Effect of TA-0910, a novel thyrotropin-releasing hormone analog, on in vivo acetylcholine release and turnover in rat brain.
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.
Kinoshita
K
K
Pharmaceutical Development Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
Kawashima
K
K
Kawashima
Y
Y
Fukuchi
I
I
Yamamura
M
M
Matsuoka
Y
Y
D015107:4-Butyrolactone / Q000494:pharmacology; D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D018697:Nootropic Agents / Q000494:pharmacology*; D010830:Physostigmine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013972:Thyrotropin / Q000494:pharmacology*; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology
D002800:Cholinesterase Inhibitors; D018757:GABA Modulators; D018697:Nootropic Agents; C065049:TA 0910; D013973:Thyrotropin-Releasing Hormone; D013972:Thyrotropin; D010830:Physostigmine; D000109:Acetylcholine; D015107:4-Butyrolactone