The role of adenosine receptors in the central action of caffeine.

The behavioral effects of caffeine appear likely to be due in large measure to antagonism of the action of endogenous adenosine at A1- and A2a-receptors in the central nervous system. Other biochemical mechanisms of action of caffeine, such as release of intracellular calcium, inhibition of phosphodiesterases and blockade of regulatory sites of GABAA-reccptors, would require much higher concentrations than the micromolar concentrations of caffeine associated with behavioral stimulation. However, micromolar concentrations of caffeine also would be expected to cause only a modest blockade of adenosine receptors. Selective adenosine agonists and xanthine antagonists have provided some insights into central roles for adenosine receptor subtypes. Thus, behavioral stimulation by xanthines appears to require blockade of both A1- and A2a-receptors. Chronic blockade of adenosine receptors by caffeine would be expected to result in alterations in the central receptors and pathways that are regulated by adenosine through A1- and A2a-receptors. Indeed, chronic caffeine docs alter the density not only of adenosine receptors, but also of adrenergic, cholinergic, GABAergic and serotonergic receptors. Behavioral responses to agents acting through dopaminergic and cholinergic pathways arc altered. As yet, a coherent explanation of the acute and chronic effects of caffeine in terms of blockade of adenosine receptors has not emerged. Interactions between pathways subserved by A1 - and A2a-adcnosine receptors complicate attempts to interpret caffeine pharmacology, as does the complex control by adenosine receptors of dopamincrgic, cholinergic and other central pathways.