HYPERPHENYLALANINEMIA IN THE DEVELOPING RAT: BIOCHEMICAL AND BEHAVIORAL ALTERATIONS.
Item
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Title
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HYPERPHENYLALANINEMIA IN THE DEVELOPING RAT: BIOCHEMICAL AND BEHAVIORAL ALTERATIONS.
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Identifier
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AAI8319747
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identifier
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8319747
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Creator
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BRASS, CLIFFORD ALAN.
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Contributor
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Prof. Olga Greengard
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Date
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1983
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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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Biophysics, Medical
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Abstract
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Hyperphenylalaninemia was produced in neonatal rats through the use of injections of alpha-methylphenylalanine (AMPHE), an in vivo inhibitor of hepatic phenylalanine hydroxylase (PAH), and phenylalanine in order to mimic the human disease state phenylketonuria (PKU). This treatment caused cerebral catecholamine depletion in young animals which could be overcome by increased levels of tyrosine in the brain due to administered or endogenously formed tyrosine. Additionally, the first permanent biochemical (enzyme) change observed in any animal model of PKU, increased striatal dopa decarboxylase activity, is described in these same animals. Other changes observed in adult rats, who had been made hyperphenylalaninemic only during the suckling period of life, include hyperactivity, and permanent brain weight deficits, decreased T-maze performance and increased lateralization in spontaneous rotational activity in female animals. Also, normal male and female rats were found to rotate in a quantitatively different manner in response to amphetamine and apomorphine injections. The basis of these sexually dimorphic responses was explored through gonadal hormone manipulation. These studies were extended to study maternal PKU with the introduction of a new model of this disease based on the dietary introduction of AMPHE and phenylalanine to rat dams. Their fetuses had more than ten-fold elevations in plasma phenylalanine and incurred many of the same cerebral changes (decreased serotonin and branched chain amino acid content, increased phosphoserine phosphatase activity, decreased body and brain weights) as noted in the postnatal model of the disease. Also, developmental changes in the net transport of phenylalanine across the 'blood-brain barrier' are detailed. The clinical relevance of these findings for alternate modes of treatment of PKU, as well as their importance in understanding normal and pathologic brain development are discussed.
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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
