Lack of behavioral tolerance by repeated treatment with taltirelin hydrate, a thyrotropin-releasing hormone analog, in rats.
In order to determine whether acute tolerance develops by taltirelin hydrate ((-)-N-[(S)-hexahydro-1-methyl-2,6-dioxo-4-pyrimidinylcarbonyl]-l-histidyl-l-prolinamide tetrahydrate; taltirelin), a thyrotropin-releasing hormone (TRH) analog, we examined the motor behavior, TRH receptors and dopamine D(2) receptors following 2 weeks treatment in rats. Taltirelin selectively bound to TRH receptors and increased the spontaneous motor activity by a single administration, suggesting that the motor effect of taltirelin is mediated by TRH receptors. Following repeated treatment with TRH, there was a significant reduction in the increment of spontaneous motor activity. In contrast, after repeated treatment with taltirelin at a dose that increased the motor activity to a similar extent to TRH by a single administration, there was no apparent change in its motor effect. In accord with the motor activity, we found a significant reduction in the [(3)H]methyl-TRH binding to TRH receptors in the brain following repeated treatment with TRH but not taltirelin. However, the [(3)H]spiperone binding to dopamine D(2) receptors in the corpus striatum did not change by repeated taltirelin and TRH treatments. Thus, the down-regulation of TRH receptors would be a main cause of the behavioral tolerance. These results suggest that taltirelin hardly develops the behavioral tolerance due to the lack of down-regulation of TRH receptors.
Asai
Hidetoshi
H
Pharmacology Research Laboratories, Tanabe Seiyaku Co., Ltd., Toda-shi, Saitama, Japan. h-asai@tanabe.co.jp
Asahi
Toshio
T
Yamamura
Michio
M
Yamauchi-Kohno
Rikako
R
Saito
Akira
A
D000223:Adaptation, Psychological / Q000187:drug effects*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D018025:Receptors, Thyrotropin-Releasing Hormone / Q000378:metabolism; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology*
D017448:Receptors, Dopamine D2; D018025:Receptors, Thyrotropin-Releasing Hormone; C065049:TA 0910; D013973:Thyrotropin-Releasing Hormone