ATP has been shown to excite neurons in various regions of the central nervous system. Whereas immunohistochemical studies show P2X receptors in the area postrema, the responsiveness of area postrema neurons to extracellular ATP has not been studied. To investigate the effects of purinoceptor activation on area postrema neuronal excitability, we performed whole-cell recordings from area postrema neurons in rat brain slices. Most area postrema neurons responded to ATP application, and most responses were excitatory. Voltage-clamp recordings showed three different types of response: (1) a postsynaptic or extrasynaptic excitatory response (inward currents; n=26/51 cells), (2) a presynaptic excitatory response (increased frequency of miniature excitatory postsynaptic currents with only a small direct postsynaptic current; n = 24/51 cells, or (3) a postsynaptic inhibitory response (outward current; n=1/51). The excitatory responses were found in both of the two major electrophysiological cell classes, i.e. cells displaying I-h and cells not displaying I-h, while the inhibitory responses were found in only cells not displaying I-h. Current-clamp recordings showed ATP-induced depolarization (n = 13/15) or hyperpolarization (n = 2/15) of membrane potential that modulated the frequency of action potentials. In the presence of CNQX, mEPSCs were abolished and bath-applied ATP did not generate mEPSCs, indicating that glutamate release was facilitated by the activation of presynaptically located ATP receptors. Our pharmacological results from studies with ATP, alpha beta me-ATP, beta me-ATP and PPADS indicate that the post- and/or extrasynaptic responses are most likely mediated by P2X(7) receptors and/or receptors composed of P2X(2) and P2X(5) subunits. We conclude that half of the presynaptic responses are most likely mediated by P2X(7) receptors and/or receptors composed of P2X(2) and P2X(5) subunits while the others also contain P2X(1) subunits. it is well known that P2X(7) subunit forms only homomultimeric P2X receptors. Finally, the present study suggests that purinoceptor activation may contribute to the control of several autonomic functions by area postrema neurons. (c) 2007 Elsevier B.V. All rights reserved.