Why Do We Drink Coffee and Tea? 
Charles F. Stevens, M.D., Ph.D. — Investigator 
Dr. Stevens is also Professor of Molecular Neurobiology at the Salk Institute for Biological Studies and 
Adjunct Professor of Pharmacology and of Neuroscience at the University of California School of Medicine, 
San Diego. He received his B.A. degree in psychology at Harvard University, his M.D. degree at Yale 
University, and his Ph.D. degree in biophysics at the Rockefeller University for studies with Keffer Hartline. 
He was a member of the faculties at the University of Washington Medical School and at Yale Medical 
School before joining the Salk Institute. Dr. Stevens is a member of the National Academy of Sciences. 
COFFEE and tea are widely used in many soci- 
eties as mild stimulants. How do they work? 
Recent research in our laboratory provides an 
answer. 
One of the more remarkable features of the 
brain is its ability to modify its own neuronal 
characteristics, a phenomenon known as neuro- 
modulation. Neurons can cause other neurons to 
alter their properties, and thus can change the 
computations carried out by the modified neuro- 
nal circuits. 
Neuromodulation occurs in many ways. One of 
the most important is the regulation of synaptic 
strength — the force and effectiveness with which 
one neuron transmits signals to another. Some 
changes in synaptic strength are very long lasting 
and are thought to underlie the storage of memo- 
ries. Other modifications of synaptic strength oc- 
cur more rapidly and constitute a moment-to- 
moment tuning up of circuit function. A major 
goal of our laboratory has been to elucidate the 
mechanisms through which synaptic strength is 
neuromodulated. In the course of this work, we 
have gained insights into the actions of caffeine 
and theophylline, the stimulants in coffee and 
tea, respectively. 
The chemical adenosine is released at synapses 
together with neurotransmitters and is present in 
the fluids bathing neurons. Neurons display on 
their surface several different types of receptors 
for adenosine, which couple adenosine binding 
to second messenger cascades (such as the one 
involving cAMP) . Adenosine is a very potent regu- 
lator of synaptic strength: concentrations above 
the usual levels result in large decreases in 
strength. Here is the interesting part: methylxan- 
thines, a family of chemicals that includes caf- 
feine and theophylline, bind to adenosine recep- 
tors and block their uptake of adenosine. 
Some "fake" agonists that bind to a receptor 
will activate it as if they were natural agonists, but 
the methylxanthines do not do this. They occupy 
the receptor's adenosine binding site and thereby 
prevent adenosine from doing so. Rather than 
mimic the action of adenosine, the methylxan- 
thines act as if taking it away. Thus they increase 
synaptic strength, indicating that the normal 
brain levels of adenosine are sufficient to pro- 
duce and maintain a partial decrease in synaptic 
strength. 
We examined the effect of adenosine itself, and 
of adenosine receptor blockers, on synaptic 
transmission in brain slices from the hippocam- 
pal region (specifically from dentate) of rats. Us- 
ing the whole-cell recording method, a tech- 
nique that permits high-resolution detection of 
currents that flow as a result of synaptic activa- 
tion, we were able to determine the specific con- 
sequences of adenosine and methylxanthine 
action. 
To interpret the effects of these drugs, one 
needs to know certain features of normal synaptic 
transmission. A synapse contains a number of mi- 
croscopic membrane-bounded spheres, known as 
synaptic vesicles, whose contents are released 
from the cell by a membrane fusion event (exo- 
cytosis). Each of these vesicles contains a unit 
amount of neurotransmitter, such as glutamate, 
that binds to special receptors in the target neu- 
ron surface membrane and produces a signal. The 
strength of a synapse therefore depends jointly on 
the number of vesicles whose contents are re- 
leased and on the size of the response produced 
by one vesicleful of the neurotransmitter. Be- 
cause the size of the synaptic response must be 
integral — a multiple of that produced by a single 
vesicle — this single-vesicle response is called a 
quantum or quantal response. The quantal size 
depends, in turn, on the number of transmitter 
molecules contained in a vesicle and on the num- 
ber and responsiveness of the receptors displayed 
by the target neuron. 
Only a certain number of vesicles are available, 
of course, to release their contained neurotrans- 
mitter. This number is usually denoted by N. 
What is interesting and significant about the neu- 
rotransmitter release process is that it is probabi- 
listic. That is, only a fraction of the N vesicles 
available to release their contents do so, and that 
number is determined the same way one would 
calculate the number of heads in A'' coin flips, 
with a probability p for heads on any flip. Thus 
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