Effect of a Selective 5‐HT Uptake Inhibitor ‐ Lu 10‐171* ‐ on Rat Brain 5‐HT Turnover

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Abstract
Changes in endogenous concentrations of 5-HT [serotonin] and 5-HIAA [5-hydroxyindoleacetic acid] and the turnover rate of 5-HT was studied in rat brain after treatment with a new potent and selective inhibitor of the neuronal 5-HT reuptake mechanism, Lu 10-171 (1-(3-(dimethylamino)propyl)-1-(p-fluorophenyl)-5-phthalancarbonitrile). After a single dose of Lu 10-171 the concentration of 5-HIAA was reduced from 1-24 h after treatment, whereas that of 5-HT was practically unchanged, indicating decreased turnover of 5-HT in the brain. This was confirmed using 3 different methods for measuring 5-HT turnover. Thus the rate of 5-HIAA accumulation in the brain after probenecid was reduced after Lu 10-171. Likewise treatment with Lu 10-171 led to a decreased fall in 5-HT and an increased fall in 5-HIAA after inhibition of 5-HT synthesis with p-chlorophenylalanine (PCPA). Unexpectedly Lu 10-171 did not change either the accumulation of 5-HT or the decrease in 5-HIAA after inhibition of MAO with pargyline. The proposed negative feedback regulation of the 5-HT neuronal firing rate due to the abundance of 5-HT at postsynaptic receptors after inhibition of the reuptake mechanism was supported.