INCREASED CEREBRAL EXCITABILITY CAUSED BY p‐CHLOROPHENYLALANINE IN YOUNG RATS

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Abstract
—Single intraperitoneal doses of p‐chlorophenylalanine (p‐CP; 100 mg/kg or more), lowered the threshold of flurothyl‐induced seizures in 1‐ and 2‐week old rats after 24 h, but not after 4 or 72 h. In older rats there was no change in cerebral excitability after a single dose, but the seizure threshold was lowered after several daily doses. Rats given p‐CP in lower doses daily from birth exhibited lowered seizure thresholds only until 3‐4 weeks of age.Depletion of brain serotonin and inhibition of liver phenylalanine hydroxylase by p‐CP exhibited time courses and dose responses similar to those reported for older animals. Activity of phenylalanine hydroxylase returned to normal more rapidly than the content of serotonin after a dose of p‐CP, and recovery of normal seizure threshold seemed to be more closely associated with recovery of the hepatic enzyme than with restoration of the brain amine. It appears, therefore, that hyperphenylalanemia or some consequence of it may be an important factor contributing to increased cerebral excitability in p‐CP intoxication and possibly in clinical phenylketonuria and that depletion of brain serotonin may not be the only or even the predominant cause of the changes in cerebral excitability in these conditions.