title: Enhancement of noradrenaline release from rat frontal cortex by thyrotropin releasing hormone and its analog, (3R,6R)-6-methyl-5-oxo-3-thiomorpholinylcarbonyl-L-histidyl-L-prolinami de, as studied by intracerebral microdialysis.
abstract: The effects of thyrotropin-releasing hormone (TRH) and NS-3 [CG-3703: (3R,6R)-6-methyl-5-oxo-3-thiomorpholinylcarbonyl-L-histidyl-L- prolinamide], a metabolically stable analog of TRH, on the extracellular concentration of noradrenaline (NA) in the frontal cortex of urethane anesthetized rats were examined by using intracerebral microdialysis coupled with high-performance liquid chromatography with electrochemical detection. NS-3 (0.1 and 0.3 mg/kg i.v.) produced a significant increase in NA release. This effect reached to its peak 20 to 40 min (174% of basal level) after NS-3 (0.3 mg/kg) injection and exhibited a duration of 80 min. TRH (10 mg/kg i.v.) also significantly increased NA concentrations to the same extent as that produced by 0.3 mg/kg of NS-3, although the effect of TRH was transient. Blockade of NA reuptake by perfusion with desipramine (10(-7) M) caused a gradual increase in extracellular NA concentration. NS-3 at 0.3 mg/kg (i.v.) produced a significant elevation of NA concentrations after desipramine perfusion. When NS-3 (10(-6) and 10(-5) M) was perfused to the frontal cortex through the dialysis probe for 1 hr, no significant change in cortical NA concentration was observed. In contrast, perfusion of NS-3 (10(-5) M) through the dialysis probe implanted into the locus ceruleus induced a significant increase in the cortical NA release. These results suggest that NS-3 is far more active than TRH in facilitating cortical NA release and that the locus ceruleus is one of sites of action of this drug.
authors.affiliation: Department of Pharmacology, Nippon Shinyaku Co., Ltd., Kyoto, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Itoh
authors.forename: T
authors.initials: T
authors.lastname: Ogasawara
authors.forename: A
authors.initials: A
authors.lastname: Yamazaki
authors.forename: Y
authors.initials: Y
authors.lastname: Ukai
authors.forename: A
authors.initials: A
authors.lastname: Miura
authors.forename: K
authors.initials: K
authors.lastname: Kimura
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004563:Electrochemistry; D005625:Frontal Lobe / Q000187:drug effects* / Q000378:metabolism; D008125:Locus Coeruleus / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: C031926:montirelin; D013973:Thyrotropin-Releasing Hormone; D009638:Norepinephrine