Effect of a selective 5-HT uptake inhibitor--Lu 10-171--on rat brain 5-HT turnover.

Changes in endogenous concentrations of 5-HT and 5-HIAA as well as 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 to 24 hours after treatment, whereas that of 5-HT was practically unchanged, indicating decreased turnover of 5-HT in the brain. This was confirmed using three 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 parachlorophenylalanine (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. By and large the results are consistent with the proposed negative feed-back regulation of 5-HT neuronal firing rate due to the abundance of 5-HT at postsynaptic receptors after inhibition of the reuptake mechanism.