title: Effects of a new analogue of thyrotropin-releasing hormone on pentobarbital-induced sleeping time in rodents.
abstract: The effects of a new analogue of TRH, YM-14673 (N-[[(S)-4-oxo-2-azetidinyl]carbonyl]-L-histidyl-L-prolinamide dihydrate) on pentobarbital-sleeping time were observed in comparison with those of TRH in rodents. The YM-14673 was administered intravenously, orally and intramuscularly. In all cases it reduced pentobarbital-sleeping time in rats and/or mice in a dose-dependent manner. The analeptic activity of YM-14673 was about 10 times greater than that of TRH. Analeptic action was also observed with successive intravenous injections of YM-14673, once daily for 5 and 14 days in mice, suggesting that the drug induced no tolerance. In addition, there was evidence that the pituitary-thyroid axis was not necessary for the analeptic effects of YM-14673. In particular, it was noted that hypophysectomy did not reduce the antagonism by YM-14673 of pentobarbital-induced sleep and intracerebrally administered YM-14673 produced analeptic actions in mice. Pretreatment with atropine and baclofen antagonized the ability of YM-14673 to reduce sleep, induced by pentobarbital in mice. However, the analeptic action of YM-14673 was not reduced by the administration of haloperidol and phentolamine. These results suggest that YM-14673 produced facilitatory effects on the central nervous system, independent of an effect on the pituitary gland, and that the antagonizing effects by YM-14673 on the actions of pentobarbital may be affected by activation of the central cholinergic system as well as by inhibition of the GABA-ergic system.
authors.affiliation: Department of Pharmacology, Central Research Laboratories, Yamanouchi Pharmaceutical Co. Ltd, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Yamamoto
authors.forename: M
authors.initials: M
authors.lastname: Shimizu
mesh_terms: D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001384:Azetidines / Q000494:pharmacology*; D001385:Azetines / Q000494:pharmacology*; D001418:Baclofen / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology*; D006220:Haloperidol / Q000494:pharmacology; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010424:Pentobarbital / Q000494:pharmacology; D010646:Phentolamine / Q000494:pharmacology; D051381:Rats; D012890:Sleep / Q000187:drug effects*; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors
chemical_list: D001384:Azetidines; D001385:Azetines; D004151:Dipeptides; D013973:Thyrotropin-Releasing Hormone; C054995:azetirelin; D001285:Atropine; D001418:Baclofen; D010424:Pentobarbital; D006220:Haloperidol; D010646:Phentolamine