Increased neurotransmitter biosynthesis in phenylketonuria induced by phenylalanine restriction or by supplementation of unrestricted diet with large amounts of tyrosine.

Seven phenylketonuria (PKU) patients aged 15-24 years were allowed unrestricted diet for 3 weeks. Three of these patients performed well on unrestricted diet according to visual reaction time variability (RTv 50-100 ms) and did not show significant changes when returning to the phenylalanine-restricted diet (RTv 70-100 ms). Neither did the concentrations of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) change significantly. Four of the patients, however, performed rather poorly (RTv 120-220 ms) on unrestricted diet and improved significantly (P less than 0.03) when the diet was restored (RTv 70-150 ms). The improvements were accompanied by significant (P less than 0.01 and P less than 0.02) increases (mean 52% and 109%) in CSF levels of HVA and 5-HIAA. Five PKU patients aged 15-23 years were allowed unrestricted diet or unrestricted diet supplemented with various amounts of tyrosine (106-194 mg/kg per 24 h). Two of these patients performed very well on unrestricted diet (RTv 60 ms) and showed little change when the unrestricted diet was supplemented with tyrosine (RTv 70 ms and 80 ms). The three other patients, who performed rather poorly (RTv 120-220 ms), improved significantly (P less than 0.03) when the unrestricted diet was supplemented with tyrosine (RTv 70-140 ms). HVA in CSF increased significantly (P less than 0.01) with the tyrosine supplement when the amount exceeded a threshold of approximately 80 mg/kg per 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Homovanillic acid in caudate and pre-frontal cortex following neuroleptics.

Homovanillic acid (HVA) was measured in rat caudate and pre-frontal cortex 3 h following a single dose of a variety of neuroleptics. Thioridazine, haloperidol, fluphenazine, and metoclopramide increased HVA levels in caudate more than in pre-frontal cortex; whereas sulpiride and clozapine produced greater increases in HVA in pre-frontal cortex. These results are consistent with the proposal that rat pre-frontal cortex is relatively deficient in dopamine autoreceptors.

[Suppressive effects of lisuride on the synthesis, release and metabolism of dopamine in rat brain].

Effects of lisuride, a central dopaminergic agonist of the ergot type, on the biosynthesis, release and metabolism of dopamine at the dopaminergic nerve terminals of the rat brain were studied under several experimental conditions. 1) In the rat whose impulse flow of dopamine neurons and the activity of aromatic amino acid decarboxylase were inhibited by the pretreatment with gamma-butyrolactone and with 3-hydroxybenzylhydrazine (NDS 1015), respectively, DOPA formation in the neostriatum and limbic forebrain were decreased significantly by the s.c. administration of lisuride at the dosage known to be ineffective on the postsynaptic dopamine receptor. 2) When it was measured by the accumulation of 3-methoxytyramine in the neostriatum and limbic forebrain of pargyline (MAO inhibitor)-pretreated rats, lisuride at the low dosage caused the inhibition of not only the spontaneous release of dopamine from the nerve terminal to the synaptic cleft, but also the release induced with methamphetamine. 3) In the rat whose dopamine biosynthesis was inhibited with alpha-methyl-p-tyrosine, lisuride caused the suppression of dopamine metabolism, resulting in significant increases of dopamine histofluorescence in the nucleus caudatus, olfactory tubercle and median eminence. As to the effect on dopamine histofluorescence, apomorphine at 1 mg/kg was equipotent to lisuride at 50 micrograms/kg. It was concluded from these results that lisuride administered at low dosage interacts preferentially with the presynaptic dopamine receptor, hereby causing the suppressive effects on the tyrosine hydroxylase reaction and the dopamine release mechanism in the dopamine nerve terminals of the brain.

Chronic haloperidol or fluphenazine: effects on dopamine metabolism in brain, cerebrospinal fluid and plasma of Cercopithecus aethiops (vervet monkey).

Chronic treatment with haloperidol for 3 to 5 weeks (0.5 mg/kg, daily) resulted in significant increases of homovanillic acid (HVA) content in dorsal and orbital frontal cortex and in cingulate cortex. No change in HVA was seen in the olfactory cortex, basal ganglia, cisternal cerebrospinal fluid or plasma of animals chronically treated with haloperidol. Treatment with a single weekly dose of fluphenazine decanoate (5 mg/kg) for 3 weeks resulted in increased HVA levels in all the above brain regions, cisternal cerebrospinal fluid and plasma. Moreover, the fluphenazine-treated group had a significantly higher incidence of extrapyramidal side effects than the haloperidol-treated group. It is concluded that chronically increased dopamine metabolite production in the basal ganglia but not in cortex is reflected by increases in the HVA level of cerebrospinal fluid and plasma and is accompanied by severe extrapyramidal side effects.

Brain tyrosine level controls striatal dopamine synthesis in haloperidol-treated rats.

Animals received either haloperidol (2 mg/kg) or probenecid (200 mg/kg) in conjunction with tyrosine (100 mg/kg) or its diluent. Striatal homovanillic acid levels increased in probenecid-treated animals to the same range whether they were given tyrosine or not. In haloperidol-treated animals the levels of homovanillic acid were significantly elevated in animals receiving tyrosine. Tyrosine and homovanillic acid levels were highly correlated as determined by linear regression analysis.