’ in amplitude of a-activity or else an increase in power in the lo-13 Hz bandwidth accompanied by a decrease of power in the 5.5-9.5 Hz band- width5’“. The divergence in results is due to differences in the dose of caffeine, to the time of recording in relation to the time of administration of methylxanthine, and to methods used to analyse the EEG4”.

The effect of caffeine on evoked brain activity are also discordant. At comparable intervals after administration of 300 mg of caffeine, amplitudes of contigent negative variations increase in one case” and decrease in another one2”‘. A bolus dose of 300 mg of caffeine either reduces334 or does not modify the amplitude of auditory evoked responsesh3x. Lastly, caffeine decreases the power of EEG in resting conditions and after stimulation by sine wave modulated lights79.

7. EFFECTS OF CAFFEINE ON BEHAVIOR

This section deals with the effects of caffeine on spontaneous motor activity, learning and memory, simple and complex coordination, endurance and athletic performance, aggressivity and mood, anxiety and sleep, in both man and animals.

7.1, Spontaneous motor activity Experimental studies on this subject have been per-

formed on the effects of caffeine given orally, subcuta- neously or intraperitoneally. Measurement of sponta-

147

neous activity is performed mainly in open fields, running wheels, and conditioning boxes crossed by two infrared beams that provide a record of an animal’s

global activity. The stimulant effects of caffeine on the motor activ-

ity of mice and rats were demonstrated in the 1930s and 1940~~~~~~~‘. This stimulant action has been later confirmed by numerous st~dies46,S5,81,115,163,213,272,275,283,

288,3”9,324,325,345,354,366,369,410,417~437~44”~442~472,S6”,~~9~6~3-6~5

Furthermore, it has been noted that the range of active do& was similar in many species33,115,148,213,278,3"9,468,

and that this range is of the same order of magnitude in the recently weaned 24day-old rat as it is in the adult anima1288. A dose-response relationship has been demonstrated224~278~283~324V58g, In animals the minimal

dose of methylxanthine to produce an effect is 1.5-10 mg/kg and the dose to produce maximal effect is

lo-20 mg/ kg 46,55,~1,272,2?5~2~3,3”2,4”9,417,437,56”,5~,589 ln

general, spontaneous motor activity does not increase with doses above 30 mg/kg, and even decreases with higher doses, between 40 and 60 mg/

kg 81~275,324*366*4r7,589. Surprisingly, the higher the caffeine dose, the longer the delay in increase of motor response 278,283*437,589_ Locomotor activity can be enhanced in rats by intrastriatal injections of caffeine. These effects are mediated by antagonism of endogenous adenosine which, in turn, functionally increases dopamine function 321. Therefore, the behavioral effects of intrastriatal caffeine are uitimately mediated by dopamine32’. At very high doses, caffeine may potenti- ate the action of other convulsants154~‘55*436.4”7 and even cause convulsions422Y424,425V483P497. Moreover, recent reports indicate that seizures may occur in both ~hiIdren457,509 and adults29.468 with so-called therapeutic or mildly toxic levels (14-35 mg/l> of theophylhne, the methylxanthine currently used to treat asthma.

Rats exposed to caffeine in utero show increased locomotor activity and decreased emotivity postnataily; this effect is more pronounced in males than in females3”“,301. Conversely, when caffeine is absorbed after birth or during the 1st week of life, as is the case in newborn infants suffering from apnea, it has a depressant effect on locomotor activity of rats according to some authors”9,655 and a delaying effect on its stimulation of locomotor activity according to othersz5’.

Only few studies have been performed on the effects of caffeine on spontaneous motor activity in man. Some investigators report increases in typing rate after caffeine285,297,298V59”, others observe no effect6p’97 or even a decrease228. Gross motor activity measured with an accelerometer worn on the belt is increased after 3 and 10 mg/kg caffeine in children. In adults, the high dose of caffeine increases activity in the ‘high’ con-

sumer group (more than 300 mg caffeine daily) but not in the ‘low’ consumer one (less than 100 mg caffeine

daiiy)“‘.

7.2. Learning, memory and mental perjormance It is difficult to establish precisely from the data

pubhshed to date if caffeine influences superior cognitive skills in animals. Some studies have clearly shown that caffeine improves learning abilities, memory, and spatial orientation in various tests98~48”~522~627, while oth-

ers have shown no changes 38**23,175x577. Rats exposed to

caffeine do not make fewer errors and do not decrease their latency in mazes of varying complexity, although exploration is stimulated 450,453*577. Thus, several authors agree that while caffeine may not improve learning ability, it might influence attention, vigilance, activity and performance, a11 of which are difficult to distin-

guish from learning per se 86*224. However, the effects of caffeine on learning vary with the degree of novelty of the task to be accomplished. Thus, caffeine would have little effect on learning, or even inhibits it, when the animal is placed in an unfamiliar environment; but it improves learning performance when the animal is familiar with its environment or with the task to be accomplished75~4w~453. In fact, caffeine seems to act by slowing habituation during repetitive stimulation, thus maintaining heightened arousal*32. Also, caffeine enhances learning in maze tests that do not include a reward, but makes no difference in tests that include a food reward453.

In operant responding tests, caffeine increases the frequency of answers when tests involve a food reward both at fIxed94,“3,134,4”3,4”5,554,555 and variable inter_

vaIs13,4”2,53’,6’9. The increase in answers varies with the dose given; however, this effect disappears or is re- versed with high doses94,175*4”*,564. In avoidance tests that use electrical shocks, noise signals, or light signals, caffeine increases the frequency of avoidance response in monkeys and rats, even at high doses, 50-80

mg/kg , 271~533 but decreases this response in hamsters and in one species of highly emotional rats99.533.

In man, memory per se is not improved but response tends to be quicker and keener37*“0,315*367. Intellectual performances such as reading, operations of arithmetic and some verbal tests might be slightly improved especially when normal performance is lowered by weariness or boredom; however, most often there is no change 37*168,202q374,482,627. The effects of methylxanthine are dose-related but high quantities of caffeine reduce performance in some tests2”i.

Susceptibility to caffeine is also linked to sex’sJ70. Results from two studies performed on women are conflicting: one study indicates that caffeine hinders

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memorization of word lists170 while the other indicates that it enhances it”. This discrepancy is attributed to differences in estrogen levels in circulating blood”.

However, the authors of this study tested memorization without taking into account the phase of the women’s menstrual cycle or whether or not they took oral contraceptives”“. By contrast, in the second study, women who were not taking oral contraceptives, which are known to contain estrogens, were tested only during the first 5 days of their cycle’s. Accordingly, it has been suggested that cognitive task performance in women varies according to the phase of menstrual cycle”j. However, variation in caffeine effects with estrogen levels in blood remains unexplained.

Susceptibility to caffeine also seems to depend on personality type; the response could be different in introverts and extroverts52~‘77~361~508~557. Introverts increase speed and precision of performance when they ingest caffeine but only at small doses; their performance decreases with high doses. On the other hand, extroverts increase their speed and precision with any given dose of caffeine . s2 Susceptibility to caffeine also varies with the subject’s degree of alertness which can be assessed by skin conductance responsezo4.

Children given a single dose of caffeine, even a high one (10 mg/kg), or daily doses of theophylline, show no change in learning ability or attention during a test measuring performance, although they appear more jittery168~s37. Chronic administration of caffeine to children does not seem to have any beneficial effects,

although some results are ambiguous”‘. Moreover, great individual variability in the effects of methylxanthine has been reported in childrens3’. Finally, it seems that children are not more sensitive to the effects of

caffeine than are adults148,537.

7.3. Simple and complex coordination activities and vigi-

lance Caffeine, in a single dose as high as 450 mg, has

little or no effect on simple coordination activities in adult men36,9s,188. One dose of 750 mg could enhance these activities2t3, but this single dose is much higher than that corresponding to average coffee or methylxanthine intake from other sources.

Complex coordination activities usually are spread out over a period of time, so that testing these activites also tests wakefulnesss6s. Caffeine increases vigilance 109,232-234,3’7,497SlO,435,656, prevents the decline

in attention usually observed after meals, especially after 1unchss6 and improves information processing after lunch2s7. Since increased vigilance induced by caffeine remains unchanged after a period of sleep deprivation, there does not seem to be any interaction

between the sleep/wake cycle and the effects of meth- ylxanthinesl”. Caffeine also improves performances such as visual perception15’,363, driving a car (speed

of reaction to road signs, braking and accelerating reaction time)30,504, or reactions in a flight simu- lator h,269,s42. Susceptibility to caffeine also depends on personality type; the acoustic vigilance of extroverts increases after a dose of 200 mg of caffeine but that of introverts does not 332.

The effects of caffeine on some activities of complex coordination are ambiguous; caffeine has no effect according to some authors6,197Z212, while others con- sider it a stimulant 297,298,s66V590V630. Moreover, the time required to accomplish a complex task varies with the dose of caffeine; time is shorter with small doses (120 mg), longer with average doses (180 to 240 mg) and biphasic with high doses (360 mg)297,29s,312,590,630.

Caffeine also seems to induce arm and hand tremors which interfere with measured performances. Arm trembling has been described in numerous studies either after a single cup of coffee312 or after administration of 300-900 mg of caffeine 228,232,298,312,358,583,584,619

Only one study failed to demonstrate the effect of caffeine on arm stability , 312 but the reason for the discrepancy might be that the subjects were tired. Coffee and caffeine can also exacerbate the arm and hand tremors observed in Parkinson’s disease and in patients treated with lithium317,339. Caffeine counter- acts the psychomotor disturbance caused by alcohol in man and animals only when caffeine doses are small, for example less than 20 mg/kg in the mouse. Surpris- ingly, high doses of caffeine actually amplify the effects of alcoholL28,448*449.

7.4. Endurance and athletic performance Many athletes absorb caffeine or methylxanthines

before a sports event. Caffeine is believed to improve performance whenever endurance is involved; however, this hypothesis is controversial because experimental procedures used to explore this matter are not stan- dardized74,141,605. This type of study is complex because the effects of caffeine vary with the weight of the subjects, the kind of physical activity considered, and the environmental conditions at the time of activity6’“. Caffeine might act directly on the central nervous system by stimulating release of p-endorphins and of hormones capable of modifying the perception of pain and discomfort caused by physical exertion’7,520.

Administration of caffeine in situ increases muscle contractility3’“. However, numerous studies have demonstrated that this methylxanthine does not have an ergogenic effect on muscle strength or fatigue54s2, work output2”, work capacity’, swimmer’s maximal

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speed266, or on any short and intense effort85. These conflicting results might be attributed to the following: at low frequencies of stimulation, i.e., at rest, caffeine

increases the tension developed by muscle, whereas it does not have such an effect at higher frequencies or during maximal voluntary contractions, i.e., during ef- fort372*“5. Caffeine does not seem to improve performance during intense muscle effort of short duration. Thus, regular coffee (containing 250 mg of caffeine) and decaffeinated coffee given in a double blind study both caused similar performance improvement in long jump, weight throwing, and lOO-meter race’@‘.

Caffeine also has contradictory effects on maximal oxygen consumption and on delay before exhaustion4”. According to some authors, caffeine has no ergogenic effect on work capacity 152,217*389,487 or during ergomet- ric cycling tests of increasing difficulty467,497,517. Yet, other authors claim that caffeine increases work capacity during exercises of increasing difficulty’96~‘98*591. Caffeine could mask fatigue, thereby increasing work productive 54.

On the other hand, it seems that caffeine can improve physical performance or work output during prolonged exercise at submaximal intensity, such as cross-country skiing, running and cycling43,122,1g5,310, 511,627. Caffeine does not modify the delay before exhaustion for an athlete who is acclimated to the environment, either at sea level or at high altitude’78~2’4, but it does attenuate perception of the effort required’78%5’7. The effect of caffeine is more pronounced in skiing at an altitude of 2900 m than at 300 m; similarly, caffeine clearly increases the delay before exhaustion in an athlete who is not acclimated to the altitude214.

Improved performance has been attributed to stimulation of lipolysis by caffeine. Hydrolysis of fatty tissue triglycerides51S,543 increases blood concentration of fatty acids1~40~41,100~s87. These are then actively used by the muscle during effort 122~‘95~203~310~591~633, thus saving glycogen”‘. This mechanism is important because depletion of muscle glycogen could be largely responsible for fatigue observed during endurance tests’72J73,507. How- ever, the increase in plasma concentration of free fatty acids elicited by caffeine152,353 is not always accompanied by a modification in substrate utilization by muscle99*338. Caffeine also increases production of plasma catecholamines during and immediately after effort116*195,203. Involvement of catecholamines is essential in helping the body adjust to the stress of exercise, as they contribute to a number of critical processes including glycogenolysis, glucose uptake, gluconeogen- esis, muscle and adipose lipolysis, ~ntractili~, in- otropic and chronotropic responses of the heart, and

circulatory adjustments 3g6. At high altitude, it increases

endurance by a mechanism other than mobilization’of

fatty acids22*2*4. However, this mechanism is not yet

understood. Some authors have suggested that only well-trained

athletes can benefit from the use of caffeine85y’72*513. However, accomplished athletes undergo intensive training which in itself produces a rise in lipolytic

activity and an increase in the size and density of mitochondria9’. In the same way, caffeine does not modify the plasma concentration of free fatty acids nor the utilisation of muscle or hepatic glycogen in endurance-trained rats”‘.

Finally, the effects of caffeine on physical performance are greatly attenuated in regular consumers of coffee or tea195.203. Thus, it seems that athletes who want to increase the effects of caffeine during prolonged exercise should abstain from consuming caffeine in the 4 days preceding the event so as to sup- press tolerance phenomenon195. It seems preferable to absorb caffeine 2-3 h prior to effort rather than 1 h before; in the first case, plasma concentration of free fatty acids will be at a peak at the time of effort624 while in the latter one, only plasma concentration of caffeine will be at a peak196.

7.5. Social behavior, aggressivity and mood It is generally agreed that consumption of caffeine

has a psychotropic effect, and that it can cause nervousness and irritability in people who absorb quite large quantities of coffees35. Given the difficult in scientifically evaluating caffeine’s effects on aggressivity and mood in man161, it is not surprising to learn that doses of caffeine ranging from 100 to 500 mg can produce either detectable effects233T352 or no effect at al128~188~197~212. Thus, caffeine could lessen aggressive- ness99, improve spirits and moods114,352,363,581 or aug- ment nervousness367V368,370. However, it is important for studies on this topic to be double blind because the effects tend to be positive when the subjects know that they are being given caffeine4**.

The effects of caffeine and theophylline on aggressivity vary with the species studied. Chronic administration of relatively high doses of theophylline or caffeine induces aggressive behavior in rats525*526, which can result in self-mutilation sometimes leading to death by hemorrhagic shock471,473. On the other hand, caffeine reduces aggressivity in cats4i6 and man”“’ and even counters aggressiveness in mice6’*.

There are only few studies on the effects of caffeine on social behavior in animals, and apparently none in man. Caffeine at a dose of 10-20 mg/kg stimulates sexual behavior654 and enhances gregarious instinct of

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the male rat”“. Caffeine reduces the amount of time rats spend in social interaction32~‘87~28y; contacts are brief but intense, sometimes accompanied by aggressive behavior. Also, caffeine at a dose of lo-40 mg/kg increases social investigation in juvenile rats of the

same species”“, but this effect is evident only starting from postnatal day 44”s.

7.6. Effects of caffeine on anxiety

Although a study of the National Institute of Mental Health performed on a large population of normal subjects did not find any relation between anxiety symptoms and tea or coffee consumption15y, the results of numerous works suggest that absorption of caffeine and anxiety are correlated in man31’63,65, "~1O2~l~~Y~227~23Y,243~277~314~335~48Y~5Y4,5Y7~SY8~636 and also in

animals”“~‘R7~‘89~28s~466. Thus, when striving to improve

their performance, regular coffee drinkers develop more anxiety after ingestion of 400 mg of caffeine than after ingestion of decaffeinated coffee545.

People who drink little or no coffee are probably more susceptible to the anxiogenic and psychotropic effects of caffeine than are regular coffee drinkers594. Caffeine administration elicits an increase in the level of anxiety which is more pronounced in patients prone to anxiety or panic attacks than in normal con- trols63,h4,103,15Y,2ss,355,356,5Y5_5Y’ Moreover these patients

are extremely sensitive to the anxiogknic effects of caffeine and tend to reduce or eliminate caffeine consumption because of its unpleasant psychological side effects5y4,5y5,5y7. There is definite improvement in their condition after caffeine has been discontinued’s. In 35-70% of patients suffering from panic attacks, ingestion of 500 mg of caffeine exacerbates their clinical symptoms and increases the attacks. In ‘normal’ subjects, these doses never trigger panic attacks. However, attacks can occur in sensitive people after absorption of only one cup of coffee (85-110 mg of caffeine)5y4.

The biochemical modifications that underlie caffeine-induced anxiety are not yet understood. Re- cently, it has been shown that concentration of kynurenine, a neuroactive metabolite of tryptophan, increases during caffeine-induced anxiety and returns to normal levels when anxiety disappears455. These studies suggest that kynurenine is involved in caffeine-induced anxiety in man, but so may be other neurochemical pathways such as serotonine and adenosine receptor systems33’.

In addition, according to several studies, anxiety associated with depression could be related to caffeine consumption. Correlation is often observed between high coffee comsumption (5 or more cups per day) and

anxiety accompanied by depressionhs,““,3’“. It also

seems that psychiatric out-patients suffering from lethargy and hypersomnia associated with depression often medicate themselves with large quantities of caffeine (an average of more than 500 mg per day), thus triggering a depressive state accompanied by extreme agitation . 445 However, it is difficult to determine if caffeine intake is the cause or the result of depression, because there is a dearth of information on this sub-

10'),314,.571 ject .

Caffeine is also used to lengthen duration of seizure episodes and to improve the efficacy of electroconvulsive therapy in severely depressed patients112~276,54h,547. Caffeine can exacerbate psychosis and state of suspi- cion in various mental diseases’“‘, induce psychosis de IZOL’O~,~~~,~~~, and aggravate symptoms of schizophre- nia34,307,376.414 or other psychotic syndromes650~651. Re- ducing caffeine intake of psychiatric patients, especially schizophrenics, ameliorates their behavior and in particular minimizes their aggressiveness which is a major problem in psychiatric hospitals1’12~“07~314~650. It is possible that psychiatric patients consume more caffeine in order to lessen intensity of depressive thoughtss3’, to pass the time, or remedy dryness in the mouth caused by medications, especially by the frequently used anticholinergic drugs5”5,“7’. Besides, Mis- sak4’s proposed that the normal human body may produce a substance similar to caffeine which main- tains the brain in a state of wakefulness; conversely to previous reports on the worsening of schizophrenia symptoms by caffeine34~307~37h~414, Missak also suggested that the deficiency of this endogenous caffeine-like substance might play a pivotal role in the pathogenesis of schizophrenia4’“,““.

Furthermore, some authors contend that coffee and tea may form insoluble precipitates with several of the antipsychotic medications, thus rendering treatment in- effective’*‘, while others have not observed this precip- itation or have not found lower blood levels of antipsychotic drugs in the blood in these cases6’. The possible interaction of caffeine with some drugs, especially ben- zodiazepines131~284~2”7, should not be underestimated. Indeed, a recent report suggests that at least part of the anxiety reaction produced by caffeine in panic disorders may be due to the combination of caffeine with a concurrently administered benzodiazepine”“. However, it has aIso been shown that 250 mg of caffeine in the morning prevents the daytime drowsiness resulting from a nocturnal dose of benzodiazepine without affecting performance or mood”‘“.

On the other hand, administration of idrocilamide, a muscle relaxant considerably alters the pharmacokinet- its of caffeine and specifically multiplies its half-life by

151

9 (refs. 70, 176). The association of caffeine and idrocilamide induces neuropsychopatic disorders, insomnia, excitation and hyperactivity, mood swings, and even episodes of delirium or confusion, which were long mistaken for amphetamine abuse before they were correctly identified . 35g The same kind of symptoms was

described with association of caffeine and phenylpropanolamine, a substance contained in over-the- counter diet aids349*350. Therefore, it is advisable to abstain from any beverage or food containing caffeine while taking idrocilamide”’ or any medication including phenylpropanolamine3.

7.7. Effects of caffeine on sleep There is a consensus of opinion concerning the

effect of caffeine on sleep. The traditional history of coffee relates that the abbot of a Yemenite monastery prescribed this beverage to his monks so that they could stay awake during nighttime prayers. 7.7.1. Animal studies. Caffeine administered to adult rats at a dose of 12.5-25 mg/kg decreases the overall dclration of sleep or of its different phases, and lengthens the latency period recorded before onset of the different phases of sleep 493.494.608.~~2. At a dose of 25

mg/kg, caffeine delays return of rapid-eye-movement (REM) sleep in sleep-deprived rats494. On the other hand, at a dose of 0.125 and 12.5 mg/kg, caffeine has no effect on total duration of sleep but increases duration of slow-wave sleep at the expense of long-wave sleepM3.

When caffeine is chronically administered to cats at a dose of 20 mg/kg, total duration of sleep is at first clearly shortened. When animals become habituated to methylxanthine, total duration of sleep returns to normal, but rapid-wave sleep (Sl) lengthens at the expense of slow-wave sleep (S2). As soon as treatment is discontinued, there is a significant increase in the ratio S2/Sl, and this ratio remains high for at least 30 daysss2.

Duration of REM sleep is increased in adult rats born of dams that were fed a diet containing 0.025% 0.1% of caffeine during pregnancy. This effect persists over two generations 169,M2. When female rats receive high doses of caffeine (60-100 mg/kg/day) in their drinking water during gestation, their offspring show longer total duration of sleep, mainly due to an increase in slow-wave sleep in males of the BALB/c strain, and to an increase in REM sleep in females of the C57BR strain552. A single dose of 10 mg/kg of theophylIine given to rabbits on day of birth greatly decreases rapid-wave sleep, delays onset of slow-wave sleep, and increases REM sleep. These modifications

disappear only at age 30 days. However, the transition between rapid- and slow-wave sleep remains disturbed

for at least 40 dayslU. Caffeine also reduces the duration of sleep in-

duced by administration of barbiturates in rats and mice3*“*264*282. This decrease varies with the dose given3~‘~2”2; decaffeinated coffee has no effect on the

duration of sleep induced by barbiturates’. 7.7.2. Human studies. In man, sleep seems to be the function most sensitive to the effects of caffeine. A

delay in sleep onset is observed when a dose of 100 mg of caffeine is ingested one-half h before retiring. How- ever, doses of less than 100 mg have no effect”“. In general, when people who usually do drink coffee, ingest some 30-60 min before going to bed, they experience a longer delay before falling asleep, and their sleep is of shorter duration and is more agitatedz4’.

A double blind study showed that students given 200

mg of caffeine fall asleep 33 min later than students given lactose2”“. Also, the subjects say they sleep Iess soundly after absorbing doses of 150-20 mg of caffeine, although this last effect is less pronounced in habitual coffee drinkers. In this study, the difference in sensitivity to the effects of caffeine does not seem attributable to the phenomenon of tolerance3h’. Rather, this difference seems linked to individual sensitivity to the effects of coffee as well as variability in the subject’s response from one night to the next2”‘.‘h’. However, other studies have shown the development of tolerance to the effects of caffeine”‘*“‘.

Habitual coffee drinkers are relatively immune to the effects of caffeine on sleep’24, while coffee abstainers experience a longer delay before onset of sleep as well as disturbances in the different sleep phasesllH. Caffeine increases duration of stage 2 sleep (also called ‘light sleep’), decreases the duration of stages 3 and 4 (or ‘deep sleep’) and has no effect on REM sleep or on duration of dream episodesy*72~‘24*247~2U. Although some of the effects of caffeine on sleep are dose- dependent 272.326, differences in sleep disturbances, which are unrelated to plasma concentration of methylxanthine, have been reported among subjects”“‘. E~e~troencepha~ographic (EEG) studies have shown that sleep is of lesser quality in the 3-4 h following ingestion of coffee, which corresponds to the time required for metabolic disposition of caffeine by the liver42x*429. According to some authors, the subjects most indisposed by coffee might metabolize caffeine more slowly than the others’h2. Actually, what seems important in the correlation between caffeine intake and insomnia is the total amount of methy~anthine consumed during the day rather than the time at which caffeine is taken before retiring326.5’0.

152

Caffeine increases motility during sleep430~s3h~s~0~s7~.

However, this increase is observed only with rather high doses of caffeine, 260-390 mg. Thus, absorption of 40 mg of caffeine does not modify the nocturnal actograms of children . 223 Also, there is no change in the actograms of adults after a total amount of 3 mg/kg of caffeine is given in 3 divided doses at 2-hr intervals before retiring”ss. Thresholds of arousal by

acoustic stimulus are definitely lower after ingestion of 400 mg of caffeine, which proves that after absorption of the methylxanthine, sleep is not as deep as usua157,“x. Finally, the nature of sleep disturbances induced by caffeine has prompted several authors to suggest using this specific methylxanthine in models of insom- nia32h.327.J5?. Since caffeine has also the property to increase nocturnal vigilance, its consumption could be beneficial to people working at night, especially if their work requires a high degree of vigilanceh16.

Finally, it has been recently proposed that the human body produces a substance similar to caffeine which would play a role in the control of the sleep/wake cycle of humans. This endogenous caffeine-like substance would maintain the brain in a state of wakefulness; when the level of this substance drops below a certain critical value, the sleep phase of the sleep/wake cycle starts”s.

7.8. Caffeine intoxication or caffeinism It is well known that excessive consumption of caf-

feine elicits symptoms of nervousness, agitation, anxiety, and insomnia242. According to a study performed in the USA, it appears that l/4 of the general population and one-half of all psychiatric patients ingest 500 mg of caffeine per day, the equivalent of 5 cups of coffee52’. The majority of patients suffering from caffeinism develop a variety of nervous, gastrointestinal or cardiac symptoms after consumption of differing quantities of caffeine, usually more than 250 mg”*242. Caf- feinism must be distinguished from other physical or mental disorders such as idiopathic anxiety6a7; it is sometimes misdiagnosed as anxiety neurosis”‘. Acute states of confusion have also been associated with very high levels of caffeine intake, more than 1000 mg per day . 42 However, anxiety or somatic abnormalities have also been observed in chronic coffee drinkers even after absorption of small quantities of caffeine, less than 250 mg. Obviously, these subjects have a great sensitivity to caffeineho7.

In addition to somatic symptoms, anxiety, or even depression, caffeinism is sometimes associated with delirium, psychoses or anorexia nervosa562.572. Caffein- ism diagnosis includes manic episodes, panic disorders,

generalized anxiety disorders and hyperthyroidism. These symptoms can mimic or aggravate psychiat- ric2IS,2”“,h2” and medica]2YY conditions. However, when these symptoms are subsequent to ingestion of a large amount of caffeine, the diagnosis is usually obvious”.

Several cases of death have also been observed following intravenous”2”, oral’0~8”~3yy or rectal’h5 ab-

sorption of an excessive quantity of caffeine. The lethal acute dose for an adult seems to be about 5-10 g of caffeine administered intravenously or orally 10,xo, 320,3y9.497, i.e., the equivalent of 75 cups of coffee. Doses of 100 mg/kg of body weight represent a definite risk of caffeine poisoning in children. Symptoms observed in caffeine poisoning are agitation, anxiety, excitation, convulsions, tachycardia, and coma with death by pul- monary edema, atelectasis, ventricular fibrillation and cardiopulmonary arrest 124.

7.9. Indiuidual Llariability and age-related variations in the effects of caffeine

Results of experiments and surveys confirm the general held opinion that the effects of caffeine on the central nervous system vary greatly from one individual to another. In addition, it is also common knowledge that people become more sensitive to caffeine as they get older. 7.9.1. Variations in the effects of caffeine among indiuid- uals. Variations are partly linked to physiological factors such as rate of gastric evacuation and intestinal absorption’97 and great differences in the metabolic half-life of caffeine2”‘. Peak plasma concentration of caffeine measured in nine subjects who, after fas’ ng, were given 250 mg of caffeine dissolved in 300 m: of fluid, ranges from 4.2 to 26 mg/12s. Furthermore, &- feine is metabolized much more slowly in women during the last trimester of pregnancy, requiring about 10.5 h 7,7’,336*460; it takes even longer in premature infants, SO-100 h14.3S7.45Y.462, compared to 3.5-6.0 h in

normal adults 53,s6,458. Since caffeine catabolism varies

with the dose, its accumulation in the body is not linear’43. The fetal liver is even capable of metaboliz- ing theophylline into caffeine’5,66. Finally, the half-life of caffeine is also lengthened in people with serious hepatic diseases’4”*567.

Simultaneous use of caffeine and substances such as tobacco and alcohol can produce interactive effects. Thus, consumption of tobacco is decreased after absorption of 75-300 mg of caffeine342. The half-life of caffeine is 55% shorter in smokers than in non-smokers; and smokers eliminate a higher percentage of non- metabolized caffeine 45x Therefore, given the same ini- .

tial sensitivity, the effects of caffeine are less pronounced in smokers than in non-smokers. Caffeine also

153

interacts with alcohol and coffee consumption is much higher in psychiatric patients who are alcoholics than

in those who abstain from alcoho127. Moreover, the daily average rate of alcohol has been shown to decrease significantly in a group of people taking strong soluble coffee and it has been suggested that some coffee brands might be of help in controlling al- coholism532. Conversely, caffeine did not counteract

the effects of alcohol, with the exception of reaction time, in students who absorbed 30 mg of caffeine and 52.5 g of ethanol for 70 kg of body weight205. Also, caffeine elimination is siower in women taking oral contraceptives87~88~46’.

Genetic and personality factors also seem to play a role in this variability. Thus homozygous twins react in a more uniform way to the effects of caffeine than heterozygous twins4695470. Similar observations have been made with barbiturates493. Reactions to caffeine also depend on personality type, especially on extroversion or introversion 159,165,274,355,489,5OO,SO8,557,597

7.9.2. Age-related variations. Many children consume caffeine every day, particularly in soft drinks like Coca-Cofa. For a long time, it has been thought that children are more susceptible to caffeine than adults”‘. At low doses, 3 mg/kg, caffeine does not have any effect either on prepubertal boys or on adults168~500~501. Caffeine at a dose of 10 mg/kg has more noticeable effects on children than on adults. On the whole, these effects are beneficial, i.e., children speak faster, react more quickly, and make fewer mistakes. Caffeine at this dose induces side effects in adults but not in .children5”. On the other hand, at high doses, sec- ondary and behavioral effects are recorded in children consuming more than 500 mg of caffeine per day500. Therefore, it does not seem that children are specially sensitive to caffeine when compared with adults, except in cases of heavy consumption. Actually, children seem to be less susceptible to methylxanthine than adults’48. There exists a positive correlation between parental and juvenile consumptions of coffee. A similar correlation has been demonstrated for maternal consumption of tobacco and paternal consumption of alcohol beveragesPz. Caffeine was long thought, especially in the USA, to be effective in the treatment of hyperactive chifdren539. However, caffeine does not significantly modify behavior, even in these children218,259,503,628. In fact, studies have confirmed that hyperactive children have no specific sensitivity to caffeine.

In older people, caffeine absorption induces increased sleep disturbances, with twice as many phases of arousal, and increases the phases of light sleep at the expense of deep sleep. On the other hand, decaf-

feinated coffee causes no modification in sleep2”. It

seems that tolerance to the effects of caffeine dimin-

ishes with age5’l. According to the results of a study

done on six young subjects and six older ones, the elderly seem more sensitive to the objective effects of caffeine and less sensitive to its subjective effects than the young people58’.

8. TOLERANCE AND DEPENDENCE TOWARDS THE

EFFECTS OF CAFFEINE

8.1. Tolerance There are very few studies concerning toierance of

human central nervous system to caffeine”8*230. An

apparent tolerance to caffeine’s effects on the central nervous system has been reported in some clinical studies. It has been noted that the sleep of people consuming average or large amounts of coffee is less disturbed than that of abstainers”8.230. However, since this tolerance to the central effects of caffeine is probably of small amplitude, it is generally agreed that the central nervous system is only slightly tolerant to the stimulant effects of the methy~anthine’04~237~5’o~5~3~627, whereas tolerance to the diuretic effects of caffeine has been described a long time ago’“‘. In fact, it is very difficult to know if moderate users of caffeine present no symptoms because they have developed a tolerance, or because, by nature, they were less sensitive than those who use small amounts”“. It was recentIy shown that regular consumption of 12 mg/kg/day of caffeine, i.e., the equivalent of 6-11 cups of coffee, is likely to produce pharmacological effects that are not entirely counterbalanced by development of tolerance. Thus, caffeine accumulates in the body in non-linear way by metabolic saturationi4*.

Studies done within the last 10 years have demonstrated tolerance to the central effects of caffeine in animals regarding locomotor activity4’10X,‘9L-193* 291*294,408, operant conditioning~4, cerebral electrica activity 108*280*433, and caffeine-induced seizures645. On the other hand, cerebral energy metabolism is only slightly tolerant to the stimulant effects of caffeine in the rat438,439. The phenomenon underlying the development of tolerance to caffeine in rodents has not yet been elucidated. Its rapid onset as well as its persis- tence seem to implicate depletion of a neurotransmitter, especially noradrenaline255.

The possible role of adenosine in the control of vigilance Ievet24’ shows that the increased number of adenosine receptors in animals chronically exposed to caffeine could be responsible for the sedative effects on activity that are observed in these animals or in humans abruptly deprived of caffeine295. In fact, some

154

consequences of caffeine withdrawal could be due to increased sensitivity of the subjects to endogenous adenosine”‘. However, according to another study, the increase in the number of adenosine receptors would not explain development of tolerance to the stimulant action of caffeine, at least not in the case of locomotor activity “‘).

8.2. Dependence and withdrawal

Dependence on caffeine has been studied more than tolerance to its effects; a recent and very detailed review is devoted to caffeine dependencez5. In ani- mais, caffeine withdrawal decreases locomotor activity2”‘. In humans, when chronic coffee drinkers stop drinking this beverage, they experience the following symptoms: feeling of weariness, apathy, weakness and drowsiness2Oh,23Y,24j,3f14,308.41 1,496,576,623

, head- aches73,2”6,22”,239,3~,496..551,6~.623

, anxiety, increased muscle tension222.“22, occasiona tremor 226*2h0, nausea, vomiting, as well as a sensation of withdrawal, These symptoms disappear after absorption of caffeine. Disap- pearance of withdrawal symptoms is strongly linked to the psychologic satisfaction given by ingestion of coffee; this is especially true for the first cup of the day. Heavy consumers of coffee show a preference for coffee containing caffeine if they have been drinking this type of coffee for 1 week or more, whereas people who have been drinking decaffeinated coffee will choose either decaffeinated or caffeine-containing coffee2481”7”. Indeed, several studies have shown that caffeine content influences coffee consumption250,341,47” and that caffeine alone is able to reverse withdrawal syndroms induced by caffeinated coffee cessation15h,2”“,2”4,2”X. The beneficial effects, derived or expected, of coffee consumption on mood or performance would also seem to incite people to drink coffee347.

In apparent contradiction to these data, it seems that an animal, rat or baboon, given the choice of beverage does not automatically choose to self-admin- ister caffeine continuously, as he would do for drugs like morphine, amphetamines or cocaine24~25’*2s4. How- ever, in rats, caffeine can serve as a discriminative stimulus at both low and high doses292S432*637. The discriminative effects of a low dose of caffeine (10 mg/kg) appear to derive from a state of behavioral arousal, possibly mediated by catecholamines, and parallel the subjective effects produced by a low dose of caffeine in humans. The origin of the discriminative effects of high dose of caffeine (56 mg/kg) is not clearly defined at this time4”“. In humans, the widely recognized behavioral stimulant and mildly reinforcing properties of caffeinel”‘,248,249.252-254,363 are probably responsible for

the maintenance of caffeine self-administration, pri- marily in the form of caffeinated beverages, such as coffee, tea and cola-i”V225. Even though important variations in individual sensitivity to the effects of caffeine have been demonstrated, both in man and animals, abuse of caffeine presents a minimal risk2“.

It appears that some coffee drinkers exhibit common signs of drug dependence1“*99,~1~. According to a

recent study, it would seem that dependence on the effects of caffeine can appear with even very slight doses (one cup of strong coffee or three cans of Coca- Cola per day) and that caffeine withdrawal can cause more numerous symptoms than hitherto believed”‘. Furthermore, it is known that coffee has a reinforcing effect on its own consumption in man and in animals2”3~254. However, this reinforcement of consumption is dose-dependent; very high doses can cause dysphoria in humans*““. Withdrawal symptoms generally begin 12-24 h after coffee consumption has CeaSed156,233,234.248,3Y2.634 and reach a peak after 20-4X hl56,206,226.634, However, these symptoms can appear within only 3-6 h”‘~“‘” and can last for 1 week243.248,2Y7,8X0, or even several months after coffee consumption has stopped4”.

A recent study has been performed on the relationship between consumptions of caffeine, alcohol and tobacco and pre- and post-operative headaches. There is a strong positive correlation between caffeine consumption and headaches before and after surgical procedures. A linear regression analysis shows that for every increase of 100 mg of caffeine (about one cup of coffee) the risk of migraine immediately before surgery is increased by 12% and after surgery by 16%. There is no relationship between this withdrawal symptom and age, sex, usual frequency of headaches, consumption of alcohol or tobacco, and anesthetic drugs or other medications used during the surgical procedureiS3. With- drawal symptoms can also be observed in newborn infants whose mothers are heavy coffee drinkers during pregnancy. These infants display unusual behavior be- ginning at birth, characterized by irritability, high emotivity and even vomiting. These symptoms disappear after a few days400.

Few animal studies have been performed on this topic, Caffeine withdrawal causes the locomotor activity of the rat to decrease by about one-half. This effect lasts for about 4 days, is dose-dependent, and is maximal on the 2nd day 4@~142 The same phenomenon is . observed in the threshold response to cerebral electrical stimulation by caffeine in the rat4”“. Also interrup- tions in operant behavior are observed in the monkey after caffeine deprivation but these disturbances are less pronounced than with other drugs’“.

9. CONCLUSION

It seems very difficult to form a definite opinion on caffeine’s effects on the central nervous system. Inter- pretation of data is highly subjective, and the effects of caffeine vary greatly from one subject to another. Moreover, most animal studies were performed with doses much higher than those corresponding to the human consumption of methylxanthine corresponding

to one or several cups of coffee. Nevertheless, it seems that caffeine increases vigi-

lance and endurance during performance of repetitive tasks. Also, it postpones onset of sleep, results in lighter sleep and increases the level of anxiety, especially in some subjects who are sensitive to this phar-

macological agent. The human central nervous system does not seem to

develop easily a tolerance to the stimulant effects of caffeine, although methylxanthine dependence has been clearly established. Withdrawal symptoms appear very quickly after caffeine is stopped.

Caffeine has a vasoconstricting effect on the brain and a vasodilating effect on peripheral blood flow. This property explains the presence of caffeine in several medications for migraine headaches.

Finally, the main mechanism of action of methylxanthines in the brain suggests their antagonistic action at the level of the adenosine receptors.

i0. SUMMARY

Caffeine is the most widely consumed central- nervous-system stimulant. Three main mechanisms of &ion of caffeine on the central nervous system have been described. Mobilization of intracellular calcium and inhibition of specific phosphodiesterases only occur at high non-physiological concentrations of caffeine. The only likely mechanism ‘of action of the methy~nthine is the antagonism at the level of adenosine receptors. Caffeine increases energy metabolism throughout the brain but decreases at the same time cerebral blood flow, inducing a relative brain hypoperfusion. Caffeine activates noradrenaline neurons and seems to affect the local release of dopamine. Many of the alerting effects of caffeine may be related to the action of the methylxanthine on serotonine neurons. The methylxanthine induces dose-response increases in locomotor activity in animals. Its psychostimulant action on man is, however, often subtle and not very easy to detect. The effects of caffeine on learning, memory, performance and coordination are rather related to the methylxanthine action on arousal, vigilance and fatigue. Caffeine exerts obvious effects on anxiety and

155

sleep which vary according to individual sensitivity to the methy~anthine. However, children in general do not appear more sensitive to methylxanthine effects than adults. The central nervous system does not seem to develop a great tolerance to the effects of caffeine although dependence and withdrawal symptoms are reported.

Acknowledgements. The authors wish to thank the Institut National de la Sante et de la Recherche Medicale (INSERM U 2721, the Centre de Nutrition Humaine and the Fondation pour la Recherche Medicale (Cornit& Lorraine) for financial support. The editorial assistance of V. Koziei is gratefully acknowledged.

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