Adenosine antagonists potentiate dopamine-mediated behaviours. A2a adenosine and D2 dopamine receptors are abundantly co-expressed within the striatopallidal subset of striatal neurons, suggesting that this is the site of interaction between A2a and D2 receptors. We show that the D2-dependent induction of the immediate early gene c-Fos occurs in striatopallidal neurons 3 h following injection of reserpine (10 mg/kg). We used this paradigm to test whether adenosine antagonists modulate D2-dependent activation of striatopallidal neurons. The non-selective A1-A2 adenosine antagonists theophylline (25 mg/kg) or 3,7-dimethyl-1-propargylxanthine (25 mg/kg) potentiated the effect of a submaximal dose of the D2 dopamine agonist quinpirole (0.05 mg/kg) to prevent the induction of striatal c-Fos following reserpine. Co-administration of the A2a receptor antagonist 8-(3-chlorostyryl) caffeine (5 mg/kg) with quinpirole (0.05 mg/kg) also attenuated striatal c-Fos induction following reserpine to a greater extent than 0.05 mg/kg quinpirole alone. When administered prior to reserpine, theophylline (25 mg/kg) or 3,7-dimethyl-1-propargylxanthine (25 mg/kg) partially attenuate the induction of striatal c-fos. These results demonstrate that systemic administration of adenosine antagonists enhance D2 dopamine receptor-dependent regulation of c-Fos in the striatopallidal pathway. These results support a functional interaction between A2a adenosine and D2 dopamine receptors in striatopallidal neurons.