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An opioid material in normal human lumbar CSF has been partially characterized and quantified. This material resembles methionine-enkephalin in its behavior in two chromatographic systems. It interacts with the opiate receptor assay and with a methionine-enkephalin radioimmunoassay. Mean human values are 3.12–3.25 pmoles of methionine-enkaphalin equivalents but the median is 1.7–1.9 pmoles. While this material resembles enkephalin, it cannot be identified as such with our current techniques.

MELATONIN (N-acetyl-O-methyl serotonin), a pineal compound discovered by Lerner1, may function as a hormone and is known to be extremely active in certain biological systems2–5. We have investigated the acute pharmacological effects of the compound with particular emphasis on the nervous and vascular systems. We find that melatonin has no acute pharmacological effects in the systems studied apart from its effect on sleep mechanisms.

The activity of-phenylethanolamine N-methyltransferase in mice of the C57Bl/Ka strain was determined after a 4 degrees C stress. The enzyme activity increased 1.2-fold at the end of 3 hours and by 1.4-fold by the end of 6 hours of the stress. The results are in contrast to those from other species with intact animals in which the enzyme changes only after several days of chronic stress. Cycloheximide prevents the rise in enzyme activity, suggesting the increase may be due to protein synthesis. The increase may provide a model system for studying regulation of catecholamine biosynthetic enzymes.

In Recent years biogenic amines have been implicated in the control mechanism for induction and maintenance of sleep processes (Jouvet, 1969). Investigators have looked for changes in the rate of synthesis of cerebral norepinephrine from [3H]tyrosine after REM sleep deprivation and reported increased rates of synthesis during REM sleep deprivation (Mark, Heiner, Mandel and Godin, 1969) and REM sleep rebound following 91 h of deprivation (Pujol, Mouret and Glowinski, 1968). Because tyrosine is thought to be the rate-limiting enzyme (Udenfriend, 1966) in the synthetic pathways for norepinephrine and since the above-mentioned studies are suggestive of changes in the activity of the enzyme, we decided to measure tyrosine hydroxylase activity following REM sleep deprivation.

KOE and Weissman have demonstrated that p-chlorophenylalanine (pCPA) depletes serotonin in the brain of mammals1. pCPA induces a variety of behaviour changes in rat, cat and other animals2,3, presumably because of the depletion of serotonin in the brain. The biochemical mechanism of the depletion remains, however, to be elucidated, although it has been proposed that pCPA might inactivate tryptophan hydroxylase in the brain4. We demonstrate here that pCPA does not inactivate tryptophan hydroxylase in rat pineal, although pCPA depletes the serotonin level in the pineal.

ADRENALINE given intraventricularly or intravenously has powerful physiological and psychological effects on the central nervous system. Although work in this laboratory and elsewhere suggests that a small amount of adrenaline may reach the brain from the peripheral circulation1,2, the amount is not enough to account for the endogenous concentrations of adrenaline that have been reported3,4. It therefore became of interest to study the uptake, metabolism and synthesis of adrenaline by mammalian brain. We have found that adrenaline is synthesized in the brain.

In a 9 month infant with the spinal fluid (CSF) NT abnormalities of biopterin synthesis defect we compared treatment with:BH4 high (20 mg/kg/d) dose only; BH4 low (3 mg/kg/d), moderate (10 mg/kg/d) or high dose with the NT precursors dopa/carbidopa (10/1 mg/kg/d) and 5-hydroxytryptophan (5 mg/kg/d); and NT precusors with phenylalanine (phe) restricted diet. Over 4 months we evaluated clinical status, CSF biopterin, CSF NT major metabolites homovanilic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol, and CSF NT minor metabolites 3,4-dihydroxy-phenylacetic acid, vanilmandelic acid, m-hydroxyphenylacetic acid (MHPAA), p-hydroxyphenylacetic acid (PHPAA) and indolacetic acid (IAA). Few control values for CSF biopterin and NT major metabolites and none for minor metabolites are known in children. Clinically the patient was well on NT precursors with or without BH4 and deteriorated on BH4 only. Liver enzymes, which were elevated at 4 months on BH4 only, remained normal and blood phe was in good control. CSF biopterin increased to at or above normal with moderate or high dose BH4 but virtually no response of HVA or 5-HIAA independent of NT precursors was seen. BH4 at any but low dose altered the IAA/5-HIAA ratio and BH4 at any dose increased PHPAA but not MHPAA. In this patient, the first in which NT minor metabolites have been measured on BH4, the CSF major metabolites could be maintained at normal levels only with NT precursors but BH4 modified the patterns of minor metabolites.

The result of the enzymatic reaction between indoleamines and a donor of one-carbon units, 5-methyl-tetrahydrofolic acid (5-MTHF), has been thought to be an N- or O-methylation of the indoleamine. We find that an enzymatic preparation from human platelets uses 5MTHF as a cofactor to convert tryptamine and two tryptamine derivatives to tryptolines (tetrahydro-β-carbolines), a class of tricyclic compounds. These products were identified by thin-layer chromatography, cocrystallization, and gas liquid chromatography/mass spectrometry. Formation of these compounds in mammalian tissues has not previously been described, to our knowledge. Platelet activity in healthy volunteers showed large individual variations; values for women were higher than those for men. These findings suggest the need for further examination of the pharmacological and psychological effects of tryptolines.

To study the effects of beta-endorphin in chronic schizophrenia, nine male patients participated in a double-blind crossover comparison of a single intravenous 20-mg injection of beta-endorphin and saline. Bolus injection of beta-endorphin from an albumin-coated syringe produced markedly higher plasma concentrations than did slow intravenous infusion from a non-albumin-coated syringe. Beta-endorphin intravenously injected in nine patients produced a statistically significant increase in serum prolactin levels. In one patient, both 10 mg of morphine sulfate and 20 mg of beta-endorphin produced similar increases in the alpha power of the EEG. In eight patients, beta-endorphin administration was associated with a statistically significant but not clinically obvious improvement in schizophrenic symptoms.

With the discovery of the opiate peptides, several major avenues of research became apparent. These peptides produced a great deal of focused attention on their anatomy, biochemistry, and physiology. In this article, we present an overview of some of the main research issues and recent findings in the field of opiate peptides. The possible relationship of the opiate peptide neuronal systems to schizophrenia is discussed in light of attempts to alter schizophrenic symptoms with opiate antagonists, beta-endorphin, and dialysis. It is hypothesized that if the opiate peptides are involved in schizophrenia, then their involvement with dopamine systems and/or with stress responses may be critical.

A case of a folate-responsive psychosis that was associated with a defect in N5-10-methylenetetrahydrofolate reductase (methylene reductase) suggested the need to examine whether abnormally low activity of this enzyme might be of etiological importance in schizophrenia. We now report that there were no statistically significant differences in the platelet methylene reductase activity of chronic schizophrenics, compared with either hospitalized or nonhospitalized age-matched control subjects. Although it is possible that a larger survey might reveal a subpopulation of schizophrenics who are characterized by abnormal methylene reductase activity, this study suggests that chronic schizophrenia is not generally associated with such changes.