Monoamine metabolites in cerebrospinal fluid of depressive subgroups

Lumbar punctures were performed on 69 patients who met Research Diagnostic Criteria (RDC) for major affective disorder, while they were drug-free and depressed. None of the patients met RDC for alcoholism. Cerebrospinal fluid 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were measured by fluorometry and 3-methoxy-4-hydroxyphenylglycol (MHPG) by gas chromatography. Family histories were ascertained by systematic interviews of patients and their relatives, and diagnoses were made by family history diagnostic criteria (Andreasen et al., 1977). Depressed patients with alcoholism in a first degree relative had significantly lower levels of 5-HIAA and MHPG than patients without a family history of alcoholism (p < 0.05). No difference in HVA levels was found. The metabolite differences remained significant when the influence of sex ratio was considered. These results are in agreement with previous work linking alcoholism to abnormal serotonin metabolism. They provide further biochemical evidence of distinct genetic subtypes of affective disorder along lines suggested by Winokur (1979a, 1979b), and illustrate the usefulness of the family history method in defining patient subgroups.     

Extrapyramidal disorders: A possible underlying mechanism

In vivo and in vitro studies have been presented to suggest an interrelationship between drugs used in the management of, or known for their induction of extrapyramidal disorder and certain dehydrogenase enzymes involved in this metabolic pathway of the biogenic amines. This relationship is discussed to advance a tentative hypothesis explaining a possible underlying mechanism and to provide an explanation for the implication of alcohol consumption in worsening of extrapyramidal symptoms during certain pharmacotherapy. The major neutral metabolites of the biogenic amines acted as substrate to or induced rat liver alcohol dehydrogenase (L-ADH) and drugs used in the management of tardive dyskinesia similarly induced L-ADH. This induction of L-ADH could enhance the metabolic biotransformation of the neutral metabolites of the monoamines. Conversely, drugs known to evoke extrapyramidal dyskinesias inhibited rat liver aldehyde dehydrogenase (L-ALDH). This inhibition of ALDH may give rise to toxic condensation products between biogenic amine aldehydes and their precursors which may be implicated in certain dyskinesias. It is proposed that one of the mechanisms underlying the biogenic amine involvement in the pathogenesis of certain extrapyramidal diseases may include a critical balance between their reductive and oxidative routes of metabolism.     

Trace amine-associated receptors and their ligands

Classical biogenic amines (adrenaline, noradrenaline, dopamine, serotonin and histamine) interact with specific families of G protein-coupled receptors (GPCRs). The term 'trace amines' is used when referring to p-tyramine, beta-phenylethylamine, tryptamine and octopamine, compounds that are present in mammalian tissues at very low (nanomolar) concentrations. The pharmacological effects of trace amines are usually attributed to their interference with the aminergic pathways, but in 2001 a new gene was identified, that codes for a GPCR responding to p-tyramine and beta-phenylethylamine but not to classical biogenic amines. Several closely related genes were subsequently identified and designated as the trace amine-associated receptors (TAARs). Pharmacological investigations in vitro show that many TAAR subtypes may not respond to p-tyramine, beta-phenylethylamine, tryptamine or octopamine, suggesting the existence of additional endogenous ligands. A novel endogenous thyroid hormone derivative, 3-iodothyronamine, has been found to interact with TAAR1 and possibly other TAAR subtypes. In vivo, micromolar concentrations of 3-iodothyronamine determine functional effects which are opposite to those produced on a longer time scale by thyroid hormones, including reduction in body temperature and decrease in cardiac contractility. Expression of all TAAR subtypes except TAAR1 has been reported in mouse olfactory epithelium, and several volatile amines were shown to interact with specific TAAR subtypes. In addition, there is evidence that TAAR1 is targeted by amphetamines and other psychotropic agents, while genetic linkage studies show a significant association between the TAAR gene family locus and susceptibility to schizophrenia or bipolar affective disorder.     

Malignant transformation of human colon epithelial cells by benzo[c]phenanthrene dihydrodiolepoxides as well as 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine

Polycyclic aromatic hydrocarbons (PAHs) and heterocyclic aromatic amines (HCAs) ingested with food have repeatedly been suggested to be involved in the malignant transformation of colon epithelial cells. In order to test this hypothesis, HCEC cells (SV40 large T antigen-immortalized human colon epithelial cells) were incubated with a racemic mixture of benzo[c]phenanthrene dihydrodiol epoxides (B[c]PhDE), extremely potent carcinogenic PAH metabolites in vivo, or with 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhIP), the N-hydroxylated metabolite of the most abundant HCA in cooked meat. First, it was shown that HCEC cells express sulfotransferase 1A1, which is needed to metabolize N-OH-PhIP to the corresponding N-sulfonyloxy derivative, the direct precursor molecule of genotoxic nitrenium ions. Thereafter, exponentially growing HCEC cells were exposed five times to 0.1 microg (0.37 nmol) B[c]PhDE/ml for 30 min or 0.72 microg (3 nmol) N-OH-PhIP/ml for 24 h. Chemically treated HCEC cells showed an enhanced saturation density and grew faster than the corresponding solvent-treated cell cultures. After five treatment cycles, HCEC(B[c]PhDE) as well as HCEC(N-OH-PhIP) cells lost cell-cell contact inhibition and started piling up and forming foci in the culture flasks. Furthermore, HCEC(B[c]PhDE) and HCEC(N-OH-PhIP) cells were injected i.m. into SCID mice. Within 6 weeks after injection, eight animals out of eight injected with HCEC(B[c]PhDE) or HCEC(N-OH-PhIP) cells developed tumors at the site of injection, thus demonstrating the high tumorigenic potential of the HCEC(B[c]PhDE) and HCEC(N-OH-PhIP) cell cultures. Taken together, we show for the first time that the abovementioned active PAH metabolites as well as N-OH-PhIP are indeed able to malignantly transform human colon epithelial cells in vitro.     

The Effect of some Sympathomimetic Amines and their Acetyl Derivatives on the Isolated Bull Retractor Penis Muscle

Abstract The bull retractor penis muscle was used to compare the α–adrenergic effect of adrenaline, noradrenaline, methoxamine, phenylephrine, metaraminol, tyramine, amphetamine, ephedrine and orciprenaline with that of some of their O– and N–acetyl derivatives. The effect of cocaine on the responses to the drugs was also examined. Methoxamine exhibited the strongest stimulant potency on this smooth muscle. The ED₅₀ of the other parent compounds decreased in the following order: adrenaline, noradrenaline, phenylephrine, ephedrine, metaraminol, amphetamine, tyramine. N–acetylation decreased very clearly or even abolished the effect of the drugs. O–acetylation also decreased the effect but not as much as N–acetylation. The effects of the O–acetyl derivatives were probably at least partly due to the corresponding parent compounds released after deacetylation. The very weak effects of the N–acetyl derivatives suggest that little if any N–deacetylation occurred during the experiments.     

A case of spinal paraganglioma

Summary The neuroradiologic finding of a paraganglioma in the vertebral canal is described here for the first time. These tumors occur more frequently than was previously presumed. Similarities with paragangliomas in the craniocervical region are apparent on angiograms. We consider angiography to be indicated when, in association with a spinal tumor, urinary biogen amine levels are elevated. When necessary, embolization can be performed after angiography.This study is dedicated to Professor Dr. J. Wappenschmidt on the occasion of his 60th birthday     

INCREASED EXCRETION OF A BRAIN DEPRESSOR AMINE IN INFANTILE COELIAC DISEASE AND IN HEALTHY INFANTS ON A HIGH PROTEIN MILK DIET

Abstract. Lindblad, B. S. and Rafter, J. J. (Department of Paediatrics at St. Göran's Children's Hospital and the Department of Medical Nutrition, Karolinska Institutet, Stockholm, Sweden). Increased excretion of a brain depressor amine in infantile coeliac disease and in healthy infants on a high protein milk diet. Acta Paediatr Scand, 69: 643, 1980.—Urinary excretion of piperidine, a heterocyclic pressor amine of gut bacterial origin and nicotine-like activity in the brain, has been estimated by a gas chromatography method in healthy men and women, in normal breast-fed and formula-fed infants and in infants with untreated coeliac disease. The excretion of piperidine cannot usually be detected during the first week of life. The amount present in urine increases upon weaning with higher excretion in formula-fed than in breast-fed infants at four to six months of age. When premature infants fed on human milk are weaned, the urinary content of piperidine rises from undetectable amounts to normal for age. The high content present in untreated coeliac disease may be responsible for the initial mental depression commonly seen in this disease and suggests that piperidine is one of the "auto-intoxicating" substances arising from the bacterial decomposition of protein postulated by Metchnikoff in 1903 but hitherto unidentified.     

Developmental protein malnutrition: Influences on the central nervous system of the rat

Our group has been carrying out interdisciplinary studies on the effects of prenatal and postnatal protein malnutrition on the developing rat brain. Anatomical, physiological, biochemical and behavioral approaches using the same animal model have revealed that protein malnutrition affects the brain at various levels, i.e., (1) anatomical, as revealed by Golgi findings of deranged dendritic trees on analysis of cortical and subcortical areas; (2) physiological, as revealed by delayed sleep pattern maturation, disturbances in seizure thresholds, slowing of sensory cortico-cortical and thalamocortical evoked potentials, and changed power in hippocampal theta activity; (3) biochemical, as revealed by marked increases in biogenic amines dating from birth, as well as modifications in tryptophan metabolism; and (4) behavioral, as revealed by various changes in responses to different kinds of aversive stimulation. Reversal studies have revealed that many changes are permanent and not amenable to nutritional rehabilitation even at birth, which is before the brain growth spurt in the rat. Our paradigm closely mimicks the human condition of low level, chronic protein undernutrition and thus reveals the underlying disturbances due to malnutrition. The dietary reversal studies are attempts at pin-pointing critical brain growth periods, beyond which recovery of functions is not possible.     

Microspectrofluorometry in biogenic amine research

Microspectrofluorometry has played an important part in the development and understanding of fluorescence techniques for the demonstration of biogenic amines. This paper reviews briefly the techniques currently available for the characterization and localization of biogenic amines, and considers the basic design considerations applicable to the construction of a microspectrofluorometer, with special emphasis on the automated correction of spectral data. Spectral data for the commonly occurring biogenic amines dopamine, noradrenaline and 5-hydroxytryptamine have been summarized and the criteria applicable to the spectral analysis of the individual amines and their mixtures discussed. Discrepancies between spectral data derived from tissues and model systems are reviewed and emphasis is given to the importance of biochemical studies of amines prior to definitive microspectrofluorometric analysis. The conceptual basis of quantitative microspectrofluorometry is reviewed with a particular emphasis on the limitations of such studies. The analysis of terminal fields by scanning microspectrofluorometry and its application to the study of extracellular amine distribution is discussed.     

Centrally administered cycloheximide in rats: behavioural concomitants and modulation of amnesic effects by biogenic amines

The behavioural consequences of centrally administered cycloheximide (400 μg, intraventricularly) were examined at various times after the injection and compared with the degree of protein synthesis inhibition. Operant behaviour (FR3 responding for water reward) was significantly depressed at 1, 2, 4, 6, 8, 10 and 12 hr after the injection but not at 24 hr, while general locomotor activity was significantly depressed at all time points except 1 and 24 hr. Amnesia for a passive avoidance response was observed when the cycloheximide was administered 1, 3, 5, 7, and 9 hr before the training trial but not at 11 or 17 hr. Protein synthesis was found to be maximally inhibited (80%) at 1 and 2 hr, moderately inhibited (60%) at 4, 6, and 8 hr, less but still significantly inhibited (40%) at 12 hr and slightly elevated (15%) at 24 hr after the central injection of cycloheximide. Posttraining administration of 1-tryptophan (100 mg/kg) or corticosterone (5 mg/kg) significantly reversed the amnesia produced by a central injection of cycloheximide given 5 hr before training, while imipramine (5 mg/kg), d-amphetamine (5 mg/kg) and hydrocortisone (5 mg/kg) were without significant effect. These results suggest that the disruption of passive avoidance memory by centrally administered cycloheximide may not be related to the inhibition of synthesis of memory-specific protein, but rather to a depression of central levels of biogenic amines, particularly serotonin.