Effect of acute treatment with YM992 on extracellular serotonin levels in the rat frontal cortex.
(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.
Hatanaka
K
K
Neuroscience Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Japan. hatanaka@yamanouchi.co.jp
Yatsugi
S
S
Yamaguchi
T
T
D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D015283:Citalopram / Q000494:pharmacology; D003511:Cyclohexanols / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000737:chemistry / Q000187:drug effects; D005464:Fluorobenzenes / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology; D005625:Frontal Lobe / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*; D018490:Serotonin Agents / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014316:Tritium; D000069470:Venlafaxine Hydrochloride; D010133:p-Chloroamphetamine / Q000494:pharmacology
D000928:Antidepressive Agents; D003511:Cyclohexanols; D005464:Fluorobenzenes; D009025:Morpholines; D010880:Piperidines; D018490:Serotonin Agents; D012702:Serotonin Antagonists; D005473:Fluoxetine; D015283:Citalopram; D014316:Tritium; C105748:lubazodone hydrochloride; D012701:Serotonin; D010133:p-Chloroamphetamine; D000069470:Venlafaxine Hydrochloride; C079049:volinanserin