Abstract To determine if chronic haloperidol (3.0 mg/kg per day) or chlorpromazine (4.2 mg/kg per day) treatment alters central β-endorphin metabolism, haloperidol and chlorpromazine were perfused via Alzet TM minipumps into male Sprague-Dawley rats for 8 days. Crude twice-washed membranes, purified synaptic plasma membranes and Golgi-enriched membranes, respectively, were isolated from rat brains and time course incubated with β-endorphin. All samples were analyzed by high resolution, reversed-phase high performance liquid chromatography. The half-lives of β-endorphin for animals treated with haloperidol or chlorpromazine were not statistically different from control animals at the crude washed membranes. At the purified synaptic plasma membranes, however, the half-lives of β-endorphin from haloperidol ( t 1 2 = 45.1 min )- and chlorpromazine ( t 1 2 = 47.0 min )-treated animals were significantly decreased as compared to the control animals ( t 1 2 = 78.0 min ). The half-life of β-endorphin at the Golgi-enriched membranes was increased for haloperidol ( t 1 2 = 112.3 min ) and chlorpromazine ( t 1 2 = 103.0 min )-treated animals when compared to control animals ( t 1 2 = 80.2 min ). The findings indicate a differential effect of the dopamine receptor antagonists haloperidol and chlorpromazine on the extracellular fate at the synaptic plasma membranes of β-endorphin and the intracellular processing at the Golgi-enriched membranes in vitro.