Hayashi Masahiro, Shirai Yoshitika, Bandoh Tsutomu, Iwamasa Kaori, Shindome Naomi, Hoshi Katsuji
Department of Clinical Pharmacology, Hokkaido College of Pharmacy, 7-1 Katsuraoka-cho, Otaru, Hokkaido 047-0264, Japan.
J Toxicol Sci. 2006 Aug;31(3):235-46. doi: 10.2131/jts.31.235.
The present studies sought to investigate the effect of tryptophan alone or coadministration of tryptophan and ethanol on the interaction of central frontal cortex and dorsal raphe nucleus serotonergic functional activities by utilizing in vivo microdialysis. Tryptophan (50 mg/kg, i.p.) led to a significant increase in the levels of 5-HIAA, a metabolite of serotonin (5-HT), in the dorsal raphe nucleus, but not in the frontal cortex. Coadministration of tryptophan and ethanol caused very marked increases in 5-hydroxyindoleacetic acid (5-HIAA) levels in both the frontal cortex and the dorsal raphe nucleus, although ethanol (1.25 g/kg) did not change 5-HIAA levels in both areas. Moreover, the application of WAY100635 (10 muM), 5-HT(1A) antagonist, into the frontal cortex after coadministration caused a marked increase in 5-HIAA levels in the frontal cortex and a decrease in the levels in the dorsal raphe nucleus, although WAY100635 alone had no effect on these levels. This may suggest that WAY100635-induced increase of 5-HIAA levels in the frontal cortex resulted from negative feedback following the blockade of serotonergic 5-HT(1A) autoreceptors, and that this increase in 5-HIAA levels decreased 5-HIAA levels in the dorsal raphe nucleus by preventing the activation of dorsal raphe 5-HT(1A) autoreceptors. WAY100635 into the dorsal raphe nucleus did not significantly change 5-HIAA levels in both areas. This may indicate that the blockade of dorsal raphe 5-HT(1A) autoreceptors by WAY100635 resulted in unchanged 5-HIAA levels in the frontal cortex. Behavioral sign of teeth-chattering was markedly observed following the coadministration and in combination with WAY100635. These results may suggest that the increased 5-HIAA levels in both areas after coadministration are indicative of the interrelation via activation of serotonergic neurons, and that the increased levels are partly responsible for behavioral activation of rats.
本研究旨在通过体内微透析技术，研究单独给予色氨酸或色氨酸与乙醇联合给药对中央额叶皮质和中缝背核血清素能功能活动相互作用的影响。色氨酸（50毫克/千克，腹腔注射）导致中缝背核中血清素（5-HT）的代谢产物5-羟吲哚乙酸（5-HIAA）水平显著升高，但额叶皮质中未出现此现象。色氨酸与乙醇联合给药导致额叶皮质和中缝背核中的5-羟吲哚乙酸（5-HIAA）水平均显著升高，尽管乙醇（1.25克/千克）并未改变这两个区域的5-HIAA水平。此外，联合给药后在额叶皮质中应用5-HT(1A)拮抗剂WAY100635（10微摩尔），导致额叶皮质中5-HIAA水平显著升高，中缝背核中5-HIAA水平降低，尽管单独使用WAY100635对这些水平没有影响。这可能表明，WAY100635诱导的额叶皮质中5-HIAA水平升高是由于血清素能5-HT(1A)自身受体被阻断后的负反馈作用，并且5-HIAA水平的这种升高通过阻止中缝背核5-HT(1A)自身受体的激活而降低了中缝背核中的5-HIAA水平。将WAY100635注入中缝背核并未显著改变这两个区域中的5-HIAA水平。这可能表明，WAY100635对中缝背核5-HT(1A)自身受体的阻断导致额叶皮质中5-HIAA水平未发生变化。联合给药并与WAY100635合用时，明显观察到牙齿打颤的行为迹象。这些结果可能表明，联合给药后两个区域中5-HIAA水平的升高表明通过血清素能神经元的激活存在相互关系，并且升高的水平部分导致了大鼠的行为激活。
