The alpha 7 nicotinic acetylcholine receptor (nAChR) has been implicated widely in behavioural functions and dysfunctions related to the hippocampus, but the detailed mechanisms by which this receptor contributes to these behavioural processes have yet to be elucidated. In the present study, sustained application (5 min) of nicotine significantly lowered the threshold for synaptic plasticity, and thus a long-lasting potentiation was induced by a stimulus that would normally evoke only a short-term potentiation. This effect appeared to be mediated by alpha 7 nAChRs, as it was inhibited by the alpha 7 nAChR-specific antagonist alpha-bungarotoxin (100 nM), but not by mecamylamine (50 microM) or dihydro-beta-erythroidine (DH beta E; 1 microM) at concentrations known to be selective for non-alpha 7 nAChRs. Further pharmacological dissection revealed that the effect was also abolished by the NMDA receptor antagonist, D-(-)-2-amino-5-phosphonopentanoic acid (D-AP5; 50 microM). This blockade, however, unmasked a slowly developing nicotine-induced potentiation of field excitatory postsynaptic potential that appeared to be dependent on both alpha 7 nAChR activation and non-alpha 7 nAChR desensitisation. This secondary effect of nicotine was blocked by a combination of picrotoxin (50 microM) and saclofen (100 microM), and thus appeared to be mediated via GABAergic interneurons. The important implication of this study was that the sustained application of alpha 7 nAChR agonists could modulate the conditions for synaptic plasticity through multiple transduction pathways, and not simply the inactivation of alpha 7 nAChRs. These alpha 7-nAChR-dependent mechanisms could reconcile the discrepancies between the previously reported behavioural versus electrophysiological effects of nicotine in the hippocampus. Effects of sustained alpha 7 nAChR stimulation Effects of sustained alpha 7 nAChR stimulation Effects of sustained alpha 7 nAChR stimulation Effects of sustained alpha 7 nAChR stimulation Effects of sustained alpha 7 nAChR stimulation