Abstract— The formation of histamine in brain was studied in mice injected with l‐[14C]‐histidine (ring 2‐14C) intravenously (i.v.) or intracerebrally; [14C]histamine appeared rapidly and exhibited a rapid rate of turnover. Drugs known to block various pathways of histamine catabolism were tested for effects on brain–[14C]histamine and [14C]‐methyl‐histamine in mice given (1) [14C]histamine i.v., (2) [14C]histamine intracerebrally, and (3) l‐[14C]histidine i.v. Blood‐borne histamine did not enter brain; brain histamine was formed locally by decarboxylation of histidine Methylhistamine did cross the blood‐brain barrier. Methylation was the major route of histamine catabolism in mouse brain and some of the methylhistamine formed was destroyed by monoamine oxidase. No evidence for catabolism by the action of diamine oxidase was found.

Tetrahydrobiopterin (BH₄) is a vital cofactor maintaining availability of the amine neurotransmitters [dopamine (DA), noradrenaline (NA), and serotonin (5-HT)], regulating the synthesis of nitric oxide (NO) by nitric oxide synthase (NOS), and stimulating and modulating the glutamatergic system (directly and indirectly). These BH₄ properties and their potential relevance to schizophrenia led us to investigate the hypothesis of a study group (healthy controls, n = 37; schizophrenics, n = 154) effect on fasting plasma total biopterin levels (a measure of BH₄). Study analysis showed a highly significant deficit of total biopterins for the schizophrenic sample after partialling out the effects of potential confounds of gender, age, ethnicity, neuroleptic use history and dose of current use, 24-hour dietary phenylalanine/protein ratio (a dietary variable relevant to BH₄ synthesis), and plasma phenylalanine (which stimulates BH₄ synthesis). A mean decrement of 34% in plasma total biopterins for schizophrenics from control values supports clinical relevance for the finding. In a subsample (21 controls and 23 schizophrenics), sequence analysis was done of the GTP cyclohydrolase I feedback regulatory gene and no mutations were found in the coding region of the gene. A deficiency of BH₄ could lead to hypofunction of the systems of DA, NA, 5-HT, NOS/NO, and glutamate, all of which have been independently implicated in schizophrenia psychopathology. Further, evidence has been accumulating which implicates the critical interdependence of these neurotransmitter systems in schizophrenia; this concept, along with the present study finding of a biopterin deficit, suggests that further study of the BH₄ system in schizophrenia is warranted and desirable.

Tetrahydrobiopterin (BH4) is an essential cofactor for amine neurotransmitter synthesis. BH4 also stimulates and modulates the glutamatergic system, and regulates the synthesis of nitric oxide by nitric oxide synthases. A connection between BH4 deficiencies and psychiatric disorders has been previously reported; major depression and obsessive-compulsive disorder have been found in subjects with a BH4 deficiency disorder and more recently we have observed a robust plasma deficit of biopterin (a measure of BH4), in a large group of schizophrenic patients compared to control subjects. To extend our previous finding in schizophrenia, we analyzed plasma biopterin levels from patients with schizoaffective and bipolar disorders. A significant difference in biopterin was seen among the diagnostic groups (P < 0.0001). Post hoc analyses indicated significant biopterin deficits relative to the normal control group for the schizoaffective group, who had biopterin levels comparable to the schizophrenic group. Bipolar disorder subjects had plasma biopterin levels that were higher that the schizoaffective disorder group and significantly higher than the schizophrenic group. The demonstrated significant biopterin deficit in both schizophrenia and schizoaffective disorder, may suggest an etiological role of a BH4 deficit in these two disorders, via dysregulation of neurotransmitter systems.

Summary . Histamine catabolism in vivo was studied in mice subjected to various forms of pretreatment; tissues from mice killed 2·5 min after intravenous injection of 14C‐histamine were assayed for 14C‐histamine, 14C‐methylhistamine and total 14C. . Pretreatment of mice with aminoguanidine, an inhibitor of diamine oxidase, strongly increased levels of 14C‐histamine in intestine; pretreatment with aminoguanidine plus a monoamine oxidase inhibitor strongly increased levels of 14C‐methylhistamine in liver. Effects in other tissues are reported and discussed. . Pretreatment of mice with non‐isotopic methylhistamine increased levels of 14C‐histamine in liver. Methylhistamine is the first known inhibitor of histamine‐methylation in vivo. . Pretreatment of mice with inhibitors of protein synthesis, drugs which reduce the basal activity of histidine decarboxylase and which block its activation, failed to affect histamine catabolism. . Pretreatment of mice with endotoxin or with Freund's adjuvant, irritants known to cause activation of histidine decarboxylase, failed to affect histamine catabolism. . There was no evidence of parallelism between the histamine‐destroying enzymes and the histamine‐forming enzyme, histidine decarboxylase, either in distribution or ability to undergo changes in activity. No support was obtained for the view that histamine‐catabolizing enzymes play a role in the local control of responses to newly formed histamine.

In previous tracer experiments on the formation of histamine from histidine in vivo, animals were injected with ('4C)-L-histidine, killed at various intervals, and tissues assayed for ("C)-histamine (Schayer, 1952;Schayer, 1959;Bjuro, Westling & Wetterqvist, 1964).For more refined studies it would be desirable to measure tissue concentrations of both ("C)-L-histidine and ("C)-histamine; certain additional inferences could then be made from the observed levels of precursor and product, and from the changes in these levels with respect to time.In the present study the tissue levels of free ('4C)-L-histidine and ("C)-histamine were measured in the same sample. Tissues were homogenized in acidic buffer and two aliquots taken. On-aliquot was incubated with a powerful specific bacterial histidine decarboxylase preparation; the second aliquot was untreated. The ("C)-histamine content of both aliquots was then determined by isotope dilution assay; the difference provides a measure of the concentration of free ("C)-L-histidine. Results of several studies on the formation and fate of newly formed histamine in vivo are reported. METHODSFemale albino CF-1 mice (Carworth, Inc., New City, New York) weighing 18-21 g were used.("-C)L-histidine and (IC)-histamine (specific activity 35.0 and 0.90 mc/m-mole respectively) were purchased from Nuclear Chicago. ("C)-L-histidine was purified before injection to remove traces of radioactive histamine (Schayer, 1968) Tissues were assayed for total (1"C), (4C)-histamine, and ("C)-L-histidine. To prepare tissue for assays, extracts were made in cold acetate buffer (0.2 M; pH 4.7) as follows. Liver was hand homogenized in 9 ml. of buffer, lung in 4 ml., and blood was mixed with 4 ml. of buffer. Tough tissues (stomach, muscle and intestine) were minced, frozen and thawed twice, 2 ml. buffer added, and freezing and thawing repeated. Tissues and extracts were kept cold at all times before the start of assay.Tissue-buffer preparations were transferred to graduated centrifuge tubes; buffer was then added to give a final volume of 12 ml. for liver, muscle and intestine, and 6 ml. for small tissues. Samples were centrifuged in the cold for 5 min at 1.000 rev/min. Without removing the sediment, portions of the samples were taken for assay.

An intradural somatic-to-autonomic anastomosis, or Xiao procedure, has been described to create a “skin-CNS-bladder” reflex that improves bladder and bowel function in patients with neurogenic bladder and bowel dysfunction. The authors present their experience with a 10-year-old boy with chronic neurogenic bladder and bowel dysfunction related to spinal cord injury who underwent the Xiao procedure. After undergoing a left L-5 ventral root to left S2–3 intradural anastomosis, the patient reported that his bladder and bowel dysfunction improved between 6 and 12 months. Two years after the procedure, however, he reported that there was no change in his bladder or bowel dysfunction as compared with his condition prior to the procedure. Frequent, systematic multidisciplinary evaluations produced conflicting data. Electrophysiological and histological evaluation of the previously performed anastomosis during surgical reexploration 3 years after the Xiao procedure revealed that the anastomosis was in anatomical continuity but neuroma formation had prevented reinnervation. Nerve action potentials were not demonstrable across the anastomosis, and stimulation of the nerve above and below the anastomosis created no bladder or perineal contractions. This is the first clinical report on the outcome of the Xiao procedure in a child with spinal cord injury outside of China. It is impossible to draw broad conclusions about the efficacy of the procedure based on a single patient with no demonstrable benefit. However, future studies should carefully interpret transient improvements in bladder function, urodynamic findings, and the patient's ability to void in response to scratching after the Xiao procedure. The authors' experience with the featured patient, in whom reinnervation could not be demonstrated, suggests that such changes could be related to factors other than the establishment of a skin-CNS-bladder reflex as a result of a somatic-to-autonomic anastomosis.

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