C

aEffect observed in experimental animals bEffect hypothesized in humans based on epidemiological studies cEffect observed at very high doses, or in individuals bearing either a pre-existing susceptibility or a pre-existing condition (disease, unbalanced diet) favoring the manifestation of the effect dEffect observed in vitro eBoth a facilitation and an impairment of this effect have been described in the literature, and results may differ between acute and chronic intake 'interspecies differences in this effect have been described gAn inverse association between caffeine consumption and type ii diabetes has been suggested by epidemiological studies hAn inverse association between caffeine consumption and different type of tumors has been suggested by epidemiological studies iEffects may vary according to the vascular district examined jBoth anti- and pro-carcinogenetic effects have been described at the preclinical level according to the type of the tumor considered

Caffeine. Fig. 1. Summary of caffeine chemical structure, receptor binding, transduction mechanisms and central effects.

activation is critically involved in promoting psychomotor stimulation, seems crucial to caffeine-elicited psychostimulant effects (Cauli and Morelli 2005). Thus, opposite functional interactions between adenosine receptors and ► dopamine receptors have been demonstrated in both animal and human brain (Fredholm and Svenningsson 2003). Stimulation of adenosine receptors depresses dopaminergic transmission while adenosine receptor blockade amplifies it (Ferre et al. 1997). Caffeine, by antagonizing adenosine receptors, boosts dopaminergic transmission, and rodent studies have substantiated the relevance of such a mechanism to caffeine's neurobehavioral effects. In this regard, an attenuation in caffeine-elicited psycho-motor stimulation has been described in mice bearing a genetic deletion of either the D2 receptor or the phos-phoprotein ► DARPP-32, a key second messenger in dopamine receptor-mediated signal transduction (Fisone et al. 2004; Zahniser et al. 2000). Interactions between adenosine and neurotransmitters other than dopamine, such as ► glutamate, ► serotonin, ► acetylcholine, and histamine, also exist in the brain which may be important to caffeine-induced central effects. In particular, adeno-sine-glutamate interactions have been suggested to participate in caffeine-elicited psychostimulant effects and to underlie the neuroprotective effects of caffeine (Schwarzschild and Ascherio 2004).

Experimental Paradigms

Several experimental models exist that are suited to the investigation of the biological effects of caffeine. These may involve either in vitro paradigms, widely used to evaluate the effects of caffeine on cell cycle, or in vivo models, employed to study caffeine-induced effects at both the peripheral and central level. The latter models can address the influence of caffeine on phenomena such as diuresis, metabolic and heart function, and neurotoxicity. The majority of the studies concerned with caffeine, however, use models aimed at investigating its effects on brain function. Such paradigms evaluate the capability of caffeine in modifying the behavioral performance of animals, mainly rodents, and they can be paired with complementary techniques (e.g., ► microdialysis) aimed at elucidating the changes in brain neurochemistry triggered by caffeine.

Thus, the magnitude of caffeine-elicited motor activity, whose increase is an index of psychostimulation, is largely measured as parameter reflecting the gross psychostimulant effects of caffeine. Next to this, caffeine influences ► conditioned place preference and ► intracranial self-stimulation, two paradigms useful to investigate drug-induced positive rewarding effects. Furthermore, caffeine affects animals' performance in different ► drug discrimination and taste preference paradigms, reflecting caffeine's influence on the perception of stimuli. Finally,

Caffeine. Table 2. Biological targets of caffeine.

Target

Action

Range of effective concentrations (mM)a

Adenosine A1 and A2A receptors

Antagonism

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