Effect of an uptake inhibitor on serotonin metabolism in rat brain: studies with 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine (Lilly 110140).

Summary Lilly 110140 is an inhibitor of serotonin uptake by brain synaptosomes. In rats, it had no effect on brain levels of tryptophan, serotonin, dopamine, or norepinephrine, but it decreased 5-hydroxyindoleacetic acid (5HIAA) levels. The decrease in 5HIAA levels was dose-related over a 1–20 mg/kg i.p. dose range and persisted for at least 24 hrs after a 10 mg/kg dose of 110140. The decline in 5HIAA levels occurred mostly in the cerebral hemispheres and midbrain and apparently resulted from a reduced turnover of serotonin. Reduced turnover was indicated by a decreased rate of fall in brain serotonin levels after p-chlorophenylalamine was given to inhibit serotonin synthesis. Turnover rates calculated from the rate of 5HIAA accumulation in brain after probenecid injection were 0.18 μg/g/hr in control rats and 0.066 μg/g/hr in 110140-treated rats. The decline in serotonin turnover presumably is a compensatory mechanism occurring when receptor sites are overstimulated due to blockade of the reuptake (inactivation) of serotonin at the nerve synapse.