The effects of purinoceptor subtypes on hippocampal extracellular serotonin levels were determined by using in vivo microdialysis. Perfusion with adenosine-5′-triphosphate (ATP) for 20 min produced concentration-dependent changes in hippocampal extracellular serotonin levels, which consisted of an initial rise phase, with levels increasing to 309% of control with 100 μM ATP, followed by a later rebound reduction phase, with levels decreasing to 6% of control. The P2X 1-7 active P2 purinoceptor agonist, 2-methylthioATP (2-MeSATP: 100 μM) increased the extracellular serotonin level drastically (638%), while the P2X 1,3 active P2 purinoceptor agonist, α,β-methylene- l-ATP (α,β-meATP: 100 μM) produced a small increase (132%) in the serotonin level. The P2X 1,2,3,5,7 active P2 purinoceptor antagonist, suramin (100 μM), reduced the basal serotonin level (86%) and the ATP-evoked initial rise phase (from 309 to 254%) without affecting the late reduction phase. The adenosine A 1 receptor antagonist, 8-cyclopentyl-1,3-dimethylxanthine (CPT: 50 μM) potentiated the rising phase (167%) and abolished the subsequent ATP-evoked reduction phase. Perfusion with CPT and an adenosine A 2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX: 10 μM), reduced the ATP-evoked initial rise (to 181%) and abolished the late reduction phases of serotonin release. These results indicate that ATP-evoked hippocampal serotonin release is composed of an initial rise phase and a later reduction phase. The ATP-evoked initial rise phase might be produced by an activation of P2X purinoceptor function, whereas the late reduction phase was modulated by the activation of adenosine A 1 receptor function by adenosine, metabolized from ATP in the synaptic cleft.