Alterations in nicotinic acetylcholine (nAChR) receptor number can be induced by chronic exposure to nicotine possibly by stabilization of the desensitized state(s) of the receptor. Since within the central nervous system (CNS), many nAChRs are localized presynaptically, we have investigated the physiological consequences of prolonged nicotine applications on spontaneous transmitter release. In the presence of glutamate receptor antagonists, bicuculline-sensitive spontaneous GABA inhibitory synaptic currents (IPSCs) could be readily resolved in whole-cell recordings from neurons in the interpeduncular nucleus (IPN) maintained as brain slices. Nicotine (300nM) caused a marked enhancement in the frequency of spontaneous events. During a 15min exposure to nicotine, the time course of changes in IPSC frequency could be divided into two groups. In most neurons, there was a fast increase in event frequency followed by a decline to a lower steady-state level that remained above baseline. In the remaining neurons, the effect of nicotine was more slowly developing and outlasted the application. Interestingly, the rapid effect was associated with a shift to higher amplitude events, whereas, no change in the IPSC amplitude histogram was observed during the slow onset effect. These data show that prolonged stimulation of presynaptic nicotinic receptors can have different outcomes that could potentially contribute to the diverse effects of nicotine on central information processing. © 2002 ISDN. Published by Elsevier Science Ltd. All rights reserved.