Although alpha7-receptors are considered the main target for neuroprotection, other receptor subtypes (alpha4beta2 or alpha3beta4) have also been implicated. Hence, we have used alpha7-transgenic mice, to study the hypothesis that alpha7-receptors play a dominant role in mediating neuroprotection in an in vitro model of ischemia. We have used rat and mouse hippocampal slices to establish the model of nicotinic neuroprotection against oxygen and glucose deprivation (OGD). Neuronal damage caused by OGD during 1 h plus 3 h re-oxygenation, was quantified by measuring lactate dehydrogenase (LDH) release from hippocampal slices. In rat hippocampal slices, OGD increased over twofold basal LDH release. Such increase was reduced when treated with 10-100 microM nicotine; maximal protection afforded by nicotine amounted to 46%. This neuroprotection was antagonized by the non-selective nicotinic receptor for acetylcholine (nAChR) blocker mecamylamine (10 microM). In hippocampal slices from wild-type control mice, nicotine (100 microM) decreased by 54.4% LDH release evoked by OGD plus re-oxygenation. In contrast, nicotine failed to exert neuroprotection in alpha7 knockout mice. This finding reinforces the view that the hippocampal neuroprotective effects of nicotine are predominantly linked to alpha7 receptors.