Actions of Caffeine on Brain Functions and Behavior
- Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use

IV. Actions of Caffeine on Brain Functions and Behavior

Having discussed the molecular and neuronal actions of caffeine, especially as they relate to a primary effect on adenosine receptors, it is important to consider some actions at a more integrated level. Even though the primary action of caffeine may be to block adenosine receptors this leads to very important secondary effects on many classes of neurotransmitters, including noradrenaline, dopamine, serotonin, acetylcholine, glutamate, and GABA (Daly, 1993). This in turn will influence a large number of different physiological functions. It would clearly be outside the scope of this review to cover all aspects of caffeine action in the CNS. Nonetheless, some specific aspects need to be brought forward as they relate directly or indirectly to the issue at hand. Below we will briefly consider a set of such responses and attempt to relate them to the primary actions of caffeine. Finally, we will briefly comment upon the similarities and dissimilarities between caffeine and known addictive drugs such as cocaine, morphine, and nicotine.

A. Activation of Dopaminergic Transmission and Effects on Motor Behavior

The interaction between adenosine A2A and dopamine D2 receptors highlighted above could provide a mechanism for several actions of caffeine and some of its metabolites on dopaminergic activity. Thus, an inhibition of A2A receptors by caffeine would be expected to increase transmission via dopamine at D2 receptors (Ferré et al., 1992

Besides the direct effects on striatopallidal neurons mediated via an antagonism of A2A receptors, caffeine---at least at high doses---has been reported to influence the turnover of dopamine [for review see Nehlig and Debry (1994)]. Adenosine A1 receptors (in contrast to adenosine A2A receptors) have been shown to influence dopamine release in slices of the striatum (Jin et al., 1993; Jin and Fredholm, 1997). Caffeine has been reported to cause a dose-dependent (30-75 mg/kg) increase in dopamine in the striatum (Morgan and Vestal, 1989). In that study electrochemistry was used, which presents a potential problem since caffeine itself appears to influence the response of the recording electrode (F. Gonon, personal communication). In a recent study, microdialysis techniques were used to study this question (Okada et al., 1997). Perfusion with a solution containing caffeine (5-50 µM in perfusate, probably corresponding to a five times lower level in brain) caused a time- and concentration-dependent increase in dopamine levels. This was mimicked by the selective adenosine A1 receptor antagonist cyclopentyltheophylline. Both drugs caused a 30 to 40% increase. Adenosine A1 agonists, but not adenosine A2A agonists, depressed the dopamine levels (Okada et al., 1997). Because the drugs were administered locally in the striatum, the effects are probably exerted at the presynaptic A1 receptors. In addition to these presynaptically located adenosine A1 receptors, A1 receptors are also present in the substantia nigra and in the VTA (Fastbom et al., 1987; Johansson et al., 1993a), where they regulate the firing of dopamine (DA) neurons (Ballarin et al., 1995). In these regions of the brain there is a marked discrepancy between the distribution of the receptor and the corresponding mRNA. This suggests that many of the adenosine A1 receptors in the area of the DA cell bodies are located not on the dopaminergic neurons, but on the terminals of the input neurons. There, they could negatively influence excitatory input to these nuclei.

Caffeine has been shown to decrease the activity of dopaminergic neurons in the VTA (Stoner et al., 1988), but not the dopaminergic neurons in substantia nigra. This was interpreted as evidence that caffeine increased the release of DA, which in turn acted on DA receptors to depress firing of the neurons. However, a direct injection of caffeine into the VTA does not increase release of DA in the nucleus accumbens (Gonon and Svenningsson, unpublished data). Furthermore, the reported effect of caffeine on VTA neurons (Stoner et al., 1988) was observed only when excessively high concentrations of caffeine were used---concentrations that as we will see below do not stimulate motor behavior or produce reinforcement, but instead have the opposite effect. Thus, caffeine may not act to stimulate motor behavior by regulating firing of DA neurons. This conclusion is reinforced by a comparison of the effects of caffeine in low, behaviorally stimulant doses of caffeine (Svenningsson et al., 1995a, 1997c) and of an electrical activation of the dopaminergic neurons from VTA to nucleus accumbens (Chergui et al., 1996, 1997). The latter is accompanied by an increase in the DA levels in accumbens and with an increase in several IEGs in the nucleus accumbens. The IEG increases are confined to the dopamine D1 receptor-containing cells and are blocked by D1 receptor antagonists (Chergui et al., 1996, 1997). By contrast, in the dopamine D2 receptor-expressing cells, caffeine does not increase IEGs and in fact decreases the expression of constitutively active IEGs. This effect is uninfluenced by D1 antagonists. Hence, caffeine differs in important respects from other stimulant drugs such as cocaine and amphetamine.

It can be concluded that the only important interaction between caffeine in relevant doses and the dopaminergic transmission is based on enhancement of postsynaptic dopamine D2 receptor transmission and of the glutamatergic input. The previously emphasized enhancement of dopamine release occurs only at high doses of caffeine and is therefore unrelated to the stimulant effects of caffeine, which occur only at low doses.

It is well known that the striatum is strongly involved in the regulation of motor behavior in animals, and presumably in humans, and the ability of caffeine to stimulate motor behavior is well documented and summarized (see Waldeck, 1975; Nehlig et al., 1992; Daly, 1993). Here it will suffice to point out a few relevant facts. Motor stimulation has been studied either by examining spontaneous locomotion or by examining the rotation behavior that can be elicited by, for example, dopamine receptor agonists in animals with unilateral lesions of the nigrostriatal dopamine pathway. The data in those two models are not exactly analogous and we will deal with them separately.

In both rats and mice the effect of caffeine on spontaneous locomotion is markedly biphasic (see Fig. 6). The threshold effect is 1 to 3 mg/kg and the peak effect is seen between 10 and 40 mg/kg (see Nikodijeviç et al., 1993; Garrett and Holtzman, 1994b). As in the case of cocaine, stimulation of motor behavior occurs at roughly similar doses as those needed for reinforcement (Bedingfield et al., 1998). In the case of cocaine the two effcts are positively correlated, but this is not the case for caffeine, suggesting differences in mechanism of action (Bedingfield et al., 1998). The effect of caffeine is shared by several other xanthines, and their potency is much better correlated with adenosine receptor blockade than with phosphodiesterase inhibition (Choi et al., 1988). Several adenosine analogs are motor depressants when given systemically or locally into the striatum (see Daly, 1993). The effect of caffeine is shared by the nonxanthine, nonselective adenosine receptor antagonist, CGS 15943, but not by the selective adenosine A1 receptor antagonist DPCPX (Griebel et al., 1991). Locomotor stimulation is also brought about by the nonxanthine, selective, adenosine A2A receptor antagonist SCH 58261 (Svenningsson et al., 1997c). The direct injection of an adenosine A2A receptor agonist into the nucleus accumbens leads to a decreased locomotion (Barraco et al., 1993; Hauber and Münkle, 1997). The effects of caffeine are synergistic with actions of dopamine or dopaminergic drugs injected into the nucleus accumbens (Andén and Jackson, 1975; Garrett and Holtzman, 1994b). Both selective dopamine D1 and dopamine D2 receptor antagonists reduced locomotion, the former being more efficacious (Garrett and Holtzman, 1994b). Under these circumstances an effect of an adenosine A1 antagonist is also revealed and is manifested as a selective enhancement of locomotion induced by a D1 receptor agonist (Popoli et al., 1996b).

As noted above caffeine can also induce contraversive rotation in animals with unilateral nigrostriatal lesions and it thus mimics the effects of dopamine receptor agonists (Fuxe and Ungerstedt, 1974; Fredholm et al., 1976). The effect is dose-dependent (Fredholm et al., 1983; Herrera-Marschitz et al., 1988; Garrett and Holtzman, 1995). If the total number of rotations is recorded over a fixed time period, the curve shows the inverted U-shape with a maximum close to 30 mg/kg (Garrett and Holtzman, 1994b). However, the effect of the high doses is very protracted, and, if rotation is recorded over a longer period, say 12 h, the maximum is seen at over 50 mg/kg (Herrera-Marschitz et al., 1988). The rotational behavior induced by caffeine varied between animals, but there was a strong correlation between rotation induced by the dopaminergic agonist apomorphine and that produced by caffeine (Casas et al., 1989). All these findings give good reason to assume a close relationship between the mechanisms that underlie caffeine-induced rotation and dopaminergic rotation. Several studies have tried to pinpoint the mechanism further.

Intrastriatal injection of an adenosine analog produces rotation in the opposite direction (Green et al., 1982; Brown et al., 1991) to an injection of caffeine (Herrera-Marschitz et al., 1988; Josselyn and Beninger, 1991). Drugs that raise the level of adenosine, including adenosine transport inhibitors and inhibitors of adenosine deaminase, reduce the rotation response induced by dopaminergic drugs (Fredholm et al., 1976, 1983). These data have been taken as support of the general idea that rotation behavior induced by caffeine is related to adenosine receptor blockade. The systemic administration of an adenosine analog also reduces rotation behavior (Fredholm et al., 1983). Furthermore, potent phosphodiesterase inhibitors that do not act as adenosine receptor antagonists reduce rather than enhance rotation behavior (Fredholm et al., 1976, 1983). The effect of caffeine is shared by some other xanthines, including its metabolites theophylline and paraxanthine (Fredholm et al., 1976; Garrett and Holtzman, 1995). However, isobutylmethylxanthine produces limited (Fredholm et al., 1976) or no (Garrett and Holtzman, 1995) effect despite the fact that it is a potent adenosine receptor antagonist. Perhaps this could be accounted for by its high potency as a phosphodiesterase inhibitor. However, 8-phenyltheophylline produced only limited rotation despite the fact that it lacks appreciable phosphodiesterase inhibitory effect but is a potent adenosine receptor antagonist. The reason may instead be that it penetrates only poorly into brain (Fredholm et al., 1983). Although the nonselective nonxanthine antagonist CGS 15943 mimics caffeine actions on spontaneous locomotor behavior, it is much less potent than caffeine in inducing rotation behavior (Garrett and Holtzman, 1994b; Pinna et al., 1996). This was taken as evidence that adenosine receptor antagonism may not be the only mechanism by which caffeine causes an increased rotation behavior (Garrett and Holtzman, 1994b). CGS 15943 did, however, potentiate the effect of a D1 receptor agonist (Pinna et al., 1996). Further studies of CGS 15943, including an examination of its pharmacokinetics, are warranted.

More recent studies have tried to examine the roles of specific adenosine and dopamine receptors by using selective agonists and antagonists. The adenosine A1selective antagonists 8-cyclopentyltheophylline and DPCPX potentiate the response to amphetamine (Popoli et al., 1994) and to the selective dopamine D1 agonist SKF 38393 (Pinna et al., 1996; Pollack and Fink, 1996). The selective adenosine A2A receptor antagonist SCH 58261 also potentiates the response to a D1 agonist (Pinna et al., 1996), as does the somewhat A2A-selective antagonist 3,7-dimethyl-1-propylargylxanthine (Pollack and Fink, 1996). The enhancement of the behavioral response was mirrored by an effect on IEGs in the striatum and globus pallidus (Pinna et al., 1996; Pollack and Fink, 1996; Fenu et al., 1997). The response to dopamine agonists is blocked by adenosine A2A and A1 agonists (Morelli et al., 1994; Popoli et al., 1994). Neither the selective A1 antagonist DPCPX nor the selective A2A receptor antagonist SCH 58261 had any effect per se (Pinna et al., 1996).

It is clear that particularly adenosine A2A receptor-blocking drugs can enhance the activity of dopaminergic drugs in the rotation model (see Ongini and Fredholm, 1996; Ferré et al., 1997; Richardson et al., 1997). This is important since it suggests the possibility of novel therapy in Parkinson's disease. It is, however, also clear that adenosine A1 receptor modulates the response. Furthermore, there are several discrepancies in the literature concerning the ability of adenosine receptor antagonists to produce rotation per se. It is conceivable that some of this variability relates to the extensiveness of the lesions and also to the tone of the dopaminergic innervation on the contralateral side. Finally, it must be borne in mind that the rotation behavior to both dopaminergic drugs and adenosine receptor antagonists requires priming of the system by a drug that activates D1 receptors. The effect is long-lasting and is blocked by NMDA receptor antagonists (Morelli et al., 1996).

B. Caffeine and Mood

Mood is a complex and poorly defined psychic phenomenon. This holds for the underlying psychological and behavioral functions as well as for the difficulties of assessment. Recently, standardized instruments such as the Profile of Mood States (POMS), the Drug-Effect Questionnaire for the assessment of liking a medication, different Visual Analog Scales for rating different aspects of the subjective state have been used increasingly for the study of mood.

The effects of caffeine on mood have been studied in human subjects. There is ample evidence that lower doses (20-200 mg) of caffeine are reliably associated with "positive" subjective effects even in the absence of acute withdrawal effects. The subjects report that they feel energetic, imaginative, efficient, self-confident, and alert; they feel able to concentrate and are motivated to work but also have the desire to socialize (see Griffiths et al., 1990

There are well-documented effects of caffeine on anxiety in humans: these have recently been summarized (Hughes, 1996). There is much less information on the effects of caffeine on anxiety in animals. In particular, we do not know much about the possible mechanism(s) involved. It is known that high concentrations of caffeine can decrease the binding of benzodiazepines, but it is generally believed that this effect on the GABAA receptor is not directly involved in producing anxiety (see Daly, 1993). There are, however, effects of caffeine on GABAA receptor channels (Lopez et al., 1989) observed at doses above 20 mg/kg, in the absence of effects on diazepam binding. Thus, further studies to explain this observation are needed. Caffeine might affect GABAA receptors indirectly. It is known that adenosine, acting via A1 receptors, can regulate the release of many different neurotransmitters, including glutamate. If the effect of adenosine is blocked, excitatory transmission would be enhanced, which could directly or indirectly influence GABAergic transmission.

About 25 years ago Greden (1974) noted that outpatients undergoing treatment for psychiatric disorders who consumed more than 1000 mg of caffeine per day had symptoms of generalized anxiety. This was denoted caffeinism and was suggested to present some diagnostic problems. Indeed caffeinism has been added to DSM-III and DSM-IV. In intervention studies the administration of high (but not low) doses of caffeine leads to a clear increase in measures of anxiety (Stern et al., 1989), which, however, are not accompanied by changes in noradrenaline turnover (Charney et al., 1984). The anxiogenic effects were greater in patients with panic disorders (Boulenger et al., 1984; Charney et al., 1985; DeMet et al., 1989), and patients who report being anxious in response to caffeine had higher prestudy anxiety scores (Lee et al., 1985). Patients with high anxiety scores due to depression do not appear to be supersensitive to caffeine (Boulenger et al., 1984). An increased anxiogenic response to caffeine was related to an increased sensitivity to caffeine as an enhancer of gustatory signals (DeMet et al., 1989). This was interpreted as evidence that patients with panic disorders have an altered sensitivity of A1 receptors, because previous data had implied a role for adenosine receptors in this response (Schiffman et al., 1985). There is no independent evidence that this is the case.

Despite all the cited evidence for an effect of caffeine on anxiety, in a rather large population study there was no clear relationship between reported caffeine intake and anxiety (Eaton and McLeod, 1984). Furthermore, there was no relationship to the intake of caffeine in patients with anxiety. In fact, subjects with high anxiety scores tended to have a lower caffeine intake (Lee et al., 1985; Rihs et al., 1996). Thus the preferred caffeine dose was negatively related to prestudy anxiety scores (Griffiths and Woodson, 1988a). Nonetheless, a subpopulation of patients with anxiety do improve when they abstain from caffeine. Thus, it seems clear that high doses of caffeine can induce a state of anxiety and that there are considerable differences between individuals in what constitutes a high, anxiogenic dose of caffeine. Most individuals seem to adapt their caffeine intake to, e.g., their susceptibility to its anxiogenic effects.

The anxiogenic effects of caffeine are related not only to the dose of caffeine but also to plasma levels (Boulenger et al., 1987), but the level of anxiety was not related to measured plasma levels of adenosine. This does not, however, mean that adenosine receptors are not involved. In the study mentioned, adenosine levels were very high, probably indicating formation of adenosine during sampling, and moreover there is no clear relationship between brain and plasma adenosine levels. The recent demonstration that mice with a targeted disruption of adenosine A2A receptors exhibit increased anxiety (Ledent et al., 1997) instead provides good evidence that adenosine receptors are involved in the anxiogenic effects of caffeine. Precisely how these effects are brought about is not known, but it is known that caffeine produces anxiety via a mechanism that is quite different from that used by the alpha2 adrenoceptor antagonist yohimbine, because the two drugs antagonize each other via complex paradigm-dependent interactions (Baldwin et al., 1989).

The possible link between caffeine intake and other psychiatric diagnoses is less evident. Among psychiatric patients, caffeine consumption is highest among diagnosed schizophrenics and lowest among depressed patients and those with anxiety disorders (Rihs et al., 1996). In view of the interactions between adenosine and DA receptors, it is possible that the intake of caffeine represents an attempt to counteract the actions of the neuroleptic medication. Indeed there are reports that high caffeine intake can exacerbate the symptoms of schizophrenia (Mikkelsen, 1978). The relationship between caffeine intake and depression is also poorly understood and poorly studied. Sleep disorders constitute a major predictor for depression (Chang et al., 1997), and caffeine is known to affect sleep. However, the relationship between poor sleep and subsequent depression holds, even after correction for the intake of caffeine (Chang et al., 1997). Among hospitalized patients there was a correlation between symptoms of depression and caffeine intake (Rihs et al., 1996). Again it is difficult to know if this related to the actions of the antidepressant medication: some of the side effects can probably be counteracted by caffeine. In a study of Japanese medical students, caffeine intake was associated with fewer depressive symptoms among female, but not male students, and in a large prospective study, coffee drinking was negatively correlated with suicide (Kawachi et al., 1996). These findings can be interpreted in two diametrically different ways: 1) caffeine decreases symptoms of depression, including the risk of suicide or 2) individuals with depressive symptoms choose to take less caffeine (in much the same way as anxious patients do). Only a carefully controlled intervention study could possibly elucidate these questions.

C. Effects of Caffeine in the Cortex and Hippocampus---Information Processing and Performance

In the rat, cortical electrical activity is stimulated by caffeine (Phillis and Kostopoulos, 1975

Methylxanthines elevate the excitability of rat hippocampal slices by antagonizing the actions of adenosine (Dunwiddie et al., 1981; Greene et al., 1985) and activate the theta rhythm of the EEG in rabbit hippocampus (Popoli et al., 1987). Adenosine depresses the development of long-term potentiation (Arai et al., 1990), whereas xanthines with adenosine receptor antagonistic effects have been reported to have the opposite effect (Arai et al., 1990; Tanaka et al., 1990). Caffeine lengthens the postfiring duration in the hippocampus, and this effect lasts longer than the changes induced by caffeine on the EEG (Dunwiddie et al., 1981; Greene et al., 1985; Popoli et al., 1987). High doses (100 mg/kg or above) of caffeine provoke electrical modifications in the hippocampus similar to those that are recorded during generalized seizures.

The effects of caffeine on cortical and hippocampal activity provide a basis for examining possible cognitive effects of caffeine. There are a few animal studies that report improved performance in a water Y-maze model or a visual discrimination task after caffeine (see Daly, 1993). Later studies have indicated that blockade of adenosine A1 receptors is more important than blockade of A2 receptors to produce this effect (Suzuki et al., 1993; Von Lubitz et al., 1993a; Ohno and Watanabe, 1996). The effect of a direct intrahippocampal injection of an A1 receptor agonist is to increase the number of errors related to working memory (Ohno and Watanabe, 1996). Interestingly, there was a major difference in the effect of chronic treatment. If an A1 receptor antagonist was injected daily, the beneficial effect decreased and a slight deterioration was observed (Von Lubitz et al., 1993a). Conversely, long-term treatment with an agonist actually improved performance dramatically (Von Lubitz et al., 1993a).

The effects of caffeine on human information processing have been well reviewed (van der Stelt and Snel, 1993). A large number of studies has been performed on human subjects (Estler, 1976; Daly et al., 1993). As for most effects of caffeine, the dose-response curve is U-shaped---doses of 500 mg causing a decrease in performance although lower doses have positive effects (Kaplan et al., 1997). Despite this, increases in caffeine consumption over an already high normal level (400-1000 mg/day) did not impair performance even in a complex setting (Streufert et al., 1997). Revelle and coworkers (1980) showed a complex interaction between the effects of caffeine on performance and parameters such as personality and time of day. Thus, the effects of caffeine are related to a level of arousal (Anderson and Revelle, 1982) and largely follow the so-called Yerkes-Dodson law that postulates that the relationship between arousal and performance follows an inverted U-shape curve. An increase in arousal improves performance of tasks where relatively few sources of information have to be monitored, particularly under conditions when the need for selective attention is stressed by time pressure. When, on the other hand, multiple sources of information or working memory have to be used, an increase in arousal and attention selectivity has no apparent beneficial effect on performance, which may consequently even decrease (see Kenemans and Lorist, 1995). Thus, it was concluded that caffeine 1) increases cortical activation, 2) increases the rate at which information about the stimulus accumulates, 3) increases selectivity particularly with regard to further processing of the primary attribute, and 4) speeds up motor processes via central and/or peripheral mechanisms (Kenemans and Lorist, 1995). In a study where caffeine significantly improved performance in a vigilance test, caffeine neither increased nor decreased the mood changes that occur after such stressful tasks (Temple et al., 1997).

Therefore it can probably be concluded that caffeine in doses that correspond to a few cups of coffee "improves behavioral routine and speed rather than cognitive functions" (Bättig et al., 1984). This probably indicates that many animal models test for psychomotor function rather than cognition, but it is of course very different from claiming that "caffeine bestows little if any benefit on... psychomotor performance" (James, 1991). The small benefits that can be shown may be considered of value by some caffeine users, and it can be expected from the above considerations that, particularly, individuals with a low level of arousal (high scores on the impulsivity subscale of Eysenck) should experience such a beneficial effect. Indeed, such individuals appear to consume more caffeine (Rogers et al., 1995). Conversely, in situations with a high level of stress, caffeine might prove detrimental, but there is no evidence that this is the case (Smith et al., 1997).

In order to perform adequately, an animal (or human) must be able to filter out irrelevant sensory input. A deficiency in this regard is believed to be a characteristic of schizophrenic subjects (Koch and Hauber, 1998). Filtering ability can be assessed by so called prepulse inhibition of the acoustic startle response (see Hauber and Koch, 1997; Koch and Hauber, 1998). Such prepulse inhibition can be attenuated by systemic or intra-accumbens administration of apomorphine, and this is counteracted by an injection of the adenosine A2A agonist CGS 21680 into the nucleus accumbens (Hauber and Koch, 1997). These results suggest that caffeine might, via an action on adenosine receptors, influence sensorimotor gating and, in this way, performance.

D. Effects on Sleep

It is well established that caffeine delays the onset of sleep (see Eichler, 1976

Caffeine in doses corresponding to one cup of coffee taken at bedtime increases sleep latency and decreases the reported quality of sleep in parallel with small changes in the EEG pattern during sleep, especially in the non-REM deep sleep (Landolt et al., 1995a). However, also a dose of caffeine taken in the morning can have such effects the following night (Landolt et al., 1995b). Thus, in humans, concentrations of caffeine as low as 3 µM can influence sleep. Indeed sleeping problems is one of the major reasons why people, on their own initiative, cease drinking coffee (Soroko et al., 1996). There is, however, no evidence that the effects of caffeine are different in subjects with poor sleep and in those with normal sleep (Tiffin et al., 1995). Indeed, there is no clear evidence that stopping caffeine intake can eliminate the problems of poor sleep (Curless et al., 1993; Searle, 1994; Tiffin et al., 1995). It is often remarked that some people seem to have no sleep problems despite taking a regular evening dose of caffeine. This clearly emphasizes that caffeine interferes with a modulatory mechanism in sleep regulation, not with a fundamental sleep regulatory brain circuit. It probably also reflects on the fact that regular sleeping habits are of fundamental importance in ensuring satisfactory sleep (Manber et al., 1996). If a regular caffeine intake is part of such a normal diurnal pattern, it is easy to understand how it could contribute to satisfactory sleep.

Performance, such as when driving a car, appears to be improved by caffeine in doses corresponding to 1 to 2 cups of coffee (Horne and Reyner, 1996). There is, however, some evidence to suggest that one may "pay" for this benefit with a lower restorative capacity of a nap after sleep deprivation (Bonnet and Arand, 1996). There is also evidence that caffeine improves work performance during night shift work, without severely compromising daytime sleep (Muehlbach and Walsh, 1995). The combination of a prophylactic afternoon nap and caffeine appears to maintain performance at a high level even for prolonged periods without sleep (Bonnet and Arand, 1996). Also some of the negative mood effects of prolonged sleep deprivation are reduced by caffeine (Penetar et al., 1993). The effects of caffeine on several different measures of performance after prolonged (45 h) sleep deprivation were additive to the effect of bright light (Wright et al., 1997). Because bright light is believed to reduce sleepiness by reducing melatonin, this finding indicates that caffeine acts independently of melatonin.

There is a link between adenosine and the sleep-wake cycle in rodents. Initial studies by Radulovacki and coworkers (see Radulovacki, 1985) showed that adenosine agonist increased sleep and altered the EEG pattern in a manner different from that brought about by barbiturates. The effect of adenosine analogs is mimicked by drugs that decrease adenosine elimination (O'Connor et al., 1991). Caffeine had effects opposite to those of adenosine on EEG (Yanik et al., 1987).

There are important circadian rhythms in adenosine receptors (Virus et al., 1984), adenosine-metabolizing enzymes (Chagoya de Sanchez, 1995), and in adenosine itself. Thus, in cortical areas of rat brain, including the hippocampus, adenosine levels were high during the active (dark) period (Chagoya de Sanchez et al., 1993; Huston et al., 1996), but they were also much increased in the beginning of the inactive (light) part of the diurnal cycle (Chagoya de Sanchez et al., 1993). The levels in the dopamine-rich areas of the brain decreased during the active period and increased transiently toward its end (Huston et al., 1996). This could mean that adenosine acts as a transient signal to go to sleep. More recently it has been shown that the levels of adenosine progressively increase in the cat basal forebrain with increasing sleep deprivation and then return toward basal during sleep (Porkka-Heiskanen et al., 1997).

Probably adenosine A1 and A2A receptors are involved in producing the sleep-promoting effects of adenosine, but these effects appear to be exerted in different parts of the brain. Local injections of adenosine A1 receptor agonists in the preoptic area of the rat produced sleep, whereas an A2A agonist did not (Ticho and Radulovacki, 1991). The administration of the adenosine A1 receptor-selective agonist cyclopentyladenosine mimicked the EEG effects of sleep deprivation (Benington et al., 1995) and non-REM sleep (Schwierin et al., 1996). Systemic administration of the relatively A1-selective antagonist 8-cyclopentyltheophylline mimicked the effect of caffeine (O'Connor et al., 1991). It has also been reported that REM sleep deprivation increases the number of A1 receptors (O'Connor et al., 1991), even though this finding is somewhat difficult to reconcile with the ability of adenosine to decrease A1 receptors and with the reported increase in adenosine. The site at which adenosine (and caffeine) exert these A1 effects related to sleep is not known, but the mesopontine cholinergic neurons that are under tonic adenosine A1 receptor control are likely candidates (Rainnie et al., 1994). Indeed, it is well established that acetylcholine turnover is increased by theophylline (Murray et al., 1982) and that caffeine can affect acetylcholine levels and metabolism in the brain (Phillis et al., 1980; Murray et al., 1982; Katsura et al., 1991; Carter et al., 1995). The caffeine-induced increase of cortical acetylcholine is dose-dependent, and the increased cholinergic activity at doses of caffeine relevant to those encountered in humans may provide a basis for the psychostimulant effects of caffeine (Carter et al., 1995). Thus, there is good evidence that adenosine acting at A1 receptors might promote sleep, perhaps in part by decreasing activity in cholinergic neurons.

On the other hand, injection of the selective adenosine A2A receptor agonist CGS 21680 into the subarachnoid space underlying the rostral basal forebrain mimicked the sleep-promoting effects of prostaglandin D2, whereas an A1 agonist did not (Satoh et al., 1996). Furthermore, in this study an A2A receptor antagonist attenuated the sleep induced by PGD2. It has also been shown that the selective adenosine A2A receptor antagonist SCH 58261 is at least as potent as the A1 receptor antagonist DPCPX in increasing wakefulness and in increasing the latency to REM sleep in rats (Bertorelli et al., 1996). The adenosine A2A receptors in the tuberculum olfactorium/ventral nucleus accumbens are a likely site of action (Satoh et al., 1996).

From the above brief summary it is evident that the ability of caffeine to increase wakefulness is an important reason why people consume caffeine-containing beverages. It is also evident that unsatisfactory sleep is one of the reasons why individuals wish to curtail their habitual caffeine intake. Hence, effects on sleep and wakefulness are intimately linked to the way that caffeine is rated in the DSM-IV scale. It is also clear that caffeine's effects on sleep are probably related to adenosine receptor antagonism, because adenosine is likely to be one of the factors that acts as endogenous sleep promoters. It is, however, less clear precisely where in the brain these effects are exerted and whether the receptors involved are A1 receptors, A2A receptors, or (possibly) both.

E. Effects of Caffeine on Cerebral Blood Flow and Metabolism

Caffeine given as an acute dose of 10 mg/kg increases the rates of cerebral energy metabolism in the rat. Increases are significant in all monoaminergic cell groupings, in structures of the extrapyramidal motor system, in thalamic relay nuclei, and in the hippocampus (Nehlig et al., 1984

Conversely to its stimulant effects on brain energy metabolism, caffeine has central vasoconstrictive properties that lead to a 20 to 30% decrease in cerebral blood flow in humans [for review see Nehlig and Debry (1994)]. In newborns treated with methylxanthines for apnea, cerebral blood flow decreases of up to 21% have been reported, that can be avoided if methylxanthine-induced hypocapnea is corrected [for review see Nehlig and Debry (1994)]. In rats, the caffeine-induced decrease in cerebral blood flow is especially marked in the regions where cerebral energy metabolism increases (Nehlig et al., 1990). Thus, caffeine is one of the rare substances able to reset the level of coupling between cerebral blood flow and metabolism in favor of an increased metabolic rate at a given rate of perfusion. However, these changes are moderate and the decrease in blood flow could be compensated for by an increase in oxygen and glucose extraction, because the consumption of moderate amounts of caffeine has positive effects on alertness. The other alternative is that the metabolic increase related to caffeine exposure might only activate the anaerobic pathway of glucose degradation, as seen in several situations of physiological activation in which metabolic increases are not coupled with a commensurate increase in oxygen consumption (Fox and Raichle, 1986; Fox et al., 1988). In the latter case, metabolic activation would rely primarily on glucose whose entry into brain is always in large excess, whereas the decrease in blood flow could reflect the decrease in oxygen needs. However, this hypothesis needs to be tested.

The acute administration of 10 mg/kg caffeine leads to widespread increases in the rates of cerebral glucose utilization in the nucleus accumbens, both the shell and the core as well as in most structures of the extrapyramidal motor system, and in many limbic regions and cortices (Nehlig et al., 1984, 1986). Conversely, amphetamine, cocaine, and nicotine increase rates of cerebral glucose utilization primarily in the nucleus accumbens (Porrino et al., 1984, 1988; Stein and Fuller, 1992; Porrino, 1993; Pontieri et al., 1996), with a specific metabolic activation only in the shell and not in the core of the nucleus accumbens, as shown in some of these studies. These effects are quite specific and occur already at rather low doses (Porrino et al., 1988; Stein and Fuller, 1992; Pontieri et al., 1996). On the other hand, one of the structures most sensitive to caffeine appears to be the caudate nucleus whose metabolic activity is increased after the injection of a very low dose of caffeine (1 mg/kg) and remains increased at 5 to 6 h after the last chronic i.p. injection of 10 mg/kg caffeine in the rat (Nehlig et al., 1984, 1986). Conversely, with cocaine, amphetamine, and nicotine, increases in cerebral glucose utilization in the dorsal caudate nucleus usually appear at doses higher than those needed to induce increases in the shell of the nucleus accumbens (Porrino et al., 1984, 1988; Orzi et al., 1993; Pontieri et al., 1996).

Taken together, these data show that caffeine has rather widespread effects on cerebral functional activity in contrast to the specific effects of amphetamine and cocaine on the neural substrates believed to underlie addiction. In fact, caffeine primarily acts on the extrapyramidal motor system and on cerebral structures related to the sleep-wake cycle such as the reticular formation, raphe nuclei, and locus ceruleus (Nehlig et al., 1984, 1986). These data are in agreement with the facilitated motor output (James, 1991; Lorist et al., 1994) and the increase in wakefulness reported in humans after caffeine ingestion (James, 1991). Caffeine is also able to increase cerebral energy metabolism in the shell of the nucleus accumbens. However, these effects occur only at doses that already increase functional activity throughout the brain and that are effective both on the shell and the core part of the nucleus accumbens (Nehlig, unpublished data). Therefore, although caffeine acts on the neural substrates of addiction, these effects are not specific, compared to those of the drugs of addiction, and occur at rather high doses, which induce the activation of other numerous brain structures and are already probably close to aversive doses in humans.

F. Other Effects

Caffeine is present in several analgesic preparations. To the extent that this is at all rational it may be related to the presence of adenosine A2A receptors in or close to sensory nerve endings that cause hyperalgesia (Ledent et al., 1997

It cannot be excluded that caffeine might have analgesic properties for specific types of pain, which may be the case for headache (Ward et al., 1991), which is significantly and dose-dependently reduced by caffeine under double-blind conditions. The effect was similar to that of acetaminophen, which is frequently combined with caffeine, and showed no relation to the effects on mood or to self-reported coffee drinking. As reviewed (Migliardi et al., 1994), patients rate caffeine-containing analgesics as superior to caffeine-free preparations for the treatment of headache. In addition, caffeine may exert an antinociceptive effect in the brain, because it can antagonize pain-related behavior in the mouse following i.c.v. injection (Ghelardini et al., 1997). Moreover, this effect may be related to antagonism of a tonic inhibitory activity of adenosine A1 receptors that reduce cholinergic transmission (cf. Rainnie et al., 1994; Carter et al., 1995).

Many central stimulants reduce appetite, via mechanisms that are incompletely understood. Caffeine appears to have a small reducing effect on caloric intake (Tremblay et al., 1988; Racotta et al., 1994; Comer et al., 1997). This effect is similar to, although less marked than, that seen after amphetamine (Foltin et al., 1995). For both stimulant drugs the effect is on the number of meals consumed rather than on meal size.

Given that many caffeine-containing drinks are typically consumed in social settings, surprisingly little is known about the possible effects of caffeine on social behavior (see Bättig and Welzl, 1993). In male rats caffeine causes a dose-dependent (10-40 mg/kg) increase in social investigation (Holloway and Thor, 1983). This was observed not only after injection of single doses but also after the addition of caffeine to the drinking water. The effect was dose-dependent from 0.12 to 0.5 g/l in the water. Finally, the effect of injecting caffeine on social investigation did not decrease in animals exposed to caffeine in the drinking water (Holloway and Thor, 1983). The recent finding that male mice---but not female mice---whose A2A receptors have been knocked out exhibit increased aggressive behavior (Ledent et al., 1997) suggests that caffeine might have similar effects in this species, but this has not been studied. In an experimental study in humans, caffeine was reported to decrease aggressive responses (Cherek et al., 1983), but the aggressive behavior was very artificial and involved push-button punishment of fictitious individuals. Reintroduction of caffeine after a brief abstinence does not significantly affect human social behavior (Comer et al., 1997). However, more information on the effect of caffeine on social behavior is clearly needed.

). Indeed, caffeine does have hypoalgesic effects in certain types of C-fiber-mediated pain (Myers et al., 1997). The analgesic effects are small (Bättig and Welzl, 1993). Under conditions of pain, however, caffeine could have an indirect beneficial effect by elevating mood and clear-headedness (Lieberman et al., 1987). In this study it was found that both mood and vigilance were more improved by aspirin in combination with caffeine than by aspirin given alone or by placebo., 1986). These increases correlate well with the known effects of caffeine on locomotor activity and on the sleep-wake cycle. Moreover, caffeine-induced increases in the rates of cerebral glucose utilization are of the same amplitude and occur in the same brain regions whether caffeine (10 mg/kg) is given as the first acute dose or after a previous 2-week chronic exposure to the methylxanthine. Thus, cerebral energy metabolism does not seem to develop tolerance to the stimulant effects of caffeine. Moreover, the structures in which cerebral energy metabolism remains increased even 5 to 6 h after the last chronic i.p. administration of caffeine are the caudate nucleus and the substantia nigra pars compacta as well as the locus ceruleus and the dorsal raphe nucleus, i.e., the structures regulating motor activity as well as the sleep-wake cycle (Nehlig et al., 1986).; Snel, 1993). It can first be noted that effects on sleep are quite variable. It has been suggested that the subjects most sensitive to the effects of coffee on sleep might metabolize caffeine more slowly than the others (Levy and Zylber-Katz, 1983). Indeed, for the same amount of caffeine ingested, the plasma concentration of the methylxanthine can vary among individuals by a factor of 15.9 (Birkett and Miners, 1991). However, as discussed elsewhere in this review, there are also major differences in the sensitivity to caffeine.; Arushanian and Belozertsev, 1978). In the cat, 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 formation (Jouvet et al., 1957), a structure which plays an important role in vigilance and awakening.; Silverman et al., 1994; Griffiths and Mumford, 1995). Schoolchildren consuming more that 50 mg of caffeine per day, mainly from soft drinks, report higher wakefulness than a control group consuming less than 10 mg per day (Goldstein and Wallace, 1997). The relative failure to demonstrate such effects in subjects that regularly consume coffee contrasts with the common perception of regular caffeine consumers (Goldstein and Kaizer, 1969). The apparent discrepancy may be related to the importance that investigators and normal consumers place on the small performance benefits discussed elsewhere. Another aspect is that the caffeine user may especially appreciate performance benefits when he or she is less alert than usual. For example, in a recent study subjects with upper respiratory tract illness ("common cold") were not only feeling more alert after consuming caffeine but were also performing better in a reaction time task, something they did not do when they were feeling well (Smith et al., 1997).). There is indeed ample evidence that caffeine (and other adenosine receptor antagonists) can increase behaviors related to dopamine. The first demonstration of an adenosinedopamine interaction on behavior was the finding that several adenosine receptor antagonists, including caffeine, theophylline, and isobutyl-methylxanthine, could increase dopamine receptor-activated rotation behavior (Fredholm et al., 1976). This finding was preceded by the observation that theophylline could enhance such rotation behavior (Fuxe and Ungerstedt, 1974), but in that study the authors proposed that the mechanism was phosphodiesterase inhibition. In the later study (Fredholm et al., 1976) this possibility was discounted. This type of finding has since been repeatedly confirmed and elaborated (see Daly, 1993; Ferré et al., 1992; Ongini and Fredholm, 1996). Indeed, dopamine receptor antagonists can inhibit the stimulatory effects of caffeine on motor behavior (Fredholm et al., 1983; Herrera-Marschitz et al., 1988; Garrett and Holtzman, 1994b), and long-term treatment of rats with caffeine reduces the effects of both caffeine and dopamine receptor agonists (Garrett and Holtzman, 1994a).

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