On the mechanism of imipramine's influence in lowering p-hydroxyphenylglycol concentrations in the brain. The role of tyrosine.

Administration of imipramine (IMI) to rats was shown to lower after 4.5 hr the brain concentration of the octopamine metabolite p-hydroxyphenylglycol (pHPG) in a dose-dependent manner over the range of 10-40 mg/kg of IMI. Assay of plasma and brain levels of tyrosine revealed that IMI produced a reduction in both but with a shorter time-course than for the depletion in pHPG, with the maximal decreases occurring at 1.5 hr, before there was any loss of pHPG. The reductions in tyrosine and pHPG levels could not be explained by an effect of IMI on food intake, since the levels were diminished even in 24-hr fasted animals. When rats were injected with IMI 4.5 hr before 200 mg/kg of tyrosine and 5.5 hr before being killed, the elevation in brain pHPG levels were attenuated by about 50%, as compared to the animals that received tyrosine alone. These data suggest that the ability of IMI to lower brain pHPG probably involves two distinct mechanisms: (1) a lowering of brain and plasma tyrosine concentrations, and (2) an inhibition of the conversion of tyrosine to pHPG. It is unclear whether these effects are due to IMI itself or to one of its metabolites, such as desmethylimipramine or didesmethylimipramine, which were found in the plasma in amounts equal to or greater than IMI.