The effects of dopamine on regulation of prolactin secretion were studied in female rhesus monkeys before cocaine exposure and again after 2 months to 2.7 years of daily cocaine self-administration. During chronic cocaine exposure, basal prolactin levels increased by 227 to 350% above drug-free control levels (P < .05). On each endocrine study day, three successive 80-min dopamine infusions (10 micrograms/kg/min i.v.) were alternated with 20-min interruptions of dopamine infusions to assess the degree of prolactin suppression and the magnitude of postdopamine prolactin increases. Dopamine significantly reduced prolactin below base-line levels within 60 to 80 min under all conditions (P < .05-.01). In four drug-naive follicular phase females, postdopamine increases in prolactin never exceeded predopamine base-line levels of 6.2 (+/- 1.8) ng/ml. After an average of 74 days of cocaine self-administration [3.7 (+/- 0.11) mg/kg/day], the postdopamine prolactin increases were significantly higher than during drug-free control conditions (P < .01) and reached hyperprolactinemic levels of 57.6 ng/ml. After an average of 300 days of cocaine self-administration [6.5 (+/- 0.06) mg/kg/day], postdopamine prolactin increases peaked at 339% above predopamine basal prolactin levels. After an average of 433 days of cocaine self-administration [6.45 (+/- 0.08) mg/kg/day] postdopamine prolactin increases remained significantly higher (P < .01) than during drug-free conditions. A similar pattern of postdopamine prolactin increases to hyperprolactinemic levels (ranging from 44.5 to 141.2 ng/ml) also were measured in two other females studied after 19 to 20 months of cocaine self-administration [6.21 (+/- 0.11) and 7.49 (+/- 0.17) mg/kg/day]. After 2.7 years of cocaine self-administration, one monkey developed persistent hyperprolactinemia and basal prolactin levels averaged 326 ng/ml after 89 days of cocaine abstinence. These data suggest that the prolactin secretory response to dopamine perturbation may provide a sensitive index of changes in dopaminergic regulation of prolactin during chronic cocaine exposure.