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B. B. FREDHOLM ANAL. REAL ACAD. NAL. FARM.

SUMMARY
Caffeine and the biological role of adenosine receptors

About thirty years ago it was realized that caffeine, the most widely used of all
psychoactive drugs, is able to antagonize the effects of adenosine at concentrations
achieved during normal human consumption. This finding had several important
implications: 1) there are receptors at which adenosine is the agonist and caffeine the
antagonist; 2) since the antagonist is biologically active it should mean that the receptors
are activated by endogenous adenosine. This brief overview, which reflects the contents
of my introductory lecture at the Academy, will present some data vindicating these
conclusions.

The metabolism of adenosine and its levels under normal and pathophysiological
conditions has been elucidated. Now four different adenosine receptors have been cloned
and pharmacologically characterized. They are all G protein coupled. Their different
signalling characteristics are briefly summarized as is their distribution. Based on these
data t is concluded that caffeine probably exerts its effects by blocking adenosine A1 and
A2A receptors. The biological role(s) of these receptors is finally presented using data
from knock-out mice.

Key words: Cafeine.— Parkinson's disease.— CREB factors.— Striatum.—
GABAergic neurons.— G proteins.— Adenosine receptors.— Dopamine receptors.

About thirty years ago it was realized, from the work of i.a. Ted
Rall and John Daly, that caffeine, the most widely used of all
psychoactive drugs, is able to antagonize the effects of adenosine at
concentrations achieved during normal human consumption (see
Fredholm; 1980). This finding had several important implications: 1)
there are receptors at which adenosine is the agonist and caffeine the
antagonist; 2) since the antagonist is biologically active it should mean
that the receptors are activated by endogenous adenosine. This brief
overview, which reflects the contents of my introductory lecture at the
Academy, will present some of the data from my own laboratory
vindicating these conclusions. The interested reader is referred to other
more compendious reviews (Ferré, Fredholm, Morelli, Popoli and Fuxe;
1997, Fredholm, Bättig, Holmén, Nehlig and Zvartau; 1999,
Svenningsson, Le Moine, Fisone and Fredholm; 1999, Fredholm,
IJzerman, Jacobson, Klotz and Linden; 2001, Fredholm; 2002,
Svenningsson and Fredholm; 2002, Fredholm and Svenningsson; 2002
Submitted, Fredholm, Cunha and Svenningsson; 2003). I also need to

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