ABSTRACT-Behavioral effects of propentofylline and N6-(L-2-phenylisopropyl)-adenosine (PIA) were evaluated by operant behavior under a punishment situation, discrete shuttle avoidance response and ambulatory activity in mice. Propentofylline (3 mg/kg, s.c.) and PIA (0.01 mg/kg, s.c.) significantly decreased the punished response without producing a significant change in the non-punished response. Propentofylline and PIA reduced the increase in the punished response induced by caffeine (30 mg/kg) and diazepam (1 mg/kg). Propentofylline and PIA also reduced the increase of ambulation induced by caffeine. Furthermore, the single administration of propentofylline and PIA decreased the response rate and/or % avoidance in the discrete shuttle avoidance situation. However, the effective doses of propentofylline and PIA to reduce the ambulation-increasing effect of caffeine and to produce a change in the avoidance behavior were much higher than those effective for eliciting a significant change in the punished response. The present results suggest that there is an intimate interaction between central adenosine and benzodiazepine systems with regards to the change of punished response.