The effect of repeated s.c. administration of various neuroleptics (haloperidol, sulpiride and cis-flupentixol) on the in vivo release and metabolism of dopamine (DA) was studied in freely moving rats using trans striatal dialysis coupled to reverse-phase high-pressure liquid chromatography with electrochemical detection. Acute administration of neuroleptics dose-dependently but transiently stimulates DA release whereas lastingly stimulating DA metabolism. Administration of a second dose of neuroleptic, 4 to 12 hr after a priming dose, fails to stimulate DA release or stimulates it less effectively than in normal rats. A normal stimulatory response of DA release is reinstated when at least a 24-hr delay between the two doses is allowed. In contrast, the ability of the second neuroleptic dose to affect DA metabolism is unchanged. The results indicate that rapid tolerance takes place to neuroleptic-induced stimulation of DA release but not of DA metabolism.