On the Mechanism of the Brain Serotonin Depletion in Experimental Phenylketonuria.

Considerable evidence supports the view (1) that the primary metabolic lesion in phenylketonuria is a block in the conversion of phenylalanine to tyrosine due to the absence of a labile protein component of the liver hydroxylating system (2). However, the mechanism by which this metabolic defect in liver is translated into the mental retardation which clinically characterizes this disease is unclear. Several approaches to the problem have been made and the experimental model introduced by Auerbach (3) has proven particularly useful in nutritionally simulating some biochemical features of this genetic disease. More recent neurochemical and behavioral studies (4, 5) have demonstrated that animals fed diets rich in phenylalanine have diminished brain serotonin accompanied by impaired behavior in some, but not all, problem-solving tasks. A necessary connection between these two phenomena has not yet been established, although suggestive evidence has been presented from several sources. The metabolism of serotonin from tryptophan to 5-hydroxyindole acetic acid is well established and all the intermediate steps are known to occur in brain with the exception of 5.hydroxylation of tryptophan. To date, attempts to demonstrate this reaction in nervous tissue have been unsuccessful. This failure, together with the observation that 5-hydroxytryptophan easily transverses the blood-brain barrier while serotonin does not, suggests that serotonin synthesis in the central nervous system may be intimately related to peripheral disposition of tryptophan and 5-hydroxytryptophan. Based on the known observations, several explanations have been advanced for the decreased brain serotonin accompanying phenylalanine loading in experimental phenylketonuria. These include (a) specific inhibition of 5-hydroxytjroptophan drcarboxylase as suggested by the findings in v&o of Davidson and Sandier (6); (b) genera& nonspecific inhibition of decarboxylases and other pyridoxal phosphatemediated enzymes as suggested by the work of Tashian (7) on glutamic acid decarboxylase; (c) inhibition of precursor transport through blood-brain barriers as indicated by the data of Schanberg and Giarman (8) and Smith (9) ; (d) inhibition of tryptophan hydroxylation as indicated by Freedland, Wadzinski, and Waisman (10) ; (e) “nutritional-stress” activation of competing corticoid activated enzymes such as tryptophan pyrrolase and tryptophan transaminase; (f) acceleration of monoamine oxidase activity; and (g) decreased serot’onin storage capacity.