A disorder of biogenic amines in dihydropteridine reductase deficiency.

A severe deficiency of dihydropteridine reductase (DHPR) in liver, brain, and cultured skin fibroblasts was demonstrated in a child with hyperphenylalaninemia and an atypical form of phenylketonuria. DHPR is required for regeneration of the cofactor, tetrahydrobiopterin. The cofactor is essential in hydroxylation of aromatic amino acid precursors in the biosynthesis of neurotransmitters, serotonin, dopamine, and norepinephrine. In gray tissue at brain biopsy, dopamine was low at 3 ng per gram of tissue, serotonin was barely detected, and norepinephrine appeared high at 1600 ng per gram. In cerebrospinal fluid, homovanillic acid (HVA) was low normal at 33 ng/ml, 5-hydroxyindoleacetic acid (5-HIAA) was low at 4.2 ng/ml, and after a high dose of oral probenecid there was impaired accumulation of HVA to 128 ng/ml and 5-HIAA to 22.4 ng/ml. When the patient was 22 months of age, treatment with hydroxylated aromatic amino acid precursors was initiated, and after three months HVA and 5-HIAA levels were increased in CSF. The apparent restoration of biogenic amines in brain appears to have delayed the rate of neurological deterioration. DHPR activity in cultured skin fibroblasts of children with persistent hyperphenylalaninemia should permit early diagnosis and early treatment of this disorder.

Possible physiological significance of the initial step in the catabolism of noradrenaline in the central nervous system of the rat.

The hypothalamus, the cerebral cortex and the cerebellar cortex of the rat were labelled in vitro with 3H-noradrenaline (3H-NA) and the metabolism of the tritiated transmitter was studied during spontaneous outflow and under conditions of release elicited by exposure to 20 mM K+. In the three areas of the central nervous system of the rat 3H-NA accounted for approximately 40% of the total radioactivity in spontaneous outflow while the 3H-O-methylated deaminated fraction (3H-OMDA) and 3H-3,4-dihydroxyphenylglycol (3H-DOPEG) were the main metabolites. Exposure to the reserpine-like agent, Ro 4-1284 induced a selective increase in the spontaneous outflow of 3H-DOPEG, while the contribution of the 3H-OMDA metabolites to the release induced by Ro 4-1284 was very small. During 3H-transmitter release elicited by exposure to 20 mM K+, approximately 80% of the radioactivity was collected as unmetabolized 3H-NA, while 3H-DOPEG was the main metabolite formed under these experimental conditions. Exposure to cocaine prevented 3H-DOPEG formation from 3H-NA released by K+, indicating that 3H-DOPEG was formed after neuronal reuptake of the transmitter released by K+. After in vitro labelling with 3H-NA, the unmetabolized transmitter represented approximately 70% of the total radioactivity retained in the tissue. However, when 3H-NA was administered in vivo, by intraventricular injection, only 30% of the total radioactivity retained by the tissue was accounted for by 3H-NA, and 60% of the radioactivity corresponded to the 3H-OMDA fraction, most of which was retained as 3H-MOPEG sulfate. When the rats were pretreated with pyrogallol, free 3H-DOPEG accounted for nearly 50% of the radioactivity retained in the three areas of the central nervous system after in vivo labelling with 3H-NA. When monoamine oxidase was inhibited by pargyline and 3H-NA was administered by intraventricular injection, 3H-NMN accounted for approximately 50% of the total radioactivity retained in the three areas of the central nervous system of the rat. The results obtained are compatible with the view that formation of the deamined glycol is the first step in the metabolism of 3H-NA in the rat central nervous system. In addition, it is concluded that the determination of the levels of some NA metabolites retained in the central nervous system does not necessarily represent an accurate reflection of the degree of central noradrenergic activity or of selective metabolic pathways. Consequently, in studies on the metabolism of NA it is important to take into account not only the transmitter and its metabolites in the tissue but also in the outflow from the structures studied either under in vivo or in vitro conditions.

Serotonin, noradrenaline, dopamine metabolites in transcendental meditation-technique.

The highly significant increase of 5-HIAA (5-hydroxyindole-3-acetic acid) in Transcendental Meditation technique suggests systemic serotonin as "rest and fulfillment hormone" of deactivation-relaxation. Furthermore 5-HT (5-hydroxytryptamine, serotonin) is considered to be the EC-cell (enterochromaffine-cell) hormone requested by Fujita and Kobayashi and its role for EEG synchronisation via area postrema chemoreceptor as anti arousal agent is being discussed. The significant decrease of the catecholamine metabolite VMA (vanillic-mandelic acid) in meditators, that is associated with a reciprocal increase of 5-HIAA supports as a feedback necessity the "rest and fulfillment response" versus "fight and flight". As the adreno medullary tissue serves for hormonal reinforcement of orthosympathetic activity, the Enterochromaffine Cell System (having taken the form of distinct organs in some species as octopus and discoglossus) is suggested to serve via serotonin for humoral reinforcement of parasympathetic activity in deep relaxation.