Kiyoshi Kinoshita (1), Kazutaka Kawashima (2), Yumiko Kawashima (3), Isao Fukuchi (1), Michio Yamamura (4) and Yuzo Matsuoka (4)
(1) Pharmaceutical Development Research Laboratory, (2) Analytical Laboratory, (3) Lead Generation Research Laboratory and (4) Lead Optimization Research Laboratory, Tanabe Seiyaku Co., Ltd., Kawagishi 2-2-50, Toda, Saitama 335, Japan
Abstract: To examine the action of a novel thyrotropin-releasing hormone (TRH) analog, TA-0910 ((-)-N-[(S)-hexahydro-1-methyl-2,6-dioxo-4-pyrimidinylcarbonyl]- L-histidyl-L-prolinamide tetrahydrate), on the cerebral cholinergic systems, the release of acetylcholine (ACh) and choline in freely-moving rats and ACh accumulation in gamma-butyrolactone (GBL, a nerve impulse flow blocker)- and physostigmine-treated rats were examined. TA-0910 (0.1 - 1 mg/kg, i.p.) caused a marked dose-dependent increase in extracellular ACh levels and a decrease in choline levels in the hippocampus of freely moving rats. These effects were significantly stronger and longer-lasting than similar effects of TRH. TA-0910 (1, 3 mg/kg, i.p.) depressed the ACh accumulation in the cerebral cortex and hippocampus of GBL (1000 mg/kg, i.p.)-treated rats. Moreover, this analog (1, 3 mg/kg, i.p.) increased the accumulation rate of ACh in these regions in physostigmine (1 mg/kg, i.p.)-treated rats. TRH (30 mg/kg, i.p.) affected the ACh accumulation only in the hippocampus of the GBL-treated rats. These results suggest that TA-0910 not only enhances the release of ACh, but also accelerates the ACh turnover, i.e., ACh release and synthesis, at the cholinergic neuronal terminals in normal rats.
TA-0910, Thyrotropin-releasing hormone, Microdialysis, Acetylcholine release,
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