Cerebral serotonin regulation by phenylalanine analogues and during hyperphenylalaninemia.
Severe hyperphenylalaninemia induced in infant rats by 3 days of treatment with p-chlorophenylalanine (p-cl phe) plus phenylalanine (phe) did not lower the tryptophan concentration of the brain, and the cerebral serotonin (5-HT) deficiency was attributable entirely to the known suppression to tryptophan hydroxylase (TPH) by p-cl phe. The decrease in 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) was thus no more pronounced than in rats which, treated with p-cl phe alone, were devoid of hyperphenylalaninemia. Suppression of TPH was found to also underlie the decrease in cerebral 5-HT caused by treatment with alpha-methylphenylalanine (alpha-mephe) alone: a 22% loss of midbrain TPH activity was detectable 24 hr after an injection only, reverted toward the normal during the next 2 days, and was clearly unrelated to the weak competitive inhibition of the enzyme by alpha-mephe in vitro. However, alpha-mephe (unlike p-cl phe), when administered together with phe, did not suppress TPH, nor did it counterbalance the reduction of cerebral tryptophan uptake by excess phe. Thus the 5-HT diminution in the rat model of phenylketonuria produced by treatment with alpha-mephe plus phe was attributable to hyperphenylalaninemia and the inhibition of tryptophan transport to the brain. Injection of tryptophan was found to restore the cerebral 5-HT level in the face of persistently severe hyperphenylalaninemia.
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D010134:Fenclonine / Q000494:pharmacology*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000097:blood* / Q000494:pharmacology; D051381:Rats; D012701:Serotonin / Q000378:metabolism*; D014364:Tryptophan / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000037:antagonists & inhibitors
D012701:Serotonin; C012436:alpha-methylphenylalanine; D010649:Phenylalanine; D006897:Hydroxyindoleacetic Acid; D014364:Tryptophan; D014365:Tryptophan Hydroxylase; D010134:Fenclonine