Novel modulatory mechanisms revealed by the sustained application of nicotine in the guinea‐pig hippocampus in vitro

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Abstract
The α7 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 α7 nAChRs, as it was inhibited by the α7 nAChR‐specific antagonist α‐bungarotoxin (100 nm), but not by mecamylamine (50 μm) or dihydro‐β‐erythroidine (DHβE; 1 μm) at concentrations known to be selective for non‐α7 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 μm). This blockade, however, unmasked a slowly developing nicotine‐induced potentiation of field excitatory postsynaptic potential that appeared to be dependent on both α7 nAChR activation and non‐α7 nAChR desensitisation. This secondary effect of nicotine was blocked by a combination of picrotoxin (50 μm) and saclofen (100 μm), and thus appeared to be mediated via GABAergic interneurons. The important implication of this study was that the sustained application of α7 nAChR agonists could modulate the conditions for synaptic plasticity through multiple transduction pathways, and not simply the inactivation of α7 nAChRs. These α7‐nAChR‐dependent mechanisms could reconcile the discrepancies between the previously reported behavioural versus electrophysiological effects of nicotine in the hippocampus.