Objective: Phenylketonuria (PKU) is an inherited metabolic disease characterized by plasma hyperphenylalaninemia and several neurological symptoms that can be controlled by rigorous dietetic treatment. The cellular mechanisms underlying impaired brain functions are still unclear. It has been proposed, however, that phenylalanine interference in cognitive functions depends on impaired dopamine (DA) transmission in the prefrontal cortical area due to reduced availability of the precursor tyrosine. Here, using Pahenu2 (ENU2) mice, the genetic murine model of PKU, we investigated all metabolic steps of catecholamine neurotransmission within the medial preFrontal Cortex (mpFC), availability of the precursor tyrosine, synthesis and release, to find an easy way to reinstate normal cortical DA neurotransmission. Methods and results: Analysis of blood and brain levels of tyrosine showed reduced plasma and cerebral levels of tyrosine in ENU2 mice. Western blot analysis demonstrated deficient tyrosine hydroxylase (TH) protein levels in mpFC of ENU2 mice. Cortical TH activity, determined in vivo by measuring the accumulation of l-3,4-dihydroxyphenylalanine (L-DOPA) in mpFC after inhibition of L-aromatic acid decarboxylase with NSD-1015, was reduced in ENU2 mice. Finally, a very low dose of L-DOPA, which bypasses the phenylalanine-inhibited metabolic steps, restored DA prefrontal transmission to levels found in healthy mice. Conclusion: The data suggests that a strategy of using tyrosine supplementation to treat PKU is unlikely to be effective, whereas small dose L-DOPA administration is likely to have a positive therapeutic effect.
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