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VOL. 69 (4) ADENOSINE RECEPTORS

the brain including caudate-putamen and tuberculum olfactorium, but not
in other brain areas. This suggested that these parts of the brain might
have a different set of adenosine receptors than other brain areas.

This contention received support during the following decade as methods
to study receptors using binding techniques were developed. The first
studies used relatively non-selective radioligands but pharmacological
means to discriminate between multiple binding sites Lee). Later studies
used a rather selective ligand for A2A receptors, including CGS 21680,
(Alexander and Reddington; 1989, Jarvis, Jackson and Williams; 1989,
Jarvis, Schulz, Hutchison, Do, Sills and Williams; 1989, Parkinson and
Fredholm; 1990). Altogether these studies vindicated the belief that a
special form of adenosine receptors, the A2A receptor, is enriched in
dopamine rich areas of the brain and that this offers a rationale for
examining the role of adenosine in mediating or modulating behaviours
and traits traditionally associated with dopamine.

The availability of more selective adenosine receptor agonists and
antagonists also enforced the idea that behavioral consequences of
adenosine-A2 and dopamine-receptor mediated effects tended to be
opposite (Fredholm, Herrera-Marschitz, Jonzon, Lindström and
Ungerstedt; 1983, Heffner, Wiley, Williams, Bruns, Coughenour and
Downs; 1989, Brown, Gill, Evenden, Iversen and Richardson; 1991).

The interactions between adenosine and dopamine receptors in striatum
continued to be studied at the biochemical level. The A2A receptor being
coupled to a member of the Gs family of G proteins, and the D2 receptor
being coupled to a Gi protein would interact negatively at the level of
second messengers and beyond. It was demonstrated that there were
interactions between adenosine A2A receptors at several levels. Using
binding it was found that high affinity binding of D2 agonists could be
reduced by stimulation of adenosine A2A receptors (Ferré, von Euler,
Johansson, Fredholm and Fuxe; 1991). This finding suggested that there
were interactions directly between the receptors (Figure 2), an issue that
has been forcefully pursued by Kjell Fuxe and his colleagues.

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