title: LY393558, a 5-hydroxytryptamine reuptake inhibitor and 5-HT(1B/1D) receptor antagonist: effects on extracellular levels of 5-hydroxytryptamine in the guinea pig and rat.
abstract: The stimulation of terminal 5-HT(1B/1D) autoreceptors limits the effects of selective serotonin reuptake inhibitors on extracellular levels of 5-hydroxytryptamine (5-HT, serotonin) in vivo. Microdialysis studies show that acute oral administration of LY393558-a 5-HT reuptake inhibitor and antagonist at both the human 5-HT(1B) and 5-HT(1D) receptor-in the dose range 1-20 mg/kg, increases extracellular levels of 5-HT in both the guinea pig hypothalamus and rat frontal cortex. In both species, the levels of 5-HT that were attained were higher than following an acute, maximally effective dose of fluoxetine (20 mg/kg orally), reaching approximately 1500% in the guinea pig hypothalamus and 700% in the rat frontal cortex. In both species, the response to LY393558 (10 mg/kg p.o.) was impulse dependent, being absent in the presence of tetrodotoxin delivered at 1 microM via the microdialysis probe. The sensitivity to tetrodotoxin contrasted with the effects seen with DL-fenfluramine. Studies in rats showed that the microdialysate 5-HT concentration achieved in the frontal cortex after an acute challenge with LY393558 (5 mg/kg p.o.) was significantly greater than following a chronic regime of fluoxetine treatment (10 mg/kg/day orally for 21 days). Moreover, in rats chronically treated with LY393558 (5 mg/kg/day orally for 21 days), the mean basal concentration, 24 h after the final pretreatment dose, was of the same magnitude as that following chronic fluoxetine. However, in contrast to the response seen in fluoxetine-pretreated animals, a challenge dose of LY393558 still elicited a further increase in extracellular 5-HT in LY393558-pretreated animals. LY393558 is a potent 5-HT reuptake inhibitor and 5-HT(1B/1D) receptor antagonist. Microdialysis studies show that acute oral administration increases extracellular levels of 5-HT, by an impulse-dependent mechanism, above those produced by a maximally effective dose of fluoxetine, and in rats to levels only achieved following chronic fluoxetine treatment. Its neurochemical profile in vivo suggests that it may be a more effective antidepressant with the potential for producing an earlier onset of clinical activity than selective serotonin reuptake inhibitors.
authors.affiliation: Eli Lilly and Company Ltd., Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK. mitchell_stephen@lilly.com
authors.forename: S N
authors.initials: SN
authors.lastname: Mitchell
authors.forename: R G
authors.initials: RG
authors.lastname: Greenslade
authors.forename: J
authors.initials: J
authors.lastname: Cooper
mesh_terms: D000284:Administration, Oral; D000818:Animals; D003499:Cyclic S-Oxides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D005277:Fenfluramine / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008297:Male; D010069:Oxadiazoles / Q000494:pharmacology; D017374:Paroxetine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013779:Tetrodotoxin / Q000494:pharmacology; D013829:Thiadiazines / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D003499:Cyclic S-Oxides; D005277:Fenfluramine; D005473:Fluoxetine; D010069:Oxadiazoles; D017374:Paroxetine; D010879:Piperazines; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D012701:Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; D013779:Tetrodotoxin; D013829:Thiadiazines; C446282:LY 393558; C090701:GR 127935