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<strong>VIII. Caffeine Discrimination and Dose Adjustment in Animals and Humans</strong><a></a><p><strong>A. Caffeine Discrimination in Animals</strong> </p> <p>Several studies have examined the discriminative stimulus properties of caffeine in rats. In most of the early studies (Modrow et al., 1981</p> <p>The observation that low stimulatory doses of caffeine have discriminative stimulus properties is largely in agreement with the idea that the effects are mediated by adenosine receptor antagonism and that adenosine A<sub>2A</sub> receptors may be particularly important. Recently, Holtzman (1996)<a href="http://pharmrev.aspetjournals.org/cgi/content/full/51/1/83#B246"><img src="http://pharmrev.aspetjournals.org/icons/ref-arrow.gif" alt=""></a> has specifically addressed this question in a series of experiments in monkeys. He trained them to discriminate between the nonxanthine, nonselective adenosine receptor antagonist and its vehicle. All monkeys generalized dose-dependently to a series of xanthine derivatives. There was no linear relationship to their potency in vitro as either A<sub>1</sub> or A<sub>2A</sub> receptor antagonists. However, these potency determinations have not been performed in monkeys and, furthermore, the relationship between the dose administered and the levels of these xanthines in brain has not been determined. Holtzman (1996)<a href="http://pharmrev.aspetjournals.org/cgi/content/full/51/1/83#B246"><img src="http://pharmrev.aspetjournals.org/icons/ref-arrow.gif" alt=""></a> also found that the adenosine analog CGS 21680 blocked the effect of CGS 15943, indicating a role of A<sub>2A</sub> receptors. However, the agonist was not able to block the effects of caffeine and theophylline. This was taken as evidence against a role of the adenosine receptor in mediating the actions of the xanthines. Before this conclusion is accepted the pharmacokinetics of these compounds in monkeys must be determined. It should also be remembered that CGS 21680 is not a potent or highly selective adenosine A<sub>2A</sub> receptor agonist in humans (Kull et al., 1999<a href="http://pharmrev.aspetjournals.org/cgi/content/full/51/1/83#B306"><img src="http://pharmrev.aspetjournals.org/icons/ref-arrow.gif" alt=""></a>), and the same may apply to monkeys.</p> <a></a><p><strong>B. Caffeine Discrimination in humans</strong> </p> <p>Several studies show that humans discriminate caffeine (for references see Griffiths and Mumford, 1995</p> <p>A later study (Evans and Griffiths, 1991<a href="http://pharmrev.aspetjournals.org/cgi/content/full/51/1/83#B133"><img src="http://pharmrev.aspetjournals.org/icons/ref-arrow.gif" alt=""></a>) tested a number of moderate caffeine users who were first trained to discriminate 0 and 300 mg of caffeine and then tested as to which other doses they might generalize this discrimination to. Training to criterion took the shortest time (6 sessions) in the subject with the lowest habitual caffeine consumption and longest (16 sessions) in the subject with the highest habitual consumption. Doses of 300 mg or more were more easily detected than the lower doses, and the data suggest that the higher doses were mainly recognized by their negative effects (e.g., the subjects felt jittery, anxious, or nervous), whereas the lower doses were detected by feelings of "no effect at all" or by the negative feelings of caffeine withdrawal such as tiredness, sluggishness, or headache. Quite strikingly, however, doses in the middle range of around 100 mg, which closely approach the caffeine content of a normal serving of coffee, were detected poorly or at chance level only.</p> <p>Such doses, which neither induce feelings of withdrawal nor of overdose, were shown by Hughes et al. (1992a)<a href="http://pharmrev.aspetjournals.org/cgi/content/full/51/1/83#B252"><img src="http://pharmrev.aspetjournals.org/icons/ref-arrow.gif" alt=""></a> to be preferred by moderate coffee drinkers. Subjects were tested for their preference under blind conditions across a range from 25 to 200 mg of caffeine added to decaffeinated coffee. Out of eight subjects, two preferred coffee with 25 mg, four preferred coffee with 50 mg, two coffee with 150 mg, and none coffee with 200 mg. In one study it was shown that subjects involved in a discrimination study were able to make an accurate choice of caffeine or placebo (Silverman et al., 1994<a href="http://pharmrev.aspetjournals.org/cgi/content/full/51/1/83#B472"><img src="http://pharmrev.aspetjournals.org/icons/ref-arrow.gif" alt=""></a>). After subjects had established an ability to discriminate caffeine (100 mg) from placebo, they were able, reliably, to choose letter-coded caffeine capsules when aiming for vigilance, and letter-coded placebo capsules when the aim was relaxation. This finding could possibly relate to the question of caffeine reinforcement (see below).</p> <p>As already noted, psychomotor stimulants do not readily generalize to caffeine (Chait and Johanson, 1988<a href="http://pharmrev.aspetjournals.org/cgi/content/full/51/1/83#B79"><img src="http://pharmrev.aspetjournals.org/icons/ref-arrow.gif" alt=""></a>). The reverse experiment was tried by Oliveto et al. (1993)<a href="http://pharmrev.aspetjournals.org/cgi/content/full/51/1/83#B385"><img src="http://pharmrev.aspetjournals.org/icons/ref-arrow.gif" alt=""></a>. Healthy volunteers were trained to discriminate between caffeine (320 mg/70 kg, p.o.) and placebo, using monetary reinforcement of correct letter code identification. After four training sessions, subjects were tested with the training conditions until they were >80% correct on four consecutive sessions. As expected, theophylline (56-320 mg/70 kg) produced 100% appropriate responding, albeit with interindividual differences in the doses required, whereas buspirone (1-32 mg/70 kg) did not. The psychostimulant methylphenidate (10-56 mg/70 kg) produced increases in caffeine-appropriate responding in most but not all subjects, and only at the highest dose. Together, these two studies indicate that in humans psychostimulants and caffeine are experienced in similar, but not identical manner.</p> <p>As discussed by Griffiths and Mumford (1996)<a href="http://pharmrev.aspetjournals.org/cgi/content/full/51/1/83#B213"><img src="http://pharmrev.aspetjournals.org/icons/ref-arrow.gif" alt=""></a> the available evidence does not favor the view that caffeine discrimination in humans requires that the subjects be in a state of withdrawal. Indeed this is what should be expected from the animal data.</p> <a></a><p><strong>C. Dose Adjustment</strong> </p> <p>It is a characteristic of several substances of abuse, including morphine and cocaine, that the intake is adjusted so that a relatively constant plasma or brain concentration is achieved: this can be called <em>dose adjustment</em> or <em>drug titration</em>. In animals, such dose titration can readily be studied provided that a sustained and relatively constant rate of a drug-induced behavior can be maintained. However, as discussed below (Section IX) such constant and regular intake has not been possible to achieve with caffeine in animals and hence there are no reliable animal data relating to this point. In the case of humans, dose adjustment could be assumed if subjects would increase coffee drinking when offered coffee containing less caffeine and vice versa. Griffiths and coworkers (1986)</p> <p>In two similarly designed field studies, there were no differences in the daily consumption between the groups offered regular or decaffeinated coffee (Höfer and Bättig, 1994a<a href="http://pharmrev.aspetjournals.org/cgi/content/full/51/1/83#B238"><img src="http://pharmrev.aspetjournals.org/icons/ref-arrow.gif" alt=""></a>,b<a href="http://pharmrev.aspetjournals.org/cgi/content/full/51/1/83#B239"><img src="http://pharmrev.aspetjournals.org/icons/ref-arrow.gif" alt=""></a>). In addition, none of the subjects were able to tell at the end of the experiments exactly on which days they had consumed regular or decaffeinated coffee. Similar results were also obtained in one laboratory experiment in which the subjects had to perform the Stroop task before and after drinking coffee containing either 250 mg or only traces of caffeine (Hasenfratz and Bättig, 1992<a href="http://pharmrev.aspetjournals.org/cgi/content/full/51/1/83#B222"><img src="http://pharmrev.aspetjournals.org/icons/ref-arrow.gif" alt=""></a>). Thus, there is no evidence in support of caffeine dose adjustment in human and animals.</p> <a href="http://pharmrev.aspetjournals.org/cgi/content/full/51/1/83#B209"><img src="http://pharmrev.aspetjournals.org/icons/ref-arrow.gif" alt=""></a> switched subjects with drug abuse histories and self-reported caffeine consumption of 100 mg or more per day under blind conditions to decaffeinated coffee. However, the number of daily cups of coffee remained practically unchanged. On the other hand, clear evidence of avoidance was obtained, when coffee with increased and nonhabituated amounts of caffeine was offered.<a href="http://pharmrev.aspetjournals.org/cgi/content/full/51/1/83#B212"><img src="http://pharmrev.aspetjournals.org/icons/ref-arrow.gif" alt=""></a>, 1996<a href="http://pharmrev.aspetjournals.org/cgi/content/full/51/1/83#B213"><img src="http://pharmrev.aspetjournals.org/icons/ref-arrow.gif" alt=""></a>). In one of the first studies (Chait and Johanson, 1988<a href="http://pharmrev.aspetjournals.org/cgi/content/full/51/1/83#B79"><img src="http://pharmrev.aspetjournals.org/icons/ref-arrow.gif" alt=""></a>), the subjects were first trained to discriminate the effects of 10 mg of amphetamine and 12.5 and 50 mg of benzphetamine against placebo and then tested whether they would generalize this discrimination to 100 and 300<sup> </sup>mg of caffeine. The subjects learned the initial task, but the generalization to caffeine was poor and hardly exceeded chance. In a study with a different design, the initial training with a classical stimulant was omitted (Griffiths et al., 1990<a href="http://pharmrev.aspetjournals.org/cgi/content/full/51/1/83#B211"><img src="http://pharmrev.aspetjournals.org/icons/ref-arrow.gif" alt=""></a>). Instead, two differently colored capsules were given each day at intervals of 1.5 h, and the task was to detect which color marked caffeine. The dose levels were decreased stepwise from an initial 178 mg as soon as the criterion of successful discrimination was reached. The subjects were also the authors of the study and, as such, experienced psychopharmacologists and informed about the research goal. All seven recognized 178 mg, three detected 56 mg and 18<sup> </sup>mg, and one subject even 10 mg after training periods lasting from a minimum of 10 to a maximum of 50 days. However, mood changes were observed only with doses of 100 mg or more, leaving open the question of which stimulus properties allowed the detection of the doses below 100<sup> </sup>mg.<a href="http://pharmrev.aspetjournals.org/cgi/content/full/51/1/83#B352"><img src="http://pharmrev.aspetjournals.org/icons/ref-arrow.gif" alt=""></a>; Winter, 1981<a href="http://pharmrev.aspetjournals.org/cgi/content/full/51/1/83#B536"><img src="http://pharmrev.aspetjournals.org/icons/ref-arrow.gif" alt=""></a>; Carney et al., 1985<a href="http://pharmrev.aspetjournals.org/cgi/content/full/51/1/83#B71"><img src="http://pharmrev.aspetjournals.org/icons/ref-arrow.gif" alt=""></a>; Holloway et al., 1985<a href="http://pharmrev.aspetjournals.org/cgi/content/full/51/1/83#B242"><img src="http://pharmrev.aspetjournals.org/icons/ref-arrow.gif" alt=""></a>; Modrow and Holloway, 1985<a href="http://pharmrev.aspetjournals.org/cgi/content/full/51/1/83#B351"><img src="http://pharmrev.aspetjournals.org/icons/ref-arrow.gif" alt=""></a>) animals were trained on 30 to 60 mg/kg caffeine, and as noted repeatedly above, this dose is definitely on the downward slope of the inverted U-shaped dose-response curve. Animals trained on a high dose of caffeine generalized to papaverine (Holloway et al., 1985<a href="http://pharmrev.aspetjournals.org/cgi/content/full/51/1/83#B242"><img src="http://pharmrev.aspetjournals.org/icons/ref-arrow.gif" alt=""></a>), and papaverine depresses motor behavior as do very high doses of caffeine (Fredholm et al., 1983<a href="http://pharmrev.aspetjournals.org/cgi/content/full/51/1/83#B164"><img src="http://pharmrev.aspetjournals.org/icons/ref-arrow.gif" alt=""></a>). This suggests that the high dose cue is not related to stimulation. This conclusion was supported in a later study where it was shown that the discriminative effect of a low-caffeine training dose (10 mg/kg) exhibits more commonalties with those of amphetamine-like drugs than do the discriminative effects of a higher training dose (30 mg/kg) (Holtzman, 1986<a href="http://pharmrev.aspetjournals.org/cgi/content/full/51/1/83#B244"><img src="http://pharmrev.aspetjournals.org/icons/ref-arrow.gif" alt=""></a>). In a follow-up study, Mumford and Holtzman (1991)<a href="http://pharmrev.aspetjournals.org/cgi/content/full/51/1/83#B361"><img src="http://pharmrev.aspetjournals.org/icons/ref-arrow.gif" alt=""></a> trained rats to discriminate 10 and 56 mg/kg caffeine over saline. Rats required a large number of training sessions (average 93) to discriminate the lower dose. However, then they generalized completely to dopaminergic drugs, including amphetamine, but also to several adenosine receptor antagonists, including the nonxanthine CGS 15943 (Mumford and Holtzman, 1991<a href="http://pharmrev.aspetjournals.org/cgi/content/full/51/1/83#B361"><img src="http://pharmrev.aspetjournals.org/icons/ref-arrow.gif" alt=""></a>). By contrast, animals required fewer training sessions (average 43) to learn to discriminate the high dose of caffeine over saline. Then they generalized to a completely different set of drugs, including benzodiazepine inverse agonists, pentylenetetrazol, and phencyclidine (Mumford and Holtzman, 1991<a href="http://pharmrev.aspetjournals.org/cgi/content/full/51/1/83#B361"><img src="http://pharmrev.aspetjournals.org/icons/ref-arrow.gif" alt=""></a>). These data indicate that a low, stimulatory dose of caffeine gives a cue that resembles a weak dopaminergic stimulus and that a high dose provides a strong cue that is difficult to define in terms of a single precise mechanism. This interpretation is reinforced by the meta-analysis of Griffiths and Mumford (1996)<a href="http://pharmrev.aspetjournals.org/cgi/content/full/51/1/83#B213"><img src="http://pharmrev.aspetjournals.org/icons/ref-arrow.gif" alt=""></a>, where an inverse relationship between the caffeine training dose and generalization to cocaine is demonstrated. The interactions between caffeine and cocaine were investigated by Harland and coworkers (1989)<a href="http://pharmrev.aspetjournals.org/cgi/content/full/51/1/83#B219"><img src="http://pharmrev.aspetjournals.org/icons/ref-arrow.gif" alt=""></a>. Animals trained to discriminate cocaine (10 mg/kg) generalized to caffeine, but only at rather high doses. However, caffeine in doses of 10 mg/kg markedly enhanced responding to low doses of cocaine, even though it reduced cocaine-induced responding when given at high doses. These findings may have a bearing on the interaction between caffeine and cocaine discussed below (Section XIB). Here it may suffice to say that these results suggest that caffeine and cocaine interact at neuronal targets, but that they probably do not share mechanism of action.
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