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Reading Passage "Caffeine" Duplicated Below






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Caffeine, the stimulant in coffee, has been called
"the most widely used psychoactive substance on Earth."
Snyder, Daly and Bruns have recently proposed that
caffeine affects behavior by countering the activity in
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.
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-
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-
buted to its inhibition of the production of phosphodiesterase,
an enzyme that breaks down the chemical
called cyclic AMP. A number of neurotransmitters exert
their effects by first increasing cyclic AMP concentrations
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 behavioral
stimulation. But Snyder et al point out that the
caffeine concentrations needed to inhibit the production
of phosphodiesterase in the brain are much higher than
those that produce stimulation. Moreover, other compounds
that block phosphodiesterase's activity are not
stimulants.
 
To buttress their case that caffeine acts instead by pre-
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 brains of mice. "In general," they reported, "the
ability of the compounds to compete at the receptors
correlates with their ability to stimulate locomotion in
the mouse; i.e., the higher their capacity to bind at the
receptors, the higher their ability to stimulate locomotion."
Theophylline, a close structural relative of caffeine
and the major stimulant in tea, was one of the most
effective compounds in both regards.
 
There were some apparent exceptions to the general
correlation observed between adenosine-receptor binding
and stimulation. One of these was a compound called
3-isobuty1-1-methylxanthine(IBMX), which bound very
well but actually depressed mouse locomotion. Snyder
et al suggest that this is not a major stumbling block to
their hypothesis. The problem is that the compound has
mixed effects in the brain, a not unusual occurrence with
psychoactive drugs. Even caffeine, which is generally
known only for its stimulatory effects, displays this
property, depressing mouse locomotion at very low
concentrations and stimulating it at higher ones.

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