Yamamoto Toshifumi, Nakayama Tomomi, Yamaguchi Junji, Matsuzawa Maaya, Mishina Masayoshi, Ikeda Kazutaka, Yamamoto Hideko
Laboratory of Molecular Psychopharmacology, Graduate School of Nanobiosciences, Yokohama City University, 22-2 Seto, Kanazawa-Ku, Yokohama 236-0027, Japan.
Laboratory of Molecular Psychopharmacology, Graduate School of Nanobiosciences, Yokohama City University, 22-2 Seto, Kanazawa-Ku, Yokohama 236-0027, Japan.
Neurosci Lett. 2016 Jan 1;610:48-53. doi: 10.1016/j.neulet.2015.10.049. Epub 2015 Oct 28.
The present study aimed to investigate the involvement of the NMDA receptor (NMDAR) and/or nitric oxide (NO) pathway in ketamine-induced behavioral sensitization. Mice received repeated subcutaneous administration of ketamine (25mg/kg), once daily or once weekly for a total of five doses. Even three administrations of ketamine, daily or weekly, induced a rapid increase in locomotor activity in wild-type (WT), but not in GluN2D knockout (GluN2D-KO) mice. Furthermore, for WT mice receiving daily ketamine, elevated locomotor activity was maintained after a 1-month withdrawal period; however, this was not the case when ketamine was administered weekly. The effect of acute ketamine on nNOS activities was estimated with nicotinamide adenine dinucleotide hydrogen phosphate-diaphorase (NADPH-d) histochemistry. Ketamine rapidly increased the number of NADPH-d activated cells and strongly stained dendrites in the dorsal striatum and prefrontal cortex of WT mice, but not GluN2D-KO mice. These results suggest that ketamine-induced locomotor sensitization and nNOS activation in the frontal cortex-striatum neuronal circuit are positively correlated and that the NMDAR GluN2D subunit plays an important role in the acquisition and maintenance of ketamine-induced behavioral sensitization.
本研究旨在探讨N-甲基-D-天冬氨酸受体（NMDAR）和/或一氧化氮（NO）途径在氯胺酮诱导的行为敏化中的作用。小鼠接受氯胺酮（25mg/kg）重复皮下给药，每日一次或每周一次，共五剂。即使每日或每周三次给予氯胺酮，也会使野生型（WT）小鼠的自发活动迅速增加，但对谷氨酸N2D亚基敲除（GluN2D-KO）小鼠则无此作用。此外，对于每日接受氯胺酮的WT小鼠，在停药1个月后自发活动仍维持在较高水平；然而，每周给予氯胺酮时情况并非如此。用烟酰胺腺嘌呤二核苷酸磷酸黄递酶（NADPH-d）组织化学法评估急性氯胺酮对神经元型一氧化氮合酶（nNOS）活性的影响。氯胺酮可迅速增加WT小鼠背侧纹状体和前额叶皮质中NADPH-d激活细胞的数量以及强染色的树突，但对GluN2D-KO小鼠则无此作用。这些结果表明，氯胺酮诱导的额叶皮质-纹状体神经回路中的运动敏化和nNOS激活呈正相关，且NMDAR的GluN2D亚基在氯胺酮诱导的行为敏化的获得和维持中起重要作用。
