The relationship between blood and brain levels of imipramine (IMI) and its demethylated and hydroxylated metabolites was studied in rats after chronic administration of IMI. It was found that the combined concentration of IMI and its metabolites was about 10-fold higher in brain than in plasma and this ratio was independent of the dose or the time of sacrifice. However, the brain-to-plasma ratio for the individual compounds varied with the time of sacrifice after the last IMI dose. The metabolite, didesmethylimipramine, was found in significant quantities in plasma and brain tissue with a distribution similar to that of desmethylimipramine. The hydroxylated metabolites constituted less than 6% of the combined concentration of IMI and its metabolites in plasma. Small amounts of 2-OH-desmethylimipramine were found in brain but 2-OH-IMI was rarely detected in cerebral tissue. With the exception of the hypothalamus, there were no significant differences in the distribution of IMI or its metabolites among various brain regions. The relationship between the concentrations of IMI or its active metabolites in plasma or brain and the extracellular availability of cerebral norepinephrine was also studied and found to be nonlinear: the concentration of norepinephrine in the cerebroventricular fluid approached a maximal value when the combined concentration of IMI and its metabolites was 10 micrograms/g in the brain or 1.5 micrograms/ml in plasma. Cerebroventricular application of IMI or each of its metabolites resulted in an increased concentration of both norepinephrine and dopamine in the cerebroventricular fluid whereas the concentrations of catecholamine metabolites remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)