IX. Reinforcing Effects of Caffeine
The literature on the reinforcing effects of caffeine has been excellently summarized (Griffiths and Mumford, 1995, 1996). In particular, the earlier article clearly summarizes the salient findings of all the relevant studies before 1995. Here we will focus on certain aspects of this phenomenon.
A. Reinforcement in Animals
1. Intravenous and Oral Self-Administration. Reinforcing efficacy of a drug refers to the relative efficacy in establishing or maintaining behavior on which the delivery of the drug is dependent. The most widely used technique in animals is i.v. self-administration. The reinforcing efficacy of caffeine has been studied after the implantation of venous catheters allowing the animals to self-administer the drug by pressing a lever or some other means, such as poking the nose at an appropriate target.
In nonhuman primates, caffeine can act as a reinforcer in some conditions (see Griffiths and Mumford, 1995
In the early studies in rats, only some rats showed a response, and the overall effect was small (Atkinson and Enslen, 1976; Collins et al., 1984). Although rats respond at higher rates for caffeine than they will for saline (Deneau et al., 1969; Griffiths and Woodson, 1988b), the level of responding maintained by caffeine is far less than that maintained by nonxanthine psychomotor stimulants, such as cocaine and amphetamine and other phenethylamines. In a recent series of experiments on mice (Kuzmin et al., unpublished data) caffeine infusion was induced by nose-poke responses. The total number of nose pokes during a 30-min session in the "active" mouse (response-contingent caffeine infusion) was higher than that of the "passive" mouse (response-noncontingent infusion for the control of caffeine effect on nose-poke behavior). In this mouse model, acquisition could thus be demonstrated, as has previously been done in rats. To our knowledge, this is a first demonstration of caffeine i.v. self-administration in mice. The efficacy of the model may be related to the fact that nose poking is a form of spontaneous natural orienting behavior in the mouse; this might facilitate learning of positively reinforced responding. In fact, spontaneous nose poke activity is usually quite high, favoring the self-infusion of the drug under investigation in pharmacologically active bolus doses which are at the same time not too high to disrupt association between nose poke and drug psychotropic effect. Moreover, the partial immobilization limits the behavioral repertoire, favoring nose pokes. Because locomotor activity is relatively high in mice, the probability of spontaneous nose pokes, with the contingent infusions of the drug, is higher than in the classical models of the acquisition of i.v. self-administration in rats. It is important that the nose-poke model makes it possible to compare reinforcing potencies and efficacy values of different compounds. For example, cocaine had a higher potency (lower EC50) and efficacy (maximal values of reinforcing criteria) than caffeine. Hence, despite the fact that caffeine can, under some experimental circumstances, support initiation of i.v. self-administration, it is markedly less efficacious than drugs such as cocaine. Just as in the case of nonhuman primates, acquisition of the drug-related behavior can be demonstrated, but it is poorly and irregularly maintained.
The interpretation of the above data is also limited by the fact that all these animal studies concern i.v. self-administration, whereas human caffeine consumption is always by the oral route. This point is particularly relevant because the effects of the drug of abuse, cocaine, differ with the route of administrationi.p. or i.v. (Porrino, 1993).
In oral self-administration studies in rats, preference for caffeine solution over water was demonstrated only at extremely low concentrations that resulted in very low intake (Heppner et al., 1986). Preference for caffeine in such high concentration in drinking water that behaviorally active amounts are ingested was demonstrated only after a 14-day period of forced exposure (Vitiello and Woods, 1977). Oral self-administration may be increased by food deprivation or chronic nicotine exposure (Heppner et al., 1986). Using a fixed-time schedule for presentation of a food pellet, it was possible to demonstrate more drinking of a caffeine solution than of water (Falk et al., 1994).
2. Reinforcing Effects of Caffeine: Place Conditioning. An animal placed in an experimental box with two identifiable compartments can be given drugs when it is in one of the compartments. If this is repeated the animal will, by a variant of classical conditioning, associate that compartment with the effects of the drug. In a test session one can then determine if the animal prefers the drug-associated compartment (conditioned place preference) or avoids it (conditioned place aversion). Conditioned place preference occurs with a low dose of caffeine (3 mg/kg) in rats (Brockwell et al., 1991
The possible involvement of adenosine receptors was tested in mice. Low doses of theophylline ( place preference, whereas doses higher than 50 mg/kg produced conditioned place aversion. 8-Phenyltheophylline, a nonselective adenosine receptor antagonist with a low ability to block phosphodiesterases, also produced conditioned place preference (Zarrindast and Moghadamnia, 1997). These authors also used adenosine receptor agonists, but the interpretation of these findings is complicated by the known effects of such drugs on, for example, the circulatory system.
In another study (Patkina and Zvartau, unpublished data) the place conditioning technique was used to compare the rewarding potential of caffeine with that of cocaine, nicotine, and ethanol. Caffeine (1.5 mg/kg, i.p.), cocaine (5 mg/kg, i.p.), nicotine (0.6 mg/kg, s.c.), and ethanol (1.5 g/kg, i.g.) did produce comparable reinforcing effects in an unbiased place conditioning paradigm in rats. The animals then had the opportunity to "compare" the rewarding effects of two drugs. All the animals preferred cocaine over caffeine, but there were no significant differences between the other three drugs.
Caffeine is thus able to act as a reinforcer in several animal species under a certain range of conditions but is unable to maintain self-administration behavior, in contrast to what is seen after other psychostimulant drugs. These data point out a marked difference between caffeine and drugs such as amphetamine and cocaine that maintain self-administration across species and conditions (Griffiths et al., 1979; Pontieri et al., 1995). The inconsistency between the data of the different studies seen with caffeine is similar to that seen in nicotine self-administration studies (Goldberg and Henningfield, 1988; Dworkin et al., 1993). The fact that regular caffeine intake is very difficult to maintain in animals also means that it has not been possible to study caffeine in reinstatement paradigms. Thus, it has been difficult to experimentally address the question of whether caffeine "craving" exists. Caffeine has, however, been shown to affect cocaine reinstatement (see below Section XIIB).
B. Reinforcement in Humans
In humans, the widely recognized behavioral stimulant and mildly reinforcing properties of caffeine are probably responsible for the maintenance of caffeine self-administration, primarily in the form of caffeinated beverages, such as coffee, tea and cola (for review see Nehlig and Debry, 1994
Most of the animal studies discussed above were performed using injection of caffeine, whereas most human studies examined oral caffeine. In a recent study (Rush et al., 1995) i.v. caffeine (37, 75, 150, or 300 mg/70 kg) was given twice with at least 24 h delay. The subjects reported a dose-dependent, rapid drug effect that was described as "a high". They liked the drug and reported overwhelmingly positive effects. Importantly, these effects were very transient: with the lower doses the effects were over within 10 min and only when the highest i.v. dose was given did the effect last for 20 to 40 min. At the highest dose, virtually all the subjects identified the drug as a stimulant (Rush et al., 1995).
Also in studies with oral intake, the reinforcing effect of caffeine varies with the dose. It has been pointed out that the dose-response relationship in humans may resemble that in animals: an inverted U-shape, with high doses sometimes associated with aversion (Griffiths and Mumford, 1995; Garrett and Griffiths, 1998). Doses of caffeine encountered in tea and coffee are high enough to act as reinforcers, but as pointed out above, a significant factor appears to be avoidance of withdrawal effects (Schuh and Griffiths, 1997). The relationship between pre-exposure to caffeine and caffeine reinforcement requires further study (Griffiths and Mumford, 1995). Caffeine users, but not people who do not consume caffeine, showed a preference for a fruit juice drink containing caffeine (100 mg) as a postlunch beverage (Richardson et al., 1996). This provides, according to the authors, evidence for the existence of a reinforcing effect of caffeine, which requires prior exposure to caffeine-containing drinks. The consumption of the caffeine-containing drink prevented a postlunch dip in mood in the habitual caffeine consumers. This is compatible with prevention of a slight withdrawal effect, but also with the effects of caffeine on blood flow distribution. A similar study (Rogers et al., 1995) investigated caffeine reinforcement by assessing changes in preference for a novel drink consumed with or without caffeine. Caffeine had no significant effects on drink preference in subjects with habitually low intakes of caffeine, whereas users of higher doses of caffeine developed a relative dislike for the drink lacking caffeine. This could be related to a lowered mood following overnight caffeine abstinence, which was significantly improved by caffeine. However, another study (Brauer et al., 1994) found that subjects' ratings of the pleasantness of the coffee taste were not significantly altered by caffeine deprivation. In several studies, only 10 to 50% of the individuals reliably chose caffeine over placebo [for review see Silverman et al., 1994] and subjects do not always show a clear caffeine withdrawal syndrome under a placebo condition (Griffiths and Mumford, 1995). One problem is that the ability to discriminate between caffeine and placebo is acquired slowly, another is that the behavioral requirements following caffeine ingestion, such as tasks requiring enhanced vigilance, can affect caffeine reinforcement (for review see Silverman et al., 1994). Therefore, many different aspects of caffeine reinforcement remain to be explored.
The reinforcing effect of any given substance can be assessed by determining how much work would be performed or money spent in order to get access to it. A series of earlier studies (in part not very systematic) documenting reinforcement through caffeine in humans and animals was reviewed by Griffiths and Woodson (1988). Griffiths et al. (1989) used more stringent conditions in a group of six consumers with excessively high caffeine intake (>1000 mg/day) by requiring ergometer cycling for getting either decaffeinated coffee with 100 mg or no caffeine or capsules with 100 mg or no caffeine. The subjects took 10 servings per day when only a few minutes of cycling were required, but this decreased to about two servings per day when the price, in minutes of cycling, was gradually increased to 32 min. Decaffeinated coffee was almost as valuable to the subjects as caffeinated coffee or caffeine capsules and it was only the placebo capsules that were not deemed worth any cycling work at all. In a later study from the same laboratory (Evans et al., 1994), caffeine reinforcement was demonstrated in a majority of moderate caffeine users. A mutually exclusive choice procedure was used to evaluate the reinforcing effects of caffeine in subjects with histories of regular caffeine consumption (256 mg/day). Subjects participated for 24 weeks; each week consisted of three consecutive daily sessions (two sampling days followed by a choice day) during which subjects were required to abstain from dietary sources of caffeine. On each sampling day, subjects ingested four capsules, one every 2 h. Capsules contained placebo on one sampling day and caffeine (50 or 100 mg/capsule) on the other sampling day. Placebo and caffeine were associated with different color-coded capsules. At the beginning of the choice day, subjects chose one of the two color-coded capsules they wished to take on that day; they were required to ingest one capsule and, thereafter, they could ingest up to six additional capsules of the same color throughout the day. Across subjects and dose, caffeine was chosen over placebo on 80% of choice occasions; nine of 11 subjects chose caffeine on more than 70% of choice occasions and caffeine choice was replicable despite changes in capsule colors across blocks.
Another study from the same laboratory (Silverman et al., 1994) revealed that situational conditions might have a substantial effect on caffeine reinforcement. Subjects previously trained to discriminate caffeine from placebo, after being given the choice between caffeine and placebo, were engaged either in relaxation or in vigilance. All six subjects chose caffeine before vigilance and four of the six consistently chose placebo before relaxation. Furthermore, six of seven subjects were ready to spend money to receive caffeine when vigilance rather than relaxation was the aim.
Another approach is to test whether consumption of a fixed-price item increases, decreases, or remains unchanged when the price of another item increases. Several studies using this technique for pharmacological questions have been reviewed (Bickel et al., 1995). Increasing consumption of a fixed-price item when the other one became more expensive, indicating thus a substitute function, was particularly apparent for different preparations of opiates, cocaine, phencyclidine, and pentobarbital. Independence of two rewards was seen between phencyclidine and saccharine, between morphine or heroin and food, between alcohol and cigarettes, and in several studies between caffeine and cigarettes. Using this method, the reward values of cigarettes and coffee were compared (Bickel et al., 1992).
When the price of coffee increased in terms of the number of responses required, coffee drinking decreased and the consumption of fixed-price cigarettes remained unchanged. On the other hand, both coffee and cigarette consumption decreased when the cigarettes became more expensive and the price of coffee remained fixed. This suggests not only a complementary function for the two rewards but also that the interaction between two substances can be asymmetrical.
In theory one might also use data on consumption versus price in the entire community. This was done by Olekalns and Bardsley (1995, 1996), and they found a high degree of price sensitivity, which in economic terms was described as rational and also forward looking.
; Griffiths and Mumford, 1995
). All in all, Griffiths and Mumford in their review (Griffiths and Mumford, 1995
) concluded that caffeine reinforcement occurred in about 45% of moderate or heavy caffeine users.
). At a dose of 30 mg/kg or higher, place preference was replaced by place aversion. The nonselective adenosine receptor antagonist CGS 15943, but not the A1
antagonist DPCPX, produced a significant conditioned place preference, suggesting that adenosine A2A
receptors are particularly important in mediating the response. A study (Patkina et al., unpublished data; see Fig. 7
) investigating the place conditioning effects of caffeine over a wider range of doses (0.8-50 mg/kg, i.p.) demonstrated the ability of caffeine, depending on the dose given, to establish both conditioned place preference and place aversion. The maximal conditioned place preference effect of caffeine was seen at the dose of 1.5 mg/kg, and significant conditioned place aversive effect was seen at the dose of 25 mg/kg.
; Howell et al., 1997
). The results range from no reinforcement at all at a low dose of caffeine (0.2 mg/kg) (Hoffmeister and Wuttke, 1973
), to maintenance of self-administration in a minority (25-33%) of the animals (Atkinson and Enslen, 1976
; Collins et al., 1984
), to an effect observed in all the animals (Deneau et al., 1969
; Griffiths et al., 1979
; Dworkin et al., 1993
). The self-administration of caffeine in nonhuman primates is quite irregular, with periods of relatively high rates alternating with periods of low rates of caffeine self-administration (Deneau et al., 1969
; Griffiths et al., 1979
; Griffiths and Mumford, 1995
), and, under conditions when cocaine and amphetamine act reliably as reinforcers, caffeine cannot consistently be shown to be self-administered. In particular, the fact that there is no maintenance of a regular rate of caffeine self-administration means that it is impossible to examine questions of dose titration, although this is readily done with drugs such as cocaine.