The striatum is the major input region of the basal ganglia, playing a pivotal role in the selection, initiation, and coordination of movement both physiologically and in pathophysiological situations such as Parkinson's disease. In the present study, we characterize interactions between NMDA receptors, adenosine receptors, and cAMP signaling within the striatum. Both NMDA (100 μm) and the adenosine A2areceptor agonist CPCA (3 μm) increased 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 were preincubated with either the NMDA receptor antagonist 7-chlorokynurenate or the adenosine A2receptor antagonist DMPX (100 μm), suggesting that striatal NMDA receptors increase cAMP indirectly via stimulation of adenosine A2areceptors. Thus, NMDA receptors and adenosine A2areceptors might share a common signaling pathway within the striatum. In striatal slices prepared from the 6-hydroxydopamine-lesioned rat model of Parkinson's disease, NMDA receptor-mediated increases in cAMP were greater on the lesioned side compared with the unlesioned side (349.6 ± 40.2% compared with 200.9 ± 21.9% of basal levels, respectively). This finding substantiates previous evidence implicating overactivity of striatal NMDA receptors in parkinsonism and suggests that a common NMDA receptor–adenosine A2areceptor–cAMP signaling cascade might be an important mechanism responsible for mediating parkinsonian symptoms.