A common signaling pathway for striatal NMDA and adenosine A(2a) receptors: Implications for the treatment of Parkinson's disease

The striatum is the major input region of the basal ganglia, playing a pivo tal role in the selection, initiation, and coordination of movement both ph ysiologically and in pathophysiological situations such as Parkinson's dise ase. In the present study, we characterize interactions between NMDA recept ors, adenosine receptors, and cAMP signaling within the striatum. Both NMDA (100 mu M) and the adenosine A(2a) receptor agonist CPCA (3 mu M) increase d cAMP levels (218.9 +/- 19.9% and 395.7 +/- 67.2%, respectively; cf. basal ). The NMDA-induced increase in cAMP was completely blocked when slices wer e preincubated with either the NMDA receptor antagonist 7-chlorokynurenate or the adenosine A(2) receptor antagonist DMPX (100 mu M), suggesting that striatal NMDA receptors increase cAMP indirectly via stimulation of adenosi ne A(2a) receptors. Thus, NMDA receptors and adenosine A(2a) receptors migh t share a common signaling pathway within the striatum. In striatal slices prepared from the 6-hydroxydopamine-lesioned rat model of Parkinson's disea se, NMDA receptor-mediated increases in cAMP were greater on the lesioned s ide compared with the unlesioned side (349.6 +/- 40.2% compared with 200.9 +/- 21.9% of basal levels, respectively). This finding substantiates previo us evidence implicating overactivity of striatal NMDA receptors in parkinso nism and suggests that a common NMDA receptor-adenosine A(2a) receptor-cAMP signaling cascade might be an important mechanism responsible for mediatin g parkinsonian symptoms.