Male brain specific 11βHSD2-/- mice and floxed controls were individually housed in metabolic cages and basal water turnover assessed over 4 days. In separate studies mice were given access to 2 bottles containing water and 1.5% NaCl and salt preference measured over 7 days. The role mineralocorticoid receptor (MR) in salt appetite was evaluated using spironolactone s.c., 60mg per mouse. Urinary sodium was measured by flame photometry. Blood was collected from a cannula in the carotid artery under terminal anaesthesia (Inactin hydrate). Plasma sodium was measured by electrolyte analyzer. Basal water and sodium turnover and plasma sodium concentrations were not altered by the deletion of 11βHSD2 in the brain. When given access to NaCl brain specific 11βHSD2-/- mice displayed a significant salt preference, 70% of total fluid intake was accounted for by NaCl. Salt appetite was significantly reduced by MR blockade. Sodium was not retained in the null mice; increased salt intake resulted in significant natriuresis and polyuria. Deletion of 11βHSD2 in the brain, which is specifically expressed in the nucleus of the solitary tract (NTS) in mice (1), resulted in an increased salt appetite. Activation of MR is implicated since spironolactone significantly reduced NaCl intake. These data are the first demonstration of salt appetite occurring in the absence of sodium depletion and with normal renal function. They suggest that activation of MR on 11βHSD2 positive neurons in the NTS increases salt appetite.