REGULATION OF CEREBRAL SEROTONIN METABOLISM IN EXPERIMENTAL PHENYLKETONURIA.
Item
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Title
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REGULATION OF CEREBRAL SEROTONIN METABOLISM IN EXPERIMENTAL PHENYLKETONURIA.
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Identifier
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AAI8611391
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identifier
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8611391
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Creator
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WOLFE, JESSIE MINAN.
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Contributor
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O. Greengard
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Date
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1986
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Language
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English
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Publisher
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City University of New York.
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Subject
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Health Sciences, Pharmacology
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Abstract
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The cerebral 5-HT deficiency characteristic of phenylketonuric children was reproduced in 2-16 day old rats by the administration of a-methylphenylalanine (a-me) plus phenylalanine (phe). The similar decrease in 5-HT found in the fetuses of pregnant rats rendered hyperphenylalaninemic indicates that the deficiency of this neurotransmitter is also present during gestation.;The mechanism of action of a-me and of p-chlorophenylalanine (p-cpa), the alternative agent used in the production of animal models of phenylketonuria, was studied under various conditions. One type of common action is the competitive inhibition of cerebral tryptophan hydroxylase and tyrosine hydroxylase in vitro. Suppression of hepatic phenylalanine hydroxylase exemplifies the other type of action of these agents which, inoperative in vitro, is characterized by a slow (24 hours) onset and by the fact that restitution of normal activity awaits resynthesis of the enzyme. Cerebral tryptophan hydroxylase but not tyrosine hydroxylase was also found to be subject to such suppression and this second type of action, rather than competitive inhibition of the enzyme, was shown to account for the gradual diminution and slow recovery of the brain's 5-HT content that follows injection of a-me or p-cpa.;In contrast to a-me, p-cpa suppressed tryptophan hydroxylase activity even in the presence of severe hyperphenylalaninemia. In addition, it counteracted the cerebral tryptophan depleting effect of these high plasma phenylalanine levels. Therefore, the 5-HT deficiency in this model is due entirely to suppression of tryptophan hydroxylase. In contrast, the 5-HT deficiency in the a-me model for phenylketonuria, as in the human disease, is attributable to hyperphenylalaninemia per se since the tryptophan hydroxylase suppression became inoperative in the presence of hyperphenylalaninemia and a-me did not counteract the diminution of cerebral tryptophan caused by excess phenylalanine monopolizing the transport system for large neutral amino acids. Moreover, tryptophan injections specifically prevented the cerebral 5-HT deficiency in this model and did so despite the persistence of hyperphenylalaninemia. Analogous observations were made with tyrosine injections which prevented the catecholamine but not the 5-HT deficit.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
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Program
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Biomedical Sciences
