piperidines and lubazodone-hydrochloride

(S)-2-[[(7-fluoroindan-4-yl)oxy]methyl]morpholine monohydrochloride (YM992) is a novel putative antidepressant exhibiting both selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibition and 5-HT(2A) receptor antagonism. In vivo microdialysis revealed that a single treatment with YM992 (3, 10, 30 mg/kg i.p.) dose-dependently increased extracellular 5-HT levels in the rat frontal cortex. Fluoxetine, citalopram and venlafaxine also produced significant increases in 5-HT levels at doses of 10-30 mg/kg. However, the increase in 5-HT levels induced by YM992 was significantly larger than increases elicited by these three compounds at 30 mg/kg. The combined administration of R-(+)-alpha-(2, 3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidine-methanol (MDL100,907) (a selective 5-HT(2A) receptor antagonist) and citalopram produced no additional increase in 5-HT levels compared with citalopram treatment alone. YM992 moderately enhanced [3H]5-HT release from rat cerebral cortex synaptosomes using different mechanisms than p-chloroamphetamine. In comparison, 10-microM fluoxetine markedly induced 5-HT release in vitro, while citalopram and venlafaxine had no noticeable effect on release. YM992 produces a more robust increase of 5-HT levels acutely than other antidepressants in vivo and the effect may be due to 5-HT releasing properties of the drug.

Topics: Analysis of Variance; Animals; Antidepressive Agents; Cerebral Cortex; Citalopram; Cyclohexanols; Dose-Response Relationship, Drug; Extracellular Space; Fluorobenzenes; Fluoxetine; Frontal Lobe; Male; Morpholines; p-Chloroamphetamine; Piperidines; Rats; Rats, Wistar; Serotonin; Serotonin Agents; Serotonin Antagonists; Synaptosomes; Tritium; Venlafaxine Hydrochloride

The effects of acute treatment with (S)-2-[[(7-fluoroindan-4-yl)oxy]methyl]morpholine monohydrochloride (YM992), venlafaxine, fluoxetine and citalopram on extracellular norepinephrine levels were examined in the rat frontal cortex by in vivo microdialysis. YM992 (3, 10, 30 mg/kg, i.p.) dose-dependently increased extracellular norepinephrine levels (3-fold at 10 mg/kg, 5. 5-fold at 30 mg/kg). While venlafaxine and 30 mg/kg fluoxetine also produced significant increases in norepinephrine levels, 30 mg/kg citalopram had no effect. The combined administration of MDL100,907 (a selective 5-HT(2A) receptor antagonist) and citalopram did significantly increase norepinephrine levels compared with either saline or citalopram treatment. Therefore, a synergistic effect due to 5-HT reuptake inhibition and 5-HT(2A) receptor antagonism of YM992 may partly contribute to the increase of extracellular norepinephrine levels. YM992 enhances the neurotransmission of not only 5-HT system but also norepinephrine, and as such may have a preclinical profile different from that of a selective serotonin reuptake inhibitor.

Topics: Analysis of Variance; Animals; Antidepressive Agents; Citalopram; Cyclohexanols; Dose-Response Relationship, Drug; Extracellular Space; Fluorobenzenes; Fluoxetine; Frontal Lobe; Male; Morpholines; Norepinephrine; Piperidines; Rats; Rats, Wistar; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists; Venlafaxine Hydrochloride