|Budget Amount *help
¥6,000,000 (Direct Cost: ¥6,000,000)
Fiscal Year 1987: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 1986: ¥3,500,000 (Direct Cost: ¥3,500,000)
In this study we dealt with the metabolic/physiological significance of the steady state levels of substrates/metabolites in vivo, as a quantitative representation of "homeostasis" in life. Rather than impairment of functional units of the system such as enzymes/recepotrs, we abopted an experimental approach of the negative perturbation (in contrast to positive perturbation alike loading) of the steady statev per se by admunistration of appropriate degrading enzymes specific for compound of out concern. level Concurrently, we assessed metabolic/physiological responses of the organs with special reference to their transient characteristic.
The first target was blood aromatic amino acids, precursors of neurotransmitters in brain, two of them being essential amino aeids To degrade phenylalaning/tyrosine we purified phenylalanine ammonialyase (PAL) and for tryptophan, tryptophan side chain oxidase 1 (TSO 1), both to homogeneity. The results taken together revealed that PAL depleted blood Ph
e/Tyr efficiently followed by their decrease in brain, but no effect was found on catecholamine metabolism. This perturbation caused no change in amino acid pattern either in blood or brain, suggesting that these amino acids may be maintained constant in levels by a certain independent mechanism, and these level may notgserve as cues for the maintenance of amino acid pattern in vivo. On other hand, the steady state level of tryptophan was found to be crucial for brain functions/metabolism and also for maintenance of blood amino acid pattern. Concurrent with tryptophan depletion on administration of TSO 1, brain tryptophan simultaneously started to decrease followed by decrease in a neurotransmitter, serotonin. %-Hydroxyindole acetic acid(5-HIAA), an indicative of the serotonin neuron activity, also followd the time course of serotonin exactly. After several hours, serotonin-5-HIAA were reduced to 1/10 of the normal values representing that serotonin metabolism and serotonin neuron activity were virtually arrested simply bo restriction of an seeential amino acid in blood stream. Concurrent with this perturbation, sleep/waking pattern of rats were markedly changed;circadian rhythm was lost, and unique EEG appeared which likely represented a prototype of alternation of "consciousness.
Foregoing results clearyl indicated the presence of a system in which the steady state level of a blood constituent(other than fuels such as glucose or oxygen) couples with the brain function and thus the relevance of this kind of approach to homeostasis and its regulation in the whole body. Furthermore, these results opened a new perspective in central serotonin issues as yet not established. Less