title: 5-Hydroxytryptophan rescues serotonin response to stress in prefrontal cortex of hyperphenylalaninaemic mice.
abstract: 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 Pah(enu2) 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 Pah(enu2) 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.
authors: Dipartimento di Psicologia and Centro 'Daniel Bovet', 'Sapienza' University, Rome, Italy. tiziana.pascucci@uniroma1.it
authors: Tiziana
authors: T
authors: Pascucci
authors: Diego
authors: D
authors: Andolina
authors: Immacolata La
authors: IL
authors: Mela
authors: David
authors: D
authors: Conversi
authors: Claudio
authors: C
authors: Latagliata
authors: Rossella
authors: R
authors: Ventura
authors: Stefano
authors: S
authors: Puglisi-Allegra
authors: Simona
authors: S
authors: Cabib
mesh_terms: D006916:5-Hydroxytryptophan / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D004038:Diet, Reducing / Q000379:methods; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D051379:Mice; D017551:Microdialysis / Q000379:methods; D009439:Neuraminidase / Q000235:genetics; D009638:Norepinephrine / Q000378:metabolism; D010649:Phenylalanine / Q000378:metabolism; D010661:Phenylketonurias / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D013997:Time Factors; D014365:Tryptophan Hydroxylase / Q000378:metabolism
chemical_list: D018687:Antidepressive Agents, Second-Generation; D012701:Serotonin; D010649:Phenylalanine; D006916:5-Hydroxytryptophan; D014365:Tryptophan Hydroxylase; C403285:NEU2 protein, human; D009439:Neuraminidase; D004298:Dopamine; D009638:Norepinephrine