Caffeine is the most widely consumed behaviorally active substance in the world. It exhibits a variety of stimulatory effects upon the CNS. In low doses, caffeine produces a state of behavioral arousal & increased alertness; higher concentrations may bring about CNS hyperexcitability characterized by restlessness & tremor, while toxic levels are associated in some cases with focal & generalized seizures (Dunwiddie et al. 1981). The mechanism(s) by which it produces these effects is not well understood although much is known of the role of caffeine in a number of well-defined pharmacological effects related to the blockade of adenosine receptors, inhibition of phosphodiesterases as well as caffeine-induced [Ca2+]i elevation in central neurons (Fredholm et al. 1999). The Na+/Ca2+-exchanger (NCX) in the plasma membrane of neurons appears to be the rapid extrusion of high concentrations of Ca2+ that has entered neurons through surface channels, or has been released from the endoplasmic reticulum (Annunziato et al. 2004). Thus, the aim of this work was to measure caffeine-induced NCX currents in isolated pyramidal neurons of the hippocampus. All experiments were performed in accordance with the guidelines set by the National Institutes of Health for the humane treatment of animals & the Animal Care Committee of Bogomoletz Institute of Physiology. The Wistar rats (P 14) were deeply anesthetized using sevoflurane & decapitated. The NCX currents were measured in acutely vibrodissociated CA1 & CA3 pyramidal neurons from hippocampal slices (400-500μm) using whole-cell patch-clamp technique (Vhold= -80 mV) in combination with extracellular solution switches. Values are means ± SEM, compared by Student`s t-test. Application of caffeine (10 mM, 5 sec) caused the inward current of maximal amplitude 50 ± 7 pA (n = 16) & 61 ± 7 pA (n = 9) in acutely isolated CA1 & CA3 pyramidal neurons respectively. These currents were suppressed by NCX mineral blocker Ni2+ (5 mM) on 87 ± 5 % (n = 20, p < 0.001). Cd2+ (15 uM – blocking concentration of voltage-gated calcium channel currents) didn`t decrease the caffeine-induced current. So, the observed caffeine-generated depolarizing current is associated with NCX activity in Ca2+ extrusion mode due to the electrogenic nature of a 3 Na+ for 1 Ca2+ exchange process. Thus, caffeine causes depolarization of hippocampal pyramidal neurons, a response which appears to be induced by activation of an inward Na+/Ca2+-exchange current, as Ca2+ is extruded through the Na+/Ca2+-exchanger, likely following local calcium release from intracellular stores.