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.
D000818:Animals; D001921:Brain / Q000378:metabolism*; D010134:Fenclonine / Q000008:administration & dosage / Q000494:pharmacology; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008297:Male; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009570:Nitriles / Q000008:administration & dosage / Q000494:pharmacology*; D010293:Pargyline / Q000494:pharmacology; D011339:Probenecid / Q000008:administration & dosage / Q000494:pharmacology; D011437:Propylamines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000096:biosynthesis / Q000378:metabolism*; D013997:Time Factors
D008996:Monoamine Oxidase Inhibitors; D009570:Nitriles; D011437:Propylamines; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D010293:Pargyline; D011339:Probenecid; D010134:Fenclonine