During stimulated neurosecretion in the rat, oxytocin neurons display a reduced glial coverage and receive an increased number of synapses, changes that are reversed on arrest of stimulation. We identified polysialic acid on the neural cell adhesion molecule (NCAM) as an important mediator of such plasticity. To investigate further the role of this cell surface glycoprotein, we examined the oxytocin system in mice genetically deficient in NCAM. First, ultrastructural analyses revealed that in wild-type mice, the supraoptic nucleus (SON) underwent the same remodelling as in the rat because oxytocin neurons had a diminished astrocytic coverage and increased synaptic input during lactation or chronic salt loading. Surprisingly, the SON displayed this morphology in NCAM-deficient mice as well, whether they were nongestating and hydrated, lactating or dehydrated. The oxytocin system in NCAM-deficient mice was abnormally hyperactive, as illustrated by enhanced plasma and intranuclear concentrations of oxytocin and reduced anxiety-related behaviour. Plasma oxytocin concentrations were also high in lactating NCAM-deficient dams but certain parameters of lactation and maternal behaviour were impaired. NCAM-deficient mice survived ingestion of 2% saline for 7 days and had increased plasma oxytocin but they did not cope with more severe osmotic challenges. Our observations highlight further the remarkable capacity of the adult oxytocin system to undergo neuronal and glial remodelling whenever it is activated. That lack of NCAM did not prevent remodelling indicates that NCAM can be substituted by other molecular mechanisms. Finally, while NCAM deficiency greatly enhanced oxytocin release, it led to impaired oxytocin-dependent physiological and behavioural responses.