5-Hydroxytryptophan rescues serotonin response to stress in prefrontal cortex of hyperphenylalaninaemic mice

Tiziana Pascucci, Diego Andolina, Immacolata La Mela, David Conversi, Claudio Latagliata, Rossella Ventura, Stefano Puglisi-Allegra, Simona Cabib

Research output: Contribution to journalArticlepeer-review


Adult early treated hyperphenylalaninaemic patients can show specific deficits of prefrontal cortical functions. The development of additional therapeutic strategies for these patients requires the understanding of the mechanisms involved in phenylalanine-dependent impairment of fronto-cortical functions. We tested the hypothesis of phenylalanine interference with aminergic neurotransmission in the prefrontal cortex by evaluating, in vivo, amine release in adult Pahenu2 mice, the genetic model of phenylketonuria. Mice of healthy background responded to a psychogenic stressor with the classic time-dependent increase of norepinephrine, dopamine and serotonin release from prefrontal cortical terminals. Neither the dopaminergic nor the serotoninergic responses were observable in the Pahenu2 mice. Temporary reduction of circulating phenylalanine, by phenylalanine-free diet without amino- acid supplement, promoted recovery of the serotonin response only, demonstrating direct interference with serotonin synthesis in the mature brain. Evaluation of different steps of serotonin synthesis in the prefrontal cortex of hyperphenylalaninaemic mice demonstrated inhibition of cortical tryptophan hydroxylase activity. Finally, systemic administration of 5-hydroxytryptophan, the product of tryptophan hydroxylase activity, allowed frontal cortical serotonin response to stress in hyperphenylalaninaemic mice. Collectively, these results demonstrate that hyperphenylalaninaemia interferes with the ability of the mature prefrontal cortex to respond to psychological challenges, point to serotonin synthesis as the target of phenylalanine interference, and support the use of 5-hydroxytryptophan in lifelong treatment of hyperphenylalaninaemic subjects.

Original languageEnglish
Pages (from-to)1067-1079
Number of pages13
JournalInternational Journal of Neuropsychopharmacology
Issue number8
Publication statusPublished - Sept 2009


  • Biogenic amines
  • Mental retardation
  • Microdialysis
  • PAH mice
  • Phenylketonuria
  • Prefrontal cortex

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Psychiatry and Mental health


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