Gravid rats were treated with methadone, 10 mg/kg/day, or vehicle, from day 5 of gestation to term. The offspring were nursed by foster mothers receiving either methadone or vehicle to form 4 groups: (A) methadone during gestation and lactation, (B) methadone during gestation, (C) methadone during lactation, and (D) no drug treatment. Brain monoamines and metabolites were examined at 21 days of age and found to be decreased in groups A and B. Animals treated comparably to group B and sacrificed at 90 days of age showed no abnormalities in brain monoamines excepting a decrease in dopamine metabolites in limbic areas. Another group treated in utero with methadone was tested at 90 days fo age for shuttle-box avoidance acquisition using massed trials. Methadone-exposed subjects exhibited more avoidances, escapes and intertrial shuttles than controls by the third day of training. These results suggest that subtle but lasting changes in limbic dopamine functions as a consequence of fetal exposure to methadone may make rats hyper-responsive in a massed-trial avoidance procedure in the shuttle-box.