We used the hippocampal slice to examine extracellular electrophysiological responses to nicotine and the difference in sensitivity to nicotine-induced electrophysiological effects between the DBA and C3H mouse strains. Nicotine enhanced CA1population spikes (PS) evoked by Schaffer collateral stimulation in a concentration-dependent manner (100μM to 3.2 mM). This enhancement was slow to appear, achieving a maximum after 15 min. The enhanced PS was accompanied by the development of epileptiform activity (multiple PS's) at nicotine concentrations≥400μM. Slices from DBA mice were significantly more sensitive than those from the C3H strain to these electrophysiological effects of nicotine. Mecamylamine (400μM) blocked both the nicotine-induced PS enhancement and secondary population spikes in both strains, suggesting the involvement of nicotinic cholinergic receptors.