Whole-cell transmembrane currents of second-order neurones in the caudal part of the nucleus tractus solitarii (cNTS) of brainstem slices of the rat were recorded to analyse the effects of adenosine 5'-triphosphate (ATP) on: (1) EPSCs evoked by the solitary tract stimulation (eEPSCs) and (2) spontaneous EPSCs (sEPSCs). ATP (10-6 to 10-4 m) significantly reduced the amplitude of eEPSCs to 46.6 +/- 7.4 % and increased the frequency of sEPSCs to 268.0 +/- 71.5 % of the control without significant changes in sEPSC amplitude. These opposite effects of ATP on eEPSCs and sEPSCs were concurrently observed in about 80 % of cNTS neurones recorded. The reduction of eEPSC amplitude by ATP was similarly observed with the addition of an equimolar solution of adenosine but not with alpha,beta-methylene ATP and was suppressed by 8-cyclopentyltheophylline (CPT) and 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). Addition of pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) did not affect the reduction of eEPSC amplitude by ATP. The increase in sEPSC frequency by ATP remained under tetrodotoxin addition but was abolished in the presence of PPADS. It is suggested that ATP activates: (1) presynaptic adenosine A1 receptors, after being hydrolysed to adenosine, reducing evoked release of glutamate from the primary afferent terminals and (2) presynaptic P2X receptors on the axon terminals of intrinsic excitatory cNTS neurones facilitating spontaneous release of glutamate. This is the first evidence that ATP modulates excitatory synaptic inputs arising from distinct origins and converging on a single postsynaptic neurone in diametrically opposite directions through activation of distinct presynaptic purinoceptors.