SHIDOJI Yoshihiro The Department of Molecular biology, Toho Medical School, Lecturer, 医学部(医), 講師 (00111518)
SHIMURA Fumio ibid., Instructor, 医学部(医), 助手 (70111523)
山田 和彦 東京大学, 医学部(医), 助手 (60158178)
|Budget Amount *help
¥7,000,000 (Direct Cost: ¥7,000,000)
Fiscal Year 1989: ¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1988: ¥4,800,000 (Direct Cost: ¥4,800,000)
Rapid and extensive depletion of a brain neurotransmitter, serotonin(-5-HT), has been achieved in vivo with rats by intraperitoneal administration of tryptophan side chain oxidase I(TSO I) from Pseudomonas.
TSO entered the circulation, degraded tryptophan specifically, and, at maximal dose, decreases its level to 1% of the control within 1 h. As brain tryptophan, a 5-HT precursor, declined following the change in blood, the brain 5-HT started to decrease, and more than 90% was depleted at around 5h. In the whole brain level, no decrease of catecholamines was observed and the change in amino acid pattern was, if any, modest. Under the conditions above, the 5-HT depletion was maintained for up to 20-30 h and then returned to normal as TSO activity disappeared from the circulation. Time course, extent, and duration of depletion were TSO-dose dependent.
On these bases, we started the analysis of the metabolic and physiological responses towards this perturbation. The assessments of local turnovers and contents of 5-HT, catecholamines, and their metabolites by in vivo microdialysis and microdissection, respectively, indicated that the rates of decrease in 5-HT turnover were comparable in most of brain regions so far tested, except striatum, and the local 5-HT content virtually paralleled the local 5-HT turnover, which reportedly, reflected the 5-HT neuron activity in situ. Local responses of catecholamine systems were observed but variable depending on the regions.
When brain activities upon 5-HT depletion were monitored by cortical brain wave, circadian rhythm of sleep/waking states was lost, and, unlike p-chlorophenylalanine(PCPA)-induced insomnia, a hitherto undescribed pattern, thealternations of a slow spindle wave and a fast desynchronized wave at 1-2 min intervals, predominated. We tentatively suggest that this pattern is a prototype of sleep/waking cycle manifested by the brain free from regulation of 5-HT.