Page 140 - 69_04

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

striatopallidal neurons. Subsequently, we developed a method to reliably
detect DARPP-32 phosphorylation in vivo and could demonstrate that the
A2A antagonist used, SCH 58261, significantly counteracted the increase
in DARPP-32 phosphorylation that was observed following treatment
with selective D2 receptor antagonists (Svenningsson, Lindskog, Ledent,
Parmentier, Greengard, Fredholm and Fisone; 2000). Likewise, the ability
of D2 antagonists to increase DARPP-32 phosphorylation was
dramatically reduced in A2A receptor KO mice. These data therefore
provided further support for the notion that adenosine acting on A2A
receptors is an important mediator of establishing a basal cyclic AMP
level, which is necessary for many effects of dopamine’s action via D2
receptors. In order to address the involvement of DARPP-32 in the
behavioural actions of caffeine and selective adenosine A2A receptor
compounds, we administred such compounds to DARPP-32 KO and
studied effects on locomotor behaviour. As expected from the
biochemical data, it was found that the ability of CGS 21680 to induce
hypolocomotion was attenuated in DARPP-32 KO mice (Lindskog,
Svenningsson, Pozzi, Kim, Fienberg, Bibb, Fredholm, Nairn, Greengard
and Fisone; 2002). Similarly, the ability of caffeine and SCH 58261 to
induce hyperlocomotion was attenuated in DARPP-32 KO mice. In this
paper, an additional effect of A2A receptors on DARPP-32
phosphorylation was shown, namely that A2A agonism via cAMP-
dependent mechanisms increases the phosphorylation of Thr34-DARPP-
32, but decreases the phosphorylation at Thr75-DARPP-32. Conversely,
caffeine and SCH 58261 increase phosphorylation at Thr75-DARPP-32.
This site has recently been shown to be phosphorylated by Cdk5 and
when this happens DARPP-32 is converted into an inhibitor of PKA.
Thus, by increasing the phosphorylation of Thr75-DARRP-32, caffeine
and selective A2A receptor antagonists will further increase the inhibition
of PKA. This feed-forward mechanism, which is also utilized by D2
receptor agonists, will therefore potentiate the inhibitory influence of
adenosine on the cAMP/PKA/CREB/IEG signaling pathway in
striatopallidal neurons (Fig 1d).

A2A receptor antagonists and Parkinson´s disease

152