Acute behavioural stress has been recognized as a strong influence on the inducibility of hippocampal long-term synaptic plasticity. We have reported previously that in adult male rats, acute behavioural stress impairs long-term potentiation (LTP) but enhances long-term depression (LTD) in the hippocampal CA1 region. In this study we report that the effects of stress on LTP and LTD were reversed when animals were introduced into a novel 'stimulus-rich' environment immediately after the stress. Novelty exploration-induced reversal of stress effects was prevented when the animals were given the NMDA receptor antagonist D-(-)-2-amino-5-phosphonopentanoic acid, the cholinergic antagonist atropine and the protein phosphatase (PP) 2B inhibitors cyclosporin A and cypermethrin, but not the alpha1-adrenergic antagonist prazosin, the beta-adrenergic antagonist propranolol or the PP1/2A inhibitor okadaic acid, respectively before being subjected to the novel environment. In addition, the ability of novelty exploration to reverse the stress effects was mimicked by a direct application of the cholinergic agonist carbachol. Exposure to the novel environment following stress was accompanied by the activation of both PP2B and striatal-enriched tyrosine phosphatase (STEP). Taken together, these findings suggest that the activation of the cholinergic system and, in turn, the triggering of an NMDA receptor-mediated activation of PP2B to increase STEP activity appear to mediate the novelty exploration-induced reversal of stress-related modulation of hippocampal long-term synaptic plasticity.