Serum and brain levels of the tricyclic antidepressant drug imipramine (IMI) were studied in the rat under a variety of conditions. IV doses (range I nmol kg-1 to 15gmol kg -1, 350ng-5mg kg -1) and administered 5rain before death, were linearly correlated with IMI levels in serum, frontal cortex, and cerebellum. In this experiment, the highest levels of IMI were achieved in the frontal and occipital cortex and the lowest levels were found in the brain stem. The regional distribution was more even in rats pretreated with thiopental or 7-hydroxybutyric acid, drugs that alter cerebral blood flow. After 20rain or more, tracer amounts of IMI injected IV to IMI-pretreated rats [1 or 17 days, daily dose 2x36~tmolkg -1 (10mgkg-1), last dose 89gmolkg -1 (25 mg kg-1), 2-3 h before death] exhibited a distribution pattern in serum and various brain regions similar to that of the unlabeled drug. In the latter experiments, content (per volume) of the tracer or unlabeled IMI was more than 25-fold higher in various brain areas than in serum. It is concluded that despite large differences in drug levels in serum or brain, a close relationship is maintained under the conditions studied.