Caffeine, the stimulant in coffee, has been called "the most widely used psychoactive substance on Earth ."

Synder, Daly and Bruns have recently proposed that caffeine affects behavior by countering the activity in (5) the human brain of a naturally occurring chemical called adenosine. Adenosine normally depresses neuron firing in many areas of the brain. It apparently does this by inhibiting the release of neurotransmitters, chemicals that carry nerve impulses from one neuron to the next. (10) Like many other agents that affect neuron firing, adenosine must first bind to specific receptors on neuronal membranes. There are at least two classes of these receptors, which have been designated A1 and A2. Snyder et al propose that caffeine, which is struc-(15) turally similar to adenosine, is able to bind to both types of receptors, which prevents adenosine from attaching there and allows the neurons to fire more readily than they otherwise would.

For many years, caffeine s effects have been attri-(20) buted to its inhibition of the production of phosphodi-esterase, an enzyme that breaks down the chemical called cyclic AMP.A number of neurotransmitters exert their effects by first increasing cyclic AMP concentra-tions in target neurons. Therefore, prolonged periods at the elevated concentrations, as might be brought about by a phosphodiesterase inhibitor, could lead to a greater amount of neuron firing and, consequently, to behav-ioral stimulation. But Snyder et al point out that the caffeine concentrations needed to inhibit the production(30) of phosphodiesterase in the brain are much higher than those that produce stimulation. Moreover, other com-pounds that block phosphodiesterase s activity are not stimulants.

To buttress their case that caffeine acts instead by pre-(35) venting adenosine binding, Snyder et al compared the stimulatory effects of a series of caffeine derivatives with their ability to dislodge adenosine from its receptors in the br

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