Gastrin acts via cholecystokinin-B/gastrin receptors to control histamine- and chromogranin A-producing ECL cells, which constitute the quantitatively predominant endocrine cell population in the acid-producing part of the rat stomach. Cholecystokinin-B receptor blockade is known to suppress the activity of ECL cells and to prevent their ability to respond to gastrin stimulation. The present study examines the reversibility of long-standing cholecystokinin-B receptor blockade of ECL cells. YM022, a potent and selective cholecystokinin-B receptor antagonist, was administered in a maximally effective dose by continuous subcutaneous infusion for 4 weeks (via osmotic minipumps). The resulting receptor blockade was manifested in elevated serum gastrin concentration (due to the ensuing acid inhibition), while the serum pancreastatin concentration, oxyntic mucosal histidine decarboxylase activity, histidine decarboxylase- and chromogranin A- mRNA levels and histamine and pancreastatin concentrations were lowered. After withdrawal of YM022, all these parameters returned to normal after varying lengths of time. The serum gastrin concentration and the oxyntic mucosal histidine decarboxylase activity returned to normal within a week after termination of treatment. The serum pancreastatin concentration and the mucosal histidine decarboxylase- and chromogranin A-mRNA levels returned to normal within 2 weeks of drug withdrawal. The mucosal pancreastatin and histamine concentrations remained unchanged for about a week before gradually returning to control levels within the next two weeks. Hence, the various effects of cholecystokinin-B receptor blockade of the ECL cells are fully reversible within 1-3 weeks of drug withdrawal.