Effect of acute treatment with YM992 on extracellular serotonin levels in the rat frontal cortex

• Published in: European journal of pharmacology 2000-04, Vol.395 (1), p.23-29
• Main Authors: Hatanaka, Ken-ichi, Yatsugi, Shin-ichi, Yamaguchi, Tokio
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Antidepressant; Antidepressive Agents - pharmacology; Biological and medical sciences; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Citalopram - pharmacology; Cyclohexanols - pharmacology; Dose-Response Relationship, Drug; Extracellular Space - chemistry; Extracellular Space - drug effects; Fluorobenzenes - pharmacology; Fluoxetine - pharmacology; Frontal Lobe - drug effects; Frontal Lobe - metabolism; Male; Medical sciences; Microdialysis; Morpholines - pharmacology; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; p-Chloroamphetamine - pharmacology; Pharmacology. Drug treatments; Piperidines - pharmacology; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Rats; Rats, Wistar; Selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor; Serotonin (5-hydroxytryptamine, 5-HT); Serotonin - metabolism; Serotonin Agents - pharmacology; Serotonin Antagonists - pharmacology; Serotoninergic system; Synaptosomes - drug effects; Synaptosomes - metabolism; Tritium; Venlafaxine; Venlafaxine Hydrochloride; YM992
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(00)00174-6

( 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-(+)-α-(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-μM 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.