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VOL. 69 (4) ADENOSINE RECEPTORS

In parallell with the development of an increasingly clear understanding
of the biochemical and molecular underpinning of the adenosine-
dopamine interactions there has been extensive work on the effectiveness
of adenosine A2A antagonists in various experimental models of PD. It
will carry too far to try to present these results. However, a recent study
showed that A2A receptor antagonism could reduce not only symptoms of
PD, but also the loss of dopamine neurons induced by MPTP (Chen, Xu,
Petzer, Staal, Xu, Beilstein, Sonsalla, Castagnoli, Castagnoli Jr and
Schwarzschild; 2001). Furthermore, it was shown that in fact persistent
L-DOPA effects require A2A receptors (Fredduzzi, Moratalla, Monopoli,
Cuellar, Xu, Ongini, Impagnatiello, Schwarzschild and Chen; 2002).

Thus, over the years the concept that A2A and D2 receptors interact in such
a way that A2A antagonists could prove to be useful in PD has developed
strongly. There are however concerns. One potential concern is related to
tolerance. It is very well known that some actions of caffeine develop
rapid tolerance (Fredholm, Bättig, Holmén, Nehlig and Zvartau; 1999,
Svenningsson, Nomikos and Fredholm; 1999). However, caffeine effects
in PD models do not (Xu, Xu, Chen and Schwarzschild; 2002), and there
is also no tolerance to selective A2A antagonsts in models that show
tolerance to caffeine (Halldner, Lozza, Lindström and Fredholm; 2000).
Another, and perhaps more serious, concern is related to the fact that A2A
receptors regulate other things than activity in striatopallidal neurons. It
has long been known that adenosine regulates platelet activation (Haslam
and Cusack; 1981), and now we know that A2A receptors are responsible
for this (Ledent, Vaugeois, Schiffmann, Pedrazzini, El Yacoubi,
Vanderhaeghen, Costentin, Heath, Vassart and Parmentier; 1997).

Similarly A2A receptors are critically important in regulating neuttrophil
leucocyte activity (Cronstein; 1994), and activity of macrophages. Even
more importantly A2A receptors do regulate inflammatory reactions in
general (Ohta and Sitkovsky; 2001). Therefore, long-term blockade of
adenosine A2A receptors might cause undesirable peripheral morbidity.

A potential way to attack this problem was afforded when it was
discovered that A2A receptors in striatum are coupled to Golf proteins
(Kull et al.; 2000), whereas on platelets, neutrophils and lymphocytes Gs

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