Effect of acute treatment with YM992 on extracellular norepinephrine levels in the rat frontal cortex.
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.
Hatanaka
K
K
Neuroscience Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki, Japan. hatanaka@yamanouchi.co.jp
Yatsugi
S
S
Yamaguchi
T
T
D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; 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*; D009638:Norepinephrine / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D000069470:Venlafaxine Hydrochloride
D000928:Antidepressive Agents; D015283:Citalopram; D003511:Cyclohexanols; D005464:Fluorobenzenes; D005473:Fluoxetine; D009025:Morpholines; D009638:Norepinephrine; D010880:Piperidines; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; D000069470:Venlafaxine Hydrochloride; C105748:lubazodone hydrochloride; C079049:volinanserin