Effects of a novel thyrotropin-releasing hormone analogue, JTP-2942, on extracellular acetylcholine and choline levels in the rat frontal cortex and hippocampus.
The effects of a novel thyrotropin-releasing hormone (TRH) analogue, N alpha-[(1S,2R)-2-methyl-4-oxocyclopentanecarbonyl]-L-histidyl-L-pr olinamide (JTP-2942) on acetylcholine (ACh) release and on the extracellular choline level were investigated in rat frontal cortex and hippocampus by microdialysis, and were compared with effects of TRH. JTP-2942 (0.3 mg/kg i.p.) produced a marked (> 300%) and persistent increase of ACh release in both the frontal cortex and hippocampus, while TRH (3 mg/kg i.p.) caused a significant but transient increase of ACh to about 200% in the frontal cortex. Both drugs significantly decreased the choline levels in both brain regions. Investigation of the effects of JTP-2942 (0.001-1 mM) and TRH (1 and 10 mM) on ACh release and choline levels when perfused through the dialysis probe revealed that JTP-2942 had a greater effect than TRH in both the frontal cortex and the hippocampus. The action of JTP-2942 was about 1000-fold more potent than that of TRH in both brain regions. Oral administration of JTP-2942 at a dose of 10 mg/kg markedly and persistently increased the release of ACh and at doses of 1-10 mg/kg decreased the extracellular choline level in the frontal cortex and hippocampus. These results also suggest that JTP-2942 has some selectivity for the hippocampus compared to the frontal cortex after both systemic administration and local injection. The increase of ACh release caused by JTP-2942 was completely antagonized by perfusion with tetrodotoxin (TTX, 1 microM), suggesting that the action of JTP-2942 on cholinergic neurons was mediated via neuronal activity.
Toide
K
K
Department of Pharmacology, Japan Tobacco Inc., Kanagawa.
Shinoda
M
M
Takase
M
M
Iwata
K
K
Yoshida
H
H
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D002794:Choline / Q000378:metabolism*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism*; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007858:Learning / Q000187:drug effects; D008297:Male; D008568:Memory / Q000187:drug effects; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D013779:Tetrodotoxin / Q000494:pharmacology; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology
C080784:JTP 2942; D013779:Tetrodotoxin; D013973:Thyrotropin-Releasing Hormone; D002794:Choline; D000109:Acetylcholine