Adenosine as a Mediator of the Behavioral Effects of Xanthines

Though caffeine has been one of the most widely used psychoactive substances throughout history, it has been difficult to work out molecular mechanisms that account for its behavioral actions. One of the first widely considered mechanisms relates to cyclic AMP. Soon after the identification of phosphodiesterase as an enzyme degrading cyclic AMP, Sutherland and associates (Sutherland and Rall 1958; Butcher and Sutherland 1962) showed that xanthines, including caffeine and theophylline, inhibit phosphodiesterase. By inhibiting this enzyme xanthines might elevate levels of cyclic AMP. However, substantial inhibition of phosphodiesterase requires millimolar concentrations of caffeine, roughly 100 times the caffeine levels in the brain after ingestion of typical doses in man. Further, some inhibitors of phosphodiesterase that are 100–1000 times more potent than caffeine lack behavioral effects.

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