Nitric oxide (NO) has been proposed to down-regulate NMDA receptors (NMDA-Rs) in a homeostatic manner. However, NMDA-R-dependent NO synthesis also can cause excitotoxic cell death. Using bicuculline-stimulated hippocampal and cortical cell cultures, we have addressed the role of the brain-derived neurotrophic factor-NO pathway in NMDA-R down-regulation. This pathway protected cortical cells from NMDA-induced death and led to NMDA-R inhibition. In contrast, no evidence was gained for the presence of this protective pathway in hippocampal neurons, in which NMDA-induced NO synthesis was confirmed to be toxic. Therefore, opposing effects of NO depended on the activation of different signalling pathways. The pathophysiological relevance of this observation was investigated in synaptosomes and post-synaptic densities isolated from rat hippocampi and cerebral cortices following kainic acid-induced status epilepticus. In cortical, but not in hippocampal synaptosomes, brain-derived neurotrophic factor induced NO synthesis and inhibited NMDA-R currents present in isolated post-synaptic densities. In conclusion, we identified a NO-dependent homeostatic response in the rat cerebral cortex induced by elevated activity. A low performance of this pathway in brain areas including the hippocampus may be related to their selective vulnerability in pathologies such as temporal lobe epilepsy.